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

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.

A 44-year-old woman with hematemesis and cutaneous hemorrhages as a result of superwarfarin poisoning.

The authors present the case of a 44-year-old American Indian woman with hematemesis, spontaneous cutaneous hemorrhages, and multiple ecchymoses. Coagulation factor analyses demonstrated both prolonged prothrombin time (PT, >40 s) and prolonged partial thromboplastin time (PTT, >120 s). Measurement of the serum level of brodifacoum (37 ng/mL), one of the superwarfarin agents commonly used in rodenticides, confirmed poisoning as the cause of the patient's symptoms. Substantial amounts of fresh frozen plasma and vitamin K were required to obtain normal coagulation parameters and maintain these parameters over a 3-week inhospital period. Oral administration of vitamin K (100 mg daily) maintained normal PT (14.1 s), PTT (33.0 s), and international normalized ratio (INR, 1.48) at 2 weeks after the patient was discharged from the hospital. By 2 months postdischarge, PT, PTT, and INR returned to elevated levels because of patient noncompliance with the prescribed tapering vitamin K regimen.