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Stephen Broderick

Bio: Stephen Broderick is an academic researcher from Johns Hopkins University. The author has contributed to research in topics: Nivolumab & Lung cancer. The author has an hindex of 11, co-authored 26 publications receiving 1981 citations. Previous affiliations of Stephen Broderick include Memorial Sloan Kettering Cancer Center & University of Texas Southwestern Medical Center.

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Journal ArticleDOI
TL;DR: Analysis of tumor samples from multiple independent patient cohorts and array-based comparative genomic hybridization suggest that MET amplification occurs independently of EGFRT790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.
Abstract: In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFRT790M mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFRT790M mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.

1,587 citations

Journal ArticleDOI
TL;DR: Neoadjuvant therapy with nivolumab was not associated with unexpected perioperative morbidity or mortality, and more than half of the video-assisted thoracoscopic surgery/robotic cases were converted to thoracotomy, often because of hilar inflammation and fibrosis.

194 citations

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TL;DR: An evidence-based guideline on treatment with stereotactic body radiotherapy (SBRT) for patients with early-stage non-small-cell lung cancer and the recommendations are clear, thorough, and based on the most relevant scientific evidence.
Abstract: PurposeThe American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on treatment with stereotactic body radiotherapy (SBRT) for patients with early-stage non–small-cell lung cancer. ASCO has a policy and set of procedures for endorsing and/or adapting clinical practice guidelines that have been developed by other professional organizations.MethodsThe ASTRO Evidence-Based Guideline for Stereotactic Body Radiotherapy for Early-Stage Non–Small-Cell Lung Cancer was reviewed for developmental rigor by methodologists. An ASCO Expert Panel updated the literature search and reviewed the guideline content and recommendations.ResultsThe ASCO Expert Panel determined that the recommendations from the ASTRO guideline, published in 2017, are clear, thorough, and based on the most relevant scientific evidence. ASCO statements and minor modifications were added to enhance the applicability of the ASTRO guideline for the broader ASCO audience.RecommendationsFor standard operative risk patients ...

112 citations

Journal ArticleDOI
TL;DR: The study met its first primary endpoint, demonstrating significa… CheckMate 816 (NCT02998528) meets its firstPrimary endpoint.
Abstract: 8503Background: CheckMate 816 (NCT02998528) is a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC. The study met its first primary endpoint, demonstrating significa...

93 citations


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Journal ArticleDOI
TL;DR: Detailed genetic and histological analysis of 37 patients with drug-resistant non–small cell lung cancers carrying EGFR mutations provides new insights into the shifting sands of drug resistance evolution in lung cancers and suggests that serial biopsies may be essential in the quest to reverse or even prevent the development ofdrug resistance.
Abstract: Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non–small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.

2,972 citations

Journal ArticleDOI
TL;DR: Striking disparities in the natural progression of different cancers raise important questions about the evolution of metastatic traits, the genetic determinants of these properties and the mechanisms that lead to the selection of metastasis cells.
Abstract: Metastasis to distant organs is an ominous feature of most malignant tumours but the natural history of this process varies in different cancers. The cellular origin, intrinsic properties of the tumour, tissue affinities and circulation patterns determine not only the sites of tumour spread, but also the temporal course and severity of metastasis to vital organs. Striking disparities in the natural progression of different cancers raise important questions about the evolution of metastatic traits, the genetic determinants of these properties and the mechanisms that lead to the selection of metastatic cells.

2,403 citations

Journal ArticleDOI
TL;DR: This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy and identifies EGFR T790M as the most common mechanism of acquired Resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently.
Abstract: Purpose: All patients with EGF receptor ( EGFR )–mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. Experimental Design: Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA , and FISH for MET and HER2 . Results: Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%–70%] and four had small cell transformation (3%, 95% CI, 0%–6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%–13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%–32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1 , or NRAS (0 of 88, 0%; 95% CI, 0%–4%). Overlap among mechanisms of acquired resistance was seen in 4%. Conclusions: This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs. Clin Cancer Res; 19(8); 2240–7. ©2013 AACR .

2,027 citations

Journal ArticleDOI
19 Sep 2013-Nature
TL;DR: The dynamic tumour topography varies drastically even throughout the same lesion, so evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount.
Abstract: Tumour formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumour vasculature and immune cells Successful outgrowth of tumours and eventual metastasis is not determined solely by genetic alterations in tumour cells, but also by the fitness advantage such mutations confer in a given environment As fitness is context dependent, evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount The dynamic tumour topography varies drastically even throughout the same lesion Heterologous cell types within tumours can actively influence therapeutic response and shape resistance

2,020 citations

Journal ArticleDOI
TL;DR: From the Departments of Thoracic/Head and Neck Medical Oncology and Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston.
Abstract: From the Departments of Thoracic/Head and Neck Medical Oncology (R.S.H., J.V.H., S.M.L.), Cancer Biology (R.S.H., J.V.H.), and Clinical Cancer Prevention (S.M.L.), University of Texas M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr. Lippman at the Department of Thoracic/Head and Neck Medical Oncology, Unit 432, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at slippman@ mdanderson.org.

1,910 citations