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

Abstract

IntroductionImpairment 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). MethodsTarget 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). ResultsCompared 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. ConclusionsDDR 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.