DNA Damage Response and Repair Pathway Alteration and Its Association With Tumor Mutation Burden and Platinum-Based Chemotherapy in SCLC

Abstract

Introduction: Impairment in DNA damage response and repair (DDR) pathway is known as a predictive biomarker of platinum sensitivity. Recently, DDR alteration is re-emphasized as a predictive biomarker of immune checkpoint inhibitor due to its positive correlation to tumor mutation burden (TMB).

Methods: Target gene sequencing (381 genes) was conducted from 100 extensive disease (ED) and 66 limited disease (LD) patients with SCLC. Detected mutations were classified as double-strand breaks (DSB) (n = 82): homologous recombination (n = 54), non-homologous end joining (n = 19), and Fanconi anemia (n = 32); or single-strand breaks (SSB) (n = 31): mismatch repair (n = 19), base excision repair (n = 7), and nucleotide excision repair (n = 6).

Results: Compared to patients with an intact DDR pathway (n = 70), a higher TMB was observed in patients with homologous recombination (p < 0.001), non-homologous end joining (p = 0.002), mismatch repair (p < 0.001), DSB (p < 0.001), and SSB (p < 0.001). Survival analyses based on TMB level showed no predictive or prognostic values in ED patients. In LD patients, prolonged progression-free survival (hazard ratio [HR] = 0.497, p = 0.015), and overall survival (HR = 0.383, p = 0.010) to concurrent chemoradiotherapy were observed in those with TMB above median. Individual DDR pathway alteration showed no survival benefit in ED patients receiving platinum-based chemotherapy. In LD patients, those with mutations in the Fanconi anemia gene set had shorter progression-free survival (HR = 2.048, p = 0.036) to initial treatment.

Conclusions: DDR pathway alterations, both DSB and SSB, in SCLC have a positive correlation with high TMB. However, it has shown limited value in prediction of platinum efficacy.

Keywords: DNA damage response; Platinum compound; SCLC; Tumor mutation burden.