Effects of mutations in SWI/SNF subunits on context-specific prognosis in driver positive and driver negative NSCLC.

person Benjamin Herzberg Columbia University Irving Medical Center, New York, NY info_outline Benjamin Herzberg, Nishant Gandhi, Brian S. Henick, Joanne Xiu, Ari M. Vanderwalde, Joshua E. Reuss, Carla Concepcion-Crisol

Authors person Benjamin Herzberg Columbia University Irving Medical Center, New York, NY info_outline Benjamin Herzberg, Nishant Gandhi, Brian S. Henick, Joanne Xiu, Ari M. Vanderwalde, Joshua E. Reuss, Carla Concepcion-Crisol Organizations Columbia University Irving Medical Center, New York, NY, Caris Life Sciences Research and Development, Phoenix, AZ, Caris Life Sciences, Phoenix, AZ, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY Abstract Disclosures Research Funding No funding received None. Background: Mutations(mt) in the Switch/Sucrose-Nonfermentable chromatin remodeling complex (SWI/SNF) are commonly found in NSCLC and have been associated with worse prognosis. However, the overall prognostic role of the individual SWI/SNF subunits in all NSCLCs and in oncogenic driver-positive (D+) and driver-negative (D-) groups remains unclear. Our study attempts to clarify the prognostic role of SWI/SNF subunit alterations in these populations. Methods: 42,379 NSCLC tumor specimens were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing (NGS) of DNA (592-gene panel or whole-exome sequencing). Based on the observed frequency of likely pathogenic/pathogenic (LP/P) mts, the four most commonly-altered SWI/SNF subunits – ARID1A (8.29%), SMARCA4 (6.29%), ARID2 (3.05%) and PBRM1 (1.98%) – were further analyzed. We divided the cohort by driver mts. D+ tumors possessed at least one of the following alterations: LP/P mts in KRAS, EGFR, BRAF, ERBB2 or MET; METex14 skipping; ERBB2 amplification, LP/P fusions in ALK (including IHC overexpression), RET, ROS1, NTRK (1-3) & NRG1. D- tumors were devoid of mts/amplifications/fusions in all genes mentioned above. Kaplan-Meier analysis was performed on real world survival data (n = 24685) obtained from insurance claims. Statistical significance was determined using chi-square and Mann-Whitney U test adjusted for multiple comparisons (q < 0.05). Results: Of the SWI/SNF genes, only SMARCA4mts were associated with worse survival in the overall (HR = 1.46), D+ (HR = 1.984) and D- (HR = 1.224) cohorts (all p < 0.01). While SMARCA4mt was associated in the D- cohort with KEAP1 and STK11 mts, the worse prognosis persisted even in their absence (HR = 1.41, p < 0.001). To understand the role of SWI/SNF mts in the context of driver co-mts, we compared the survival of D+ vs D- tumors for each SWI/SNF subunit. As expected, D+ tumors were associated with better survival in SWI/SNF wild-type (wt) tumors (HRs 0.76-0.78, p < 0.00001). There was no survival effect of ARID1A, ARID2 or PBRM1 mts (HRs = 0.9-1, p = ns). In contrast, in SMARCA4mts, D+ tumors had much worse survival than D- (HR = 1.295, p = 0.003). This effect is driven by the KRASmt cohort, as KRASmt/SMARCA4mt tumors had significantly worse survival compared with D- tumors (HR = 1.882, p < 0.001). Of note, KRASmts are enriched in the D+/SMARCA4mt subgroup (78% of all oncogenic drivers). When KRASmts were removed from the D+ group, no survival difference was observed between D+ and D- SMARCA4mt tumors (HR = 0.938, p = ns). Conclusions: In this largest-ever retrospective cohort of NSCLC patients with SWI/SNF mutations, SMARCA4mt is the only SWI/SNF alteration broadly associated with worse survival. SMARCA4mt is associated with particularly short survival in KRASmt tumors. These data suggest underlying biology which may inform further investigation and therapeutic development.