DataSheet_1_Germline DNA damage response gene mutations as predictive biomarkers of immune checkpoint inhibitor efficacy.docx

BackgroundImpaired DNA damage response (DDR) can affect immune checkpoint inhibitors (ICI) efficacy and lead to heightened immune activation. We assessed the impact of pathogenic or likely pathogenic (P/LP) germline DDR mutations on ICI response and toxicity.
Materials and methodsA retrospective analysis of 131 cancer patients with germline DNA testing and ICI treatment was performed.
ResultsNinety-two patients were DDR-negative (DDR-), and 39 had ≥1 DDR mutation (DDR+). DDR+ patients showed higher objective response rates (ORRs) compared to DDR- in univariate and multivariable analyses, adjusting for age and metastatic disease (62% vs. 23%, unadjusted OR = 5.41; 95% CI, 2.41-12.14; adjusted OR 5.94; 95% CI, 2.35-15.06). Similar results were seen in mismatch repair (MMR), DDR pathways with intact MMR (DDR+MMRi), and homologous recombination (HR) subgroups versus DDR- (adjusted OR MMR = 24.52; 95% CI 2.72-221.38, DDR+MMRi = 4.26; 95% CI, 1.57-11.59, HR = 4.74; 95% CI, 1.49-15.11). DDR+ patients also had higher ORRs with concurrent chemotherapy (82% vs. 39% DDR-, p=0.03) or concurrent tyrosine kinase inhibitors (50% vs. 5% DDR-, p=0.03). No significant differences in immune-related adverse events were observed between DDR+ and DDR- cohorts.
ConclusionP/LP germline DDR mutations may enhance ICI response without significant additional toxicity.

研究背景：DNA损伤反应（DNA damage response, DDR）受损可影响免疫检查点抑制剂（immune checkpoint inhibitors, ICI）的疗效，并导致免疫激活增强。本研究旨在评估致病性或可能致病性（pathogenic or likely pathogenic, P/LP）种系DDR突变对ICI治疗应答及毒性的影响。材料与方法：本研究对131例接受种系DNA检测且接受ICI治疗的癌症患者开展了回顾性分析。结果：本研究纳入的131例癌症患者中，92例为DDR阴性（DDR-），39例携带至少1项DDR突变（DDR+）。单因素及校正年龄、转移性疾病因素的多因素分析结果显示，DDR+患者的客观缓解率（objective response rate, ORR）显著高于DDR-患者（62% vs 23%，未校正比值比[OR]=5.41，95%置信区间[CI]：2.41~12.14；校正OR=5.94，95%CI：2.35~15.06）。在错配修复（mismatch repair, MMR）、错配修复完整的DDR通路（DDR+MMRi）及同源重组（homologous recombination, HR）亚组中，同样观察到DDR+患者的ORR优于DDR-患者的结果（校正OR：MMR组为24.52，95%CI：2.72~221.38；DDR+MMRi组为4.26，95%CI：1.57~11.59；HR组为4.74，95%CI：1.49~15.11）。此外，DDR+患者在同步化疗（82% vs DDR-组39%，p=0.03）或同步酪氨酸激酶抑制剂治疗（50% vs DDR-组5%，p=0.03）时的ORR同样更高。DDR+与DDR-队列的免疫相关不良事件发生率无显著差异。结论：P/LP种系DDR突变可增强ICI治疗应答，且不会带来显著的额外毒性。