Heather Wakelee, MD

All Publications

• Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial LANCET ONCOLOGY Neal, J. W., Dahlberg, S. E., Wakelee, H. A., Aisner, S. C., Bowden, M., Huang, Y., Carbone, D. P., Gerstner, G. J., Lerner, R. E., Rubin, J. L., Owonikoko, T. K., Stella, P. J., Steen, P. D., Khalid, A. A., Ramalingam, S. S. 2016; 17 (12): 1661-1671

  Abstract

  Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC.This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA. Patients were eligible if they had received one or two previous treatments for advanced non-squamous, EGFR wild-type, NSCLC. Patients were stratified by performance status and line of therapy, and randomly assigned using permuted blocks within strata to receive open-label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was done every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single-drug group to receive combination treatment. The primary endpoint was to compare progression-free survival in patients given erlotinib alone versus cabozantinib alone, and in patients given erlotinib alone versus the combination of erlotinib plus cabozantinib. We assessed the primary endpoint in the per-protocol population, which was defined as all patients who were eligible, randomly assigned, and received at least one dose of treatment. The safety analysis population included all patients who received study treatment irrespective of eligibility. This trial is registered with ClinicalTrials.gov, number NCT01708954.Between Feb 7, 2013, and July 1, 2014, we enrolled and randomly assigned 42 patients to erlotinib treatment, 40 patients to cabozantinib treatment, and 43 patients to erlotinib plus cabozantinib treatment, of whom 111 (89%) in total were included in the primary analysis (erlotinib [n=38], cabozantinib [n=38], erlotinib plus cabozantinib [n=35]). Compared with erlotinib alone (median 1·8 months [95% CI 1·7-2·2]), progression-free survival was significantly improved in the cabozantinib group (4·3 months [3·6-7·4]; hazard ratio [HR] 0·39, 80% CI 0·27-0·55; one-sided p=0·0003) and in the erlotinib plus cabozantinib group (4·7 months [2·4-7·4]; HR 0·37, 0·25-0·53; one-sided p=0·0003). Among participants included in the safety analysis of the erlotinib (n=40), cabozantinib (n=40), and erlotinib plus cabozantinib (n=39) groups, the most common grade 3 or 4 adverse events were diarrhoea (three [8%] cases in the erlotinib group vs three [8%] in the cabozantinib group vs 11 [28%] in the erlotinib plus cabozantinib group), hypertension (none vs ten [25%] vs one [3%]), fatigue (five [13%] vs six [15%] vs six [15%]), oral mucositis (none vs four [10%] vs one [3%]), and thromboembolic event (none vs three [8%] vs two [5%]). One death due to respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug, and one death due to pneumonitis occurred in the erlotinib plus cabozantinib group, deemed related to either drug or the combination.Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population.ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health.

  View details for DOI 10.1016/S1470-2045(16)30561-7

  View details for Web of Science ID 000389537700035

  View details for PubMedID 27825638

  View details for PubMedCentralID PMC5154681

• Integrated digital error suppression for improved detection of circulating tumor DNA NATURE BIOTECHNOLOGY Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Diehn, M., Alizadeh, A. A. 2016; 34 (5): 547-555

  Abstract

  High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

  View details for DOI 10.1038/nbt.3520

  View details for Web of Science ID 000375735000036

  View details for PubMedID 27018799

  View details for PubMedCentralID PMC4907374

• Racial and Ethnic Variations in Lung Cancer Incidence and Mortality: Results From the Women's Health Initiative. Journal of clinical oncology Patel, M. I., Wang, A., Kapphahn, K., Desai, M., Chlebowski, R. T., Simon, M. S., Bird, C. E., Corbie-Smith, G., Gomez, S. L., Adams-Campbell, L. L., Cote, M. L., Stefanick, M. L., Wakelee, H. A. 2016; 34 (4): 360-368

  Abstract

  This study aimed to evaluate racial/ethnic differences in lung cancer incidence and mortality in the Women's Health Initiative Study, a longitudinal prospective cohort evaluation of postmenopausal women recruited from 40 clinical centers.Lung cancer diagnoses were centrally adjudicated by pathology review. Baseline survey questionnaires collected sociodemographic and health information. Logistic regression models estimated incidence and mortality odds by race/ethnicity adjusted for age, education, calcium/vitamin D, body mass index, smoking (status, age at start, duration, and pack-years), alcohol, family history, oral contraceptive, hormones, physical activity, and diet.The cohort included 129,951 women--108,487 (83%) non-Hispanic white (NHW); 10,892 (8%) non-Hispanic black (NHB); 4,882 (4%) Hispanic; 3,696 (3%) Asian/Pacific Islander (API); 534 (< 1%) American Indian/Alaskan Native; and 1,994 (1%) other. In unadjusted models, Hispanics had 66% lower odds of lung cancer compared with NHW (odds ratio [OR], 0.34; 95% CI, 0.2 to 0.5), followed by API (OR, 0.45; 95% CI, 0.27 to 0.75) and NHB (OR, 0.75; 95% CI, 0.59 to 0.95). In fully adjusted multivariable models, the decreased lung cancer risk for Hispanic compared with NHW women attenuated to the null (OR, 0.59; 95% CI, 0.35 to 0.99). In unadjusted models Hispanic and API women had decreased risk of death compared with NHW women (OR, 0.30 [95% CI, 0.15 to 0.62] and 0.34 [95% CI, 0.16 to 0.75, respectively); however, no racial/ethnic differences were found in risk of lung cancer death in fully adjusted models.Differences in lung cancer incidence and mortality are associated with sociodemographic, clinical, and behavioral factors. These findings suggest modifiable exposures and behaviors may contribute to differences in incidence of and mortality by race/ethnicity for postmenopausal women. Interventions focused on these factors may reduce racial/ethnic differences in lung cancer incidence and mortality.

  View details for DOI 10.1200/JCO.2015.63.5789

  View details for PubMedID 26700122

  View details for PubMedCentralID PMC4872034

• Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. Cancer discovery Piotrowska, Z., Niederst, M. J., Karlovich, C. A., Wakelee, H. A., Neal, J. W., Mino-Kenudson, M., Fulton, L., Hata, A. N., Lockerman, E. L., Kalsy, A., Digumarthy, S., Muzikansky, A., Raponi, M., Garcia, A. R., Mulvey, H. E., Parks, M. K., DiCecca, R. H., Dias-Santagata, D., Iafrate, A. J., Shaw, A. T., Allen, A. R., Engelman, J. A., Sequist, L. V. 2015; 5 (7): 713-722

  Abstract

  Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required.This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms. Cancer Discov; 5(7); 713-22. ©2015 AACR.See related commentary by Ichihara and Lovly, p. 694.This article is highlighted in the In This Issue feature, p. 681.

  View details for DOI 10.1158/2159-8290.CD-15-0399

  View details for PubMedID 25934077

  View details for PubMedCentralID PMC4497836

• Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors. Journal of thoracic oncology Padda, S. K., Riess, J. W., Schwartz, E. J., Tian, L., Kohrt, H. E., Neal, J. W., West, R. B., Wakelee, H. A. 2015; 10 (3): 500-508

  Abstract

  Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA).The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. Those cases with all cores scoring three in the epithelial component were categorized as PD-L1 and the remaining as PD-L1.PD-L1 scores were more frequent in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/sex), PD-L1 TETs had a significantly worse overall survival (hazard ratio: 5.40, 95% confidence interval: 1.13-25.89; p = 0.035) and a trend for worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 0.94-9.24; p = 0.064).PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than in controls, and PD-L1 TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD-1/PD-L1 therapy in this rare tumor type.

  View details for DOI 10.1097/JTO.0000000000000429

  View details for PubMedID 25402569

• An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature medicine Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 548-554

  Abstract

  Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

  View details for DOI 10.1038/nm.3519

  View details for PubMedID 24705333

• Scientific Advances in Thoracic Oncology 2016. Journal of thoracic oncology Soo, R. A., Stone, E. C., Cummings, K. M., Jett, J. R., Field, J. K., Groen, H. J., Mulshine, J. L., Yatabe, Y., Bubendorf, L., Dacic, S., Rami-Porta, R., Detterbeck, F. C., Lim, E., Asamura, H., Donington, J., Wakelee, H. A., Wu, Y. L., Higgins, K., Senan, S., Solomon, B., Kim, D., Johnson, M., Yang, J. C., Sequist, L. V., Shaw, A. T., Ahn, M., Costa, D. B., Patel, J. D., Horn, L., Gettinger, S., Peters, S., Wynes, M. W., Faivre-Finn, C., Rudin, C. M., Tsao, A., Baas, P., Kelly, R. J., Leighl, N. B., Scagliotti, G. V., Gandara, D. R., Hirsch, F. R., Spigel, D. R. 2017

  Abstract

  Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The IASLC and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for non-small cell lung cancer, small cell lung cancer, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.

  View details for DOI 10.1016/j.jtho.2017.05.019

  View details for PubMedID 28579481

• -Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy. oncologist Baik, C. S., Myall, N. J., Wakelee, H. A. 2017

  Abstract

  Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B-Raf proto-oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%-4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen-activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF-mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF-mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy. The Oncologist 2017;22:1-11 IMPLICATIONS FOR PRACTICE: Personalized medicine has begun to provide substantial benefit to patients with oncogene-driven non-small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase has the potential to change the course of the disease for patients with BRAF-mutant NSCLC, as it has in BRAF-mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.

  View details for DOI 10.1634/theoncologist.2016-0458

  View details for PubMedID 28487464

• Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry JOURNAL OF CLINICAL ONCOLOGY Gautschi, O., Milia, J., Filleron, T., Wolf, J., Carbone, D. P., Owen, D., Camidge, R., Narayanan, V., Doebele, R. C., Besse, B., Remon-Masip, J., Janne, P. A., Awad, M. M., Peled, N., Byoung, C., Karp, D. D., van den Heuvel, M., Wakelee, H. A., Neal, J. W., Mok, T. S., Yang, J. C., Ou, S. I., Pall, G., Froesch, P., Zalcman, G., Gandara, D. R., Riess, J., Velcheti, V., Zeidler, K., Diebold, J., Frueh, M., Michels, S., Monnet, I., Popat, S., Rosell, R., Karachaliou, N., Rothschild, S. I., Shih, J., Warth, A., Muley, T., Cabillic, F., Mazieres, J., Drilon, A. 2017; 35 (13): 1403-?

  Abstract

  Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

  View details for DOI 10.1200/JCO.2016.70.9352

  View details for Web of Science ID 000400335500005

  View details for PubMedID 28447912

• A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer CANCER CHEMOTHERAPY AND PHARMACOLOGY Wakelee, H. A., Gettinger, S., Engelman, J., Janne, P. A., West, H., Subramaniam, D. S., Leach, J., Wax, M., Yaron, Y., Miles, D. R., Lara, P. N. 2017; 79 (5): 923-932

  Abstract

  Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.

  View details for DOI 10.1007/s00280-017-3283-z

  View details for Web of Science ID 000400070400009

  View details for PubMedID 28352985

• Case Series of MET Exon 14 Skipping Mutation-positive Non-Small Cell Lung Cancers and Response to Crizotinib. International journal of radiation oncology, biology, physics Wang, S. X., Zhang, B., Wakelee, H. A., Diehn, M., Kunder, C., Neal, J. W. 2017; 98 (1): 239-?

  View details for DOI 10.1016/j.ijrobp.2017.01.170

  View details for PubMedID 28587017

• Elusive Target of Angiogenesis in Small-Cell Lung Cancer. Journal of clinical oncology Neal, J. W., Wakelee, H. A. 2017: JCO2016716084-?

  View details for DOI 10.1200/JCO.2016.71.6084

  View details for PubMedID 28165898

• ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies. Journal of thoracic oncology Chuang, J. C., Stehr, H., Liang, Y., Das, M., Huang, J., Diehn, M., Wakelee, H. A., Neal, J. W. 2017

  Abstract

  Erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies.Here we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies.Four of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms.We showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.

  View details for DOI 10.1016/j.jtho.2017.01.023

  View details for PubMedID 28167203

  View details for PubMedCentralID PMC5402884

• Neoadjuvant and Adjuvant Therapy for Non-Small Cell Lung Cancer HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Chuang, J. C., Liang, Y., Wakelee, H. A. 2017; 31 (1): 31-?

  Abstract

  The use of 4 cycles of cisplatin-based adjuvant chemotherapy is now the standard of care for patients with resected stage II and IIIA non-small cell lung cancer. Neoadjuvant chemotherapy lacks the same level of data as adjuvant treatment, but meta-analyses of this approach support its use. Selection of patients who are most likely to benefit from chemotherapy remain elusive. Ongoing adjuvant trials are exploring biomarkers, molecularly targeted agents, postoperative radiation therapy, and immunotherapy.

  View details for DOI 10.1016/j.hoc.2016.08.011

  View details for Web of Science ID 000390984800004

  View details for PubMedID 27912832

• Overview of Thoracic Oncology Trials in Cooperative Groups Around the Globe. Clinical lung cancer Salahudeen, A. A., Patel, M. I., Baas, P., Curran, W. J., Bradley, J. D., Gandara, D. R., Goss, G. D., Mok, T. S., Ramalingam, S. S., Vokes, E. E., Malik, S. M., Wakelee, H. A. 2017; 18 (1): 5-12

  Abstract

  Survival rates of patients with either early and advanced stage non-small-cell lung cancer (NSCLC) have improved with newer systemic therapy and radiation techniques, including combination regimens, targeted therapies, and immunotherapies. The cancer cooperative groups have historically played a critical role in the advancement of NSCLC therapy. Annually, representatives from cooperative groups worldwide convene at the International Lung Cancer Congress (ILCC). In summer 2015, the ILCC reached its 16th anniversary. This article highlights the NSCLC studies presented by participating groups in 2015.

  View details for DOI 10.1016/j.cllc.2016.06.007

  View details for PubMedID 27473736

• Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non Small-Cell Lung Cancer CLINICAL LUNG CANCER Wakelee, H., Zvirbule, Z., de Braud, F., Kingsley, C. D., Mekhail, T., Lowe, T., Schuette, W., Lena, H., Lawler, W., Braiteh, F., Cosgriff, T., Kaen, D., Boyer, M., Hsu, J., Phan, S., Novello, S. 2017; 18 (1): 50-59

  Abstract

  Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non-small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC.Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics.Efficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%).Onartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.

  View details for DOI 10.1016/j.cllc.2016.09.013

  View details for Web of Science ID 000394078900007

  View details for PubMedID 27856142

• Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry JOURNAL OF THORACIC ONCOLOGY Burt, B. M., Yao, X., Shrager, J., Antonicelli, A., Padda, S., Reiss, J., Wakelee, H., Su, S., Huang, J., Scott, W. 2017; 12 (1): 129-136

  View details for DOI 10.1016/j.jtho.2016.08.131

  View details for Web of Science ID 000391518500015

• Reply to Comment on 'Statin use and all-cancer survival: prospective results from the Women's Health Initiative'. British journal of cancer Wang, A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Chlebowski, R. T., Simon, M., Desai, P., Wassertheil-Smoller, S., Liu, S., Kritchevsky, S., Wakelee, H. A., Stefanick, M. L. 2017; 116 (3)

  View details for DOI 10.1038/bjc.2016.396

  View details for PubMedID 27923034

• Molecular profiling of single circulating tumor cells from lung cancer patients PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Park, S., Wong, D. J., Ooi, C. C., Kurtz, D. M., Vermesh, O., Aalipour, A., Suh, S., Pian, K. L., Chabon, J. J., Lee, S. H., Jamali, M., Say, C., Carter, J. N., Lee, L. P., Kuschner, W. G., Schwartz, E. J., Shrager, J. B., Neal, J. W., Wakelee, H. A., Diehn, M., Nair, V. S., Wang, S. X., Gambhir, S. S. 2016; 113 (52): E8379-E8386

  Abstract

  Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.

  View details for DOI 10.1073/pnas.1608461113

  View details for Web of Science ID 000391090800003

  View details for PubMedID 27956614

  View details for PubMedCentralID PMC5206556

• Protective Effects of Statins in Cancer: Should They Be Prescribed for High-Risk Patients? Current atherosclerosis reports Wang, A., Wakelee, H. A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Stefanick, M. L. 2016; 18 (12): 72-?

  Abstract

  Statins are one of the most widely prescribed drug classes in the USA. This review aims to summarize recent research on the relationship between statin use and cancer outcomes, in the context of clinical guidelines for statin use in patients with cancer or who are at high risk for cancer.A growing body of research has investigated the relationship between statins and cancer with mixed results. Cancer incidence has been more extensively studied than cancer survival, though results are inconsistent as some large meta-analyses have not found an association, while other studies have reported improved cancer outcomes with the use of statins. Additionally, two large studies reported increased all-cancer survival with statin use. Studies on specific cancer types in relation to cancer use have also been mixed, though the most promising results appear to be found in gastrointestinal cancers. Few studies have reported an increased risk of cancer incidence or decreased survival with statin use, though this type of association has been more commonly reported for cutaneous cancers. The overall literature on statins in relation to cancer incidence and survival is mixed, and additional research is warranted before any changes in clinical guidelines can be recommended. Future research areas include randomized controlled trials, studies on specific cancer types in relation to statin use, studies on populations without clinical indication for statins, elucidation of underlying biological mechanisms, and investigation of different statin types. However, studies seem to suggest that statins may be protective and are not likely to be harmful in the setting of cancer, suggesting that cancer patients who already take statins should not have this medication discontinued.

  View details for PubMedID 27796821

• Physical activity and sedentary behavior in relation to lung cancer incidence and mortality in older women: The Women's Health Initiative. International journal of cancer Wang, A., Qin, F., Hedlin, H., Desai, M., Chlebowski, R., Gomez, S., Eaton, C. B., Johnson, K. C., Qi, L., Wactawski-Wende, J., Womack, C., Wakelee, H. A., Stefanick, M. L. 2016; 139 (10): 2178-2192

  Abstract

  Physical activity has been associated with lower lung cancer incidence and mortality in several populations. We investigated these relationships in the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT) prospective cohort of postmenopausal women. The WHI study enrolled 161,808 women aged 50-79 years between 1993-1998 at 40 U.S. clinical centers; 129,401 were eligible for these analyses. Cox proportional hazards models were used to assess the association of baseline physical activity levels [metabolic equivalent (MET)-minutes/week: none <100 (reference), low 100-<500, medium 500-<1200, high 1200+] and sedentary behavior with total lung cancer incidence and mortality. Over 11.8 mean follow-up years, 2,148 incident lung cancer cases and 1,365 lung cancer deaths were identified. Compared to no activity, higher physical activity levels at study entry were associated with lower lung cancer incidence [p=0.009; hazard ratios (95% confidence intervals) for each physical activity category: low, HR: 0.86 (0.76-0.96); medium, HR: 0.82 (0.73-0.93); and high, HR: 0.90 (0.79-1.03)], and mortality [p<0.0001; low, HR: 0.80 (0.69-0.92); medium, HR: 0.68 (0.59-0.80); and high, HR: 0.78 (0.66-0.93)]. Body mass index (BMI) modified the association with lung cancer incidence (p=0.01), with a stronger association in women with BMI<30 kg/m(2) . Significant associations with sedentary behavior were not observed. In analyses by lung cancer subtype, higher total physical activity levels were associated with lower lung cancer mortality for both overall NSCLC and adenocarcinoma. In conclusion, physical activity may be protective for lung cancer incidence and mortality in postmenopausal women, particularly in non-obese women. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.30281

  View details for PubMedID 27439221

• Corrigendum: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nature communications Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Thomas Purcell, W., Ross Camidge, D., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7: 13513-?

  View details for DOI 10.1038/ncomms13513

  View details for PubMedID 27841271

  View details for PubMedCentralID PMC5114547

• PS01.77: Risk-Stratification for Second Primary Lung Cancer: Topic: Medical Oncology. Journal of thoracic oncology Han, S., Rivera, G. A., Cheng, I., Gomez, S., Plevritis, S. K., Wakelee, H. 2016; 11 (11S): S319-S320

  View details for DOI 10.1016/j.jtho.2016.09.112

  View details for PubMedID 27969544

• PS01.55: IMpower010: Phase III Study of Atezolizumab vs BSC After Adjuvant Chemotherapy in Patients with Completely Resected NSCLC: Topic: Medical Oncology. Journal of thoracic oncology Vallieres, E., Felip, E., Altorki, N., Zhou, C., Zuo, Y., Howland, M., Xia, F., Hoang, T., Sandler, A., Wakelee, H. 2016; 11 (11S): S304-?

  View details for DOI 10.1016/j.jtho.2016.09.090

  View details for PubMedID 27969522

• PS01.04: A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer: Topic: Medical Oncology. Journal of thoracic oncology Neal, J. W., Wakelee, H., Padda, S. K., Bertrand, S., Acevedo, B., Holmes Tisch, A., Pagtama, J. Y., Soltys, S. G., Nagpal, S. 2016; 11 (11S): S271-S272

  View details for DOI 10.1016/j.jtho.2016.09.040

  View details for PubMedID 27969472

• PS01.67: Case Series of MET Exon 14 Skipping Mutation-Positive Non-Small Cell Lung Cancers and Response to Crizotinib: Topic: Medical Oncology. Journal of thoracic oncology Wang, S. X., Zhang, B. M., Wakelee, H., Diehn, M., Kunder, C. A., Neal, J. W. 2016; 11 (11S): S312-S313

  View details for DOI 10.1016/j.jtho.2016.09.102

  View details for PubMedID 27969534

• PS01.66: Biomarker Stratification of Outcomes of Third-Generation EGFR TKI Therapy in Patients with Previously-Treated Advanced NSCLC: Topic: Medical Oncology. Journal of thoracic oncology Wakelee, H., Goldman, J. W., Gadgeel, S., Camidge, D. R., Reckamp, K. L., Ou, S. I., Yu, H. A., Solomon, B., Liu, S. V., Pérol, M., Dupuis, N. F., Nickel, A., Karlovich, C., Raponi, M., Yurasov, S., Litten, J., Despain, D., Soria, J., Sequist, L., Carbone, D. 2016; 11 (11S): S311-S312

  View details for DOI 10.1016/j.jtho.2016.09.101

  View details for PubMedID 27969533

• ORAL01.04: Phase II Trial of Atezolizumab for Patients with PD-L1-Selected Advanced NSCLC (BIRCH): Updated Efficacy and Exploratory Biomarker Results: Topic: Medical Oncology. Journal of thoracic oncology Wakelee, H., Patel, J. D., Heist, R., Balmanoukian, A., Besse, B., Felip, E., Carcereny Costa, E., Chow, L. Q., Koczywas, M., Garassino, M. C., Christoph, D., Toh, C. K., Johnson, M. L., Chaft, J., Kurata, T., Qiu, J., Kowanetz, M., Coleman, S., Mocci, S., Sandler, A., Gettinger, S. N., Peters, S. 2016; 11 (11S): S251-S252

  View details for DOI 10.1016/j.jtho.2016.09.009

  View details for PubMedID 27969443

• Adding to the targeted therapy toolbox: BRAF and MEK inhibition in the treatment of BRAF V600E metastatic non-small cell lung cancer TRANSLATIONAL CANCER RESEARCH Myall, N. J., Wakelee, H. A. 2016; 5: S1233-S1240

  View details for DOI 10.21037/tcr.2016.11.50

  View details for Web of Science ID 000393328100052

• PS01.22: Novel 3-Dimensional Preclinical Models: Topic: Medical Oncology. Journal of thoracic oncology Salahudeen, A., De La O, S., Padda, S. K., Neal, J. W., Wakelee, H., Kuo, C. 2016; 11 (11S): S282-?

  View details for DOI 10.1016/j.jtho.2016.09.057

  View details for PubMedID 27969489

• The Burden of Cancer in Asian Americans: A Report of National Mortality Trends by Asian Ethnicity CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Thompson, C. A., Gomez, S. L., Hastings, K. G., Kapphahn, K., Yu, P., Shariff-Marco, S., Bhatt, A. S., Wakelee, H. A., Patel, M. I., Cullen, M. R., Palaniappan, L. P. 2016; 25 (10): 1371-1382

  Abstract

  Asian Americans (AA) are the fastest growing U.S. population, and when properly distinguished by their ethnic origins, exhibit substantial heterogeneity in socioeconomic status, health behaviors, and health outcomes. Cancer is the second leading cause of death in the United States, yet trends and current patterns in the mortality burden of cancer among AA ethnic groups have not been documented.We report age-adjusted rates, standardized mortality ratios, and modeled trends in cancer-related mortality in the following AA ethnicities: Asian Indians, Chinese, Filipinos, Japanese, Koreans, and Vietnamese, from 2003 to 2011, with non-Hispanic whites (NHW) as the reference population.For most cancer sites, AAs had lower cancer mortality than NHWs; however, mortality patterns were heterogeneous across AA ethnicities. Stomach and liver cancer mortality was very high, particularly among Chinese, Koreans, and Vietnamese, for whom these two cancer types combined accounted for 15% to 25% of cancer deaths, but less than 5% of cancer deaths in NHWs. In AA women, lung cancer was a leading cause of death, but (unlike males and NHW females) rates did not decline over the study period.Ethnicity-specific analyses are critical to understanding the national burden of cancer among the heterogeneous AA population.Our findings highlight the need for disaggregated reporting of cancer statistics in AAs and warrant consideration of tailored screening programs for liver and gastric cancers. Cancer Epidemiol Biomarkers Prev; 25(10); 1371-82. ©2016 AACR.

  View details for DOI 10.1158/1055-9965.EPI-16-0167

  View details for Web of Science ID 000385642800002

  View details for PubMedID 27694108

  View details for PubMedCentralID PMC5218595

• A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma. Journal of thoracic oncology Reckamp, K. L., Melnikova, V. O., Karlovich, C., Sequist, L. V., Camidge, D. R., Wakelee, H., Perol, M., Oxnard, G. R., Kosco, K., Croucher, P., Samuelsz, E., Vibat, C. R., Guerrero, S., Geis, J., Berz, D., Mann, E., Matheny, S., Rolfe, L., Raponi, M., Erlander, M. G., Gadgeel, S. 2016; 11 (10): 1690-1700

  Abstract

  In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible.Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC.Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with rociletinib, a rapid decrease in urine T790M levels was observed by day 21.DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples.

  View details for DOI 10.1016/j.jtho.2016.05.035

  View details for PubMedID 27468937

• Clinicopathologic Features of Advanced Squamous NSCLC. Journal of thoracic oncology Socinski, M. A., Obasaju, C., Gandara, D., Hirsch, F. R., Bonomi, P., Bunn, P., Kim, E. S., Langer, C. J., Natale, R. B., Novello, S., Paz-Ares, L., Pérol, M., Reck, M., Ramalingam, S. S., Reynolds, C. H., Spigel, D. R., Stinchcombe, T. E., Wakelee, H., Mayo, C., Thatcher, N. 2016; 11 (9): 1411-1422

  Abstract

  Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.

  View details for DOI 10.1016/j.jtho.2016.05.024

  View details for PubMedID 27296106

• Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment. Journal of thoracic oncology Langer, C. J., Obasaju, C., Bunn, P., Bonomi, P., Gandara, D., Hirsch, F. R., Kim, E. S., Natale, R. B., Novello, S., Paz-Ares, L., Pérol, M., Reck, M., Ramalingam, S. S., Reynolds, C. H., Socinski, M. A., Spigel, D. R., Wakelee, H., Mayo, C., Thatcher, N. 2016

  Abstract

  Squamous cell lung cancer (sqCLC) is an aggressive form of cancer that poses many therapeutic challenges. Patients tend to be older, present at a later stage, and have a high incidence of comorbidities, which can compromise treatment delivery and exacerbate toxicity. In addition, certain agents routinely available for nonsquamous cell histologic subtypes, such as bevacizumab and pemetrexed, are contraindicated or lack efficacy in sqCLC. Therapeutic progress has been much slower for advanced sqCLC, with median survival times of approximately 9 to 11 months in most studies. Herein, we discuss the current therapeutic landscape for patients with sqCLC versus with nonsquamous NSCLC. Current evidence indicates that new targeted treatments, notably monoclonal antibodies such as ramucirumab and necitumumab, and immunotherapies such as nivolumab and pembrolizumab can provide survival prolongation, although the benefits are still relatively modest. These incremental improvements, all realized since 2012, in aggregate, will very likely have a clinically meaningful impact for patients with sqCLC. We also discuss recent genomic studies of sqCLC that have identified potentially actionable molecular targets, as well as the relevant targeted agents in clinical development. Finally, we discuss the magnitude of survival benefit and the risk-to-benefit ratio that would prove clinically meaningful in this underserved patient population with unmet needs.

  View details for DOI 10.1016/j.jtho.2016.08.138

  View details for PubMedID 27575423

• Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry. Journal of thoracic oncology Burt, B. M., Yao, X., Shrager, J., Antonicelli, A., Padda, S., Reiss, J., Wakelee, H., Su, S., Huang, J., Scott, W. 2016

  Abstract

  Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database.The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed.A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection.The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.

  View details for DOI 10.1016/j.jtho.2016.08.131

  View details for PubMedID 27566187

• Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2. Journal of clinical oncology Crinò, L., Ahn, M., De Marinis, F., Groen, H. J., Wakelee, H., Hida, T., Mok, T., Spigel, D., Felip, E., Nishio, M., Scagliotti, G., Branle, F., Emeremni, C., Quadrigli, M., Zhang, J., Shaw, A. T. 2016; 34 (24): 2866-2873

  Abstract

  Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy.Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires).All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment.Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases.

  View details for DOI 10.1200/JCO.2015.65.5936

  View details for PubMedID 27432917

• Pretreatment biopsy for thymic epithelial tumors-does histology subtype matter for treatment strategy? Journal of thoracic disease Padda, S. K., Keijzers, M., Wakelee, H. A. 2016; 8 (8): 1895-1900

  View details for DOI 10.21037/jtd.2016.06.77

  View details for PubMedID 27618984

• Concordant and Discordant EGFR Mutations in Patients With Multifocal Adenocarcinomas: Implications for EGFR-Targeted Therapy. Clinical therapeutics Chuang, J. C., Shrager, J. B., Wakelee, H. A., Neal, J. W. 2016; 38 (7): 1567-1576

  Abstract

  Adenocarcinoma remains the most common subtype of lung cancer in the United States. Most patients present with tumors that are invasive and often metastatic, but in some patients, multiple precursor in situ or minimally invasive adenocarcinoma tumors develop that can be synchronous and metachronous. These precursor lesions harbor the same spectrum of genetic mutations found in purely invasive adenocarcinomas, such as EGFR, KRAS, and p53 mutations. It is less clear, however, whether separate lesions in patients who present with multifocal disease share common underlying genetic driver mutations.Here we review the relevant literature on molecular driver alterations in adenocarcinoma precursor lesions. We then report 4 patients with multifocal EGFR mutant adenocarcinomas in whom we performed molecular testing on 2 separate lesions.In 2 of these patients, the mutations are concordant, and in 2 patients, the mutations are discordant. A review of the literature demonstrates increasing evidence that lesions with discordant mutations may confer a more favorable prognosis because they are unlikely to represent metastases.Our findings suggest that the emergence of the dominant EGFR driver alteration is often independent between lesions in patients with multifocal adenocarcinomas, and thus the same targeted therapy may not be effective for all lesions. However, genetic testing of multiple lesions can help to distinguish separate primary tumors from metastatic disease.

  View details for DOI 10.1016/j.clinthera.2016.06.005

  View details for PubMedID 27368115

  View details for PubMedCentralID PMC4985173

• Statin use and all-cancer survival: prospective results from the Women's Health Initiative BRITISH JOURNAL OF CANCER Wang, A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Chlebowski, R. T., Simon, M., Desai, P., Wassertheil-Smoller, S., Liu, S., Kritchevsky, S., Wakelee, H. A., Stefanick, M. L. 2016; 115 (1): 129-135

  Abstract

  This study aims to investigate the association between statin use and all-cancer survival in a prospective cohort of postmenopausal women, using data from the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT).The WHI study enrolled women aged 50-79 years from 1993 to 1998 at 40 US clinical centres. Among 146 326 participants with median 14.6 follow-up years, 23 067 incident cancers and 3152 cancer deaths were observed. Multivariable-adjusted Cox proportional hazards models were used to investigate the relationship between statin use and cancer survival.Compared with never-users, current statin use was associated with significantly lower risk of cancer death (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.71-0.86, P<0.001) and all-cause mortality (HR, 0.80; 95% CI, 0.74-0.88). Use of other lipid-lowering medications was also associated with increased cancer survival (P-interaction (int)=0.57). The lower risk of cancer death was not dependent on statin potency (P-int=0.22), lipophilicity/hydrophilicity (P-int=0.43), type (P-int=0.34) or duration (P-int=0.33). However, past statin users were not at lower risk of cancer death compared with never-users (HR, 1.06; 95% CI, 0.85-1.33); in addition, statin use was not associated with a reduction of overall cancer incidence despite its effect on survival (HR, 0.96; 95% CI, 0.92-1.001).In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications was associated with decreased cancer death, regardless of the type, duration, or potency of statin medications used.British Journal of Cancer advance online publication, 9 June 2016; doi:10.1038/bjc.2016.149 www.bjcancer.com.

  View details for DOI 10.1038/bjc.2016.149

  View details for Web of Science ID 000378880400020

  View details for PubMedID 27280630

• Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization ONCOLOGIST Ali, S. M., Hensing, T., Schrock, A. B., Allen, J., Sanford, E., Gowen, K., Kulkarni, A., He, J., Suh, J. H., Lipson, D., Elvin, J. A., Yelensky, R., Chalmers, Z., Chmielecki, J., Peled, N., Klempner, S. J., Firozvi, K., Frampton, G. M., Molina, J. R., Menon, S., Brahmer, J. R., MacMahon, H., Nowak, J., Ou, S. I., Zauderer, M., Ladanyi, M., Zakowski, M., Fischbach, N., Ross, J. S., Stephens, P. J., Miller, V. A., Wakelee, H., Ganesan, S., Salgia, R. 2016; 21 (6): 762-770

  Abstract

  For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care.Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements.A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months.Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.

  View details for DOI 10.1634/theoncologist.2015-0497

  View details for Web of Science ID 000378353100019

  View details for PubMedID 27245569

• Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients NATURE COMMUNICATIONS Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Purcell, W. T., Camidge, D. R., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7

  Abstract

  Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

  View details for DOI 10.1038/ncomms11815

  View details for Web of Science ID 000378007200001

  View details for PubMedID 27283993

  View details for PubMedCentralID PMC4906406

• Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686) CLINICAL CANCER RESEARCH Karlovich, C., Goldman, J. W., Sun, J., Mann, E., Sequist, L. V., Konopa, K., Wen, W., Angenendt, P., Horn, L., Spigel, D., Soria, J., Solomon, B., Camidge, D. R., Gadgeel, S., Paweletz, C., Wu, L., Chien, S., O'Donnell, P., Matheny, S., Despain, D., Rolfe, L., Raponi, M., Allen, A. R., Park, K., Wakelee, H. 2016; 22 (10): 2386-2395

  Abstract

  The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors.Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing.The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 - 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 - 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response.These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-15-1260

  View details for Web of Science ID 000375839200011

  View details for PubMedID 26747242

• Scientific Advances in Lung Cancer 2015 JOURNAL OF THORACIC ONCOLOGY Tsao, A. S., Scagliotti, G. V., Bunn, P. A., Carbone, D. P., Warren, G. W., Bai, C., de Koning, H. J., Yousaf-Khan, A. U., McWilliams, A., Tsao, M. S., Adusumilli, P. S., Rami-Porta, R., Asamura, H., Van Schil, P. E., Darling, G. E., Ramalingam, S. S., Gomez, D. R., Rosenzweig, K. E., Zimmermann, S., Peters, S., Ignatius, S., Reungwetwattana, T., Jaenne, P. A., Mok, T. S., Wakelee, H. A., Pirker, R., Mazieres, J., Brahmer, J. R., Zhou, Y., Herbst, R. S., Papadimitrakopoulou, V. A., Redman, M. W., Wynes, M. W., Gandara, D. R., Kelly, R. J., Hirsch, F. R., Pass, H. I. 2016; 11 (5): 613-638

  Abstract

  Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a "role model" for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene-driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year.

  View details for DOI 10.1016/j.jtho.2016.03.012

  View details for Web of Science ID 000375372500001

  View details for PubMedID 27013409

• Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. Journal of cutaneous pathology Schaberg, K. B., Novoa, R. A., Wakelee, H. A., Kim, J., Cheung, C., Srinivas, S., Kwong, B. Y. 2016; 43 (4): 339-346

  Abstract

  Recent advances in the immunotherapeutic treatment of cancer have led to the development of multiple new directed therapies including monoclonal antibodies that block the immune checkpoint T-cell receptor programmed death 1 (PD-1) and the PD-1 ligand, programmed death ligand 1 (PD-L1). Various immune-related toxicities have been associated with these drugs including, most commonly, skin rashes.Five cases of lichenoid dermatitis, including one case of lichenoid mucositis and one case of lichen sclerosus, associated with anti-PD-L1 and anti-PD1 therapy were compared with three biopsies of non-drug-related lichen planus (LP) and three lichen planus-like keratoses (LPLK) used as controls.Histopathologic and immunophenotypic analysis of these lichenoid lesions demonstrated significantly greater histiocytic infiltrates than observed in control lichenoid reactions (p = 0.0134). We also observed increased spongiosis and epidermal necrosis. No significant differences were seen in expression of CD3, CD4:CD8, CD20, PD-1, CD25, Foxp3, CXCL13 and PD-L1 expression.These findings expand the literature of immune-related toxicities of PD-L1 and PD-1 blockade to include lichenoid dermatitis and lichenoid mucositis. Of note, these cutaneous side effects were amenable to topical treatment, without the need for medication dose reduction or discontinuation.

  View details for DOI 10.1111/cup.12666

  View details for PubMedID 26762844

• Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene. Clinical lung cancer Myall, N. J., Neal, J. W., Cho-Phan, C. D., Zhou, L. Y., Stehr, H., Zhou, L., Diehn, M., Wakelee, H. A. 2016; 17 (2): e17-21

  View details for DOI 10.1016/j.cllc.2015.12.001

  View details for PubMedID 26776917

• Lung Cancer in Never Smokers. Advances in experimental medicine and biology Rivera, G. A., Wakelee, H. 2016; 893: 43-57

  Abstract

  Lung cancer is predominantly associated with cigarette smoking; however, a substantial minority of patients with the disease have never smoked. In the US it is estimated there are 17,000-26,000 annual deaths from lung cancer in never smokers, which as a separate entity would be the seventh leading cause of cancer mortality. Controversy surrounds the question of whether or not the incidence of lung cancer in never-smokers is increasing, with more data to support this observation in Asia. There are several factors associated with an increased risk of developing lung cancer in never smokers including second hand smoke, indoor air pollution, occupational exposures, and genetic susceptibility among others. Adenocarcinoma is the most common histology of lung cancer in never smokers and in comparison to lung cancer in smokers appears less complex with a higher likelihood to have targetable driver mutations.

  View details for DOI 10.1007/978-3-319-24223-1_3

  View details for PubMedID 26667338

• Estrogen Plus Progestin and Lung Cancer: Follow-up of the Women's Health Initiative Randomized Trial CLINICAL LUNG CANCER Chlebowski, R. T., Wakelee, H., Pettinger, M., Rohan, T., Liu, J., Simon, M., Tindle, H., Messina, C., Johnson, K., Schwartz, A., Gass, M., Wactawski-Wende, J. 2016; 17 (1): 10-?

  View details for DOI 10.1016/j.cllc.2015.09.004

  View details for Web of Science ID 000367538900002

• Rociletinib, a third generation EGFR tyrosine kinase inhibitor: current data and future directions EXPERT OPINION ON PHARMACOTHERAPY Chuang, J. C., Salahudeen, A. A., Wakelee, H. A. 2016; 17 (7): 989-993

  Abstract

  Major advances have been made since the discovery of driver mutations and their targeted therapies, especially in the treatment of patients with epidermal growth factor receptor (EGFR) mutations. Despite their initial efficacy in the majority of the patients with such driver mutations, all targeted therapies are limited by the eventual development of resistance mechanisms.EGFR T790M mutation is a common resistance mechanism after treatment with first or second generation EGFR tyrosine kinase inhibitors (TKI). Rociletinib is one of the third generation EGFR TKIs with activity against T790M and activating EGFR mutations while sparing the wild-type EGFR. In this review, we discuss the current understanding and available data on rociletinib, including the side effects associated with the medication. We will also review the BEAMing plasma test to detect T790M mutation without the need for repeat biopsy. Lastly, we review the potential resistance mechanisms after progression on rociletinib, and future directions.It is important to note that there are other 3(rd) generation EGFR TKIs with activity against T790M already approved by the US FDA (osimertinib) and many others in development. Future research will focus on figuring out which patients can benefit the most from a particular medication with minimal side effects, and further resistance mechanisms after rociletinib.

  View details for DOI 10.1517/14656566.2016.1162786

  View details for Web of Science ID 000374999200010

  View details for PubMedID 26950414

• Resistance to Therapy. Cancer treatment and research Rivera, G., Wakelee, H. A. 2016; 170: 183-202

  Abstract

  Identification of driver mutations in adenocarcinoma of the lung has revolutionized the treatment of this disease. It is now standard of care to look for activating mutations in epidermal growth factor receptor (EGFR), and translocations in anaplastic lymphoma kinase (ALK) or ROS1 in all newly diagnosed adenocarcinoma of the lung, and in many patients with squamous cell carcinoma as well. Recognition of multiple other lung cancer driver mutations has also expanded treatment options. Targeted treatments of these mutations lead to rapid and prolonged responses, but resistance inevitably develops. Until recently, traditional chemotherapy was the only alternative at that time, but better understanding of resistance mechanisms has lead to additional therapeutic options. These mechanisms of resistance and treatments are the focus of this chapter. Understanding of mechanisms of chemotherapy resistance is touched upon, along with a brief discussion of immune checkpoint inhibitors.

  View details for DOI 10.1007/978-3-319-40389-2_9

  View details for PubMedID 27535395

• Survival among Never-Smokers with Lung Cancer in the Cancer Care Outcomes Research and Surveillance Study. Annals of the American Thoracic Society Clément-Duchêne, C., Stock, S., Xu, X., Chang, E. T., Gomez, S. L., West, D. W., Wakelee, H. A., Gould, M. K. 2016; 13 (1): 58-66

  Abstract

  Differences in patient characteristics and outcomes have been observed among current, former, and never-smokers with lung cancer, but most prior studies included few never-smokers and were not prospective.We used data from a large, prospective study of lung cancer care and outcomes in the United States to compare characteristics of never-smokers and smokers with lung cancer and to examine survival among the never-smokers.Smoking status at diagnosis was determined by self-report and survival was determined from medical records and cancer registries, with follow-up through June 2010 or later. Cox regression was used to examine the association between smoking and survival, and to identify predictors of survival among never-smokers.Among 3,410 patients with lung cancer diagnosed between September 1, 2003 and October 14, 2005 who completed a baseline patient survey, there were 274 never-smokers (8%), 1,612 former smokers (47%), 1,496 current smokers or smokers who quit recently (44%), and 28 with missing information about smoking status (<1%). Never-smokers appeared more likely than former and current/recent smokers to be female and of Asian or Hispanic race/ethnicity, and to have adenocarcinoma histology, fewer comorbidities, private insurance, and higher income and education. Compared with never-smokers, the adjusted hazard of death from any cause was 29% higher among former smokers (hazard ratio, 1.29; 95% confidence interval, 1.08-1.55), and 39% higher among current/recent smokers (hazard ratio, 1.39; 95% confidence interval, 1.16-1.67). Factors predicting worse overall survival among never-smokers included Hispanic ethnicity, severe comorbidity, undifferentiated histology, and regional or distant stage. Never-smoking Hispanics appeared more likely to have regional or advanced disease at diagnosis and less likely to undergo surgical resection, although these differences were not statistically significant.Never-smokers with lung cancer are more likely than ever-smokers to be female, Asian or Hispanic, and more advantaged socioeconomically, suggesting possible etiologic differences in lung cancer by smoking status. Among never-smokers, Hispanics with lung cancer had worse survival than non-Hispanic whites.

  View details for DOI 10.1513/AnnalsATS.201504-241OC

  View details for PubMedID 26730864

• Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens JOURNAL OF THORACIC ONCOLOGY Paz-Ares, L., Hirsh, V., Zhang, L., De Marinis, F., Yang, J. C., Wakelee, H. A., Seto, T., Wu, Y., Novello, S., Juhasz, E., Aren, O., Sun, Y., Schmelter, T., Ong, T. J., Pena, C., Smit, E. F., Mok, T. S. 2015; 10 (12): 1745-1753

  View details for DOI 10.1097/JTO.0000000000000693

  View details for Web of Science ID 000365575100015

• MISSION Trial - A phase III, multi-center, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly non-squamous NSCLC after 2 or 3 previous treatment regimens. Journal of thoracic oncology Paz-Ares, L., Hirsh, V., Zhang, L., De Marinis, F., Yang, J. C., Wakelee, H. A., Seto, T., Wu, Y., Novello, S., Juhász, E., Arén, O., Sun, Y., Schmelter, T., Ong, T. J., Peña, C., Smit, E. F., Mok, T. S. 2015: -?

  Abstract

  Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC).The phase III, multinational, double-blind, placebo-controlled MISSION trial randomized patients with advanced relapsed/refractory NSCLC, following 2 or 3 prior treatment regimens, to sorafenib 400 mg bid (n=353) or matching placebo (n=353) plus best supportive care. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and time-to-progression (TTP). EGFR and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening.Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 months; hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.17, p=0.47). Median PFS (2.8 versus 1.4 mo; HR 0.61; 95% CI 0.51-0.72, p<0.0001) and TTP (2.9 versus 1.4 months; HR 0.54; 95% CI 0.45-0.65, p<0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with EGFR mutations, OS (13.9 versus 6.5 months; HR 0.48; 95% CI 0.30-0.76, p=0.002) and PFS (2.7 versus 1.4 months; HR 0.27; 95% CI 0.16-0.46, p<0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea and fatigue, consistent with the safety profile of sorafenib.Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.

  View details for PubMedID 26551592

• Pruritus as a Paraneoplastic Symptom of Thymoma JOURNAL OF THORACIC ONCOLOGY Padda, S. K., Shrager, J. B., Riess, J. W., Pagtama, J. Y., Tisch, A. J., Kwong, B. Y., Liang, Y., Schwartz, E. J., Loo, B. W., Neal, J. W., Hardy, R., Wakelee, H. A. 2015; 10 (11): E110-E112

  View details for DOI 10.1097/JTO.0000000000000623

  View details for Web of Science ID 000363312300001

  View details for PubMedID 26536199

• Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy. American journal of ophthalmology Leung, L. B., Neal, J. W., Wakelee, H. A., Sequist, L. V., Marmor, M. F. 2015; 160 (4): 799-805 e1

  Abstract

  To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer.Retrospective observational case series.Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The US Food & Drug Administration-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG).Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss.These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision.

  View details for DOI 10.1016/j.ajo.2015.07.012

  View details for PubMedID 26189086

• Adjuvant therapy for EGFR mutant and ALK positive NSCLC: Current data and future prospects. Lung cancer Chuang, J. C., Neal, J. W., Niu, X., Wakelee, H. A. 2015; 90 (1): 1-7

  Abstract

  Tyrosine kinase inhibitors (TKIs) against targetable mutations such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are highly effective in treating advanced stage lung cancers harboring such mutations. Questions remain, however, about whether these agents can improve cure rates for early stage lung cancers in the adjuvant setting. Here, we examine the current data and ongoing trials addressing this issue.

  View details for DOI 10.1016/j.lungcan.2015.07.016

  View details for PubMedID 26275476

• Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy. American journal of ophthalmology Leung, L. B., Neal, J. W., Wakelee, H. A., Sequist, L. V., Marmor, M. F. 2015; 160 (4): 799-805 e1

  View details for DOI 10.1016/j.ajo.2015.07.012

  View details for PubMedID 26189086

• Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction LUNG CANCER Das, M., Padda, S. K., Frymoyer, A., Zhou, L., Riess, J. W., Neal, J. W., Wakelee, H. A. 2015; 89 (3): 280-286

  Abstract

  Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.

  View details for DOI 10.1016/j.lungcan.2015.06.011

  View details for Web of Science ID 000360513200010

• Overcoming Resistance Without the Risk of Reaction: Use of Afatinib and Panitumumab in Two Cases of Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer With T790M Mutations CLINICAL LUNG CANCER Castellanos, E. H., Rivera, G., Wakelee, H., Horn, L. 2015; 16 (5): E97-E99

  View details for DOI 10.1016/j.cllc.2015.02.005

  View details for Web of Science ID 000360182100009

  View details for PubMedID 25842367

• Relationship of Driver Oncogenes to Long-Term Pemetrexed Response in Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Liang, Y., Wakelee, H. A., Neal, J. W. 2015; 16 (5): 366-373

  View details for DOI 10.1016/j.cllc.2014.12.009

  View details for Web of Science ID 000360182100017

• Treatment, overall survival, and costs in patients with ALK-positive non-small-cell lung cancer after crizotinib monotherapy CURRENT MEDICAL RESEARCH AND OPINION Guerin, A., Sasane, M., Wakelee, H., Zhang, J., Culver, K., Dea, K., Nitulescu, R., Galebach, P., Macalalad, A. R. 2015; 31 (8): 1587-1597

  Abstract

  Limited post-crizotinib treatment options for ALK-positive non-small cell lung cancer (NSCLC) might lead to poor survival and high economic burden.To evaluate real-world treatment patterns, overall survival (OS), and costs following crizotinib discontinuation.This study used chart review and claims data. First, 27 participating US oncologists reviewed medical records of ALK-positive NSCLC patients who discontinued crizotinib monotherapy and reported patient demographic and clinical information, including post-crizotinib treatment and mortality. OS was estimated using Kaplan-Meier analyses. Second, three large administrative US claims databases were pooled. NSCLC patients were selected if they discontinued crizotinib monotherapy. Post-crizotinib costs were analyzed separately for patients who did or did not discontinue antineoplastic treatment after crizotinib monotherapy. All data were collected prior to ceritinib approval for this patient population.A total of 119 ALK-positive NSCLC patients discontinued crizotinib monotherapy. Upon discontinuation, 42% had no additional antineoplastic treatment and 13% received radiation therapy only. The median OS post-crizotinib was 61 days; patients with brain metastases had shorter OS than those who did not (44 vs. 69 days, P = 0.018), and patients without further antineoplastic treatment had shorter OS than those who did (17 vs. 180 days, P < 0.001). From claims data, 305 ALK-positive NSCLC patients discontinued crizotinib monotherapy. After discontinuation, 72% had no additional antineoplastic treatment. Among patients who continued antineoplastic treatment, monthly healthcare costs averaged $22,160, driven by pharmacy ($9202), inpatient ($6419), and outpatient radiotherapy ($2888) and imaging ($1179) costs. Among patients who discontinued any antineoplastic treatment, monthly healthcare costs averaged $3423, mostly driven by inpatient costs ($2074).After crizotinib monotherapy, most patients either received radiotherapy only or discontinued antineoplastic treatment altogether. OS after discontinuing crizotinib was poor and shorter among those with brain metastases than without, and among those without subsequent antineoplastic treatment than with. Patients who continued antineoplastic treatment incurred substantial healthcare costs.

  View details for DOI 10.1185/03007995.2015.1057115

  View details for Web of Science ID 000361264300016

  View details for PubMedID 26029864

• Incidence Trends of Lung Cancer by Immigration Status among Chinese Americans CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gomez, S. L., Yang, J., Lin, S., McCusker, M., Sandler, A., Cheng, I., Wakelee, H. A., Patel, M., Clarke, C. A. 2015; 24 (8): 1157-1164

  Abstract

  Lung cancer is the leading cause of cancer-related death among Chinese Americans. A detailed examination of incidence trends by immigration status and histology may inform the etiology of lung cancer in this growing population.California Cancer Registry data were enhanced with data on patient nativity. Lung cancer incidence rates for Chinese males and females were computed for the years 1990-2010, and rates by immigration status and histology were computed for 1990-2004. Trends were assessed with annual percentage change (APC) statistics (two-sided P values) based on linear regression.A total of 8,167 lung cancers were diagnosed among California Chinese from 1990 to 2010. Overall incidence increased nonstatistically among U.S.-born males (APC, 2.1; 95% CI, -4.9 to 9.7), but decreased significantly among foreign-born (APC, -1.7; 95% CI, -2.9 to -0.6). Statistically significant decreasing trends were observed for non-small cell lung cancer (NSCLC), specifically the squamous cell and large cell carcinoma subtypes among foreign-born males. Among females, incidence decreased nonsignificantly among U.S.-born (APC, -2.8; 95% CI, -9.1 to 4.0) but was stable among foreign-born (APC, -0.4; 95% CI, -1.7 to 1.0). A statistically significant decreasing trend was observed for squamous cell among foreign-born females.These data provide critical evidence base to inform screening, research, and public health priorities in this growing population.Given the low smoking prevalence among Chinese Americans, especially females, and few known lung cancer risk factors in U.S. never-smoker populations, additional research of etiologic genetic or biologic factors may elucidate knowledge regarding lung cancer diagnosed in never smokers. Cancer Epidemiol Biomarkers Prev; 24(8); 1157-64. ©2015 AACR.

  View details for DOI 10.1158/1055-9965.EPI-15-0123

  View details for Web of Science ID 000359320500002

  View details for PubMedID 25990553

• Hormone Use, Reproductive History, and Risk of Lung Cancer The Women's Health Initiative Studies JOURNAL OF THORACIC ONCOLOGY Schwartz, A. G., Ray, R. M., Cote, M. L., Abrams, J., Sokol, R. J., Hendrix, S. L., Chen, C., Chlebowski, R. T., Hubbell, F. A., Kooperberg, C., Manson, J. E., O'Sullivan, M. J., Rohan, T., Stefanick, M. L., Wactawski-Wende, J., Wakelee, H., Simon, M. S. 2015; 10 (7): 1004-1013

  Abstract

  Results from the Women's Health Initiative clinical trials demonstrated no increase in the risk of lung cancer in postmenopausal women treated with hormone therapy (HT). We conducted a joint analysis of the Women's Health Initiative observational study data and clinical trials data to further explore the association between estrogen and estrogen-related reproductive factors and lung cancer risk.Reproductive history, oral contraceptive use, and postmenopausal HT were evaluated in 160,855 women with known HT exposures. Follow-up for lung cancer was through September 17, 2012; 2467 incident lung cancer cases were ascertained, with median follow-up of 14 years.For all lung cancers, women with previous use of estrogen plus progestin of less than 5 years (hazard ratio = 0.84; 95% confidence interval = 0.71-0.99) were at reduced risk. A limited number of reproductive factors demonstrated associations with risk. There was a trend toward decreased risk with increasing age at menopause (ptrend = 0.04) and a trend toward increased risk with increasing number of live births (ptrend = 0.03). Reduced risk of non-small-cell lung cancer was associated with age 20-29 years at first live birth. Risk estimates varied with smoking history, years of HT use and previous bilateral oophorectomy.Indirect measures of estrogen exposure to lung tissue, as used in this study, provide only weak evidence for an association between reproductive history or HT use and risk of lung cancer. More detailed mechanistic studies and evaluation of risk factors in conjunction with estrogen receptor expression in the lung should continue as a role for estrogen cannot be ruled out and may hold potential for prevention and treatment strategies.

  View details for DOI 10.1097/JTO.0000000000000558

  View details for Web of Science ID 000356944100004

  View details for PubMedID 25852020

• A phase II study of saracatinib (AZD0530), a Src inhibitor, administered orally daily to patients with advanced thymic malignancies LUNG CANCER Gubens, M. A., Burns, M., Perkins, S. M., Pedro-Salcedo, M. S., Althouse, S. K., Loehrer, P. J., Wakelee, H. A. 2015; 89 (1): 57-60

  Abstract

  Thymic malignancies are rare, and options are limited for metastatic disease. Src plays a role in normal thymic epithelial maturation, and its inhibition with the oral compound saracatinib was postulated to be effective in controlling thymic malignancy.Patients with unresectable thymic malignancy were treated with saracatinib 175mg by mouth daily in 28 days cycles with radiographic evaluation at cycle 2 day 1 for safety, then cycle 3 day 1 and every 8 weeks thereafter. Response was evaluated by RECIST 1.0. A two-stage optimal design was used, powered to detect a true response rate of 20%.21 patients were enrolled at two institutions, 12 of them with thymoma, 9 with thymic carcinoma. Thymoma patients received a median of 4.5 cycles and thymic carcinoma patients a median of 1 cycle. There were no responses, so accrual was halted after the first stage per protocol. 9 patients had stable disease beyond the first assessment. Median time to progression was 5.7 months for thymoma patients and 3.6 months for thymic carcinoma patients. Saracatinib was well tolerated.Src inhibition by saracatinib did not produce any radiographic responses, though some patients did experience stable disease. Though negative, this study shows the feasibility of completing a trial in this rare disease, and of accruing reasonably significant numbers of thymic carcinoma patients. More clinical trials are required for this population (NCT00718809).

  View details for DOI 10.1016/j.lungcan.2015.04.008

  View details for Web of Science ID 000356546300011

  View details for PubMedID 26009269

• ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer CANCER EPIDEMIOLOGY Guerin, A., Sasane, M., Zhang, J., Macalalad, A. R., Galebach, P., Jarvis, J., Kageleiry, A., Culver, K., Wu, E. Q., Wakelee, H. 2015; 39 (3): 307-312

  Abstract

  Approximately 2-8% of non-small cell lung cancer (NSCLC) patients have rearrangements in the anaplastic lymphoma kinase gene (ALK). ALK-targeted therapy is available to patients with tumors known to be ALK+. This chart review study described characteristics of patients with ALK+ NSCLC, patterns of ALK testing and subsequent treatments, and oncologists' experience with ALK testing in the US.US oncologists provided information in September and October of 2013 on patients from their practice diagnosed with ALK+ locally advanced or metastatic NSCLC, including the timing of ALK testing and treatment received after testing. Participating oncologists were also surveyed about their experience with ALK testing.27 oncologists provided data on 273 ALK+ NSCLC patients. Patients' median age was 67 years upon NSCLC diagnosis. Smoking history varied, with 33% nonsmokers, 33% light smokers, and 33% heavy smokers. Patients were racially diverse: 59% White, 18% Black, 13% Asian, and 10% other. Upon diagnosis of advanced/metastatic NSCLC, patients who were either not tested (19%) or initially tested negative/inconclusive (1%) all received first-line chemotherapy; the other 219 patients (80%) tested positive, with 133 (61%) receiving an ALK inhibitor and 78 (29%) receiving chemotherapy as first-line treatment. Many oncologists stated being more likely to test for ALK rearrangements among Asians, nonsmokers, and light smokers.In this sample, ALK+ NSCLC patients were racially diverse with mixed smoking history. One in five patients were not tested before first-line therapy. Oncologists reported being more likely to consider ALK testing for patients with particular smoking and race characteristics.

  View details for DOI 10.1016/j.canep.2015.04.005

  View details for Web of Science ID 000355822600008

  View details for PubMedID 25914136

• Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer NEW ENGLAND JOURNAL OF MEDICINE Sequist, L. V., Soria, J., Goldman, J. W., Wakelee, H. A., Gadgeel, S. M., Varga, A., Papadimitrakopoulou, V., SOLOMON, B. J., Oxnard, G. R., Dziadziuszko, R., Aisner, D. L., Doebele, R. C., Galasso, C., Garon, E. B., Heist, R. S., Logan, J., Neal, J. W., Mendenhall, M. A., Nichols, S., Piotrowska, Z., Wozniak, A. J., Raponi, M., Karlovich, C. A., Jaw-Tsai, S., Isaacson, J., Despain, D., Matheny, S. L., Rolfe, L., Allen, A. R., Camidge, D. R. 2015; 372 (18): 1700-1709

  Abstract

  Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles.A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

  View details for DOI 10.1056/NEJMoa1413654

  View details for Web of Science ID 000353655000005

  View details for PubMedID 25923550

• GLI1, CTNNB1 and NOTCH1 protein expression in a thymic epithelial malignancy tissue microarray. Anticancer research Riess, J. W., West, R., Dean, M., Klimowicz, A. C., Neal, J. W., Hoang, C., Wakelee, H. A. 2015; 35 (2): 669-676

  Abstract

  Thymic epithelial tumors (TET) are rare. Wingless and INT (WNT), NOTCH and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to thymus and T-cell development. We analyzed a thymoma tissue microarray (TMA) for glioma associated oncogene homolog 1 (GLI1), NOTCH1 and catenin (cadherin-associated protein, beta 1) (CTNNB1) expression as surrogate markers of sonic hedgehog, NOTCH and WNT pathway activity.GLI1, NOTCH1 and CTNNB1 expression were assayed in a tissue microarray of 68 TET and eight benign thymus by fluorescent immunohistochemistry (AQUA) as surrogates for activity of the sonic hedgehog, NOTCH and WNT pathways respectively.No difference in tumor GLI1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 222 vs. 306, p=0.66) or NOTCH1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumor and benign thymus.No evidence for preferential expression of GLI1, NOTCH1 or CTNNB1 was noted. High-throughput immunofluorescence using AQUA technology can help overcome limitations of small sample size and tissue heterogeneity when analyzing protein expression in thymic tumors.

  View details for PubMedID 25667444

• GLI1, CTNNB1 and NOTCH1 Protein Expression in a Thymic Epithelial Malignancy Tissue Microarray. Anticancer research Riess, J. W., West, R., Dean, M., Klimowicz, A. C., Neal, J. W., Hoang, C., Wakelee, H. A. 2015; 35 (2): 669-676

  View details for PubMedID 25667444

• Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung cancer Liang, Y., Padda, S. K., Riess, J. W., West, R. B., Neal, J. W., Wakelee, H. A. 2015; 87 (1): 34-38

  Abstract

  Thymic malignancies are rare, with limited published trials of chemotherapy activity. We performed a retrospective analysis of pemetrexed activity in patients with thymic malignancies.Patients with unresectable histologically confirmed invasive, recurrent, or metastatic thymoma or thymic carcinoma seen at the Stanford Cancer Center between January 2005 and November 2013 were identified, and those who were treated with pemetrexed in the second-line setting and beyond were included in this analysis.A total of 81 thymic malignancy patients were identified, of whom 16 received pemetrexed alone (N=14) or in combination (N=2). There were 10 patients (62.5%) with thymic carcinoma and 6 patients (37.5%) with thymoma. Among the 6 patients with thymoma, best response was 1 (17%) with a partial response (PR) and 5 (83%) with stable disease (SD). At a median follow-up of 21.2 months, the median PFS in the thymoma patients was 13.8 months (95% CI, 4.9-22.6 months) and the median OS was 20.1 months (95% CI, 16.4-23.9 months). Among the 10 patients with thymic carcinoma, best response to treatment was 1 (10%) PR, 5 (50%) SD, and 4 (40%) progressive disease (PD). At a median follow-up of 13.5 months, the median PFS in patients with thymic carcinoma was 6.5 months (95% CI, 0.2-12.8 months) and the median OS was 12.7 months (95% CI, 2.9-22.5 months).This small retrospective study demonstrates modest pemetrexed activity and disease stabilization in thymic malignancies with a clinically meaningful duration, and supports previous reports of pemetrexed efficacy in these rare diseases.

  View details for DOI 10.1016/j.lungcan.2014.11.006

  View details for PubMedID 25443273

• Novel Treatments for Thymoma and Thymic Carcinoma. Frontiers in oncology Rajan, A., Wakelee, H., Giaccone, G. 2015; 5: 267-?

  View details for DOI 10.3389/fonc.2015.00267

  View details for PubMedID 26649279

• Are Patients With Thoracic Malignancies at Risk for Uncontrolled Symptoms? Journal of oncology practice / American Society of Clinical Oncology Patel, M. I., Williams, D. C., Wohlforth, C., Fisher, G., Wakelee, H. A., Blayney, D. W. 2015; 11 (1): e98-e102

  Abstract

  Patients with cancer often develop symptoms and contact their oncologists and care teams after normal clinic operating hours. Better understanding of these after-hours telephone calls can inform efforts to improve cancer care and to reduce health care spending. We sought to evaluate after-hours calls at Stanford Cancer Institute (SCI) Thoracic Oncology Clinic.We retrospectively analyzed content of telephone call notes made to SCI during weekends and from 5 pm to 8 am on weekdays. Chief complaint, caller and patient demographics, patient diagnosis, advice given, and disposition were analyzed. χ(2) tests were used to analyze differences in proportions.There were a total of 263 after-hours telephone calls during the 6 months of the study. After exclusions, there were 241 telephone calls for analysis. The majority of calls occurred between 5 pm to 11 pm (n = 175 [73%]; P < .001), followed by daytime calls on weekends (n = 157 [65%]; P < .001). Common symptoms were cough (28%) and dyspnea (27%). Of the calls, 62% (150 patients) resulted in emergency department (ED) referral, and 77% of patients (115 of 150) evaluated in the ED were admitted to the hospital.Most after-hours telephone calls from patients with lung cancer are related to symptoms. Many patients were referred to the ED and subsequently required hospitalization. Analysis of call content and prior events leading to after-hours calls may predict hospital admissions in this group of patients and can inform development of proactive interventions to improve quality of care and patient-centered outcomes.

  View details for DOI 10.1200/JOP.2014.001502

  View details for PubMedID 25271246

• Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative Observational Study prospective cohort†. Annals of oncology Wang, A., Kubo, J., Luo, J., Desai, M., Hedlin, H., Henderson, M., Chlebowski, R., Tindle, H., Chen, C., Gomez, S., Manson, J. E., Schwartz, A. G., Wactawski-Wende, J., Cote, M., Patel, M. I., Stefanick, M. L., Wakelee, H. A. 2015; 26 (1): 221-230

  Abstract

  Lung cancer is the leading cause of worldwide cancer deaths. While smoking is its leading risk factor, few prospective cohort studies have reported on the association of lung cancer with both active and passive smoking. This study aimed to determine the relationship between lung cancer incidence with both active and passive smoking (childhood, adult at home, and at work).The Women's Health Initiative Observational Study (WHI-OS) was a prospective cohort study conducted at 40 US centers that enrolled postmenopausal women from 1993 to 1999. Among 93 676 multiethnic participants aged 50-79, 76 304 women with complete smoking and covariate data comprised the analytic cohort. Lung cancer incidence was calculated by Cox proportional hazards models, stratified by smoking status.Over 10.5 mean follow-up years, 901 lung cancer cases were identified. Compared with never smokers (NS), lung cancer incidence was much higher in current [hazard ratio (HR) 13.44, 95% confidence interval (CI) 10.80-16.75] and former smokers (FS; HR 4.20, 95% CI 3.48-5.08) in a dose-dependent manner. Current and FS had significantly increased risk for all lung cancer subtypes, particularly small-cell and squamous cell carcinoma. Among NS, any passive smoking exposure did not significantly increase lung cancer risk (HR 0.88, 95% CI 0.52-1.49). However, risk tended to be increased in NS with adult home passive smoking exposure ≥30 years, compared with NS with no adult home exposure (HR 1.61, 95% CI 1.00-2.58).In this prospective cohort of postmenopausal women, active smoking significantly increased risk of all lung cancer subtypes; current smokers had significantly increased risk compared with FS. Among NS, prolonged passive adult home exposure tended to increase lung cancer risk. These data support continued need for smoking prevention and cessation interventions, passive smoking research, and further study of lung cancer risk factors in addition to smoking.NCT00000611.

  View details for DOI 10.1093/annonc/mdu470

  View details for PubMedID 25316260

• Angiogenesis and lung cancer: ramucirumab prolongs survival in 2(nd)-line metastatic NSCLC. Translational lung cancer research Das, M., Wakelee, H. 2014; 3 (6): 397-399

  Abstract

  In the REVEL trial, ramucirumab, a monoclonal antibody to VEGFR-2, improved overall survival in combination with docetaxel compared to docetaxel alone in the second-line setting of non-small cell lung cancer (NSCLC). Along with bevacizumab and nintedanib, ramucirumab is the third anti-angiogenic agent that has yielded positive overall survival results in a phase III trial of patients with advanced NSCLC. Given the lack of effective therapies in the relapsed setting and the disappointing results of many other VEGF-targeted agents in lung cancer, the results from REVEL are encouraging. One of the major remaining hurdles is the identification of reliable predictive biomarkers in order to predict which patients are most likely to benefit from anti-angiogenic therapies. Despite the positive results seen in REVEL, the exact role of ramucirumab in the treatment paradigm of lung cancer remains to be seen given the modest survival benefit of 1.4 months and the lack of predictive biomarkers at this time.

  View details for DOI 10.3978/j.issn.2218-6751.2014.09.05

  View details for PubMedID 25806332

• Lung Cancer Incidence Trends by Histology Type among Asian American, Native Hawaiian, and Pacific Islander Populations in the United States, 1990-2010 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Cheng, I., Le, G. M., Noone, A., Gali, K., Patel, M., Haile, R. W., Wakelee, H. A., Gomez, S. L. 2014; 23 (11): 2250-2265

  Abstract

  Lung cancer is one of the leading cancer sites diagnosed among Asian Americans, Pacific Islanders, and Native Hawaiians (AANHPI). To better understand the patterns of lung cancer incidence among AANHPIs, we examined the incidence trends of five histologic cell types of lung cancer across ten AANHPI populations in comparison with non-Hispanic Whites.Lung cancer incidence data from 1990 through 2010 were obtained from 13 U.S. population-based cancer registries. Age-adjusted histologic cell-type-specific incidence rates and 95% confidence intervals were calculated. Joinpoint regression models and annual percentage change (APC) statistics were used to characterize the magnitude and direction of trends.From 1990 through 2010, incidence rates of adenocarcinoma increased significantly for Filipino and Korean women with a 2.6% and 3.0% annual percentage increase, respectively. More recently, a significant rise in the incidence of adenocarcinoma was observed for Chinese men (1996-2010; APC = 1.3%). Squamous cell carcinoma (SCC) increased 2.4% per year among Japanese women. For SCC, small cell lung carcinoma, large cell and other specified carcinoma, and unspecified types, stable or decreasing trends were observed in most AANHPI groups and non-Hispanic Whites.AANHPIs demonstrate a range in the burden of lung cancer across histologies and specific populations.These findings illustrate the importance of disaggregating AANHPIs into their specific populations. The rise in incidence of adenocarcinoma and SCC among certain AANHPIs demonstrates the need for research into non-tobacco associated risk factors for these populations and targeted efforts for tobacco prevention.

  View details for DOI 10.1158/1055-9965.EPI-14-0493

  View details for Web of Science ID 000345279600007

  View details for PubMedCentralID PMC5738466

• Review of the current targeted therapies for non-small-cell lung cancer. World journal of clinical oncology Nguyen, K. H., Neal, J. W., Wakelee, H. 2014; 5 (4): 576-587

  Abstract

  The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

  View details for DOI 10.5306/wjco.v5.i4.576

  View details for PubMedID 25302162

  View details for PubMedCentralID PMC4129523

• Development of the International Thymic Malignancy Interest Group International Database: An Unprecedented Resource for the Study of a Rare Group of Tumors JOURNAL OF THORACIC ONCOLOGY Huang, J., Ahmad, U., Antonicelli, A., Catlin, A. C., Fang, W., Gomez, D., Loehrer, P., Lucchi, M., Marom, E., Nicholson, A., Ruffini, E., Travis, W., Van Schil, P., Wakelee, H., Yao, X., Detterbeck, F. 2014; 9 (10): 1573-1578

  Abstract

  Our knowledge of thymic malignancies has largely been derived from small, single-institution series. Recognition of the need for broad collaboration led to the creation of the International Thymic Malignancy Interest Group (ITMIG) and the development of a large, centralized database to advance knowledge of these rare tumors.A multidisciplinary Database Committee was convened to define a common set of data elements a priori. Retrospective data were solicited from ITMIG members and collated using standardized fields. Patients with thymoma, thymic carcinoma, or thymic carcinoid were included.Over a 6-month period, 47 institutions spanning 15 countries contributed a total of 6097 cases (mean, 129 [range, 10-1209]). The sex distribution was equal for thymomas, but there was a greater proportion of men with thymic carcinoma and thymic carcinoid (p < 0.0001). Nearly all cases (99%) were treated surgically. WHO type B2 was the most frequent histologic classification among thymomas, whereas squamous was the most common among thymic carcinomas. In total, 38% of patients with thymoma had myasthenia gravis compared with less than or equal to 5% for thymic carcinoma and thymic carcinoid. Median overall survival was 18.9 years (95% confidence interval [CI], 17.4-20.3) for thymoma, 6.8 years (95% CI, 5.5-7.9) for thymic carcinoma, and 7.5 years (95% CI, 6.5-8.5) for thymic carcinoid.The rapid creation of the ITMIG database demonstrates the feasibility of international collaboration for this rare set of malignancies and attests to the engagement of its membership. This database represents the largest collective data set ever assembled and provides an unprecedented resource for research of these tumors.

  View details for DOI 10.1097/JTO.0000000000000269

  View details for Web of Science ID 000344368000025

  View details for PubMedID 25521402

• Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clinical lung cancer Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Ramchandran, K., Neal, J. W., Wakelee, H. A. 2014; 15 (3): 202-206

  Abstract

  Leptomeningeal carcinomatosis (LM) is a severe complication of non-small-cell lung cancer (NSCLC) historically associated with poor prognosis. New chemotherapeutic and targeted treatments could potentially affect the natural history of LM.Patients with a pathologic diagnosis of NSCLC with LM treated at Stanford between 2003 and 2011 were identified via institutional databases and medical records. LM was defined by cerebrospinal fluid (CSF) that was positive for malignant cells or by LM enhancement on magnetic resonance imaging with gadolinium contrast. Retrospective, landmark analyses were performed to estimate survival. Statistical analyses were performed using SAS Enterprise Guide, version 4.3.LM was identified in 30 patients. All cases were adenocarcinoma; 60% of patients had a known or suspected driver mutation. The mean age was 58 years. Of the 30 patients, 67% were women; 70% were nonsmokers; 27% initially presented with LM; 84% received systemic treatment at or after development of LM; and 53% of these patients received modern systemic therapy for their LM, defined as a regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor. Mean overall survival after LM diagnosis was 6 months (95% CI, 3-12). Patients who received modern systemic therapy for LM had decreased hazard of death (hazard ratio [HR], 0.24; P = .007).In this retrospective, single-institution analysis, median survival with LM was higher compared with historical experience. Patients who received modern systemic therapy for their LM had particularly good outcomes. These data provide evidence for improving survival outcomes in the modern treatment era for this difficult-to-treat complication.

  View details for DOI 10.1016/j.cllc.2013.12.009

  View details for PubMedID 24524822

• An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage NATURE MEDICINE Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 552-558

  Abstract

  Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

  View details for DOI 10.1038/nm.3519

  View details for Web of Science ID 000335710700028

• Immune correlates of talactoferrin alfa in biopsied tumor of relapsed/refractory metastatic non-small cell lung cancer patients. Immunopharmacology and immunotoxicology Riess, J. W., Bhattacharya, N., Blenman, K. R., Neal, J. W., Hwang, G., Pultar, P., San-Pedro Salcedo, M., Engleman, E., Lee, P. P., Malik, R., Wakelee, H. A. 2014; 36 (2): 182-186

  Abstract

  Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth.Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients.Talactoferrin was administered orally at 1.5 g bid weeks 1-12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens.Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies.Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF.

  View details for DOI 10.3109/08923973.2013.864671

  View details for PubMedID 24494587

• A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer. British journal of cancer Chen, H., Modiano, M. R., Neal, J. W., Brahmer, J. R., Rigas, J. R., Jotte, R. M., Leighl, N. B., Riess, J. W., Kuo, C. J., Liu, L., Gao, B., DiCioccio, A. T., Adjei, A. A., Wakelee, H. A. 2014; 110 (3): 602-608

  Abstract

  Background:This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).Methods:This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients.Results:The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months.Conclusion:Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.

  View details for DOI 10.1038/bjc.2013.735

  View details for PubMedID 24292447

  View details for PubMedCentralID PMC3915116

• Early-stage non-small cell lung cancer: surgery, stereotactic radiosurgery, and individualized adjuvant therapy. Seminars in oncology Padda, S. K., Burt, B. M., Trakul, N., Wakelee, H. A. 2014; 41 (1): 40-56

  Abstract

  Despite cures in early stage (IA-IIB) non-small cell lung cancer (NSCLC), the 5-year survival rate is only 36%-73%. Surgical resection via lobectomy is the treatment of choice in early-stage NSCLC, with the goal being complete anatomic resection of the tumor and mediastinal lymph node evaluation. Newer technologies, including the minimally invasive thoracoscopic approach and the many techniques available to stage the mediastinum, have introduced advantages over traditional approaches in achieving this goal. The advent of stereotactic ablative radiotherapy (SABR) has changed how we treat those patients who cannot undergo surgery secondary to comorbidities or patient preference. SABR allows for precise radiation delivery in a short course and at high doses. Adjuvant cisplatin-based chemotherapy is the standard of care for completely resected high-risk stage IB and stage II NSCLC based on a ~5% improvement in 5-year overall survival. The concept of customized adjuvant chemotherapy is emerging, and we will explore the potential value of targeting tumor mutations with available drugs (ie, epidermal growth factor receptor [EGFR] mutations with erlotinib), a strategy that for the moment should be restricted to clinical trials.

  View details for DOI 10.1053/j.seminoncol.2013.12.011

  View details for PubMedID 24565580

• [Chemotherapy definitions and policies for thymic malignancies]. Zhongguo fei ai za zhi = Chinese journal of lung cancer Girard, N., Lal, R., Wakelee, H., Riely, G. J., Loehrer, P. J. 2014; 17 (2): 116-121

  View details for DOI 10.3779/j.issn.1009-3419.2014.02.09

  View details for PubMedID 24581162

• Response. Chest Xu, Y., Zheng, M., Khuong, A., Merritt, R. E., Shrager, J. B., Wakelee, H. A., Kratzke, R. A., Hoang, C. D. 2013; 144 (6): 1971-1972

  View details for DOI 10.1378/chest.13-1931

  View details for PubMedID 24297135

• Isolation and mutational analysis of circulating tumor cells from lung cancer patients with magnetic sifters and biochips. Lab on a chip Earhart, C. M., Hughes, C. E., Gaster, R. S., Ooi, C. C., Wilson, R. J., Zhou, L. Y., Humke, E. W., Xu, L., Wong, D. J., Willingham, S. B., Schwartz, E. J., Weissman, I. L., Jeffrey, S. S., Neal, J. W., Rohatgi, R., Wakelee, H. A., Wang, S. X. 2013; 14 (1): 78-88

  Abstract

  Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of "liquid biopsies" from cancer patients.

  View details for DOI 10.1039/c3lc50580d

  View details for PubMedID 23969419

• miR-1 Induces Growth Arrest and Apoptosis in Malignant Mesothelioma CHEST Xu, Y., Zheng, M., Merritt, R. E., Shrager, J. B., Wakelee, H. A., Kratzke, R. A., Hoang, C. D. 2013; 144 (5): 1632-1643

  Abstract

  We investigated microRNA expression profiles of malignant pleural mesothelioma (MPM) specimens to identify novel microRNA that are potentially involved in the oncogenic transformation of human pleural cells.microRNA microarray transcriptional profiling studies of 25 MPM primary tumors were performed. We used normal pleural from an unmatched patient cohort as normal comparators. To confirm microarray data, we used real-time quantitative PCR. Representative cell lines H513 and H2052 were used in functional analyses of microRNA-1.In addition to several novel MPM-associated microRNAs, we observed that the expression level of microRNA-1 was significantly lower in tumors as compared to normal pleural specimens. Subsequently, pre-mir of microRNA-1 was introduced into MPM cell lines to overexpress this microRNA. Phenotypic changes of these altered cells were assayed. The cellular proliferation rate was significantly inhibited after overexpression of microRNA-1. Early and late apoptosis was increased markedly in microRNA-1-transfected cell lines. Taken together, these data suggested that overexpression of microRNA-1 induced apoptosis in these MPM cell lines, acting as a tumor suppressor. We confirmed our observations by assessing in the transduced MPM cells cell cycle-related genes, pro-apoptotic and anti-apoptotic genes, which all showed coordinated, significant changes characteristic of the apoptotic phenotype.Thus, further investigation and validation of our microRNA database of MPM may elucidate previously unrecognized molecular pathways and/ or mechanisms by identifying novel microRNAs that are involved in malignant transformation. Our study has now found microRNA-1 to be one of these MPM-associated microRNAs, with potential pathogenic and therapeutic significance.

  View details for DOI 10.1378/chest.12-2770

  View details for Web of Science ID 000327143700033

  View details for PubMedID 23828229

• How do social factors explain outcomes in non-small-cell lung cancer among hispanics in california? Explaining the Hispanic paradox. Journal of clinical oncology Patel, M. I., Schupp, C. W., Gomez, S. L., Chang, E. T., Wakelee, H. A. 2013; 31 (28): 3572-3578

  Abstract

  Hispanics in the United States have lower age-adjusted mortality resulting from non-small-cell lung cancer (NSCLC) compared with non-Hispanic whites (NHWs). The purpose of this study was to evaluate individual, clinical, and neighborhood factors in survival among Hispanics with NSCLC.We performed a retrospective analysis of NHWs and Hispanics with NSCLC between 1998 and 2007 in the California Cancer Registry (follow-up to December 2009). Kaplan-Meier curves depict survival by nativity for Hispanics with NSCLC. Cox proportional hazards models estimated hazard of mortality by race with adjustment for individual (age, sex, marital status), clinical (histologic grade, surgery, irradiation, chemotherapy), and neighborhood factors (neighborhood socioeconomic status, ethnic enclave).We included 14,280 Hispanic patients with NSCLC. Foreign-born Hispanics had 15% decreased risk of disease-specific mortality resulting from NSCLC compared with NHWs (hazard ratio [HR], 0.85; 95% CI, 0.83 to 0.88) after adjustment for individual, clinical, and neighborhood factors. After adjustment for individual factors, compared with US-born Hispanics, foreign-born Hispanics had 10% decreased risk of disease-specific mortality (HR, 0.90; 95% CI, 0.87 to 0.96). Clinical and neighborhood factors slightly moderated the survival benefit for foreign-born patients. A modestly more pronounced survival advantage was seen for foreign-born Hispanics living in low socioeconomic and high Hispanic enclave neighborhoods as compared with US-born Hispanics (HR, 0.86; 95% CI, 0.81 to 0.90).Foreign-born Hispanics with NSCLC have a decreased risk of disease-specific mortality compared with NHWs and US-born Hispanics with NSCLC. Neighborhood factors slightly moderate this survival advantage. This survival advantage is slightly more pronounced in lower socioeconomic and higher Hispanic enclave neighborhoods.

  View details for DOI 10.1200/JCO.2012.48.6217

  View details for PubMedID 23960183

• A Case Series of Lengthy Progression-Free Survival With Pemetrexed-Containing Therapy in Metastatic Non-Small-Cell Lung Cancer Patients Harboring ROS1 Gene Rearrangements. Clinical lung cancer Riess, J. W., Padda, S. K., Bangs, C. D., Das, M., Neal, J. W., Adrouny, A. R., Cherry, A., Wakelee, H. A. 2013; 14 (5): 592-595

  View details for DOI 10.1016/j.cllc.2013.04.008

  View details for PubMedID 23810364

• Phase I and pharmacokinetic study of bexarotene in combination with gefitinib in the third-line treatment of non-small-cell lung cancer: brief report. Anti-cancer drugs Padda, S. K., Chhatwani, L., Zhou, L., Jacobs, C. D., Lopez-Anaya, A., Wakelee, H. A. 2013; 24 (7): 731-735

  Abstract

  Gefitinib (an epidermal growth factor receptor tyrosine kinase inhibitor) and bexarotene (a rexinoid) affect similar oncogenic pathways and are both metabolized through cytochrome P450 CYP3A4. We studied the combination of bexarotene and gefitinib in the third-line treatment of advanced non-small-cell lung cancer to examine pharmacokinetic interactions and establish the maximum tolerated dose. This was a single-institution, nonrandomized, open-label, phase I clinical trial with a standard 3+3 dose escalation. Three patients were enrolled at each dose level on the basis of pharmacokinetic analysis with dose level 1 including gefitinib (Iressa) 250 mg oral daily and bexarotene (Targretin) 400 mg/m oral daily and dose level +1 including gefitinib 500 mg oral daily and bexarotene 400 mg/m oral daily. Patients received gefitinib alone for 2 weeks to allow for steady state and thereafter, bexarotene was added. In dose level 1, two of three patients had undetectable gefitinib levels at day 15 for unknown reasons. However, the peak levels on day 29 for all three patients receiving 250 mg of gefitinib with bexarotene are lower than published peak levels. Among the three patients in dose level +1, ∼40% lower gefitinib plasma concentrations were noted on day 29 compared with day 15 along with a mean 44% reduction in area under the plasma concentration-time curve from 0 to 24 h (AUC0-24). Bexarotene appears to lower the Cmax and AUC0-24 of gefitinib through cytochrome P450 CYP3A4. Our results have pharmacokinetic implications for ongoing trials that combine bexarotene with other small molecules in the era of personalized cancer therapy.

  View details for DOI 10.1097/CAD.0b013e32836100d7

  View details for PubMedID 23552470

• A Patient With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer With Development of Leptomeningeal Carcinomatosis While on Targeted Treatment With Crizotinib JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Riess, J. W., Nagpal, S., Neal, J. W., Wake, H. A. 2013; 11 (4): 389-394

  Abstract

  Leptomeningeal carcinomatosis (LM) is an infrequent yet morbid and often fatal complication of non-small cell lung cancer (NSCLC). Management of LM is multimodal, often involving systemic chemotherapy, radiotherapy, and a variety of symptom management maneuvers to address elevated intracranial pressure, pain, and mood changes that can accompany the disease. It is increasingly recognized that tumors with actionable mutations in NSCLC, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, respond well to systemic therapy with tyrosine kinase inhibitors yet often progress in the central nervous system. More information is needed regarding the natural history and optimal management of LM in specific molecular subtypes of NSCLC. This case report summarizes the management of a patient with ALK-positive NSCLC who developed LM while on targeted treatment with crizotinib within the context of current NCCN Clinical Practice Guidelines in Oncology and recently published studies.

  View details for Web of Science ID 000317543800006

  View details for PubMedID 23584342

• A Case Series of NSCLC Patients with Different Molecular Characteristics and Choroidal Metastases Improvement in Vision with Treatment Including Pemetrexed and Bevacizumab JOURNAL OF THORACIC ONCOLOGY Riess, J. W., Nagpal, S., Das, M., Neal, J. W., Kim, J. W., Wakelee, H. A. 2013; 8 (2): E17-E18

  View details for DOI 10.1097/JTO.0b013e31827690da

  View details for Web of Science ID 000316204900003

  View details for PubMedID 23328555

• A case series of NSCLC patients with different molecular characteristics and choroidal metastases: improvement in vision with treatment including pemetrexed and bevacizumab. Journal of thoracic oncology Riess, J. W., Nagpal, S., Das, M., Neal, J. W., Kim, J. W., Wakelee, H. A. 2013; 8 (2): e17-8

  View details for DOI 10.1097/JTO.0b013e31827690da

  View details for PubMedID 23328555

• Aflibercept in lung cancer EXPERT OPINION ON BIOLOGICAL THERAPY Neal, J. W., Wakelee, H. A. 2013; 13 (1): 115-120

  Abstract

  Angiogenesis, the recruitment and growth of blood vessels, is a process central to the growth of solid tumors. One of the key mediators of angiogenesis is the vascular endothelial growth factor (VEGF) family of ligands. An antibody to VEGF-A, bevacizumab, has demonstrated a survival benefit in conjunction with platinum-based doublet chemotherapy in non-small-cell lung cancer (NSCLC). Aflibercept (VEGF Trap) is a recombinant VEGF receptor-antibody protein fusion with higher affinity for VEGF-A than bevacizumab, plus affinity for VEGF-B and placental growth factor (PlGF). AREAS COVERED: This article reviews recent clinical trials investigating the role of aflibercept in the treatment of lung cancer, both published in the literature and those for which preliminary data have been presented at major scientific meetings. EXPERT OPINION: Aflibercept has proven Phase III efficacy in metastatic colorectal cancer, but in lung cancer, large clinical trials have not yielded positive results. There remains hope that identification of biomarkers of response will one day help select patients most likely to benefit from antiangiogenesis therapy.

  View details for DOI 10.1517/14712598.2013.745847

  View details for Web of Science ID 000312219700010

  View details for PubMedID 23199019

• Treatment of Leptomeningeal Spread of NSCLC: A Continuing Challenge CURRENT TREATMENT OPTIONS IN ONCOLOGY Nagpal, S., Riess, J., Wakelee, H. 2012; 13 (4): 491-504

  Abstract

  OPINION STATEMENT: Leptomeningeal metastasis is a serious and frequently fatal complication of non-small cell lung cancer. Curative treatment remains elusive, but careful use of radiation, systemic chemotherapy, intrathecal chemotherapy, and symptoms management can greatly improve quality of life and survival. For most patients, we recommend a combination of skull-based radiation with focal radiation to any symptomatic spinal segments followed by systemic chemotherapy. For patients with EGFR mutations, erlotinib may be used as first-line therapy in a daily or high-dose regimen. Pemetrexed has promise for use in patients with brain and leptomeningeal metastases. Patients with multiple comorbidities or low performance status may tolerate intrathecal therapy better than systemic chemotherapy. The most commonly used intrathecal chemotherapies are methotrexate and liposomal cytarabine, although newer agents, such as topotecan and mafosfamide, may be more effective. Elevated intracranial pressure, which causes headaches, vertigo, nausea, and vomiting, should be treated with dexamethasone and acetazolamide. In select patients, cerebrospinal fluid shunting may be considered. The use of antidepressants, central nervous system stimulants, benzodiazepines, antiemetics, and pain medications can increase quality of life in patients with leptomeningeal metastases.

  View details for DOI 10.1007/s11864-012-0206-4

  View details for Web of Science ID 000311292500006

  View details for PubMedID 22836285

• MET inhibitors in combination with other therapies in non-small cell lung cancer. Translational lung cancer research Padda, S., Neal, J. W., Wakelee, H. A. 2012; 1 (4): 238-253

  Abstract

  MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.

  View details for DOI 10.3978/j.issn.2218-6751.2012.10.08

  View details for PubMedID 25806189

  View details for PubMedCentralID PMC4367550

• Angiogenesis inhibitors. Journal of thoracic oncology Das, M., Wakelee, H. 2012; 7 (16): S397-8

  View details for DOI 10.1097/JTO.0b013e31826df227

  View details for PubMedID 23160332

• A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer LUNG CANCER Clement-Duchene, C., Natale, R. B., Jahan, T., Krupitskaya, Y., Osarogiagbon, R., Sanborn, R. E., Bernstein, E. D., Dudek, A. Z., Latz, J. E., Shi, P., Wakelee, H. A. 2012; 78 (1): 57-62

  Abstract

  Regardless of epidermal growth factor receptor (EGFR) mutation status, erlotinib improves survival for patients with advanced non-small cell lung cancer (NSCLC) after one or more chemotherapy regimens. Enzastaurin is an oral serine/threonine kinase inhibitor. This phase II study was designed to evaluate the efficacy and safety of erlotinib and enzastaurin in NSCLC, a combination with promise to overcome EGFR resistance based on preclinical models.Eligible patients with advanced NSCLC (IIIB or IV) who had failed one or two prior systemic treatment regimen(s) were enrolled and received erlotinib 150 mg/day and enzastaurin 500 mg/day (after a 1125-mg loading dose on day 1, cycle 1), both orally in 28-day cycles. The primary endpoint was progression-free survival (PFS).From January 2008 to July 2009, 49 patients were enrolled: 29 (59%) men and 20 (41%) women; 8 (16%) were non-smokers. The median PFS was 1.7 months (one-sided 90% CI: 1.5-NA) and median overall survival (OS) was 8.3 months (95% CI: 5.3-14.3). Five patients had partial response, for an overall response rate of 10.2%; the disease control rate was 30.6% (responders+10 patients with stable disease). Grade 3-4 drug-related adverse events in ≥5% of patients were diarrhea, acne, and nausea. One possibly drug-related death due to interstitial lung disease occurred during the study.In previously treated, unselected, advanced NSCLC patients, the addition of enzastaurin to erlotinib did not improve PFS, response, or OS compared with historical data of single-agent erlotinib, but was well tolerated.

  View details for DOI 10.1016/j.lungcan.2012.06.003

  View details for Web of Science ID 000309801700009

  View details for PubMedID 22809813

• A Double-Blind Randomized Discontinuation Phase-II Study of Sorafenib (BAY 43-9006) in Previously Treated Non-Small-Cell Lung Cancer Patients Eastern Cooperative Oncology Group Study E2501 JOURNAL OF THORACIC ONCOLOGY Wakelee, H. A., Lee, J., Hanna, N. H., Traynor, A. M., Carbone, D. P., Schiller, J. H. 2012; 7 (10): 1574-1582

  Abstract

  Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase-II study in heavily pretreated non-small-cell lung cancer (NSCLC) patients (≥ 2 prior therapies) used a randomized discontinuation design.Patients received 400 mg of sorafenib orally twice daily for two cycles (2 months) (step 1). Responding patients on step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease 2 months after randomization.There were 299 patients evaluated for step 1; of these, 81 eligible patients were randomized on step 2 and received sorafenib (n = 50) or placebo (n = 31). The 2-month disease control rates after randomization were 54% and 23% for patients initially receiving sorafenib and placebo, respectively, p = 0.005. The hazard ratio for progression on step 2 was 0.51 (95% [confidence interval] CI 0.30, 0.87, p = 0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), hazard ratio 0.67 (95% CI 0.40-1.11), p = 0.117. A dispensing error occurred, which resulted in the unblinding of some patients, but not before completion of the 8-week initial step 2 therapy. Toxicities were manageable and as expected.The results of this randomized discontinuation trial suggest that sorafenib has single-agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC.

  View details for DOI 10.1097/JTO.0b013e31826149ba

  View details for Web of Science ID 000308919400020

  View details for PubMedID 22982658

  View details for PubMedCentralID PMC3444827

• Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Trakul, N., Chang, C. N., Harris, J., Chapman, C., Rao, A., Shen, J., Quinlan-Davidson, S., Filion, E. J., Wakelee, H. A., Colevas, A. D., Whyte, R. I., Dieterich, S., Maxim, P. G., Hristov, D., Tran, P., Quynh-Thu Le, Q. T., Loo, B. W., Diehn, M. 2012; 84 (1): 231-237

  Abstract

  Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy.We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2).The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02).A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

  View details for DOI 10.1016/j.ijrobp.2011.10.071

  View details for Web of Science ID 000308061900060

  View details for PubMedID 22381907

• Prolonged Survival in Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Metastases (LM) in the Modern Treatment Era Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2012: S243–S243

  View details for Web of Science ID 000317035000106

• How Do Social Factors Explain Outcomes In Non-small Cell Lung Cancer Among Hispanic/latinos In California? Patel, M. I., Chang, E., Gomez, S., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2012: S216–S216

  View details for Web of Science ID 000317035000036

• A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours BRITISH JOURNAL OF CANCER Diaz-Padilla, I., Siu, L. L., San Pedro-Salcedo, M., Razak, A. R., Colevas, A. D., Shepherd, F. A., Leighl, N. B., Neal, J. W., Thibault, A., Liu, L., Lisano, J., Gao, B., Lawson, E. B., Wakelee, H. A. 2012; 107 (4): 604-611

  Abstract

  To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

  View details for DOI 10.1038/bjc.2012.319

  View details for Web of Science ID 000307770300005

  View details for PubMedID 22805331

  View details for PubMedCentralID PMC3419963

• ERCC1 expression in circulating tumor cells (CTCs) using a novel detection platform correlates with progression-free survival (PFS) in patients with metastatic non-small-cell lung cancer (NSCLC) receiving platinum chemotherapy. Lung cancer Das, M., Riess, J. W., Frankel, P., Schwartz, E., Bennis, R., Hsieh, H. B., Liu, X., Ly, J. C., Zhou, L., Nieva, J. J., Wakelee, H. A., Bruce, R. H. 2012; 77 (2): 421-426

  Abstract

  To utilize a novel circulating tumor cell (CTC) technology to quantify ERCC1 expression on CTCs and determine whether ERCC1 expression levels predict efficacy of platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC).ERCC1 expression was measured in 17 metastatic NSCLC patients who received platinum-based therapy and had ≥2 intact CTCs with acceptable ERCC1 expression assay results. ERCC1 levels were determined from average expression on individual CTCs in each sample. Progression-free survival (PFS) was calculated from the date of therapy initiation.PFS decreased with increasing ERCC1 expression (p<0.04, F-test, linear regression). Lack of ERCC1 expression was associated with longer PFS (266 days versus 172 days, log-rank, p<0.02) in a Kaplan-Meier analysis using ERCC expression level of 1 as a cutoff (range 0-30). The difference in survival was statistically significant with a hazard ratio of 4.20 (95% CI 1.25-14.1, p<0.02, log-rank). PFS was also observed to decrease with increased cytokeratin (CK) expression (p<0.01 long-rank (Cox regression) and F-test (linear regression)). The hazard ratio is 4.38 (95% CI 1.76-10.9) for each log-change in CK value until progression was noted on imaging.Low expression of ERCC1 on CTCs correlates with PFS in patients with metastatic NSCLC receiving platinum-based therapy.

  View details for DOI 10.1016/j.lungcan.2012.04.005

  View details for PubMedID 22555222

• ERCC1 expression in circulating tumor cells (CTCs) using a novel detection platform correlates with progression-free survival (PFS) in patients with metastatic non-small-cell lung cancer (NSCLC) receiving platinum chemotherapy LUNG CANCER Das, M., Riess, J. W., Frankel, P., Schwartz, E., Bennis, R., Ben Hsieh, H., Liu, X., Ly, J. C., Zhou, L., Nieva, J. J., Wakelee, H. A., Bruce, R. H. 2012; 77 (2): 421-426

  View details for DOI 10.1016/j.lungcan.2012.04.005

  View details for Web of Science ID 000307036500030

• Differential effect of age on survival in advanced NSCLC in women versus men: Analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab LUNG CANCER Wakelee, H. A., DAHLBERG, S. E., Brahmer, J. R., Schiller, J. H., Perry, M. C., Langer, C. J., Sandler, A. B., Belani, C. P., Johnson, D. H. 2012; 76 (3): 410-415

  Abstract

  The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex.Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort.The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men.In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

  View details for DOI 10.1016/j.lungcan.2011.12.006

  View details for Web of Science ID 000304688300023

  View details for PubMedID 22266041

• How do social factors explain outcomes in non-small cell lung cancer among Hispanics/Latinos in California? 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Patel, M. I., Chang, E. T., Gomez, S. L., Schupp, C., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009801334

• Correlation of ERCC1 expression on circulating tumor cells with progression-free survival in metastatic non-small cell lung cancer patients treated with platinum-based chemotherapy 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Riess, J., Das, M. S., Frankel, P. H., Schwartz, E., Bennis, R., Ben Hsieh, H., Liu, X., Ly, J., Zhou, L. Y., Nieva, J. J., Bruce, R., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009800395

• A phase II multicenter study of aflibercept (AFL) in combination with cisplatin (C) and pemetrexed (P) in patients with previously untreated advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC). 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chen, H., Modiano, M. R., Neal, J. W., Brahmer, J. R., Rigas, J. R., Jotte, R. M., Leighl, N. B., Liu, L., Lisano, J. M., Adjei, A. A., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009804215

• A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors CANCER CHEMOTHERAPY AND PHARMACOLOGY Padda, S. K., Krupitskaya, Y., Chhatwani, L., Fisher, G. A., Colevas, A. D., Pedro-Salcedo, M. S., Decker, R., Latz, J. E., Wakelee, H. A. 2012; 69 (4): 1013-1020

  Abstract

  Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated.This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with advanced solid malignancies including non-small-cell lung cancer (NSCLC). Two dose levels of enzastaurin (with loading doses) were explored: 250 mg daily and 500 mg daily. Erlotinib was given at 150 mg daily.Sixteen patients were enrolled in this study (median age, 64 years). Most patients were heavily pre-treated, female, and Caucasian and had NSCLC. The highest dose of enzastaurin, 500 mg daily, was tolerated with no unexpected adverse events and no alteration in the pharmacokinetics of either drug at this dose level. The mean clearance was 5.75 L/h for erlotinib and 53.8 L/h for enzastaurin. The most common possibly drug-related grade 3-4 adverse events included diarrhea (25.0%), neurologic symptoms (18.8%), and vomiting (18.8%). Activity was noted, with a partial response in one patient and prolonged disease stability for >12 cycles in three patients.The combination of enzastaurin 500 mg daily and erlotinib 150 mg daily is well tolerated and does not alter the pharmacokinetics of the individual drugs, with clinical activity seen. A phase II trial of this combination has been initiated in patients with advanced-stage NSCLC.

  View details for DOI 10.1007/s00280-011-1792-8

  View details for Web of Science ID 000302327300019

  View details for PubMedID 22160298

• Targeting VEGF in lung cancer EXPERT OPINION ON THERAPEUTIC TARGETS Das, M., Wakelee, H. 2012; 16 (4): 395-406

  Abstract

  VEGF promotes tumor angiogenesis and is an important target in various malignancies, including NSCLC. AREAS COVERED: Here, the authors review the data that led to the approval of bevacizumab, a monoclonal antibody against VEGF, in the treatment of lung cancer. The authors also review the key results from a number of Phase II and Phase III trials involving other anti-angiogenic agents being studied in NSCLC, including small-molecule tyrosine kinase inhibitors against the VEGF-receptor and vascular-disrupting agents (VDAs). EXPERT OPINION: Results from ongoing studies and the identification of reliable biomarkers remain critical goals in understanding the exact role of these anti-angiogenic agents in the treatment paradigm of NSCLC.

  View details for DOI 10.1517/14728222.2012.669752

  View details for Web of Science ID 000302458200006

  View details for PubMedID 22439677

• Metastatic non-small cell lung cancer management: novel targets and recent clinical advances. Clinical advances in hematology & oncology : H&O Riess, J. W., Wakelee, H. A. 2012; 10 (4): 226-234

  Abstract

  Lung cancer continues to be the most common cause of cancer-related mortality in the United States and other developed countries. The most common subtype is non-small cell lung cancer (NSCLC). Within NSCLC, we are discovering remarkable molecular heterogeneity. Most current actionable mutations have been identified in patients with adenocarcinoma histology, but now new mutations are being discovered in squamous cell histology patients as well. This molecular heterogeneity provides an opportunity for clinical trials to exploit various candidate oncogene-addicted pathways in NSCLC. This article focuses on 2 shifting paradigms in NSCLC management: the recent advances in targeted therapy and maintenance treatment.

  View details for PubMedID 22706483

• A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC) CANCER CHEMOTHERAPY AND PHARMACOLOGY Wakelee, H. A., Middleton, G., Dunlop, D., Ramlau, R., Leighl, N., Hao, D., Lopez-Anaya, A., Zatloukal, P., Jacobs, C. D. 2012; 69 (3): 815-824

  Abstract

  This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin(®)) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination.Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m(2) on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m(2) weekly. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2-4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods.Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents.Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).

  View details for DOI 10.1007/s00280-011-1771-0

  View details for Web of Science ID 000302325600025

  View details for PubMedID 22057854

• A phase I pharmacokinetic study of bexarotene with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC) CANCER CHEMOTHERAPY AND PHARMACOLOGY Rodon, J., Jacobs, C. D., Chu, Q., Rowinsky, E. K., Lopez-Anaya, A., Takimoto, C. H., Wakelee, H. A. 2012; 69 (3): 825-834

  Abstract

  Preclinical data suggest that the synthetic retinoid bexarotene may be an effective chemopreventive agent and that it may act synergistically in combination with platinum-based chemotherapy. The primary objective of this study was to determine whether repeated doses of bexarotene capsules affect pharmacokinetic parameters of paclitaxel or carboplatin in patients with advanced non-small cell lung cancer.Patients received treatment with paclitaxel (200 mg/m(2)) and carboplatin to provide a target AUC of 6 mg min/mL (day 1) every 3 weeks. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated on Day 4, and patients started lipid-lowering therapy prior to beginning chemotherapy. Blood sampling to characterize the pharmacokinetic profiles of the chemotherapeutic agents with or without bexarotene was performed during cycle 1 (without concomitant bexarotene) and during cycle 2 (with concomitant bexarotene).An analysis of drug concentration data from 16 patients indicated that bexarotene did not affect the pharmacokinetics of paclitaxel, free carboplatin, or total carboplatin concentrations. However, both maximal plasma concentrations and total exposure of bexarotene increased by 80% in the presence of paclitaxel-carboplatin by an, as of yet, unexplained mechanism. The toxicities observed resembled those of either the chemotherapy regimen or bexarotene alone, and there was no evidence for an enhancement of any drug-related toxicity with the combined treatment.The administration of bexarotene, paclitaxel, and carboplatin is feasible and safe; however, the increased bexarotene plasma concentrations and exposure warrant further investigation if this combination is to be utilized clinically.

  View details for DOI 10.1007/s00280-011-1770-1

  View details for Web of Science ID 000302325600026

  View details for PubMedID 22057853

• Maintenance Bevacizumab is Associated With Increased Hemoglobin in Patients With Advanced, Nonsquamous, Non-Small Cell Lung Cancer CANCER INVESTIGATION Riess, J. W., Logan, A. C., Krupitskaya, Y., Padda, S., Clement-Duchene, C., Ganjoo, K., Colevas, A. D., San Pedro-Salcedo, M., Kuo, C. J., Wakelee, H. A. 2012; 30 (3): 231-235

  Abstract

  We retrospectively analyzed hematologic parameters in 22 patients with advanced, nonsquamous, NSCLC undergoing VEGF inhibition on a phase II clinical trial of bevacizumab, carboplatin, and gemcitabine. We also examined TTP in relation to hemoglobin changes. Median hemoglobin increased significantly from a 12.9 g/dL pretreatment to 13.8 g/dL (p =.01) after the second cycle of maintenance bevacizumab until the first off cycle measurement. There was no difference in TTP in patients who achieved a rise in hemoglobin compared with patients who did not (median 238 days vs. 268 days, p =.38.) Maintenance bevacizumab is associated with increased hemoglobin in advanced, nonsquamous, NSCLC patients.

  View details for DOI 10.3109/07357907.2012.656862

  View details for Web of Science ID 000300657200005

  View details for PubMedID 22360362

• The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer CANCER CHEMOTHERAPY AND PHARMACOLOGY Wakelee, H. A., Takimoto, C. H., Lopez-Anaya, A., Chu, Q., Middleton, G., Dunlop, D., Ramlau, R., Leighl, N., Rowinsky, E. K., Hao, D., Zatloukal, P., Jacobs, C. D., Rodon, J. 2012; 69 (2): 563-571

  Abstract

  Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents.Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene).Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions.A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.

  View details for DOI 10.1007/s00280-011-1772-z

  View details for Web of Science ID 000299516700030

  View details for PubMedID 22057855

• Metabolic Tumor Volume is an Independent Prognostic Factor in Patients Treated Definitively for Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Lee, P., Bazan, J. G., Lavori, P. W., Weerasuriya, D. K., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Graves, E. E., Loo, B. W. 2012; 13 (1): 52-58

  Abstract

  Fluorine-18 flurodeoxyglucose positron emission tomography (FDG-PET) imaging has rapidly become the standard of care for staging patients with lung cancer. We evaluated the prognostic value of metabolic tumor volume (MTV), a measure of tumor burden on FDG-PET imaging, in patients with non-small-cell lung cancer (NSCLC) treated definitively.A retrospective review identified 61 patients with NSCLC who underwent FDG-PET imaging for pretreatment staging. Metabolically active tumor regions were segmented on the PET scans semiautomatically to calculate the total body MTV. We determined the relationship of overall survival (OS) and progression-free survival (PFS) with MTV in the entire cohort, and in the subgroup treated definitively.The estimated median PFS and OS for the entire cohort were 11.1 months and 18.9 months. Higher MTV was significantly associated with worse OS (P = 0.00075) and PFS (P = 0.00077). For definitively treated patients, when MTV was analyzed as a binary value above or below the median value, 2-year PFS was 60% versus 39.7% (median PFS 34.9 vs. 11.9 months) and 2-year OS was 79.7% versus 33.3% (median OS 41.9 vs. 18.9 months), respectively (log-rank P = 0.12 for PFS and P = 0.066 for OS). When MTV was analyzed as a continuous variable, multivariate Cox proportional hazards analysis demonstrated a trend to worse PFS (hazard ratio [HR] = 1.31; P = 0.12) and significantly worse OS (HR = 1.53; P = 0.018) with increasing MTV after controlling for known prognostic variables.Tumor burden as assessed by MTV yields prognostic information on survival beyond that of established prognostic factors in patients with NSCLC treated definitively.

  View details for DOI 10.1016/j.cllc.2011.05.001

  View details for Web of Science ID 000299270900008

  View details for PubMedID 21703935

• XL647-A Multitargeted Tyrosine Kinase Inhibitor Results of a Phase II Study in Subjects with Non-small Cell Lung Cancer Who Have Progressed after Responding to Treatment with Either Gefitinib or Erlotinib JOURNAL OF THORACIC ONCOLOGY Pietanza, M. C., Lynch, T. J., Lara, P. N., Cho, J., Yanagihara, R. H., Vrindavanam, N., Chowhan, N. M., Gadgeel, S. M., Pennell, N. A., Funke, R., Mitchell, B., Wakelee, H. A., Miller, V. A. 2012; 7 (1): 219-226

  Abstract

  Although patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring T790M.Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. XL647 300 mg was administered once daily. The primary end point was objective response rate. Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA.Forty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (response rate 3% and 90% confidence interval, 0% to 14%). Of patients whose tumors harbored T790M, 67% (8/12) had progression of disease as best response compared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35%) of which were found to have EGFR mutations.The 3% response rate observed did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to erlotinib or gefitinib. Patients with T790M had a significantly worse progression-free survival.

  View details for DOI 10.1097/JTO.0b013e31822eebf9

  View details for Web of Science ID 000300305600032

  View details for PubMedID 22011666

• Current Management of Small Cell Lung Cancer CLINICS IN CHEST MEDICINE Neal, J. W., Gubens, M. A., Wakelee, H. A. 2011; 32 (4): 853-?

  Abstract

  Confined to one side of the chest, limited stage small cell lung cancer is treated with a combination of chemotherapy and radiotherapy, yet has a long-term survival rate of only 15%. Extensive stage disease has initial response rates to chemotherapy exceeding 70%. However, the disease almost invariably progresses and becomes fatal. Many recent clinical trials have failed to show superiority of newer chemotherapeutics or targeted therapies compared with the standard chemotherapy backbone of platinum plus etoposide. Numerous promising targeted therapies and other agents are still in development.

  View details for DOI 10.1016/j.ccm.2011.07.002

  View details for Web of Science ID 000297822700017

  View details for PubMedID 22054891

• Angiogenesis Inhibitors JOURNAL OF THORACIC ONCOLOGY Das, M., Wakelee, H. 2011; 6 (11): S1801-S1802

  View details for DOI 10.1097/01.JTO.0000407564.91781.ab

  View details for Web of Science ID 000296705500009

  View details for PubMedID 22005536

• Results from a Single Institution Phase II Trial of Concurrent Docetaxel/Carboplatin/Radiotherapy Followed by Surgical Resection and Consolidation Docetaxel/Carboplatin in Stage III Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Das, M., Donington, J. S., Murphy, J., Kozak, M., Eclov, N., Whyte, R. I., Hoang, C. D., Zhou, L., Le, Q., Loo, B. W., Wakelee, H. 2011; 12 (5): 280-285

  Abstract

  The optimal treatment of locally advanced non-small-cell lung cancer (NSCLC) remains controversial. We hypothesized that using a trimodality approach in selected patients with stage IIIA/IIIB disease would be both feasible and efficacious with reasonable toxicity.We enrolled 13 patients with resectable stage III NSCLC on a prospective phase II trial of trimodality therapy. Induction treatment consisted of weekly docetaxel 20 mg/m(2) and weekly carboplatin at an area under curve (AUC) of 2 concurrent with 45 Gy thoracic radiotherapy. Resection was performed unless felt to be unsafe or if patients had progressive disease. Postoperative consolidation consisted of docetaxel 75 mg/m(2) and carboplatin at an AUC of 6 every 3 weeks for 3 cycles with growth factor support.All patients responded to induction chemoradiotherapy as measured by total gross tumor volume reductions of 43% on average (range, 27%-64%). Twelve patients underwent resection of the tumor and involved nodes, yielding a resectability rate of 92%. The primary endpoint of 2-year overall survival (OS) was 72% (95% confidence interval [CI], 36%-90%), and 2-year progression-free survival (PFS) was 36% (95% CI, 9%-64%). The maximal toxicity observed per patient was grade II in 5 patients (38%); grade III in 7 patients (54%); grade IV in 1 patient (8%); and grade V in none.This trimodality approach resulted in promising outcomes with reasonable toxicity in carefully selected patients with stage III NSCLC at a single institution.

  View details for DOI 10.1016/j.cllc.2011.06.003

  View details for Web of Science ID 000294600800003

  View details for PubMedID 21752720

• Chemotherapy Definitions and Policies for Thymic Malignancies JOURNAL OF THORACIC ONCOLOGY Girard, N., Lal, R., Wakelee, H., Riely, G. J., Loehrer, P. J. 2011; 6 (7): S1749-S1755

  View details for Web of Science ID 000292277900011

  View details for PubMedID 21847058

• MAINTENANCE BEVACIZUMAB MONOTHERAPY INCREASES HEMOGLOBIN (HGB) IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG ADENOCARCINOMA (NSCLC-AD) Riess, J. W., Logan, A., Krupitskaya, Y., Clement-Duchene, C., Kuo, C., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: S962–S963

  View details for Web of Science ID 000291769800090

• American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy JOURNAL OF CLINICAL ONCOLOGY Keedy, V. L., Temin, S., Somerfield, M. R., Beasley, M. B., Johnson, D. H., McShane, L. M., Milton, D. T., Strawn, J. R., Wakelee, H. A., Giaccone, G. 2011; 29 (15): 2121-2127

  Abstract

  An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the clinical utility of using epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer (NSCLC) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor (TKI). CLINICAL CONTEXT: Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib. In the United States, approximately 15% of patients with adenocarcinoma of the lung harbor activating EGFR mutations. EGFR mutation testing is widespread at academic medical centers and in some locales in community practice. As of yet, there is no evidence of an overall survival (OS) benefit from selecting treatment based on performing this testing. RECENT DATA: One large phase III trial (the Iressa Pan-Asia Study [IPASS] trial), three smaller phase III randomized controlled trials using progression-free survival as the primary end point, and one small phase III trial with OS as the primary end point, all involving first-line EGFR TKIs and chemotherapy doublets, form the basis of this PCO. PROVISIONAL CLINICAL OPINION: On the basis of the results of five phase III randomized controlled trials, patients with NSCLC who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.

  View details for DOI 10.1200/JCO.2010.31.8923

  View details for Web of Science ID 000290716900044

  View details for PubMedID 21482992

• Tumor Volume as a Potential Imaging-Based Risk-Stratification Factor in Trimodality Therapy for Locally Advanced Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Kozak, M. M., Murphy, J. D., Schipper, M. L., Donington, J. S., Zhou, L., Whyte, R. I., Shrager, J. B., Hoang, C. D., Bazan, J., Maxim, P. G., Graves, E. E., Diehn, M., Hara, W. Y., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Loo, B. W. 2011; 6 (5): 920-926

  Abstract

  The role of trimodality therapy for locally advanced non-small cell lung cancer (NSCLC) continues to be defined. We hypothesized that imaging parameters on pre- and postradiation positron emission tomography (PET)-computed tomography (CT) imaging are prognostic for outcome after preoperative chemoradiotherapy (CRT)/resection/consolidation chemotherapy and could help risk-stratify patients in clinical trials.We enrolled 13 patients on a prospective clinical trial of trimodality therapy for resectable locally advanced NSCLC. PET-CT was acquired for radiation planning and after 45 Gy. Gross tumor volume (GTV) and standardized uptake value were measured at pre- and post-CRT time points and correlated with nodal pathologic complete response, loco-regional and/or distant progression, and overall survival. In addition, we evaluated the performance of automatic deformable image registration (ADIR) software for volumetric response assessment.All patients responded with average total GTV reductions after 45 Gy of 43% (range: 27-64%). Pre- and post-CRT GTVs were highly correlated (R² = 0.9), and their respective median values divided the patients into the same two groups. ADIR measurements agreed closely with manually segmented post-CRT GTVs. Patients with GTV ≥ median (137 ml pre-CRT and 67 ml post-CRT) had 3-year progression-free survival (PFS) of 14% versus 75% for GTV less than median, a significant difference (p = 0.049). Pre- and post-CRT PET-standardized uptake value did not correlate significantly with pathologic complete response, PFS, or overall survival.Preoperative CRT with carboplatin/docetaxel/45 Gy resulted in excellent response rates. In this exploratory analysis, pre- and post-CRT GTV predicted PFS in trimodality therapy, consistent with our earlier studies in a broader cohort of NSCLC. ADIR seems robust enough for volumetric response assessment in clinical trials.

  View details for DOI 10.1097/JTO.0b013e31821517db

  View details for Web of Science ID 000289554100012

  View details for PubMedID 21774104

• Survival following Non-Small Cell Lung Cancer among Asian/Pacific Islander, Latina, and Non-Hispanic White Women Who Have Never Smoked CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gomez, S. L., Chang, E. T., Shema, S. J., Fish, K., Sison, J. D., Reynolds, P., Clement-Duchene, C., Wrensch, M. R., Wiencke, J. L., Wakelee, H. A. 2011; 20 (3): 545-554

  Abstract

  Lung cancer is the leading cause of cancer death among U.S. Asian/Pacific Islander (API) and Latina women despite low smoking prevalence. This study examined survival patterns following non-small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS).Women diagnosed with lung cancer from 1998 to 2003 and 2005 to 2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic (NH) white, 23 U.S.-born Latina, 32 foreign-born Latina, 30 U.S.-born API, and 190 foreign-born API never-smokers diagnosed with lung cancer and followed through 2008.All-cause survival was poorer among APIs [HR=1.7 (95% CI: 1.0-2.8) among U.S.-born APIs and HR=1.2 (95% CI: 0.9-1.5) among foreign-born APIs] and Latinas [HR=2.1 (95% CI: 1.2-3.6) among U.S.-born Latinas; HR=1.4 (95% CI: 0.9-2.3) among foreign-born Latinas] relative to NH whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors.Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations as possible explanations for these striking racial/ethnic differences.Latina and API female never-smokers diagnosed with lung cancer were up to two times more likely to die than NH whites, highlighting the need for additional research to identify the underlying reasons for the disparities and heightened clinical awareness.

  View details for DOI 10.1158/1055-9965.EPI-10-0965

  View details for Web of Science ID 000288067200017

  View details for PubMedID 21239685

• Changes in FDG-PET/CT Parameters on Serial Pre-radiotherapy Scans Predict Disease Progression and Survival in Patients with Non-small Cell Lung Cancer Bazan, J. G., Chung, M. P., Eastham, D. V., Wakelee, H., Hara, W. Y., Maxim, P. G., Graves, E., Le, Q. T., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S579–S580

  View details for Web of Science ID 000296411701268

• Adjuvant chemotherapy for early stage non-small cell lung cancer. Frontiers in oncology Patel, M. I., Wakelee, H. A. 2011; 1: 45-?

  Abstract

  For many years adjuvant chemotherapy has been a standard treatment after complete resection in malignancies such as breast and colon but only recently has its use become standard in early stage non-small cell lung cancer (NSCLC). Although surgery is regarded as the best possible treatment for early stage NSCLC, only 20-25% of patients have resectable disease at presentation. Despite optimal surgical treatment, 5-year survival rates for NSCLC remain 50-60% for stage IB, 40-50% for stage II, and 20-30% for stage III (Kohler et al., 2011; Siegel et al., 2011). Adjuvant chemotherapy provides additional survival benefit in resected NSCLC but questions remain as to how to select patients for therapy and which regimen is best. Other than work with tegafur/uracil in Japan, the positive adjuvant trials have all utilized a cisplatin backbone, but the drug(s) to pair with cisplatin are a matter of debate and will be discussed further in this manuscript.

  View details for DOI 10.3389/fonc.2011.00045

  View details for PubMedID 22655247

• A Quantitative Assay of ERCC1 Expression in Circulating Tumor Cells (CTCs) in Non-small Cell Lung Cancer (NSCLC): A Potential Predictor of Treatment Response Das, M., Hsieh, B. H., Krivacic, R. T., Lazarus, N., Bennis, R., Ly, J., Schwartz, E., Zhou, L., Bruce, R. H., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2010: S535–S535

  View details for Web of Science ID 000284994100090

• Vascular Disrupting Agents JOURNAL OF THORACIC ONCOLOGY Das, M., Wakelee, H. 2010; 5 (12): S482-S483

  View details for Web of Science ID 000284994000016

  View details for PubMedID 21102249

• A Phase II Study Of Saracatinib (AZD0530), A Src Inhibitor, Administered Orally Daily To Patients With Advanced Thymic Malignancies Wakelee, H. A., Gubens, M. A., Burns, M., Barbeau, S. L., Perkins, S., Pedo-Salcedo, M. G., Loehrer, P. J. LIPPINCOTT WILLIAMS & WILKINS. 2010: S528–S528

  View details for Web of Science ID 000284994100072

• A Phase II First-Line Study of Gemcitabine, Carboplatin, and Bevacizumab in Advanced Stage Nonsquamous Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Clement-Duchene, C., Krupitskaya, Y., Ganjoo, K., Lavori, P., McMillan, A., Kumar, A., Zhao, G., Padda, S., Zhou, L., San Pedro-Salcedo, M., Colevas, A. D., Wakelee, H. A. 2010; 5 (11): 1821-1825

  Abstract

  Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab.Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity.From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1-42) with 37 patients (78.7%) completing ≥4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8-7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0-16.5). The OS is 57% at 1 year and 10% at 2 years.Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.

  View details for DOI 10.1097/JTO.0b013e3181f1d23c

  View details for Web of Science ID 000283491100017

  View details for PubMedID 20881641

• Lung Cancer Among Postmenopausal Women Treated With Estrogen Alone in the Women's Health Initiative Randomized Trial JOURNAL OF THE NATIONAL CANCER INSTITUTE Chlebowski, R. T., Anderson, G. L., Manson, J. E., Schwartz, A. G., Wakelee, H., Gass, M., Rodabough, R. J., Johnson, K. C., Wactawski-Wende, J., Kotchen, J. M., Ockene, J. K., O'Sullivan, M. J., Hubbell, F. A., Chien, J. W., Chen, C., Stefanick, M. L. 2010; 102 (18): 1413-1421

  Abstract

  In the Women's Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer.The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50-79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non-small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided.After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non-small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79).Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.

  View details for DOI 10.1093/jnci/djq285

  View details for Web of Science ID 000282176600010

  View details for PubMedID 20709992

  View details for PubMedCentralID PMC2943522

• AMG-386, a selective angiopoietin-1/-2-neutralizing peptibody for the potential treatment of cancer CURRENT OPINION IN MOLECULAR THERAPEUTICS Neal, J., Wakelee, H. 2010; 12 (4): 487-495

  Abstract

  The VEGF/VEGFR and angiopoietin/Tie-2 signaling pathways are important in the process of vascular endothelial growth (angiogenesis) and in the maintenance of tumor-associated blood vessels. While there are several agents targeting the VEGF/VEGFR signaling pathway, there are none available that target the angiopoietin/Tie-2 signaling pathway. The first such agent to reach clinical trials is AMG-386 (2xCon4C), being developed by Amgen Inc and licensed in Japan to Takeda Bio Development Center Ltd. AMG-386 is an anti-angiopoietin peptibody comprising a peptide with angiopoietin-binding properties that is fused to the Fc (crystallizable fragment) region of an antibody and inhibits the interaction between the ligands angiopoietin-1 and angiopoietin-2 with the Tie-2 receptor. AMG-386 significantly inhibited the growth of tumors in a variety of mouse xenograft models. In phase I trials of AMG-386 as a monotherapy or in combination with chemotherapy in patients with advanced solid tumors, AMG-386 demonstrated only mild toxicities, and one complete response and several partial responses were achieved in patients. Phase II trials of AMG-386 in combination with chemotherapy were ongoing in a variety of solid tumors, including breast, ovarian, colorectal, gastric and renal cell cancers. If safe and effective, AMG-386 could be an exciting addition to other antiangiogenic therapies in solid tumors.

  View details for Web of Science ID 000280507000013

  View details for PubMedID 20677100

• Estrogen Alone and Lung Cancer in Postmenopausal Women Chlebowski, R., Anderson, G., Manson, J., Schwartz, A., Wakelee, H., Gass, M., Rodabough, R., Johnson, K., Wactawski-Wende, J., Stefanick, M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: 394–94

  View details for Web of Science ID 000277538600050

• Voreloxin, a First-in-Class Anticancer Quinolone Derivative, in Relapsed/Refractory Solid Tumors: A Report on Two Dosing Schedules CLINICAL CANCER RESEARCH Advani, R. H., Hurwitz, H. I., Gordon, M. S., Ebbinghaus, S. W., Mendelson, D. S., Wakelee, H. A., Hoch, U., Silverman, J. A., Havrilla, N. A., Berman, C. J., Fox, J. A., Allen, R. S., Adelman, D. C. 2010; 16 (7): 2167-2175

  Abstract

  Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity.Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history.In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m(2)). At 60 mg/m(2), four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m(2), two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for >29 days (n = 1). Therefore, the MTD was 48 mg/m(2) (HP patients) and 60 mg/m(2) (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m(2)). At 18 mg/m(2), two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m(2). Voreloxin exhibited low clearance (2 L/h/m(2)), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria.Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia.

  View details for DOI 10.1158/1078-0432.CCR-09-2236

  View details for Web of Science ID 000278595800021

  View details for PubMedID 20233886

• Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors ANNALS OF ONCOLOGY Wakelee, H. A., Patnaik, A., Sikic, B. I., Mita, M., Fox, N. L., Miceli, R., Ullrich, S. J., Fisher, G. A., Tolcher, A. W. 2010; 21 (2): 376-381

  Abstract

  Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity. Materials and methods: This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors.Thirty-one patients received lexatumumab over five dose levels (0.1-10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (+/-standard deviation) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected.Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.

  View details for DOI 10.1093/annonc/mdp292

  View details for Web of Science ID 000274087600029

  View details for PubMedID 19633048

• Antiangiogenic Agents and Vascular Disrupting Agents for the Treatment of Lung Cancer A Review JOURNAL OF THORACIC ONCOLOGY Clement-Duchene, C., Wakelee, H. 2010; 5 (1): 129-139

  Abstract

  Although lung cancer therapy has slowly improved with standard cytotoxic chemotherapy drugs, we have reached an efficacy plateau. The addition of targeted agents, such as those with antiangiogenesis activity, to chemotherapy can improve response and survival outcomes. The first of these agents to gain approval in lung cancer in October 2006 was the antivascular endothelial growth factor antibody, bevacizumab. Small molecule tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor also have proven activity and are under active investigation. Vascular disrupting agents target existing tumor vasculature leading to tumor necrosis, and are being studied in solid tumors, including lung cancer, both as single agents and in combination with chemotherapy. This article will review these new targeted antiangiogenic and antivascular agents with a focus on their use as lung cancer therapeutics.

  View details for Web of Science ID 000273496000022

  View details for PubMedID 19952799

• Docetaxel in the treatment of non-small cell lung carcinoma: an update and analysis. Lung Cancer (Auckland, N.Z.) Gubens, M. A., Wakelee, H. A. 2010; 1: 63-76

  Abstract

  Docetaxel, a semisynthetic taxane, was the first agent to show efficacy in the second-line treatment of non-small cell lung cancer (NSCLC), and has since become a mainstay of NSCLC therapy. We review its mode of action, pharmacology, toxicity and efficacy and describe both its established role in the treatment of NSCLC and future directions in research. Docetaxel works primarily by promoting microtubule assembly and polymerization, and through this hyperstabilization, causes cell cycle arrest and death. The primary toxicity of docetaxel is neutropenia, which can be mitigated by weekly administration in selected patients. Less common toxicities are peripheral edema, which can be reduced by appropriate premedication and interstitial pneumonitis. Hypersensitivity reactions are less frequent than with paclitaxel. Docetaxel has shown a survival and quality of life advantage as a single agent first- and second-line versus placebo, as well as first-line in a platinum-based doublet therapy compared to a single agent. Increasingly docetaxel has also been used effectively in adjuvant regimens in earlier stages of the disease. Future areas of research include combinations with novel targeted therapies, and a greater understanding of biomarkers that might help predict efficacy and personalize therapy.

  View details for PubMedID 28210107

• Marked Tumor Response and Fatal Hemoptysis During Radiation for Lung Cancer in a Human Immunodeficiency Virus-Positive Patient Taking Nelfinavir JOURNAL OF THORACIC ONCOLOGY Chapman, C. H., Shen, J., Filion, E. J., Tran, P. T., Hara, W., Asuncion, A., Marko, D., Wakelee, H., Berry, G. J., Dimmick, K. W., Loo, B. W., Green, J. 2009; 4 (12): 1587-1589

  View details for Web of Science ID 000272095500025

  View details for PubMedID 20009915

• Cooperative Group Research Efforts in Thoracic Malignancies 2009: A Review From the 10th Annual International Lung Cancer Congress CLINICAL LUNG CANCER Wakelee, H., Loo, B. W., Kernstine, K. H., Putnam, J. B., Edelman, M. J., Vokes, E. E., Schiller, J. H., Baas, P., Saijo, N., Adjei, A., Goss, G., Choy, H., Gandara, D. R. 2009; 10 (6): 395-404

  Abstract

  Critical advances in the treatment of patients with lung cancer have occurred in the past few years. The cooperative groups in North America and internationally have played crucial roles in these advances. The leaders of the groups meet on a regular basis to review the progress of their trials. However, they rarely have a chance to discuss all ongoing and planned trials, except at the annual Lung Cancer Congress held each June. This article captures this exchange from the 10th Annual Lung Cancer Congress held in June 2009. Exciting efforts are ongoing for all stages of non-small-cell lung cancer, small-cell lung cancer, and mesothelioma. A major focus of the groups at this time is a push toward more personalized medicine, as reflected in the selection criteria for many of the trials, along with planned correlates to better define populations most likely to benefit. Agents targeting the vascular endothelial growth factor (VEGF) pathway, including many tyrosine kinase inhibitors against the VEGF receptor, and those targeting the epidermal growth factor receptor pathway, are under extensive development with many combination trials ongoing.

  View details for DOI 10.3816/CLC.2009.n.075

  View details for Web of Science ID 000271378500002

  View details for PubMedID 19900856

• Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial LANCET Chlebowski, R. T., Schwartz, A. G., Wakelee, H., Anderson, G. L., Stefanick, M. L., Manson, J. E., Rodabough, R. J., Chien, J. W., Wactawski-Wende, J., Gass, M., Kotchen, J. M., Johnson, K. C., O'Sullivan, M. J., Ockene, J. K., Chen, C., Hubbell, F. A. 2009; 374 (9697): 1243-1251

  Abstract

  In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period.The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611.After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups.Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer.National Heart, Lung and Blood Institute, National Institutes of Health.

  View details for DOI 10.1016/S0140-6736(09)61526-9

  View details for Web of Science ID 000270852500030

  View details for PubMedID 19767090

• A phase II first line study of gemcitabine, carboplatin and bevacizumab in advanced stage non-squamous non-small cell lung cancer Clement-Duchene, C., Krupitskaya, Y., Ganjoo, K., Lavori, P., Kumar, A., Zhao, G., Padda, S., San Pedro-Salcedo, M., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2009: S674–S674

  View details for Web of Science ID 000269496002133

• A single arm phase 2 study of enzastaurin in combination with erlotinib, both administered orally daily, to patients with advanced non-small cell lung cancer (NSCLC) Wakelee, H. A., Dubey, S., Krupitskaya, Y., Osarogiagbon, R. U., Sanborn, R. E., Bernstein, E. D., Dudek, A. Z., Latz, J. E., Yuan, Z., Natale, R. B. LIPPINCOTT WILLIAMS & WILKINS. 2009: S445–S445

  View details for Web of Science ID 000269496001254

• Mid-treatment PET predicts progression in hypofractionated accelerated radiation therapy for lung tumors Chang, C. N., Fillion, E., Chapman, C., Rao, A., Wakelee, H., Ganjoo, K., Le, Q., Maxim, P., Quon, A., Graves, E. E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S939–S939

  View details for Web of Science ID 000269496002721

• Excellent early local control with tumor volume adapted dosing of stereotactic body radiation therapy for pulmonary tumors Chang, C. N., Zhou, L. Y., MacFarlane, G., Tran, P., Rao, A., Chapman, C., Le, Q., Wakelee, H., Colevas, A. D., Whyte, R., Hristov, D., Dieterich, S., Maxim, P., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S938–S939

  View details for Web of Science ID 000269496002720

• Quantification of pre-treatment metabolic tumor growth rate in lung cancer Eastham, D., Chapman, C. H., Rao, A. K., Balasubramanian, N., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, D. A., Maxim, P. A., Graves, E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S733–S733

  View details for Web of Science ID 000269496002262

• Uncovering Disparities in Survival after Non-Small-Cell Lung Cancer among Asian/Pacific Islander Ethnic Populations in California CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chang, E. T., Shema, S. J., Wakelee, H. A., Clarke, C. A., Gomez, S. L. 2009; 18 (8): 2248-2255

  Abstract

  Asians may have better survival after non-small-cell lung cancer (NSCLC) than non-Asians. However, it is unknown whether survival varies among the heterogeneous U.S. Asian/Pacific Islander (API) populations. Therefore, this study aimed to quantify survival differences among APIs with NSCLC. Differences in overall and disease-specific survival were analyzed in the California Cancer Registry among 16,577 API patients diagnosed with incident NSCLC between 1988 and 2007. Adjusted hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression models with separate baseline hazards by disease stage. Despite better overall and disease-specific survival among APIs compared with non-Hispanic Whites, differences were evident across API populations. Among women, Japanese (overall survival HR, 1.16; 95% CI, 1.06-1.27) and APIs other than those in the six largest ethnic groups (other APIs; HR, 1.19; 95% CI, 1.07-1.33) had significantly poorer overall and disease-specific survival than Chinese. By contrast, South Asian women had significantly better survival than Chinese (HR, 0.79; 95% CI, 0.63-0.97). Among men, Japanese (HR, 1.15; 95% CI, 1.07-1.24), Vietnamese (HR, 1.07; 95% CI, 1.00-1.16), and other APIs (HR, 1.18; 95% CI, 1.08-1.28) had significantly poorer overall and disease-specific survival than Chinese. Other factors independently associated with poorer survival were lower neighborhood socioeconomic status, involvement with a non-university hospital, unmarried status, older age, and earlier year of diagnosis. APIs have significant ethnic differences in NSCLC survival that may be related to disparate lifestyles, biology, and especially health care access or use. To reduce the nationwide burden of lung cancer mortality, it is critical to identify and ameliorate hidden survival disparities such as those among APIs.

  View details for DOI 10.1158/1055-9965.EPI-09-0332

  View details for Web of Science ID 000268958600016

  View details for PubMedID 19622719

• Non-small cell lung cancer and estrogen plus progestin use in postmenopausal women in the Women's Health Initiative randomized clinical trial 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chlebowski, R. T., Schwartz, A., Wakelee, H., Anderson, G. L., Stefanick, M. L., Manson, J. E., Chien, J. W., Chen, C., Wactawski-Wende, J., Gass, M. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276607000022

• Ramucirumab, a fully human mAb to the transmembrane signaling tyrosine kinase VEGFR-2 for the potential treatment of cancer CURRENT OPINION IN INVESTIGATIONAL DRUGS Krupitskaya, Y., Wakelee, H. A. 2009; 10 (6): 597-605

  Abstract

  Angiogenesis is essential for tumor growth, invasion and metastasis, and is mediated, at least in part, by a large family of VEGF ligands and receptors. Ramucirumab, which is being developed by ImClone Systems Inc, is a fully human mAb that binds human VEGFR-2, thus blocking VEGF binding and inhibiting angiogenesis. Proof-of-concept preclinical studies with the mouse mAb DC-101 supported this hypothesis, and ramucirumab inhibited cell proliferation in vitro, as well as tumor progression in mouse xenograft models of human cancer. Ramucirumab was well tolerated on weekly and fortnightly schedules in phase I clinical trials in patients with advanced cancers; mechanism-related DLTs were hypertension and deep venous thrombosis. Stable disease was also observed in several patients treated on either schedule, and several patients on the weekly schedule exhibited partial responses. At the time of publication, ramucirumab was undergoing assessment in phase II trials as a monotherapy in hepatocellular, renal cell and ovarian carcinomas. Ramucirumab was also in phase II trials in combination with dacarbazine in melanoma, with mitoxantrone/prednisone in prostate cancer, with carboplatin/paclitaxel in NSCLC and with oxaliplatin/folinic acid/5-fluorouracil in colorectal cancer. A phase III trial in combination with docetaxel in breast cancer was also ongoing. Pending results from these trials, ramucirumab may be a useful addition to current antiangiogenic therapies. The results are awaited with interest.

  View details for Web of Science ID 000266692900010

  View details for PubMedID 19513949

• A phase II first-line study of gemcitabine, carboplatin, and bevacizumab (GCB) in advanced (adv) stage non-squamous non-small cell lung cancer (NSCLC) 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Krupitskaya, Y., Ganjoo, K., Lavori, P. W., Kumar, A., Clement-Duchene, C., Zhao, G., Padda, S., San Pedro-Salcedo, M., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605334

• Non-small cell lung cancer and estrogen plus progestin use in postmenopausal women in the Women's Health Initiative randomized clinical trial 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chlebowski, R. T., Schwartz, A., Wakelee, H., Anderson, G. L., Stefanick, M. L., Manson, J. E., Chien, J. W., Chen, C., Wactawski-Wende, J., Gass, M. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606602097

• Gemcitabine and pemetrexed administered in rapid sequence as front-line chemotherapy for advanced non-small-cell lung cancer: a phase II clinical trial ANNALS OF ONCOLOGY West, H. L., Wakelee, H. A., Perry, M. C., Belt, R. J., Chen, R., Obasaju, C. 2009; 20 (5): 850-856

  Abstract

  Previous studies of the gemcitabine-pemetrexed combination in patients with late-stage non-small-cell lung cancer (NSCLC) utilized a 90-min delay between gemcitabine and pemetrexed administration. This phase II study evaluated activity when these agents were administered in rapid succession.Chemonaive patients with late-stage NSCLC received gemcitabine 1250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) immediately following day 8 gemcitabine every 21 days for six cycles, folic acid, B(12), and steroid prophylaxis.Fifty-four enrolled patients (53 treated) completed a median of four cycles. Median dose intensity was 84% (gemcitabine) and 83% (pemetrexed); 68% of patients required dose adjustments. Response was as follows: complete response, 0; partial response, 7 (13%); stable disease, 29 (54%); progressive disease, 9 (17%); and unknown/unavailable, 9 (17%). Median progression-free and overall survival was 4.6 and 12.4 months, respectively. Common grade 3 or 4 toxic effects were as follows: neutropenia (40%); fatigue and dyspnea (21% each); pneumonia (17%); febrile neutropenia and thrombocytopenia (11% each); and anemia (6%).The gemcitabine-pemetrexed combination is minimally active in late-stage NSCLC, with a high incidence of grade 3 or 4 toxic effects requiring frequent dose adjustments. A gemcitabine dose <1250 mg/m(2) warrants consideration for future trials exploring this doublet. Administering day 8 pemetrexed immediately after gemcitabine does not appear to negatively impact therapeutic index.

  View details for DOI 10.1093/annonc/mdn715

  View details for Web of Science ID 000265739700008

  View details for PubMedID 19150937

• Osteoblastic Bone Flare on F18-FDG PET in Non-small Cell Lung Cancer (NSCLC) Patients Receiving Bevacizumab in Addition to Standard Chemotherapy JOURNAL OF THORACIC ONCOLOGY Krupitskaya, Y., Eslamy, H. K., Nguyen, D. D., Kumar, A., Wakelee, H. A. 2009; 4 (3): 429-431

  Abstract

  Positron emission tomography (PET) is used routinely to follow therapeutic response in patients treated for non-small cell lung cancer (NSCLC). In responding patients it is generally expected that the observed decrease in fluorodeoxyglucose uptake should be similar in all lesions. In other disease entities though, isolated cases have been documented of asynchronous increases in activity in metastatic bone lesions ("bone flare") despite evidence of therapeutic response or stability in other lesions. Here, we describe four NSCLC cases in which the results of interim PET scans were misleading due to osteoblastic flare phenomenon. In all four cases, patients were treated with bevacizumab in addition to standard chemotherapy. All four patients developed isolated worsening of their skeletal metastases on PET/CT (computed tomography) analysis (increase in fluorodeoxyglucose activity) despite apparent response or stable disease elsewhere. Subsequent scans confirmed that the "worsening" was transient, consistent with a flare response. Awareness of the phenomena is important for physicians treating NSCLC patients, particularly with bevacizumab.

  View details for Web of Science ID 000263961500026

  View details for PubMedID 19247091

• Monoclonal Antibodies Targeting Vascular Endothelial Growth Factor Current Status and Future Challenges in Cancer Therapy BIODRUGS Hsu, J. Y., Wakelee, H. A. 2009; 23 (5): 289-304

  Abstract

  The use of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) pathway has been a significant addition to cancer therapy. One of the VEGF family members, VEGF-A (commonly referred to as VEGF), has been demonstrated to be important in angiogenesis. Although the mechanism of action of these antibodies is still under study, the anti-VEGF antibody bevacizumab has been approved for treatment of various solid cancers including colorectal, lung, and breast cancers as well as glioblastoma and renal cell carcinoma. Addition of bevacizumab to chemotherapy as adjuvant therapy in colorectal cancer did not improve disease-free survival. Bevacizumab is being tested in other clinical settings such as adjuvant therapy, maintenance therapy, and in combination with both chemotherapy and other targeted agents such as the epidermal growth factor receptor kinase inhibitor erlotinib. In addition to bevacizumab, other antibody-based therapies targeting the VEGF pathway are being tested. Ramucirumab and IMC-18F1 are monoclonal antibodies that target the VEGF receptors VEGFR-2 and VEGFR-1, respectively. Aflibercept (VEGF-Trap), a peptide-antibody fusion targeting VEGF ligand, is being tested in clinical trials. Much research is focused on identifying biomarkers to predict which patients will benefit from anti-VEGF therapy. Recent results suggest that VEGF single nucleotide polymorphisms may be predictive of patient response to bevacizumab. Improved imaging modalities such as dynamic contrast-enhanced MRI (DCE-MRI) can better characterize the efficacy of anti-angiogenic agents. As anti-VEGF treatments such as bevacizumab have been integrated into the treatment of many different types of cancers, the development of bevacizumab-resistant tumors has become more common. Recent studies show that targeting other angiogenesis signaling pathways such as platelet-derived growth factor-C (PDGF-C), Bombina variagata peptide 8 (Bv8, also known as prokineticin-2), and VEGFR-3 may lead to enhanced response in anti-VEGF resistant tumors. In the future, tailored treatments consisting of combinations of chemotherapy, other targeted therapies, and anti-angiogenesis agents will hopefully result in better patient outcomes.

  View details for Web of Science ID 000271048500003

  View details for PubMedID 19754219

• Does Pre-treatment Metabolic Tumor Growth Rate (MTGR) Predict Progression in Lung Cancer? 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Eastham, D. V., Chapman, C. H., Rao, A. K., Narasimhan, B., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, A. D., Loo, B. W. ELSEVIER SCIENCE INC. 2009: S446–S446

  View details for Web of Science ID 000270573601456

• Systemic VEGF Inhibition Induces Hepatic EPO Production and Erythrocytosis Via HIF-2a-Dependent and -Independent Mechanisms 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Wei, K., Logan, A. C., Wakelee, H., Simon, M. C., Kuo, C. J. AMER SOC HEMATOLOGY. 2008: 183–84

  View details for Web of Science ID 000262104700483

• Cooperative Group Research Efforts in Lung Cancer 2008: Focus on Advanced-Stage Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Wakelee, H., Kernstine, K., Vokes, E., Schiller, J., Baas, P., Saijo, N., Adjei, A., Goss, G., Gaspar, L., Gandara, D. R., Choy, H., Putnam, J. ". 2008; 9 (6): 346-351

  Abstract

  Clinical trials performed within the cooperative group system play a substantial role in the advancing of lung cancer therapy. Interactions between the leaders of the cooperative groups are critical and occur regularly throughout the year, but the annual Lung Cancer Congress provides a unique forum for representatives from each group to present ongoing and planned studies in an interactive forum. Herein, we highlight discussion from the 9th annual Lung Cancer Congress in June 2008, focused on advanced-stage non-small-cell lung cancer (NSCLC). Many studies are looking at the addition of targeted agents such as bevacizumab, cetuximab, vascular endothelial growth factor receptor inhibitors, and apoptosis-inducing agents to chemotherapy. Personalizing therapy by better selection of patients for particular drugs is also being emphasized, most notably epidermal growth factor receptor fluorescence in situ hybridization overexpression and other predictions of response with cetuximab. Future articles in this series will address early and locally advanced NSCLC as well as other thoracic malignancies such as small-cell lung cancer and mesothelioma. Ongoing trials within the cooperative groups are an essential component of the persistent improvement in the treatment of lung cancer.

  View details for DOI 10.3816/CLC.2008.n.050

  View details for Web of Science ID 000261302100005

  View details for PubMedID 19073517

• Adjuvant chemotherapy for resected non-small cell lung cancer. Seminars in thoracic and cardiovascular surgery Wakelee, H., Chhatwani, L. 2008; 20 (3): 198-203

  Abstract

  Surgery remains the mainstay of therapy for early stage non-small cell lung cancer (NSCLC), but even for stage IA, disease relapse rates remain as high as 30%. Patients with completely resected (R0) N1 disease have about a 50% chance of relapse. In the past 5 years, the benefit of adjuvant chemotherapy has finally been demonstrated for patients with lung cancer. Improvements of 5% to 10% 5-year survival have been reported with cisplatin-based chemotherapy. Still, cure rates have significant room for improvement and ongoing trials with "targeted" agents such as those active against the vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and vaccine therapy will hopefully further increase the odds for patients with resected disease. Other studies looking at tumor gene and protein expression will lead us toward better identification of patients most likely to benefit from therapy.

  View details for DOI 10.1053/j.semtcvs.2008.09.001

  View details for PubMedID 19038728

• PEMETREXED DISODIUM FOR THE TREATMENT OF NSCLC: AN UPDATE DRUGS OF TODAY Hsu, J. Y., Wakelee, H. 2008; 44 (9): 669-678

  Abstract

  Pemetrexed disodium is a multitargeted antifolate cytotoxic chemotherapy agent approved by the U.S. Food and Drug Administration (FDA) initially for the treatment of malignant pleural mesothelioma, and in August 2004 for second-line treatment of non-small cell lung cancer (NSCLC). In September 2008, the FDA also approved pemetrexed and cisplatin as first-line therapy for NSCLC. Pemetrexed is also no longer recommended for treatment of NSCLC with squamous cell carcinoma histology. Pemetrexed is currently being tested in clinical trials as part of second-line combination, first-line, adjuvant and maintenance therapies.

  View details for DOI 10.1358/dot.2008.44.9.1250412

  View details for Web of Science ID 000261367100004

  View details for PubMedID 19137122

• Sex differences in lung-cancer susceptibility: a smoke screen? LANCET ONCOLOGY Wakelee, H. A., Gomez, S. L., Chang, E. T. 2008; 9 (7): 609-610

  View details for Web of Science ID 000257527400006

  View details for PubMedID 18598927

• Summary statement - Novel Agents in the Treatment of Lung Cancer: Fifth Cambridge Conference assessing opportunities for combination therapy JOURNAL OF THORACIC ONCOLOGY Lynch, T. J., Blumenschein, G. R., Engelman, J. A., Espinoza-Delgado, I., Govindan, R., Hanke, J., Hanna, N. H., Heymach, J. V., Hirsch, F. R., Janne, P. A., Lilenbaum, R. C., Natale, R. B., Riely, G. J., Sequist, L. V., Shapiro, G. T., Shaw, A., Shepherd, F. A., Socinski, M., Sorensen, A. G., Wakelee, H. A., Weitzman, A. 2008; 3 (6): S107-S112

  Abstract

  The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective "drugs" for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1-2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme.

  View details for Web of Science ID 000256828300001

  View details for PubMedID 18520291

• Antibodies to vascular endothelial growth factor in non-small cell lung cancer JOURNAL OF THORACIC ONCOLOGY Wakelee, H. 2008; 3 (6): S113-S118

  Abstract

  Angiogenesis, formation of new vasculature, is critical to cancer growth. Agents that block angiogenesis, in particular bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor, the key ligand in angiogenesis, have become an important option for many patients with non-small cell lung cancer (NSCLC). Activity was first demonstrated in Eastern Cooperative Oncology Group E4599, a large phase 3 trial that randomized patients with newly diagnosed, nonsquamous NSCLC to receive carboplatin/paclitaxel with or without bevacizumab at 15 mg/kg every 3 weeks. The study demonstrated significant improvements in response rate, progression-free survival, and overall survival with the addition of bevacizumab. Median overall survival improved from 10.3 to 12.3 months (p = 0.003). Significant toxic effects, including fatal hemoptysis, however, resulted in 15 treatment-related deaths in the bevacizumab arm. The beneficial results were recently confirmed in the European Avastin in Lung Cancer B017704 (AVAiL) trial. In AVAiL, patients with newly diagnosed nonsquamous NSCLC were randomized to receive cisplatin/gemcitabine with or without bevacizumab at doses of either 7.5 or 15 mg/kg every 3 weeks. Both doses resulted in statistically significant improvements in response rate and progression-free survival, but overall survival results have yet to be presented. Based on these encouraging results, the drug is now being studied in earlier-stage disease as neoadjuvant or adjuvant therapy and in locally advanced NSCLC. Exploration of the safety and efficacy of the drug in combination with other chemotherapeutics and targeted agents, and in previously excluded patient populations such as those with brain metastases, is also ongoing.

  View details for Web of Science ID 000256828300002

  View details for PubMedID 18520292

• Diagnosis in oncology - Lung cancer presenting with amegakaryocytic thrombocytopenia JOURNAL OF CLINICAL ONCOLOGY Witteles, W. H., Schrier, S. L., Wakelee, H. A. 2008; 26 (7): 1171-1174

  View details for DOI 10.1200/JCO.2007.14.8106

  View details for Web of Science ID 000254178100025

• Cooperative group portfolio in locally advanced non-small-cell lung cancer: Are we making progress? CLINICAL LUNG CANCER Langer, C. J., Wakelee, H., Schiller, J., Choy, H., Shepherd, F., Vokes, E. E., Adjei, A. A., Baas, P., Saijo, N., Gandara, D. R. 2008; 9 (2): 85-91

  Abstract

  Combined-modality therapy has emerged as the standard of care for fit patients with unresectable, locally advanced non-small-cell lung cancer (NSCLC). Concurrent chemotherapy/radiation has demonstrated therapeutic superiority compared with sequential or asynchronous chemotherapy and radiation in this setting. The role of consolidation or maintenance therapy with targeted agents or conventional cytotoxic agents remains unclear. We explore the portfolio of clinical trials being conducted in locally advanced NSCLC by North American cooperative oncology groups as well as ongoing trials in Europe and Japan. These efforts focus on radiation dose escalation using image-guided radiation therapy as well as newer cytotoxic agents (eg, pemetrexed) and targeted therapies (eg, cetuximab, bevacizumab, and etc) thus far unexplored in this setting.

  View details for Web of Science ID 000255039000004

  View details for PubMedID 18501094

• Lung cancer presenting with amegakaryocytic thrombocytopenia. Journal of clinical oncology Witteles, W. H., Schrier, S. L., Wakelee, H. A. 2008; 26 (7): 1171-1174

  View details for DOI 10.1200/JCO.2007.14.8106

  View details for PubMedID 18309955

• Complications of ablative therapies in lung cancer CLINICAL LUNG CANCER Padda, S., Kothary, N., Donington, J., Cannon, W., Loo, B. W., Kee, S., Wakelee, H. 2008; 9 (2): 122-126

  Abstract

  Two cases of complications secondary to the use of microwave ablation (MWA) in non-small-cell lung cancer (NSCLC) are discussed herein. The first case involves a 62-year-old man with stage IB NSCLC who declined surgery and pursued MWA. Within 7 months, he had residual disease at the MWA treatment site, and surgery was performed. The patient was found to have pleural and chest wall involvement, making complete resection impossible. The second case involves an 86-year-old woman with a second local recurrence of NSCLC and previous treatment including surgery and chemoradiation therapy. She was initially a surgical candidate but declined surgery and pursued MWA. Within 6 months, she had residual disease at the MWA treatment site. A second MWA was performed, and she developed a large cavitary abscess at the MWA site and had subsequent clinical decline. Less invasive ablation therapies and stereotactic radiosurgery are being developed for patients with inoperable lung cancer. Because these modalities have recently been developed, trials that clearly show efficacy and survival benefit are yet to be completed. Ablation procedures can result in complications, including residual disease and cavitary lesions susceptible to infection. These cases highlight the caution that should still be observed when recommending lung ablation strategies and the importance of selecting appropriate patients.

  View details for Web of Science ID 000255039000010

  View details for PubMedID 18501100

• Tumor size is a critical determinant of local control in single fraction stereotactic radiotherapy of pulmonary tumors 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Loo, B. W., Shen, J., Quinlan-Davidson, S., Filion, E., Dieterich, S., Maxim, P. G., Wakelee, H. A., Whyte, R. I., Le, Q. ELSEVIER SCIENCE INC. 2008: S467–S468

  View details for Web of Science ID 000258805301520

• Cooperative group research efforts in lung cancer: Focus on early-stage non-small-cell lung cancer CLINICAL LUNG CANCER Wakelee, H., Langer, C., Vokes, E., Schiller, J., Baas, P., Saijo, N., Adjei, A., Shepherd, F., Choy, H., Gandara, D. R. 2008; 9 (1): 9-15

  Abstract

  Many of the most significant advances in the treatment of lung cancer have come from trials run within the cooperative group system. The leaders of the lung cancer section of each group interact throughout the year, but an annual lung cancer congress in Hawaii provides a forum for extensive discussions of ongoing and planned trials. This article is the first in a series that will focus on the key points of this discussion held at the 8th Annual Lung Cancer Congress in June 2007. Early-stage non-small-cell lung cancer trials are highlighted in this manuscript. Current work in adjuvant therapy is focused on exploring the use of bevacizumab in addition to chemotherapy for resected disease in a large Intergroup study and the use of more "personalized" chemotherapy based on specific genomic or protein expression profiles of individual tumors in smaller exploratory studies. The question of postoperative radiation therapy is being addressed within the cooperative groups. Alternative approaches to surgery, such as lesser resections in smaller tumors and accelerated radiation including stereotactic radiosurgery, are also under investigation within this framework. Ongoing trials within the cooperative groups continue to drive steady improvement in the treatment of lung cancer and offer great promise for the future.

  View details for Web of Science ID 000252840000002

  View details for PubMedID 18282352

• Review of erlotinib in the treatment of advanced non-small cell lung cancer. Biologics : targets & therapy Ganjoo, K. N., Wakelee, H. 2007; 1 (4): 335-346

  Abstract

  Epidermal growth factor receptor (EGFR) is a transmembrane receptor with a cytoplasmic tyrosine kinase (TK) domain present on many solid tumors including non-small cell lung cancer (NSCLC). Once stimulated by ligand, the downstream pathway is activated leading to cell growth, survival, and carcinogenesis. There are several methods of EGFR inhibition including monoclonal antibodies directed against the external region and small molecule inhibitors of TK domain. Erlotinib and gefitinib are orally available small molecule EGFR TK inhibitors, with proven efficacy in NSCLC. The most common side effects are skin toxicity and diarrhea. Erlotinib has been shown to improve survival compared to placebo in second or third-line therapy for NSCLC. However, erlotinib in combination with chemotherapy failed to show a survival advantage in two first-line studies which could be due to the timing of chemotherapy administration. In general, patients with adenocarcinoma histology, female gender, Asian ethnicity, and never smokers have a better response when treated with erlotinib. This could be related to the presence of EGFR mutations, lack of KRAS mutations, or overexpression of EGFR as measured by fluorescent in-situ hybridization (FISH) analysis. Future studies should concentrate on further development of predictors of clinical benefit with erlotinib, overcoming resistance to erlotinib that develops in initial responders, as well as more effective sequencing of erlotinib with chemotherapy and combinations of the drug with other "targeted" therapeutic agents.

  View details for PubMedID 19707304

• Metabolic tumor burden predicts for disease progression and death in lung cancer 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Lee, P., Weerasuriya, D. K., Lavori, P. W., Quon, A., Hara, W., Maxim, P. G., Le, Q., Wakelee, H. A., Donington, J. S., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2007: 328–33

  Abstract

  In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging.We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV).The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS.In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

  View details for DOI 10.1016/j.ijrobp.2007.04.036

  View details for Web of Science ID 000249796100002

  View details for PubMedID 17869659

• Adjuvant chemotherapy of stage I non-small cell lung cancer in North America Workshop on Development of an International Cooperative Clinical Trail Comparing Stereotactic Radiation Therapy with Surgery for Stage I NSCLC Gandara, D. R., Wakelee, H., Calhoun, R., Jablons, D. LIPPINCOTT WILLIAMS & WILKINS. 2007: S125–S127

  Abstract

  The utility of adjuvant chemotherapy after surgical resection for early-stage non-small cell lung cancer (NSCLC) is now well established. Although a number of randomized clinical trials have demonstrated the efficacy of platinum-based chemotherapy in the overall population treated, subset analysis, excepting Japanese studies, has uniformly shown the greatest efficacy for patients with stage II and III disease and the least benefit for patient with stage I disease. We review data regarding adjuvant therapy of stage I NSCLC from clinical trials performed in North America and Europe. Pertinent trials from Japan are discussed elsewhere in this issue.

  View details for Web of Science ID 000247937100007

  View details for PubMedID 17603308

• Lung cancer incidence in never smokers JOURNAL OF CLINICAL ONCOLOGY Wakelee, H. A., Chang, E. T., Gomez, S. L., Keegan, T. H., Feskanich, D., Clarke, C. A., Holmberg, L., Yong, L. C., Kolonel, L. N., Gould, M. K., West, D. W. 2007; 25 (5): 472-478

  Abstract

  Lung cancer is a leading cause of cancer death worldwide. Although smoking remains the predominant cause of lung cancer, lung cancer in never smokers is an increasingly prominent public health issue. However, data on this topic, particularly lung cancer incidence rates in never smokers, are limited.We reviewed the existing literature on lung cancer incidence and mortality rates among never smokers and present new data regarding rates in never smokers from the following large, prospective cohorts: Nurses' Health Study; Health Professionals Follow-Up Study; California Teachers Study; Multiethnic Cohort Study; Swedish Lung Cancer Register in the Uppsala/Orebro region; and First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study.Truncated age-adjusted incidence rates of lung cancer among never smokers age 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never smokers.Lung cancer in never smokers is an important public health issue, and further exploration of its incidence patterns, etiology, and biology is needed.

  View details for DOI 10.1200/JCO.2006.07.2983

  View details for Web of Science ID 000244176000003

  View details for PubMedID 17290054

• Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Current treatment options in oncology Cabebe, E., Wakelee, H. 2007; 8 (1): 15-27

  Abstract

  OPINION STATEMENT: Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has improved the efficacy seen with standard cytotoxic therapy in NSCLC. The addition of bevacizumab to first-line chemotherapy improved response rate and progression free survival and added 2 months to median overall survival for those patients with advanced stage NSCLC on the treatment arm of E4599. Bevacizumab is now a standard agent to add to frontline carboplatin and paclitaxel for patients with newly diagnosed NSCLC who meet the eligibility criteria from the landmark E4599 trial. Unfortunately about half of all patients are not eligible either because they have squamous histology, brain metastases, or are on anti-coagulation. Ongoing trials are further exploring the safety of bevacizumab in these patient populations, as well as in combination with other cytotoxic regimens. Exploration of other applications of bevacizumab in the second-line and adjuvant setting are ongoing as well. The largest class of drugs that block angiogenesis are the multi-targeted tyrosine kinase inhibitors (TKIs) that target the VEGF receptor (VEGFR). These drugs are still in development, and though two are now on the market for treating other malignancies, their role in NSCLC is under investigation. These agents have the advantages of hitting multiple targets, convenient oral administration, and potential for lower cost. Their lack of target specificity leads to unexpected toxicity, but also promising efficacy. For example, the overall objective response rate of 9.5% with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients, but toxicity, notably fatigue, lead to discontinuation in 38% of patients. Hypertension, hemorrhage and cavitation are common toxicities amongst this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with TKIs. These compounds may also be synergistic or additive with traditional cytotoxic chemotherapy drugs and other novel compounds. In early trials sorafenib as a single agent has shown no clinical response in previously treated NSCLC patients, whereas clinical benefit in combination with erlotinib or chemotherapy has been seen in early studies. Vandetanib has demonstrated objective responses as a single agent and in combination with chemotherapy in previously treated NSCLC patients. A phase I trial of AZD2171 with carboplatin and paclitaxel in newly diagnosed advanced stage NSCLC also demonstrated promising results with 6 of 15 patients achieving partial responses. NSCLC specific trials are also underway, or in development for pazopanib, axitinib, AMG 706, XL647, enzastaurin, and other TKIs. Other anti-angiogenesis agents with different mechanisms of action include thalidomide and its derivatives, monoclonal antibodies to the VEGFRs, and VEGF Trap, a chimeric molecule which combines extracellular portions of VEGFR1 and VEGFR2 with the Fc portion of immunoglobulin G1 to form a molecule that binds and "traps" VEGF. Despite modest improvements, prognosis continues to be poor for patients with advanced NSCLC. Bevacizumab is a first step into the world of angiogenesis inhibitors for NSCLC and though it only offers a modest survival benefit in a limited patient population, it paves the way for the development of the next generation of anti-angiogenesis inhibitors. We can hope that further improvements in survival will follow.

  View details for PubMedID 17634832

• Optimal adjuvant therapy for non-small cell lung cancer - How to handle stage I disease ONCOLOGIST Wakelee, H., Dubey, S., Gandara, D. 2007; 12 (3): 331-337

  Abstract

  The standard of care for resected stage II-IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens--the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuvant Navelbine International Trialist Association trial. The role of adjuvant chemotherapy for stage I disease remains controversial. A recent meta-analysis (the Lung Adjuvant Cisplatin Evaluation) showed potential harm with the addition of adjuvant cisplatin for stage IA disease and no survival benefit for this modality in stage IB disease. Updated results from the Cancer and Leukemia Group B 9633 trial, the only trial to focus exclusively on stage IB patients, no longer show a statistically significant survival benefit from adjuvant chemotherapy in this population, except for the subgroup of patients with larger tumors. It may be that trials have been underpowered to detect a small benefit for patients with stage IB disease, or there may really not be benefit to adding adjuvant therapy for this stage of disease. Additional markers, such as tumor size or the presence or absence of certain tumor proteins like ERCC1, may help to determine which patients with resected stage I NSCLC may benefit from adjuvant chemotherapy. Strategies such as inhibition of angiogenesis pathways and the epidermal growth factor receptor are under exploration.

  View details for DOI 10.1634/theoncologist.12-3-331

  View details for Web of Science ID 000245543600012

  View details for PubMedID 17405898

• A phase I dose-escalation and pharmacokinetic (PK) study of XL647, a novel spectrum selective kinase inhibitor, administered orally to patients with advanced solid malignancies (ASM) Sikic, B. I., Wakelee, H. A., Adjei, A. A., Halsey, J., Lensing, J. L., Dugay, J. D., Hanson, L. J., Reid, J. M., Piens, J. R. PERGAMON-ELSEVIER SCIENCE LTD. 2006: 106–7

  View details for Web of Science ID 000242688500338

• Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q., Loo, B. W., Ho, A., Cotrutz, C., Koong, A. C., Wakelee, H., Kee, S. T., Constantinescu, D., Whyte, R. I., Donington, J. LIPPINCOTT WILLIAMS & WILKINS. 2006: 802–9

  Abstract

  The purpose of this study was to report initial results of a phase I study using single-fraction stereotactic radiotherapy (RT) in patients with inoperable lung tumors.Eligible patients included those with inoperable T1-2N0 non-small cell lung cancer (NSCLC) or solitary lung metastases. Treatments were delivered by means of the CyberKnife. All patients underwent computed tomography-guided metallic fiducial placement in the tumor for image-guided targeting. Nine to 20 patients were treated per dose cohort starting at 15 Gy/fraction followed by dose escalation of 5 to 10 Gy to a maximal dose of 30 Gy/fraction. A minimal 3-month period was required between each dose level to monitor toxicity.Thirty-two patients (21 NSCLC and 11 metastatic tumors) were enrolled. At 25 Gy, pulmonary toxicity was noted in patients with prior pulmonary RT and treatment volumes greater than 50 cc; therefore, dose escalation to 30 Gy was applied only to unirradiated patients and treatment volume less than 50 cc. Ten patients received doses less than 20 Gy, 20 received 25 Gy, and two received 30 Gy. RT-related complications were noted for doses greater than 25 Gy and included four cases of grade 2 to 3 pneumonitis, one pleural effusion, and three possible treatment-related deaths. The 1-year freedom from local progression was 91% for dose greater than 20 Gy and 54% for dose less than 20 Gy in NSCLC (p = 0.03). NSCLC patients had significantly better freedom from relapse (p = 0.003) and borderline higher survival than those with metastatic tumors (p = 0.07).Single-fraction stereotactic RT is feasible for selected patients with lung tumors. For those with prior thoracic RT, 25 Gy may be too toxic. Higher dose was associated with improved local control. Longer follow-up is necessary to determine the treatment efficacy and toxicity.

  View details for Web of Science ID 000241649300008

  View details for PubMedID 17409963

• A multidisciplinary approach to management in a patient with bilateral superior sulcus non-small-cell lung carcinoma CLINICAL LUNG CANCER Roy, M. S., Le, Q., Donington, J. S., Wakelee, H. A. 2006; 8 (2): 146-148

  Abstract

  Superior sulcus tumors comprise a rare subset of non-small-cell lung carcinomas that are particularly challenging to treat because of their location and extent of nerve and vessel involvement. In this report, we present a case illustrating the uncommon situation of a patient presenting with bilateral superior sulcus tumors, and we review the latest combined therapeutic approach developed to aggressively treat the more common unilateral presentation of these tumors.

  View details for Web of Science ID 000242173600010

  View details for PubMedID 17026817

• Lung cancer in women: Exploring sex differences in susceptibility, biology, and therapeutic response CLINICAL LUNG CANCER Donington, J. S., Le, Q., Wakelee, H. A. 2006; 8 (1): 22-29

  Abstract

  Src tyrosine kinases regulate a large number of important mechanisms in normal and cancerous cells, are overexpressed in a broad range of tumors including lung cancer, and thus represent a potential target for cancer therapy. Preclinical experiments indicate that small-molecule inhibitors of Src block tumor growth, metastasis, and angiogenesis. Phase I data from healthy volunteers also suggest that inhibitors of Src prevent bone resorption. Several phase II trials with small-molecule inhibitors of Src are under way or have been initiated in lung cancer and in other malignancies, as discussed herein.

  View details for Web of Science ID 000242173500003

  View details for PubMedID 16870042

• Current status of adjuvant chemotherapy for stage IB non-small-cell lung cancer: Implications for the new intergroup trial CLINICAL LUNG CANCER Wakelee, H. A., Schiller, J. H., Gandara, D. R. 2006; 8 (1): 18-21

  Abstract

  Adjuvant chemotherapy after resection of stage II-IIIA non-small-cell lung cancer is now the standard of care based on the results of 3 phase III studies using cisplatin-based regimens, IALT (International Adjuvant Lung Trial), The National Cancer Institute of Canada JBR.10, and ANITA (Adjuvant Navelbine International Trialist Association). The role of adjuvant chemotherapy for stage IB disease remains controversial, even more so now that the updated results from CALGB (Cancer and Leukemia Group B) trial 9633 are statistically negative. CALGB 9633 was the only randomized adjuvant trial to use a carboplatin backbone and focused exclusively on patients with stage IB disease. Initial results, reported in 2004, showed a significant survival advantage with the addition of chemotherapy, but the 2006 updated results are no longer statistically significant. The next large intergroup adjuvant trial in non-small-cell lung cancer will look at bevacizumab in combination with chemotherapy. Because of the recent update, this trial will now limit patients with stage IB disease to those with larger tumors (>or= 4 cm) and will likely include only cisplatin-based regimens.

  View details for Web of Science ID 000242173500002

  View details for PubMedID 16870041

• A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM). 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Wakelee, H. A., Adjei, A. A., Halsey, J., Lensing, J. L., Dugay, J. D., Hanson, L. J., Reid, J. M., Piens, J. R., Sikic, B. I. AMER SOC CLINICAL ONCOLOGY. 2006: 131S–131S

  View details for Web of Science ID 000239009400515

• Sunitinib: A newly approved small-molecule inhibitor of angiogenesis DRUGS OF TODAY Cabebe, E., Wakelee, H. 2006; 42 (6): 387-398

  Abstract

  The advent of targeted therapies has allowed treatment to be directed at signaling pathways integral to tumor growth and survival. Sunitinib (SU11248, sunitinib malate; Pfizer Inc., New York, NY, USA) is a novel oral small-molecule multitargeted receptor tyrosine kinase inhibitor that has demonstrated direct antitumor activity and antiangiogenic action. It targets the vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), stem-cell factor receptor and Fms-like tyrosine kinase receptor 3 receptor tyrosine-kinases. In January 2006, sunitinib malate was granted approval by the U.S. Food and Drug Administration for the treatment of gastrointestinal stromal tumor after disease progression on, or intolerance to, imatinib mesylate, as well as for the treatment of metastatic renal cell cancer. This review will discuss the development of sunitinib, particularly in acute myeloid leukemia, imatinib-resistant gastrointestinal stromal tumors and renal cell cancer. The review will also discuss ongoing trials with sunitinib in other malignancies such as neuroendocrine tumors and breast cancer, as well as its potential future development in combination therapy with other agents and in other malignancies.

  View details for DOI 10.1358/dot.2006.42.6.985633

  View details for Web of Science ID 000240040300004

  View details for PubMedID 16845442

• Survival differences by sex for patients with advanced non-small cell lung cancer on Eastern Cooperative Oncology Group trial 1594 11th World Conference on Lung Cancer Wakelee, H. A., Wang, W., Schiller, J. H., Langer, C. J., Sandler, A. B., Belani, C. P., Johnson, D. H. LIPPINCOTT WILLIAMS & WILKINS. 2006: 441–46

  Abstract

  Previous data suggest that women may live longer with advanced non-small cell lung cancer (NSCLC) than men. We evaluated whether sex affected survival in the Eastern Cooperative Oncology Group (ECOG) E1594 trial. E1594 randomized patients with advanced NSCLC to one of four platinum doublets and found that all four regimens had comparable efficacy.Patients in the E1594 database were divided into male and female cohorts; response and survival were calculated separately for each cohort. Known prognostic factors and differences in toxicity profiles were compared between the two cohorts.All 1157 eligible patients (431 women, 726 men) from E1594 were included in this analysis. There was no statistically significant difference in performance status, weight loss of >10%, stage, or incidence of brain metastases between women and men. Response rates were similar (19% for both; P = 0.15). The median survival time for women, however, was significantly longer at 9.2 months (95% CI, 8.1-10.4 months) versus only 7.3 months for men (95% CI, 6.8-8.0 months) (P = 0.004 log-rank test). Toxicity was generally greater in women than in men.Women in ECOG 1594 had a 1.9-month statistically significant improvement in median survival compared with men, despite similar response rates and greater toxicity and no difference in other known prognostic factors. These data strongly support the significance of sex as a separate prognostic factor in advanced NSCLC and emphasize the importance of sex as a stratification factor in future phase III NSCLC trials.

  View details for Web of Science ID 000239233300011

  View details for PubMedID 17409897

• Changes in the natural history of nonsmall cell lung cancer (NSCLC) - Comparison of outcomes and characteristics in patients with advanced NSCLC entered in Eastern Cooperative Oncology Group trials before and after 1990 38th Annual Meeting of the American-Society-of-Clinical-Oncology Wakelee, H. A., Bernardo, P., Johnson, D. H., Schiller, J. H. JOHN WILEY & SONS INC. 2006: 2208–17

  Abstract

  Demographic factors and treatment regimens were evaluated in relation to differences in outcome between patients with advanced nonsmall cell lung cancer (NSCLC) who were diagnosed and treated on Eastern Cooperative Oncology Group Phase II and III trials from 1981 to 1990 and from 1991 to 2000.In this retrospective analysis, 6 advanced NSCLC trials were identified between 1981 and 1990, and 3 trials were identified after 1990. Patient characteristics (n = 3398 patients) and other clinical outcomes were analyzed, including progression-free survival (PFS) and overall survival (OS).Patients who entered on trials after 1990 more likely were women, received a cisplatin-containing regimen, had a performance status of 0 or 1, had Stage IIIB (vs. Stage IV) disease, had tumors with adenocarcinoma histology, had weight loss < or = 10%, and had pulmonary-only metastases (although more total metastases and brain metastases) compared with patients who were diagnosed before 1990. OS was longer post-1990 than pre-1990 (8.2 months vs. 5.8 months pre-1990), and PFS was longer post-1990 (3.5 months vs. 2.6 months pre-1990; P<.001 for both). In addition, the median interval from the date of disease progression to death increased by nearly 62% in the later decade.Improved survival in more recent NSCLC trials was explained in part by the enrollment of patients with more favorable prognostic factors. A change in the natural history of the disease was reflected by some of these changes, including increased numbers of women with the disease and changes in the patterns of metastases. Changes in eligibility criteria also accounted for some improvements in prognostic factors and improved second line therapies in the later decade. Thus, the survival improvements are likely to be multifactorial, with improved therapies also playing a major role.

  View details for DOI 10.1002/cncr.21869

  View details for Web of Science ID 000237278300016

  View details for PubMedID 16604529

• An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers CLINICAL CANCER RESEARCH Le, Q. T., Chen, E., Salim, A., Cao, H. B., Kong, C. S., Whyte, R., Donington, J., Cannon, W., Wakelee, H., Tibshirani, R., Mitchell, J. D., Richardson, D., O'Byrne, K. J., Koong, A. C., Giaccia, A. J. 2006; 12 (5): 1507-1514

  Abstract

  To directly assess tumor oxygenation in resectable non-small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes.Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes.The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001).Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.

  View details for DOI 10.1158/1078-0432.CCR-05-2049

  View details for Web of Science ID 000235988000016

  View details for PubMedID 16533775

• Second- and third-line treatments in non-small cell lung cancer. Current treatment options in oncology Kumar, A., Wakelee, H. 2006; 7 (1): 37-49

  Abstract

  Slow but steady progress has been made in the treatment of advanced non-small cell lung cancer. For first-line therapy, multiple chemotherapy combination therapies can extend survival and improve quality of life. And recently, for the first time ever, a noncytotoxic agent, the antivascular endothelial growth factor antibody bevacizumab, has been shown to improve survival when added to chemotherapy. Striking improvements have also been made in second-line treatment. In August 2004, only one agent was US Food and Drug Administration (FDA) approved in this setting, docetaxel, but by the beginning of 2005, two more were available, pemetrexed and erlotinib. All three of these drugs can significantly benefit patients, with 1-year survival in excess of 30%. Choosing between the three agents can be challenging, and this review focuses on the toxicity differences and predictors of response that can help guide this decision. Docetaxel and pemetrexed, both traditional intravenous cytotoxins, are excellent options for patients who have shown some response to first-line chemotherapy, but at this time, no other means exist to determine likelihood of response. When choosing between the two, pemetrexed causes significantly less neutropenia than does docetaxel, at least on the standard every-3-week regimen. With erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, there are factors that can predict for response, including little or no smoking history, and adenocarcinoma histology. Therefore, patients who fit these characteristics are good candidates for second-line erlotinib. However, the relationship between response to erlotinib and improved survival remains unclear, and several laboratory analyses that may help further, such as evaluation of EGFR gene copy number, are still under development. Although erlotinib is the only FDA-approved option currently available for third-line therapy, many patients with good performance status may benefit from third-line therapy and beyond. In addition to the approved second-line options, other single-agent chemotherapies to consider for treatment beyond second-line are gemcitabine, irinotecan, and oral topotecan. Many new drugs, including bevacizumab, ZD6474 (AstraZeneca, Wilmington, DE), sorafenib, cetuximab, paclitaxel poliglumex, epothilones, and others, alone or in combination with traditional agents, are currently undergoing investigation and hold great promise.

  View details for PubMedID 16343367

• A phase 1 dose-escalation and pharmacokinetic (PK) study of a novel spectrum-selective kinase inhibitor (SSKI), XL647, in patients with advanced solid malignancies. 17th EORTC/AACR/NCI International Conference on Molecular Targets and Cancer Therapeutics Wakelee, H., Adjei, A. A., Halsey, J., Lensing, J., Dugay, J., Hanson, L., Reid, J., Hutchison, S., Piens, J., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2005: 9029S–9029S

  View details for Web of Science ID 000234382700263

• Activity of novel cytotoxic agents in lung cancer: Epothilones and topoisomerase I inhibitors CLINICAL LUNG CANCER Wakelee, H. A., Sikic, B. I. 2005; 7: S6-S12

  Abstract

  The treatment of lung cancer--small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC)--is a significant challenge in oncology. The best reported median survival remains near 1 year in advanced NSCLC despite several decades of steady improvement and extensive research with traditional chemotherapy drugs and novel compounds targeted to different aspects of tumor cell growth and function (such as the epidermal growth factor receptor). Extensive-stage SCLC survival is only slightly better. Novel "targeted" therapeutic agents hold promise, but cytotoxic therapy remains the backbone of treatment. Many new cytotoxic agents are currently in development. In this review, we will focus on 2 classes of cytotoxins: epothilones and topoisomerase I inhibitors. Epothilones are microtubule stabilizers with a mechanism of action similar to that of the taxanes, with preclinical activity superior to that of the taxanes. Phase I trials have been completed for patupilone and ixabepilone, and there are encouraging phase II data with ixabepilone in NSCLC. A phase II trial of patupilone is ongoing. The camptothecins, which are topoisomerase I inhibitors, have a long history in the treatment of lung cancer, but the currently available drugs, topotecan and irinotecan, have limitations. Gimatecan and other novel camptothecins have superior preclinical activity and promising phase I/II data in NSCLC and SCLC.

  View details for Web of Science ID 000242719700002

  View details for PubMedID 16159420

• Targeting angiogenesis with vascular endothelial growth factor receptor small-molecule inhibitors: Novel agents with potential in lung cancer CLINICAL LUNG CANCER Wakelee, H. A., Schiller, J. H. 2005; 7: S31-S38

  Abstract

  The treatment of lung cancer remains a significant challenge. Although chemotherapy remains the standard approach, a plateau has been reached in its efficacy. The development of novel targeted agents, particularly those targeting the epidermal growth factor receptor, has given us another approach. Developments with antiangiogenesis agents hold promise as new approaches in lung cancer therapy. Much of the work to date has focused on the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. In this article we will focus on the tyrosine kinase inhibitors of the VEGF receptors. These compounds, including sunitinib (SU11248; Sutent), vatalanib (PTK787), ZD6474, AZD2171, GW786034, sorafenib (BAY 43-9006), CP-547,632, and AG013736, are still at an early stage of development. We present phase I data (and phase II/III data when available) of these compounds and discuss their potential development in the treatment of lung cancer.

  View details for Web of Science ID 000242719700005

  View details for PubMedID 16159417

• Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer 40th Annual Meeting of the American-Society-of-Clinical-Oncology Kuo, T., Cho, C. D., Halsey, J., Wakelee, H. A., Advani, R. H., Ford, J. M., Fisher, G. A., Sikic, B. I. AMER SOC CLINICAL ONCOLOGY. 2005: 5613–19

  Abstract

  To investigate the gefitinib, fluorouracil (FU), leucovorin, and oxaliplatin regimen (IFOX) in previously treated patients with metastatic colorectal cancer.Eligible patients had stage IV colorectal adenocarcinoma and had demonstrated progression or intolerance to a prior chemotherapy regimen not including oxaliplatin. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin 85 mg/m2 intravenously (IV) during 2 hours on day 1, hours 0 to 2; leucovorin 200 mg/m2 IV on days 1 and 2, hours 0 to 2; FU 400 mg/m2 IV push on days 1 and 2; and FU 600 mg/m2 IV on days 1 and 2, hours 2 to 24 (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg/d administered orally throughout the 14-day cycle.Twenty-seven patients were enrolled onto the study. The median number of prior chemotherapy regimens was two, and 74% of all patients received prior irinotecan. Nine of the 27 patients (33%) and six of the 20 patients (30%) who had prior FU and irinotecan had a partial response by Response Evaluation Criteria in Solid Tumors Group criteria. Median overall survival was 12.0 months. Median event-free survival was 5.4 months. Grade 3 to 4 toxicities included neutropenia (48%), diarrhea (48%), nausea (22%), and vomiting (15%).IFOX is an active regimen in patients with previously treated metastatic colorectal adenocarcinoma, demonstrating higher response rates than those reported with FOLFOX-4 alone in a similar patient population.

  View details for DOI 10.1200/JCO.2005.08.359

  View details for Web of Science ID 000231371700034

  View details for PubMedID 16110021

• Effect of bexarotene on vinorelbine and cisplatin pharmacokinetics during a Phase I study in patients with advanced non-small cell lung cancer (NSCLC) 11th World Conference on Lung Cancer Wakelee, H., Middleton, G., Dunlop, D., Kelly, C., Ramlau, R., Leighl, N., Hao, D., Zatloukal, P., Cox, K., Loewen, G. ELSEVIER IRELAND LTD. 2005: S274–S274

  View details for Web of Science ID 000231307802071

• A phase I trial of irinotecan (CPT-11) with amifostine in patients with metastatic colorectal cancer INVESTIGATIONAL NEW DRUGS Wakelee, H., Fisher, G. A. 2005; 23 (3): 241-242

  View details for DOI 10.1007/s10637-005-6732-1

  View details for Web of Science ID 000228876800006

  View details for PubMedID 15868380

• Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590 39th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Wakelee, H. A., Stephenson, P., Keller, S. M., Wagner, H., Herskovic, A., Komaki, R., Marks, R. S., Perry, M. C., Livingston, R. B., Johnson, D. H. ELSEVIER IRELAND LTD. 2005: 389–97

  Abstract

  To determine the influence of adjuvant therapy on the risk of DID following resection of NSCLC, we compared the actuarial rate of non-cancer related deaths of patients who had been entered in Eastern Cooperative Oncology Group E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIA NSCLC) to the actuarial death rate of age and gender matched controls. Following surgery, patients were randomized to receive either PORT (5040 cGy in 28 daily fractions) or CPORT (PORT plus four cycles of cisplatin (60 mg/m2, day 1) and etoposide (120 mg/m2, days 1-3) administered concurrently). The study accrued 488 patients, 242 to the PORT only arm and 246 to the CPORT arm. The overall 4 years actuarial rate of DID for the two arms combined, with a median follow-up of 82 months, was 12.9%, not significantly different from the 10.1% expected rate of DID, based on mortality rates for age and gender matched controls derived from US vital statistics and corrected for smoking status (p=0.16). Survival distributions with regard to DID did not differ between the two treatment arms (p=0.96). DID increased with age (treated as a continuous variable, p<0.01), but was not affected by histology, side of chest irradiated, type of surgery, FEV1 or weight loss in the previous 6 months. The risk of DID following resection of stages II and IIIA NSCLC is not increased in patients who received PORT or CPORT.

  View details for DOI 10.1016/j.lungcan.2004.11.007

  View details for Web of Science ID 000229645600012

  View details for PubMedID 15893008

• A phase I trial of oblimersen and gemcitabine in refractory and advanced malignancies 41st Annual Meeting of the American-Society-of-Clinical-Oncology Fisher, G., Advani, R., Wakelee, H., Jacobs, C., Gladysheva, K., Fitzgerald, A. M., Sikic, B. AMER SOC CLINICAL ONCOLOGY. 2005: 234S–234S

  View details for Web of Science ID 000230326601349

• A phase I dose-escalation and pharmacokinetic (PK) study of a novel multiple-targeted receptor tyrosine kinase (RTK) inhibitor, XL647, in patients with advanced solid malignancies 41st Annual Meeting of the American-Society-of-Clinical-Oncology Wakelee, H., Adjei, A. A., Keer, H., Halsey, J., Hanson, L., Reid, J., Hutchison, S., Piens, J., Lacy, S., Sikic, B. I. AMER SOC CLINICAL ONCOLOGY. 2005: 227S–227S

  View details for Web of Science ID 000230326601318

• Docetaxel in advanced non-small cell lung cancer EXPERT REVIEW OF ANTICANCER THERAPY Wakelee, H., Ramalingam, S., Belani, C. P. 2005; 5 (1): 13-24

  Abstract

  Based on the survival benefit demonstrated in large randomized clinical trials, docetaxel is approved for the treatment of advanced non-small cell lung cancer (NSCLC) in both the first- and second-line settings. The efficacy of docetaxel in combination with cisplatin is equivalent to some, and superior to other, platinum-based doublets for first-line management of NSCLC, and has a manageable toxicity profile. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy of patients with advanced NSCLC. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II studies. This article reviews recent studies of docetaxel as a single agent and in combination regimens with cytotoxic and more recent targeted agents in the management of advanced NSCLC.

  View details for Web of Science ID 000233979300003

  View details for PubMedID 15757434

• Optimizing first-line treatment options for patients with advanced NSCLC ONCOLOGIST Wakelee, H., Belani, C. P. 2005; 10: 1-10

  Abstract

  The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane-platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane-gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.

  View details for Web of Science ID 000234419400001

  View details for PubMedID 16368866

• Results of a phase I dose escalation study using single fraction stereotactic radiosurgery (SFSR) for lung tumors 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. X., Ho, A., Cotrutz, C., Loo, B., Petrik, D., Wakelee, H., Kee, S. T., Whyte, R. I., Donington, J. S. ELSEVIER SCIENCE INC. 2005: S226–S226

  View details for Web of Science ID 000232083300377

• Single fraction stereotactic radiosurgery (SFSR) for lung tumors - A phase I dose escalation trial. 40th Annual Meeting of the American-Society-of-Clinical-Oncology Le, Q. T., Ho, A., Cotrutz, C., Wakelee, H., Kee, S. T., Donington, I., Whyte, R. I. AMER SOC CLINICAL ONCOLOGY. 2004: 673S–673S

  View details for Web of Science ID 000223512402672

• A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. 40th Annual Meeting of the American-Society-of-Clinical-Oncology Fishe, G. A., Kuo, T., Cho, C. D., Halsey, J., Jambalos, C. N., Schwartz, E. J., Robert, R. V., Advani, R. H., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2004: 248S–248S

  View details for Web of Science ID 000223512400981

• Novel approaches for the treatment of small cell lung cancer HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Wakelee, H., Kelly, K. 2004; 18 (2): 499-?

  View details for DOI 10.1016/j.hoc.2004.01.001

  View details for Web of Science ID 000221346600014

  View details for PubMedID 15094184

• A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Cho, C. D., Fisher, G. A., Halsey, J., Jambalos, C. N., Schwartz, E. J., Rouse, R. V., Advani, R. H., Wakelee, H. A., Lum, B. L., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2003: 6103S–6103S

  View details for Web of Science ID 000187467300140

• Delta F508-CFTR channels: Kinetics, activation by forskolin, and potentiation by xanthines AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY HAWS, C. M., Nepomuceno, I. B., Krouse, M. E., Wakelee, H., Law, T., Xia, Y., Nguyen, H., Wine, J. J. 1996; 270 (5): C1544-C1555

  Abstract

  Trafficking, activation, and kinetics of delta F508-cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR were compared in stably transduced C127I mouse mammary epithelial cells. Western blots detected a small amount of fully glycosylated delta F508-CFTR Efflux of 125I was stimulated by forskolin with the same mean effective concentration (EC50; approximately 0.5 microM) for CFTR and delta F508-CFTR cells, but the maximum response was reduced more than fivefold and its latency increased approximately threefold in delta F508-CFTR cells. In delta F508-CFTR cells, 3-isobutyl-1-methylxanthine (IBMX; EC50 = 1.45 microM) and 8-cyclopentyl-1,3-dipropylxanthine (CPX; EC50 = 58 microM) increased the peak forskolin-stimulated efflux rate approximately 2.5-fold and decreased the time to peak. A sevenfold increase in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels accompanied potentiation of forskolin-induced 125I efflux by IBMX but not by CPX. Elevation of intracellular cAMP increased linear voltage-independent whole cell currents 30-fold in CFTR and 4-fold in delta F508-CFTR cells; the response rate in delta F508-CFTR cells was much slower. Single-channel currents were detected in 57 of 68 cell-attached patches from forskolin-prestimulated CFTR cells vs. 6 of 35 patches in delta F508-CFTR cells. Mean number of active channels per patch was 4.1 for CFTR [open probability (Po) = 0.34] and 0.2 for delta F508-CFTR (Po = 0.11). The lower Po of delta F508-CFTR resulted from an approximately threefold longer mean interburst interval. We estimate that forskolin-stimulated chloride conductance of delta F508-CFTR C127I cells is < 5% of CFTR cells. CPX is approximately 25-fold more potent than IBMX in potentiating delta F508-CFTR and may operate by a mechanism other than elevation of cAMP.

  View details for Web of Science ID A1996UJ81400034

  View details for PubMedID 8967457