同源重组缺陷 (HRD) 肿瘤对铂类化疗极其敏感，与放疗联合使用可提高多种癌症类型的总体生存率。具有独特分子特征的肿瘤子集是否表现出顺铂和放疗 (c-RT) 的获益增加尚不清楚。我们假设 HRD 肿瘤，无论是与 BRCA 突变还是与 HRD 的基因组疤痕相关，都对 c-RT 表现出极高的敏感性，并且 HRD 可能是 c-RT 获益的重要驱动因素。使用等基因和散发性检查对 c-RT 的敏感性乳腺癌细胞系。 HRD 使用四种测定进行评估：RT 诱导的 Rad51 灶、DR-GFP 报告基因测定、基因组疤痕（大规模状态转换，LST）和克隆生存测定（CSA）。对来自三阴性乳腺癌 (TNBC) 新辅助 c-RT 2 期临床试验的 4 个乳腺肿瘤进行全基因组测序，并利用 HRDetect 定义 HRD。BRCA1/2 缺陷细胞系基于 Rad51 功能测定显示功能性 HRD，对于 2uM 顺铂和 6Gy 的 BRCA1 同基因对，c-RT 与 RT 或顺铂相互作用比 (IR) 分别为 1.11 和 26.84。最高的 LST 系表现出 HRD 和对 c-RT 的合成细胞毒性，IR 为 2Gy，顺铂 20uM 为 7.50，最低的 LST 系的 IR 为 0.65。在 2 期试验的 4 名可评估患者中，与没有 pCR.HRD 乳腺癌的患者相比，无论是否通过 BRCA1/2 突变识别，根据包括 HRDetect 和 LST 评分在内的多个基因组疤痕评分，1 名患者实现了具有相应 HRD 的病理完全缓解 (pCR)与同基因对照或没有 HRD 突变特征的肿瘤相比，状态、功能测试或突变特征似乎对 c-RT 更加敏感。 HRD 肿瘤可能对 c-RT 极其敏感，需要进一步的临床研究来指导精准肿瘤学方法。版权所有 © 2024。由 Elsevier Inc. 出版。

Homologous recombination deficient (HRD) tumors are exquisitely sensitive to platinum-based chemotherapy and when combined with RT, leads to improved overall survival in multiple cancer types. Whether a subset of tumors with distinct molecular characteristics demonstrate increased benefit from cisplatin and RT (c-RT) is unclear. We hypothesized that HRD tumors, whether associated with BRCA mutations or genomic scars of HRD, exhibit exquisite sensitivity to c-RT, and that HRD may be a significant driver of c-RT benefit.Sensitivity to c-RT was examined using isogenic and sporadic breast cancer cell lines. HRD was assessed using four assays: RT-induced Rad51 foci, a DR-GFP reporter assay, a genomic scar (large scale state transitions, LST), and clonogenic survival assays (CSA). Whole genome sequencing of 4 breast tumors from a phase 2 clinical trial of neoadjuvant c-RT in triple negative breast cancer (TNBC) was performed and defined HRD utilizing HRDetect.BRCA1/2 deficient cell lines displayed functional HRD based on the Rad51 functional assay, with c-RT to RT or cisplatin interaction ratios (IR) of 1.11 and 26.84 for the BRCA1 isogenic pair at 2uM Cisplatin and 6Gy, respectively. The highest LST lines demonstrated HRD and synthetic cytotoxicity to c-RT with IR at 2Gy and Cisplatin 20uM of 7.50, and the lowest LST line with IR of 0.65. Of 4 evaluable patients on the Phase 2 trial, one achieved pathologic complete response (pCR) with corresponding HRD based on multiple genomic scar scores including HRDetect and LST scores, compared with patients without pCR.HRD breast cancers, whether identified by BRCA1/2 mutation status, functional tests or mutational signatures, appear to be significantly more sensitive to c-RT compared to isogenic controls or tumors without HRD mutational signature. HRD tumors may be exquisitely sensitive to c-RT and warrants further clinical investigation to guide a precision oncology approach.Copyright © 2024. Published by Elsevier Inc.