Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling.
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.



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.



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.



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.
Foundation Medicine, Inc., Cambridge, Massachusetts. Electronic address: Aschrock@foundationmedicine.com.
Alexa B
AB
Schrock
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
Shuyu D
SD
Li
Foundation Medicine, Inc., Cambridge, Massachusetts.
Garrett M
GM
Frampton
Foundation Medicine, Inc., Cambridge, Massachusetts.
James
J
Suh
Michiana Hematology-Oncology, Mishawaka, Indiana.
Eduardo
E
Braun
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Ranee
R
Mehra
Tulsa Cancer Institute, Tulsa, Oklahoma.
Steven C
SC
Buck
Michiana Hematology-Oncology, Mishawaka, Indiana.
Jose A
JA
Bufill
Davidoff Cancer Center, Petach-Tiqwa, Tel Aviv University, Israel.
Nir
N
Peled
Division of Hematology/Oncology, Department of Medicine, The University of Cincinnati.
Nagla Abdel
NA
Karim
Illinois CancerCare, Peoria, Illinois.
K Cynthia
KC
Hsieh
Illinois CancerCare, Peoria, Illinois.
Manuel
M
Doria
Illinois CancerCare, Peoria, Illinois.
James
J
Knost
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
Rong
R
Chen
Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, California.
Sai-Hong Ignatius
SI
Ou
Foundation Medicine, Inc., Cambridge, Massachusetts; Albany Medical College, Albany, New York.
Jeffrey S
JS
Ross
Foundation Medicine, Inc., Cambridge, Massachusetts.
Philip J
PJ
Stephens
Illinois CancerCare, Peoria, Illinois.
Paul
P
Fishkin
Foundation Medicine, Inc., Cambridge, Massachusetts.
Vincent A
VA
Miller
Foundation Medicine, Inc., Cambridge, Massachusetts.
Siraj M
SM
Ali
Montefiore Medical Center, Bronx, New York.
Balazs
B
Halmos
Illinois CancerCare, Peoria, Illinois.
Jane J
JJ
Liu
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002296:Carcinosarcoma / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D000090063:Proto-Oncogene Mas
D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas
BRAF; Genomic profiling; Immunotherapy; Lung sarcomatoid; MET exon 14; Tumor mutational burden