Wang Yanxia, Kong Fancheng, Situ Xiaohua, Yang Tiantian, Sun Tianqi, Xie Zhongpeng, Wang Pingling, Chen Yu, Jiang Neng, Dong Yu, Luo Zhaofan, Ke Zunfu
Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; Molecular Diagnosis and Gene Test Centre, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
Precision Scientific (Beijing) Co., Ltd., Beijing 100080, China.
Drug Resist Updat. 2025 Aug 13;83:101291. doi: 10.1016/j.drup.2025.101291.
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 ), 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 ), with mutations observed in 46.15 % (6/13) of BRCA1/2 versus 72.91 % (183/251) of BRCA1/2 patients. The median HRD score (23) in patients with DNA damage repair (DDR) gene BILOF mutations was notably higher than that in those with non-BILOF mutations in DDR genes (9). HRD-positive patients demonstrated markedly longer progression-free survival (PFS) (median PFS 44.1 months) than HRD-negative patients (median PFS 12.2 months) when the patients received first-line platinum-based adjuvant treatment (P = 0.035). Specifically, patients with BRCA1/2 BILOF exhibited a substantial clinical benefit from platinum therapy, with none of these patients experiencing disease progression or death during follow-up.
BRCA1/2 BILOF plays a crucial role in identifying PDAC patients for first-line platinum-based adjuvant treatment, and HRD positive status, defined by BRCA1/2 BILOF and/or an HRD score ≥ 42, broadens the pool of eligible patients, and helps avoid ineffective treatment due to intrinsic drug resistance.
胰腺导管腺癌（PDAC）仍然是一种治疗选择有限的恶性肿瘤；需要有效的生物标志物来改善其治疗决策。本研究的目的是评估同源重组缺陷（HRD）在评估PDAC对铂类化疗反应中的作用。
对264例诊断为PDAC的患者进行回顾性分析。对肿瘤组织样本进行二代测序（NGS），以评估DNA损伤修复（DDR）基因突变谱和HRD评分。综合HRD评分计算为杂合性缺失（LOH）、端粒等位基因不平衡（TAI）和大规模状态转换（LST）评分的未加权总和。系统分析接受铂类治疗患者的HRD状态与临床结局之间的关联。
将具有BRCA1/2双等位基因功能丧失（BILOF）状态和/或HRD评分≥42的患者预先定义为HRD阳性。根据这一HRD状态定义，264例患者中有4.9%（n = 13）被确定为HRD阳性，与仅使用BRCA1/2 BILOF相比，确定了更广泛的人群（1.9%，n = 5）。与BRCA1/2野生型（BRCA1/2⁺）患者相比，携带BRCA1/2突变（BRCA1/2⁻）的患者在与非同源末端连接（NHEJ）和错配修复（MMR）相关基因中的改变频率较低，BRCA1/2⁻患者中有46.15%（6/13）发生突变，而BRCA1/2⁺患者中有72.91%（183/251）发生突变。DNA损伤修复（DDR）基因BILOF突变患者的HRD评分中位数（23）显著高于DDR基因非BILOF突变患者（9）。当患者接受一线铂类辅助治疗时，HRD阳性患者的无进展生存期（PFS）明显长于HRD阴性患者（PFS中位数44.1个月对PFS中位数12.2个月）（P = 0.035）。具体而言，具有BRCA1/2 BILOF的患者从铂类治疗中获得了显著的临床益处，这些患者在随访期间均未出现疾病进展或死亡。
BRCA1/2 BILOF在识别适合一线铂类辅助治疗的PDAC患者中起关键作用，由BRCA1/2 BILOF和/或HRD评分≥42定义的HRD阳性状态扩大了符合条件的患者群体，并有助于避免因内在耐药性导致的无效治疗。
