Contribution of DNA damage repair gene mutations and concomitant TP53 variations to the efficacy of platinum-based chemotherapy as initial therapeutic option in Chinese NSCLC patients.

Abstract

e21002 Background: Though targeted, immune-, even combinational therapies have been applied widely, platinum-based chemotherapy still plays irreplaceable role as initial management for patient with either resected or advanced NSCLC without actionable target. Platinum is sought to increase DNA damage burden inducing cell death, especially in cells with intrinsic DNA damage repair (DDR) dysfunction. This study aims to explore impact of DDR genes as well as co-occurrence of TP53 mutations on prognosis of NSCLC patients. Methods: 110 NSCLC patients were consecutively recruited from 2016-2018. 508 cancer related genes were sequenced by BGI-seq 500. COX regression was used to evaluate risk of disease progression as well as cancer-related death among patients with various DDR/TP53 status. Results: 61 NSCLC patients with stage II-IV (median age of onset: 55 years) were recruited who received platinum-based therapy as adjuvant or 1st line systemic therapy. Till 15th.Oct.2019, median follow-up time was 24 months. 21 patients (34.4% of 61) carried DDR mutations. TP53 mutations were detected in 36 patients (59% of 61). 11 patients (18% of 61) displayed TP53/DDR co-mutations. COX regression analysis indicated NSCLC patients with DDR mutation would have lower risk of disease progression (HR:0.37, P = 0.19) as well as superior overall survival time (HR:0.35, P = 0.035). Patients with DDR co-mutations had no superior survival benefit. Patients with HRR mutations presented similar result. Patients with TP53 mutations had similar risk as ones with other mutations. While those with DDR concomitant mutations showed significantly improved clinical benefit (HR for PFS:0.28, P = 0.05; HR for OS:0.22, P = 0.023). Conclusions: DNA damage repair genes in Chinese NSCLC patients may play vital roles in predicting efficacy of platinum-based chemotherapy even in the context of TP53 co-mutation. Further, combination of BRCA2 and PALB2 may be better associated with patients’ prognosis. Large cohort should be set up to validate this finding in near future. [Table: see text]