DNA damage and repair (DDR) gene mutation profiles in driver gene wild-type advanced non-small cell lung cancer and the predictive role of response to platinum-based chemotherapy.

Background: Platinum-based chemotherapy is an important therapeutic approach for patients with advanced non-small cell lung cancer (NSCLC) without driver gene mutations. DNA damage and repair (DDR) gene can mitigate platinum-induced DNA damage and induce resistance to platinum agents. The status of DDR gene in advanced driver gene wild-type NSCLC and their role in determining response and prognosis to platinum-based chemotherapy need to be investigated. This study used next-generation sequencing (NGS) to detect the mutation status of 47 DDR genes in seven DDR signaling pathways in driver gene wild-type NSCLC patients and to investigate their association with cisplatin-based chemotherapy.

Methods: From November 2016 to September 2021, 182 cases of treatment-naïve patients with advanced driver gene wild-type NSCLC were prospectively studied. Either tumor tissue or serum circulating tumor DNA (ctDNA) was used to assess the status of 47 DDR gene using NGS. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). The DDR mutation was analyzed in relation to response to platinum-based chemotherapy and clinical outcomes.

Results: There were 136 of 182 patients who received first-line platinum-based chemotherapy included. DDR mutations from 101 NSCLC patients were sequenced and analyzed. The median follow-up time was 17.6 (interquartile range, 15.4-19.8) months. There were 66.33% of patients in this cohort having a DDR gene mutation. When treated with first-line platinum-based chemotherapy, the ORR of DDR-mutant (DDRmut) patients was significantly higher than that of DDR-wild type (DDRwt) patients (52.2% vs. 23.5%, P<0.001). In addition, DDRmut patients experienced longer PFS (6.30 vs. 3.30 months, P<0.001) and improved OS (16.80 vs. 9.40 months, P=0.007).

Conclusions: There was a high prevalence of DDR mutation in advanced NSCLC harboring wild-type epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 (ROS1). DDR deficiency, manifested by an alteration in 47-gene DDR panel readout, is a favorable predictive biomarker for first-line platinum-based chemotherapy in patients with advanced NSCLC.