Introduction: Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described and proposed to represent thoracic sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare with those of nonsarcomatoid SMARCA4-deficient non–small cell lung carcinomas (SD-NSCC). Methods: We identified 22 SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) with round cell and/or rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical, and genomic characteristics using 341–468 gene next-generation sequencing and other molecular platforms. Results: The relationship of SD-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-TSTs exhibited considerably larger primary tumor size ( p < 0.0001), worse survival ( p = 0.004), and more frequent presentation at younger age (30–50 years) despite heavier smoking history. Distinctive pathologic features of SD-TSTs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) codeficiency, and frequent expression of stem cell markers. Conclusions: SD-TSTs represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.

Background: Patients with lung cancers may have disproportionately severe coronavirus disease 2019 outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of COVID-19 may inform optimal cancer care during this pandemic. Patients and methods: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n ¼ 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate ([ICU/intubation/DNI] a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n ¼ 46) and compared with controls with lung cancer and no known non-COVID-19 (n ¼ 5166). Results: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease [odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07e9.44 comparing the median (23.5 packyears) to never-smoker and 3.87, 95% confidence interval 1.35e9.68, respectively]. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. Conclusion: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

III.

Purpose: SMARCA4 mutations are among the most common recurrent alterations in non-small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established.Experimental Design: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering.Results: In 4,813 tumors from patients with NSCLC, we identified 8% (n ¼ 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P < 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P < 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (P < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4mutant tumors (P ¼ 0.01), with class 1 mutations having the best response to ICIs (P ¼ 0.027).Conclusions: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.