Background: The location of BRCA mutations within functional domains may affect sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. This study aimed to evaluate the progression-free survival (PFS) benefit from the PARP inhibitor in relation to the location of mutations inBRCA1/BRCA2in newly diagnosed ovarian cancer. Materials and methods: Patients with advanced stage III-IV epithelial ovarian cancer who had deleteriousBRCA1orBRCA2were analyzed. PFS and clinical and molecular data were compared between patients who received olaparib or niraparib as frontline maintenance therapy and those who did not. Subgroup analyses were conducted based on the location ofBRCAmutations within the functional domain or the ovarian cancer cluster region (OCCR). Results: Of the 380 patients, 242 (63.7%) harboredBRCA1mutation, 137 (36.1%) harboredBRCA2, and one (0.3%) harbored bothBRCA1andBRCA2. With a median follow-up of 35.8 months, the DNA binding domain inBRCA1(HR, 0.34; 95% CI, 0.15–0.79;p= 0.01) andBRCA2(HR, 0.25; 95% CI, 0.08–0.78;p= 0.01) demonstrated particularly significant benefit. In patients who harboredBRCA1mutation in the C-terminal domain (BRCT), no statistically significant PFS benefit from PARP inhibitor was observed (HR, 0.76; 95% CI, 0.39–1.52;p= 0.44). PFS benefit from PARP inhibitor maintenance was observed in both OCCR (HR, 0.49; 95% CI, 0.32–0.74;p< 0.01) and non-OCCR (HR, 0.51; 95% CI, 0.27–0.63;p< 0.01). Conclusions: Frontline PARP inhibitor maintenance therapy demonstrated a significant PFS benefit in patients withBRCA1/2mutations, with particularly pronounced benefits for those with mutations located in the DBD ofBRCA1andBRCA2. However, the benefit was less evident for patients withBRCA1mutations located in the BRCT domain.
背景：BRCA基因突变在功能域内的位置可能影响对聚腺苷二磷酸核糖聚合酶（PARP）抑制剂和铂类化疗的敏感性。本研究旨在评估新诊断卵巢癌患者中，PARP抑制剂带来的无进展生存期（PFS）获益与BRCA1/BRCA2基因突变位置的关系。材料与方法：本研究分析了携带BRCA1或BRCA2有害突变的晚期III-IV期上皮性卵巢癌患者。比较了接受奥拉帕利或尼拉帕利作为一线维持治疗的患者与未接受此类治疗患者的PFS、临床及分子数据。根据BRCA突变位于功能域或卵巢癌聚集区（OCCR）的情况进行了亚组分析。结果：在380例患者中，242例（63.7%）携带BRCA1突变，137例（36.1%）携带BRCA2突变，1例（0.3%）同时携带BRCA1和BRCA2突变。中位随访时间为35.8个月，结果显示，位于BRCA1（HR，0.34；95% CI，0.15–0.79；p=0.01）和BRCA2（HR，0.25；95% CI，0.08–0.78；p=0.01）DNA结合域的突变患者获益尤为显著。对于BRCA1基因C末端结构域（BRCT）突变的患者，未观察到PARP抑制剂带来具有统计学意义的PFS获益（HR，0.76；95% CI，0.39–1.52；p=0.44）。在OCCR（HR，0.49；95% CI，0.32–0.74；p<0.01）和非OCCR（HR，0.51；95% CI，0.27–0.63；p<0.01）突变患者中均观察到PARP抑制剂维持治疗带来的PFS获益。结论：一线PARP抑制剂维持治疗在BRCA1/2突变患者中显示出显著的PFS获益，尤其是对于BRCA1和BRCA2基因DNA结合域突变的患者获益更为明显。然而，对于BRCA1基因BRCT结构域突变的患者，其获益则不甚显著。
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