Alexa B Schrock1, Shuyu D Li2, Garrett M Frampton3, James Suh3, Eduardo Braun4, Ranee Mehra5, Steven C Buck6, Jose A Bufill4, Nir Peled7, Nagla Abdel Karim8, K Cynthia Hsieh9, Manuel Doria9, James Knost9, Rong Chen2, Sai-Hong Ignatius Ou10, Jeffrey S Ross11, Philip J Stephens3, Paul Fishkin9, Vincent A Miller3, Siraj M Ali3, Balazs Halmos12, Jane J Liu9. 1. Foundation Medicine, Inc., Cambridge, Massachusetts. Electronic address: Aschrock@foundationmedicine.com. 2. Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York. 3. Foundation Medicine, Inc., Cambridge, Massachusetts. 4. Michiana Hematology-Oncology, Mishawaka, Indiana. 5. Fox Chase Cancer Center, Philadelphia, Pennsylvania. 6. Tulsa Cancer Institute, Tulsa, Oklahoma. 7. Davidoff Cancer Center, Petach-Tiqwa, Tel Aviv University, Israel. 8. Division of Hematology/Oncology, Department of Medicine, The University of Cincinnati. 9. Illinois CancerCare, Peoria, Illinois. 10. Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, California. 11. Foundation Medicine, Inc., Cambridge, Massachusetts; Albany Medical College, Albany, New York. 12. Montefiore Medical Center, Bronx, New York.
Abstract
INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization. METHODS: Hybrid capture-based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA. RESULTS: The median age of the patients with PSC was 67 years (range 32-87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease. CONCLUSION: Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.
INTRODUCTION:Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization. METHODS: Hybrid capture-based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA. RESULTS: The median age of the patients with PSC was 67 years (range 32-87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease. CONCLUSION: Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.
Authors: J K Sabari; G C Leonardi; C A Shu; R Umeton; J Montecalvo; A Ni; R Chen; J Dienstag; C Mrad; I Bergagnini; W V Lai; M Offin; K C Arbour; A J Plodkowski; D F Halpenny; P K Paik; B T Li; G J Riely; M G Kris; C M Rudin; L M Sholl; M Nishino; M D Hellmann; N Rekhtman; M M Awad; A Drilon Journal: Ann Oncol Date: 2018-10-01 Impact factor: 32.976