Benz, Edward J., Jr., MD 5P30CA-06516-45 8.4.8 Progress Report: Lung Cancer Program Program Code: 34 Program Leader: Bruce E. Johnson, MDDFCI Program Co-Leader: David Christiani, MD MPHHSPH, MGH Program Clinical Trials Subcommittee Chair: Bruce E. Johnson, MDDFCI I. Overview The Lung Cancer Program seeks to exploit the resources provided by the consortium of DF/HCC institutions to conduct innovative population-based research on the causes and pathogenesis of lung cancer, focusing on discoveries that will ultimately lead to improvements in prevention, diagnosis, prognosis, and therapy. The Program has focused on making discoveries about the pathogenesis of lung cancer and using these discoveries to apply novel therapies to both prevent and treat the different types of lung cancer. Members of the Program have expertise in smoking cessation, genetic susceptibility to tobacco smoke, the genetic changes in lung cancer, mRNA expression patterns, and novel therapeutic approaches, including pre-clinical modeling, conducting clinical trials of novel therapies, and outcomes after the therapies. The Lung Cancer Program has benefited from ongoing review by the DF/HCC Executive Committee and the External Advisory Board of the DF/HCC in 2006 and 2007, and the review of our DF/HCC Lung Cancer SPORE submission in 2007. The Program continues to make improvements based on these recommendations. The leadership of the Lung Cancer Cancer Program has changed. Dr. Thomas Lynch, the previous Clinical Trials Subcommittee Chair, has left to become the Director of Yale Cancer Center and Physician-in-Chief of the new Smilow Cancer Hospital at Yale-New Haven. Bruce E. JohnsonDFCI, the Director of the Lung Cancer Program, has stepped in again as the Clinical Trials Subcommittee Chair. Membership The Program added new members to in order to expand its areas of expertise. John Iafrate, MD, PhDMGH has provided genomics expertise which has led to the consistent characterization of genetic changes in lung cancers, a crucial step for allocation into clinical trials based on the tumor specific changes in our patients. Leena Gandhi, MD, PhDDFCI has provided expertise in drug development and works with the members of the Translational Pharmacology and Early Therapeutic Trials. Augustine Choi, MDBWH, is the Parker B. Francis Professor of Medicine and Head of the Division of Pulmonary and Critical Care Medicine. Dr. Choi studies the pathogenesis of lung injury. Several members have left the DF/HCC in the past year. Nathanael Gray, PhDDFCI , who has been able to synthesize compounds specific for mutated receptors and actively collaborates with multiple members of the Lung Cancer Program joined the DF/HCC. The following table provides a list of all our new members: New Member Institution Academic Title Iafrate, A. John MGH Assistant Professor of Pathology, HMS Gandhi, Leena DFCI Instructor, Department of Medicine, HMS Choi, Augustine BWH Professor of Medicine, HMS Members of the program are based in multiple institutions, departments, and disciplines. Therefore, regular program meetings are vital to assure communication and coordinate project planning. The Program continues to hold regular sets of meetings aimed at programmatic development and management, clinical trials development, prioritization and operations, SPORE-related activities, and resident and fellow training. The Program hosts regular seminars, bi-weekly joint lab meetings, and symposia. This year the Lung Cancer Program held a symposium on May 6, 2009 at Joseph P. Martin Conference Center at Harvard Medical School in Boston, MA. The DF/HCC continues to provide Benz, Edward J., Jr., MD 5P30CA-06516-45 ongoing clinical trials infrastructure and education, shared resources, and administrative leadership that support the Program. Shared resources that play a prominent role in the ongoing research of the program include Biostatistics, Cancer Pharmacology, Cancer Proteomics, Cytogenetics, DNA Resource, Health Communications, Monoclonal Antibody, Pathology Specimen Locator, Rodent Histopathology, Specialized Histopathology, Tissue Microarray and Imaging, and the Vector Core. Specific Aims The specific aims of the Program have not changed since the competitive renewal. They are: 1. Identify germline polymorphisms and determine their role in the susceptibility, pathogenesis and prognosis of lung cancer. 2. Define pathogenic mechanisms underlying the development of lung cancer. 3. Exploit the discoveries in pathogenesis to develop novel therapeutic approaches to thoracic malignancies. II. Scientific Accomplishments Members of the DF/HCC Lung Cancer Program initially reported the association between somatic mutations in the epidermal growth factor receptor and response to epidermal growth factor receptor tyrosine kinase inhibitors in 2004 (Paez et al., Science 2004; 304:1497 and Lynch et al., NEJM 2004; 350:2129). The discovery has led to a series of laboratory experiments, transgenic murine models, clinical observations, and the development of clinical trials studying the epidermal growth factor receptor and the effect of different epidermal growth factor receptor inhibitors, as well as the development of resistance to epidermal growth factor receptor inhibitors. Members of the Lung Cancer Program continue their studies to characterize other genomic changes and develop therapeutic interventions based on these genomic changes. The characterization of somatic changes in lung cancers takes place as part of a multi-institutional Tumor Sequencing Project supported by the National Human Genome Research Institute and National Cancer Institute led by Matthew MeyersonDFCI. Members of the Program have contributed patient samples and expertise to increase the ability to identify circulating tumor cells and use the cells to detect genomic changes in these circulating malignant cells. Program members have assembled patients from 5 different prospective trials of patients with previously untreated advanced non-small cell lung cancer initially treated with either gefitinib or erlotinib (three from the DF/HCC). The analyses of these trials showed a clear relationship between changes in the somatic mutational status of EGFR and KRAS and outcome of the patients when treated with erlotinib or gefitinib. Aim 1. Identify germline polymorphisms and determine their role in the susceptibility, pathogenesis and prognosis of lung cancer. The polymorphisms in tumor DNA from two different cohorts of patients were studied to determine DNA copy number losses and gains. One hundred early-stage NSCLC patients from Massachusetts General Hospital (MGH) were used as a discovery set and 89 NSCLC patients collected by the National Institute of Occupational Health, Norway, were used as a validation set. DNA was extracted from flash- frozen lung tissue with at least 70% tumor cellularity. Genome-wide genotyping was done using the high-density SNP chip. Copy numbers were inferred using median smoothing after intensity normalization. Cox models were used to screen and validate significant SNPs associated with the overall survival. There were copy number gains in chromosomes 3q, 5p, and 8q in the tumors from patients in both the MGH and Norwegian cohorts. The top 50 SNPs associated with overall survival in the MGH cohort (P 2.5 x 10–4) were selected and examined using the Norwegian cohort. Five of the top 50 SNPs were validated in the Norwegian cohort with false discovery rate lower than 0.05 (P < .016) and all five were located in known genes: STK39, PCDH7, A2BP1, and EYA2. The numbers of risk alleles of the five SNPs showed a cumulative effect on overall survival (Ptrend = 3.80 x 10–12 and 2.48 x 10–7 for MGH and Norwegian cohorts, respectively) and the outcomes are shown in Figure 1 (Huang et al J Clin Oncol 27:2660, 2009 Benz, Edward J., Jr., MD 5P30CA-06516-45 Figure 1. Kaplan-Meier survival estimates of overall survival among the Massachusetts General Hospital (MGH) and Norwegian cohorts and relapse-free survival among the MGH cohort according to the numbers of risk alleles of the five single nucleotide polymorphisms (rs10176669, rs4438452, rs12446308, rs13041757, and rs10517215) in (A-C) total MGH and Norwegian cases. Aim 2. Define pathogenic mechanisms underlying the development of lung cancer. Characterizing the cancer genome in lung adenocarcinoma MeyersonDFCI is one of the leaders of the international efforts to systemically characterize the genomic changes in lung cancer. The National Human Genome Research Institute continues to support investigators from multiple institutions in a program called the Tumor Sequencing Project. This project includes investigators from the Dana-Farber Cancer Institute, Broad Institute, Memorial Sloan Kettering, University of Michigan, Washington University, MD Anderson and many other centers around the world. The results from the somatic mutations from 188 human lung adenocarcinomas have been reported this year (Ding et al. Nature 455:1069, 2008). DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. The analyses identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumor suppressor genes involved in other cancers—including NF1, APC, RB1 and ATM—and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. The findings shed further light on several important signaling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment Benz, Edward J., Jr., MD 5P30CA-06516-45 Figure 2. Significantly mutated genes in lung adenocarcinoma samples. The height of the bars represents the number of somatic mutations in each indicated gene in 188 tumor and normal pairs. Ten genes were found to be significantly mutated by all three statistical methods (red bars), 7 genes by at least two methods (blue bars) and 9 genes by one of the three methods (green bars), for up to 26 significantly mutated genes in total. Isolation of rare circulating tumor cells in cancer patients by microchip technology Investigators from the Massachusetts General Hospital and Massachusetts Institute of Technology continue to develop and apply their new techniques for isolating tumor-derived epithelial cells from the peripheral blood from cancer patients (Maheswaran et al New Engl J Med 359:366, 2008). Circulating tumor cells from the blood of patients with NSCLC were captured using the microfluidic device containing microposts coated with antibodies against epithelial cells. EGFR mutational analysis on DNA recovered from circulating tumor cells using allele-specific polymerase-chain-reaction amplification was performed and results were compared to the results from concurrently isolated free plasma DNA and from the original tumor-biopsy specimens from the same patient. Circulating tumor cells from 27 patients with metastatic non–small-cell lung cancer were isolated (median number, 74 cells per milliliter). The expected EGFR activating mutation in circulating tumor cells matched the mutation in the tumor from the same patient in 11 of 12 studied (92%) and in matched free plasma DNA from 4 of 12 patients (33%) (P=0.009). The T790M mutation, which confers drug resistance,was identified in circulating tumor cells collected from patients with EGFR mutations who had received tyrosine kinase inhibitors. When the T790M was detectable in pretreatment tumor-biopsy specimens, the presence of the mutation correlated with reduced progression-free survival (7.7 months vs. 16.5 months, P<0.001). Serial analysis of circulating tumor cells showed that a reduction in the number of captured cells was associated with a radiographic tumor response; an increase in the number of cells was associated with tumor progression, with the emergence of additional EGFR mutations in some cases. Benz, Edward J., Jr., MD 5P30CA-06516-45 Figure 3. Correlation between the presence of T790M mutations in tumor-biopsy specimens and decreased progression-free survival. Patients with non–small-cell lung cancer with EGFR mutations who were receiving therapy with gefitinib or erlotinib had decreased progression-free survival if the drug-resistance mutation T790M was present before initiation of treatment. Aim 3. Exploit the discoveries in pathogenesis to develop novel therapeutic approaches to thoracic malignancies. Prospective Trials of Patients with Advanced Non-Small Cell Lung Cancer The impact of epidermal growth factor receptor (EGFR) and KRAS genotypes on outcomes with erlotinib or gefitinib therapy is becoming more clear in patients from East Asia. Members of the DF/HCC combined their data with other investigators from the United States and Europe. Five trials in predominantly Western populations were studied to assess the impact of EGFR and KRAS mutations on outcome of patients treated with first-line therapy with the EGFR–tyrosine kinase inhibitor, gefitinib and erlotinib. Previously untreated patients with advanced non–small cell lung cancer and known EGFR mutation status treated with erlotinib or gefitinib monotherapy as part of a clinical trial were eligible for inclusion. Patients were treated with daily erlotinib (150 mg) or gefitinib (250 mg) until disease progression or unacceptable toxicity. Data were collected in a password-protected web database. Clinical outcomes were analyzed to look for differences based on EGFR and KRAS genotypes, as well as clinical characteristics. Two hundred twenty-three patients from five clinical trials were analyzed. Sensitizing EGFR mutations were associated with a 67% response rate, time to progression of 12 months, and overall survival of 24 months. Exon 19 deletions were associated with longer median time to progression and overall survival compared with L858R mutations. Wild-type EGFR was associated with poorer outcomes (response rate, 3%; time to progression of 3.2 months) irrespective of KRAS status. No difference in outcome was seen between patients harboring KRAS transition versus transversion mutations. EGFR genotype was more effective than clinical characteristics at selecting appropriate patients for consideration of first-line therapy with an EGFR-TKI. Benz, Edward J., Jr., MD 5P30CA-06516-45 Figure. 4. Overall survival in patients based on EGFR and KRAS status III. Developmental Plans The DF/HCC Lung Cancer Program plans to capitalize on our scientific efforts to develop new clinical protocols arising from our ongoing research and to organize program-wide grants. We continue to integrate the suggestions made by the Executive Committee of DF/HCC, review by the DF/HCC External Advisory Board, and review of our Lung Cancer Specialized Program of Research Excellence grant application submitted in May of 2007 and refunded since 2008. Described below are several high priority research efforts that are ongoing. EML4-ALK Translocations in Lung Cancer EML4-ALK translocation in lung cancers were described by investigators from Japan (M Soda et al Nature 2007 448:561). Two to 3% of lung cancers have the translocation where a transcription factor (EML4) translocates into the ALK tyrosine kinase. This activates the ALK kinase similar to the abelson kinase (abl) in chronic myelogenous leukemia. Members of DF/HCC have published four different articles on the characterization of lung cancer cell lines and patients with this translocation (Shaw et al J Clin Oncol Aug 10; Epub ahead of print, 2009; Rodig et al Clinical Cancer Research 15, 5216, 2009; Koivunen Clin Cancer Res. 14:4275, 2008; McDermott Cancer Res 68:3389, 2008). The pathology laboratories at the BWH and MGH have developed FISH tests to detect the translocation and are described in the previous publications. The NSCLC patients with the EML4-ALK translocations have been referred to the phase I expansion cohort of the ALK and MET inhibitor, PF-02341066 (DF/HCC 06-068). Alice ShawMGH reported the findings at the American Society of Clinical Oncology and International Association for the Study of Lung Cancer meetings in 2009. The majority of patients with NSCLC and EML4-ALK translocations had a partial response to therapy and we await further follow-up to establish the time to progression and survival. ShawMGH and JänneDFCI have worked with Pfizer to write a phase III study comparing the outcome of patients with NSCLC and EML4-ALK translocation treated with either PF-02341066 or pemetrexed. Both are members of the DF/HCC Lung Cancer Program and are on the Steering Committee of the trial. The efforts to characterize our lung cancer patients for EML4-ALK translocations and treatment with the ALK inhibitor, PF-02341066, and other inhibitors will continue. Circulating tumor cells in cancer patients by microchip technology Benz, Edward J., Jr., MD 5P30CA-06516-45 Investigators from MGH and MIT have led the efforts within the DF/HCC to develop this technology to characterize circulating tumor cells as described earlier in this progress report. Daniel HaberMGH led a team of investigators from MGH, DFCI, Memorial Sloan Kettering, and MD Anderson in a grant application to the AACR for a Stand Up to Cancer translational research project which will be funded in October of 2009. Tumor cells from patients with NSCLC and EGFR mutations will be serially monitored for cell number and emergence of the known mechanisms of resistance, T790M mutations and MET amplification. The findings on the circulating cells will be compared to biopsies from the patients, both before and after treatment with erlotinib and other epidermal growth factor receptor inhibitors. Development of therapies directed against other genomic targets The plans for treating patients with sensitizing mutations of the epidermal growth factor receptor and EML4-ALK translocations are relatively clear and have been described in this Progress Report. The ability to target other genomic changes are less clear. Meyerson is meeting regularly with members of the DF/HCC to organize and submit a PO1 grant application in early 2010. He has met with members of the Grants and Contracts Operations Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis and Research Programs Review Branch, Division of Extramural Activities in July of 2009 to seek advice on revising the project titles and specific aims of the proposal. This will focus on the preclinical development and analysis of agents directed against specific genomic changes. This will include KRAS mutations, ephrin receptor kinase mutations, and ERBB2 mutations. Characterization of Early Stage NSCLCs The DF/HCC Lung Cancer Program continues to respond to the previous suggestion from the External Advisory Board that we consider studying cohorts of Caucasians from the US and Asians in molecular pathology studies of their lung cancers. David ChristianiHSPH organized a submission of a P50 grant to the National Institute of Environmental Health Sciences in 2006 to study the lung cancers from 2000 Caucasians collected within the DF/HCC and 2000 patients from Korea and Taiwan. This project involves using the same epidemiology instrument to collect information on exposures including cigarette smoke. The instrument has been translated from English into both Korean and Chinese and several hundred patients’ tumors, normal DNA, and epidemiology information has been collected. The tumor and normal DNA are being collected to assess the single nucleotide polymorphisms and their impact on risk and specific genomic changes in the tumors. The proposal is for the tumors to undergo genomic characterization for EGFR, KRAS and LKB1 mutations and then determine if there is a relationship between SNP changes in the germline DNA and these different somatic changes. The plans are for ChristianiHSPH and JohnsonDFCI to submit the proposal as a large R01 Grant in early 2010. Benz, Edward J., Jr., MD 5P30CA-06516-45 Lung Cancer Select Publications + = inter-institutional collaborations # = intra-programmatic collaborations * = inter-programmatic collaborations Bolded names indicate members of this program Underlined names indicate members of other programs 1. Ahn MJ, Park BB, Ahn JS, Kim SW, Kim HT, Lee JS, Kang JH, Cho JY, Song HS, Park SH, Sohn CH, Shin SW, Choi JH, Ki CS, Park CK, Holmes AJ, Janne PADFCI, Park K. Are there any ethnic differences in molecular predictors of erlotinib efficacy in advanced non-small cell lung cancer? Clin Cancer Res, 2008 14:3860-6. 2. Barletta JA, Perner S, Iafrate AJ, Yeap BYMGH, Weir BA, Johnson LA, Johnson BEDFCI, Meyerson MDFCI, Rubin MABWH, Travis WD, Loda MDFCI, Chirieac LRBWH. Clinical Significance #*+ of TTF-1 Protein Expression and TTF-1 Gene Amplification in Lung Adenocarcinoma. J Cell Mol Med, 2008. 3. Bell DW, Brannigan BW, Matsuo K, Finkelstein DMMGH, Sordella R, Settleman JMGH, Mitsudomi T, Haber DAMGH. Increased prevalence of EGFR-mutant lung cancer in women and in #* East Asian populations: analysis of estrogen-related polymorphisms. Clin Cancer Res, 2008 14:4079-84. 4. Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller RU, Straka E, Su L, Burki EA, Crowell RE, Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DCHSPH, Belinsky SA, Slack FJ, Weidhaas JB. A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk. Cancer Res, 2008 68:8535- 40. 5. Chin TM, Quinlan MP, Singh A, Sequist LVMGH, Lynch TJMGH, Haber DAMGH, Sharma SV, Settleman JMGH. Reduced Erlotinib sensitivity of epidermal growth factor receptor-mutant non- #* small cell lung cancer following cisplatin exposure: a cell culture model of second-line erlotinib treatment. Clin Cancer Res, 2008 14:6867-76. 6. Christensen BC, Godleski JJHSPH, Roelofs CR, Longacker JL, Bueno RBWH, Sugarbaker #*+ DJBWH, Marsit CJ, Nelson HHHSPH, Kelsey KTHSPH. Asbestos burden predicts survival in pleural mesothelioma. Environ Health Perspect, 2008 116:723-6. 7. Christensen BC, Houseman EA, Godleski JJHSPH, Marsit CJ, Longacker JL, Roelofs CR, Karagas MR, Wrensch MR, Yeh RF, Nelson HHHSPH, Wiemels JL, Zheng S, Wiencke JK, Bueno #*+ RBWH, Sugarbaker DJBWH, Kelsey KTHSPH. Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome. Cancer Res, 2009 69:227-34. 8. Cooley MEDFCI, Sarna L, Kotlerman J, Lukanich JM, Jaklitsch MBWH, Green SB, Bueno #+ RBWH. Smoking cessation is challenging even for patients recovering from lung cancer surgery with curative intent. Lung Cancer, 2009. 9. Costa DBBIDMC, Nguyen KS, Cho BC, Sequist LVMGH, Jackman DM, Riely GJ, Yeap BYMGH, Halmos B, Kim JH, Janne PADFCI, Huberman MSBIDMC, Pao W, Tenen DGBIDMC, Kobayashi #*+ BIDMC S . Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res, 2008 14:7060-7. 10. Court LE, Ching D, Schofield D, Czerminska M, Allen AMDFCI. Evaluation of the dose calculation accuracy in intensity-modulated radiation therapy for mesothelioma, focusing on low doses to the contralateral lung. J Appl Clin Med Phys, 2009 10:2850. Benz, Edward J., Jr., MD 5P30CA-06516-45 11. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez- Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, #+ Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LRBWH, Dutt A, Fennell T, Hanna M, Johnson BEDFCI, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson MDFCI, Wilson RK. Somatic mutations affect key pathways in lung adenocarcinoma. Nature, 2008 455:1069-75. 12. Dovey JS, Zacharek SJ, Kim CFCHB, Lees JA. Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc Natl Acad Sci U S A, 2008 105:11857-62. 13. Engelman JAMGH, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LRBWH, Kaur R, Lightbown A, Simendinger J, Li T, #*+ Padera RF, Garc� a-Echeverr� C, Weissleder RMGH, Mahmood UMGH, Cantley LCBIDMC, Wong a DFCI KK . Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med, 2008 14:1351-6. 14. Gandhi LDFCI, McNamara KL, Li D, Borgman CL, McDermott U, Brandstetter KA, Padera RF, Chirieac LRBWH, Settleman JEMGH, Wong KKDFCI. Sunitinib prolongs survival in genetically #+ engineered mouse models of multistep lung carcinogenesis. Cancer Prev Res (Phila Pa), 2009 2:330-7. 15. Girnun GD, Chen L, Silvaggi J, Drapkin RDFCI, Chirieac LRBWH, Padera RF, Upadhyay R, Vafai SB, Weissleder RMGH, Mahmood UMGH, Naseri E, Buckley S, Li D, Force J, McNamara K, #*+ Demetri G, Spiegelman BMDFCI, Wong KKDFCI. Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin. Clin Cancer Res, 2008 14:6478-86. 16. Gordon GJBWH, Dong L, Yeap BYMGH, Richards WG, Glickman JNBWH, Edenfield H, Mani M, Colquitt R, Maulik G, Van Oss B, Sugarbaker DJBWH, Bueno RBWH. Four-gene expression ratio #*+ test for survival in patients undergoing surgery for mesothelioma. Journal of the National Cancer Institute, 2009 101:678-86. 17. Greer JA, Pirl WF, Park ERMGH, Lynch TJMGH, Temel JSMGH. Behavioral and psychological #* predictors of chemotherapy adherence in patients with advanced non-small cell lung cancer. J Psychosom Res, 2008 65:549-52. 18. Griset AP, Walpole J, Liu R, Gaffey A, Colson YLBWH, Grinstaff MW. Expansile nanoparticles: synthesis, characterization, and in vivo efficacy of an acid-responsive polymeric drug delivery system. J Am Chem Soc, 2009 131:2469-71. 19. Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, Rinehart C, Seidel B, Yee D, Arteaga CL, Engelman JAMGH. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest, 2008 118:2609-19. 20. Hanrahan EO, Ryan AJ, Mann H, Kennedy SJ, Langmuir P, Natale RB, Herbst RS, Johnson BEDFCI, Heymach JV. Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small cell lung cancer. Clin Cancer Res, 2009 15:3600-9. #+ 21. Heist RSMGH, Fidias PMGH, Huberman MBIDMC, Ardman B, Sequist LVMGH, Temel JSMGH, Benz, Edward J., Jr., MD 5P30CA-06516-45 Lynch TJMGH. A phase II study of oxaliplatin, pemetrexed, and bevacizumab in previously treated advanced non-small cell lung cancer. J Thorac Oncol, 2008 3:1153-8. 22. Heist RSMGH, Zhou W, Wang Z, Liu G, Neuberg DDFCI, Su L, Asomaning K, Hollis BW, Lynch TJMGH, Wain JCMGH, Giovannucci EHSPH, Christiani DCHSPH. Circulating 25-hydroxyvitamin D, #*+ VDR polymorphisms, and survival in advanced non-small-cell lung cancer. J Clin Oncol, 2008 26:5596-602. 23. Heymach JV, Paz-Ares L, De Braud F, Sebastian M, Stewart DJ, Eberhardt WE, Ranade AA, Cohen G, Trigo JM, Sandler AB, Bonomi PD, Herbst RS, Krebs AD, Vasselli J, Johnson BEDFCI. Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first- line treatment for advanced non-small-cell lung cancer. J Clin Oncol, 2008 26:5407-15. 24. Huang G, Eisenberg R, Yan M, Monti S, Lawrence E, Fu P, Walbroehl J, Lowenberg E, Golub TDFCI, Merchan J, Tenen DGBIDMC, Markowitz SD, Halmos B. 15-Hydroxyprostaglandin *+ dehydrogenase is a target of hepatocyte nuclear factor 3beta and a tumor suppressor in lung cancer. Cancer Res, 2008 68:5040-8. 25. Huang YT, Heist RSMGH, Chirieac LRBWH, Lin XHSPH, Skaug V, Zienolddiny S, Haugen A, #+ Wu MC, Wang Z, Su L, Asomaning K, Christiani DCHSPH. Genome-wide analysis of survival in early-stage non-small-cell lung cancer. J Clin Oncol, 2009 27:2660-7. 26. Hung RJ, Christiani DCHSPH, Risch A, Popanda O, Haugen A, Zienolddiny S, Benhamou S, Bouchardy C, Lan Q, Spitz MR, Wichmann HE, LeMarchand L, Vineis P, Matullo G, Kiyohara C, Zhang ZF, Pezeshki B, Harris C, Mechanic L, Seow A, Ng DP, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Caporaso N, Chen C, Duell EJ, Goodman G, Field JK, Houlston RS, Hong YC, Landi MT, Lazarus P, Muscat J, McLaughlin J, Schwartz AG, Shen H, Stucker I, Tajima K, Matsuo K, Thun M, Yang P, Wiencke J, Andrew AS, Monnier S, Boffetta P, Brennan P. International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways. Cancer Epidemiol Biomarkers Prev, 2008 17:3081-9. 27. Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, Choi HG, Kim J, Chiang D, Thomas R, Lee J, Richards WG, Sugarbaker DJBWH, Ducko C, Lindeman NBWH, #*+ Marcoux JP, Engelman JAMGH, Gray NSDFCI, Lee CBWH, Meyerson MDFCI, Janne PADFCI. EML4- ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res, 2008 14:4275-83. 28. Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJBWH, Rosenzweig KE, Flores R, Friedberg JS, Pisters K, Monberg M, Obasaju CK, Vogelzang NJ. Multicenter Phase II Trial of Neoadjuvant Pemetrexed Plus Cisplatin Followed by Extrapleural Pneumonectomy and Radiation for Malignant Pleural Mesothelioma. J Clin Oncol, 2009. 29. Kuang Y, Rogers A, Yeap BYMGH, Wang L, Makrigiorgos M, Vetrand K, Thiede S, Distel RJ, #+ Janne PADFCI. Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin Cancer Res, 2009 15:2630-6. 30. Lanuti M, Sharma A, Digumarthy SR, Wright CD, Donahue DM, Wain JCMGH, Mathisen # DJMGH, Shepard JA. Radiofrequency ablation for treatment of medically inoperable stage I non- small cell lung cancer. J Thorac Cardiovasc Surg, 2009 137:160-6. 31. Lathan CSDFCI, Neville BA, Earle CCDFCI. Racial composition of hospitals: effects on surgery # for early-stage non-small-cell lung cancer. J Clin Oncol, 2008 26:4347-52. 32. Maheswaran SMGH, Sequist LVMGH, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, #* Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman JMGH, Benz, Edward J., Jr., MD 5P30CA-06516-45 Tompkins RG, Lynch TJMGH, Toner M, Haber DAMGH. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med, 2008 359:366-77. 33. McMahon PMMGH, Kong CY, Weinstein MCHSPH, Tramontano AC, Cipriano LE, Johnson #*+ BEDFCI, Weeks JCDFCI, Gazelle GSMGH. Adopting helical CT screening for lung cancer : potential health consequences during a 15-year period. Cancer, 2008 113:3440-9. 34. Miksad RABIDMC, Gonen M, Lynch TJMGH, Roberts TG Jr. Interpreting trial results in light of + conflicting evidence: a Bayesian analysis of adjuvant chemotherapy for non-small-cell lung cancer. J Clin Oncol, 2009 27:2245-52. 35. Naumov GN, Nilsson MB, Cascone T, Briggs A, Straume O, Akslen LA, Lifshits E, Byers LA, Xu L, Wu HK, Janne PDFCI, Kobayashi SBIDMC, Halmos B, Tenen DBIDMC, Tang XM, Engelman #+ JMGH, Yeap BMGH, Folkman J, Johnson BEDFCI, Heymach JV. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin Cancer Res, 2009 15:3484-94. 36. Neragi-Miandoab S, Richards WG, Sugarbaker DJBWH. 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