Defining homologous recombination deficiency status in pancreatic ductal adenocarcinoma: Clinical implications for evaluating response to platinum chemotherapy

作者：Yanxia Wang, Fan-Cheng Kong, Xiaohua Situ, Tiantian Yang, T. Sun, Zhongpeng Xie, Wang Pingling, Yu Chen, Neng Jiang, Yu Dong, Zhaofan Luo, Zunfu Ke · 发表于：Drug Resistance Updates · 年份：2025 · DOI：10.1016/j.drup.2025.101291 · 被引用次数：2 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、Genetic factors in colorectal cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a daunting malignancy with limited therapeutic options; effective biomarkers are needed to improve its treatment decision-making. The aim of this study is to evaluate the role of homologous recombination deficiency (HRD) in assessing the response to platinum chemotherapy in PDAC. A retrospective analysis was conducted on 264 patients diagnosed with PDAC. Tumor tissue samples were subjected to next-generation sequencing (NGS) to assess DNA damage repair (DDR) gene mutation landscape and HRD score. The integrated HRD score was calculated as the unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transition (LST) scores. The associations between HRD status and clinical outcomes in patients receiving platinum treatment were systematically analyzed. Patients with BRCA1/2 biallelic loss-of-function (BILOF) status and/or an HRD score ≥ 42 were predefined as HRD-positive. According to this HRD status definition, 4.9 % (n = 13) of the 264 patients were identified as HRD-positive, identifying a broader population than using BRCA1/2 BILOF alone (1.9 %, n = 5). Patients with BRCA1/2 mutations ( BRCA1/2 m ), presented a lower frequency of alteration in genes related to non-homologous end joining (NHEJ) and mismatch repair (MMR) genes than those with BRCA1/2 wild-type ( BRCA1/2 wt ), with mutations observed in 46.15 % (6/13) of BRCA1/2 m versus 72.91 % (183/251) of BRCA1/2 wt patients. The ...