卵巢癌中PARPi一线维持治疗疗效获益异质性的研究

Study on the Heterogeneity of Efficacy Benefit of PARPi First-Line Maintenance Therapy in Ovarian Cancer

摘要: 目的：聚腺苷二磷酸核糖聚合酶抑制剂(PARPi)已成为BRCA突变上皮性卵巢癌患者的一线标准维持治疗方案，显著改善患者预后，但临床实践中发现同为BRCA突变的患者其PARPi疗效存在异质性。本研究旨在分析BRCA1/2基因突变特征，建立基于BRCA功能结构域的新分组，评估不同分层下患者的PFS获益，识别优势获益人群。方法：在一项对787例上皮性卵巢癌患者的单中心、回顾性研究中，筛选出由211例FIGO II~IV期且携带BRCA1/2致病或可能致病突变的患者作为核心队列用于疗效分析。基于突变所在的功能结构域将患者划分为3个核心结构亚组(Group A~C)，采用Kaplan‑Meier法评估预后。结果：PARPi显著改善了核心队列的总体PFS (HR = 0.28, P < 0.001)，中位随访时间为34.4个月，PARPi治疗组的中位PFS为59.4个月，而非PARPi组为24.4个月(HR = 0.28; 95% CI, 0.17~0.44; P < 0.001)。PAPRi疗效在BRCA1/2、外显子11位置、胚系体系间未显示统计学差异。错义突变获益尤为突出(HR, 0.06; P = 0.010)；位于BRCA2 RAD51结合域的突变显示出最强的治疗获益(HR, 0.08; P = 0.002)。本研究建立的新分组结果显示，Group C组获益最大(HR = 0.10, P < 0.001)，Group A的获益未达统计学显著性(P = 0.132)。结论：BRCA突变卵巢癌患者对一线PARPi维持治疗普遍获益，但疗效存在显著异质性，这种异质性可能与突变类型及其在功能结构域的位置相关。本研究建立的新分组方法可将患者有效分层识别获益人群，为临床精准化治疗提供了依据。

Abstract: Objective: Poly (ADP-ribose) polymerase inhibitors (PARPi) have become the standard first-line maintenance therapy for patients with BRCA-mutated epithelial ovarian cancer, significantly improving prognosis. However, clinical practice reveals heterogeneity in PARPi efficacy among patients with BRCA mutations. This study aims to analyze the characteristics of BRCA1/2 mutations, establish a novel grouping system based on BRCA functional domains, evaluate progression-free survival (PFS) benefits across different stratifications, and identify populations that derive the greatest benefit. Methods: In a single-center, retrospective study of 787 patients with epithelial ovarian cancer, 211 patients with FIGO stage II~IV disease harboring pathogenic or likely pathogenic BRCA1/2 mutations were selected as the core cohort for efficacy analysis. Based on the functional domain in which the mutation was located, patients were classified into three core structural subgroups (Group A~C). Prognosis was assessed using the Kaplan-Meier method. Results: PARPi significantly improved overall PFS in the core cohort (HR = 0.28, P < 0.001). The median follow-up period was 34.4 months. The median PFS in the PARPi treatment group was 59.4 months, compared to 24.4 months in the non-PARPi group (HR = 0.28; 95% CI, 0.17~0.44; P < 0.001). No statistically significant differences in PARPi efficacy were observed based on BRCA1/2 mutation status, exon 11 location, or germline versus somatic origin. Patients with missense mutations derived particularly pronounced benefit (HR = 0.06; P = 0.010). Mutations located in the RAD51-binding domain of BRCA2 were associated with the greatest treatment benefit (HR = 0.08; P = 0.002). The newly established grouping system revealed that Group C derived the most substantial benefit (HR = 0.10, P < 0.001), whereas the benefit in Group A did not reach statistical significance (P = 0.132). Conclusion: Patients with BRCA-mutated ovarian cancer generally benefit from first-line PARPi maintenance therapy, but significant heterogeneity in efficacy exists, potentially related to mutation type and its location within functional domains. The novel grouping system established in this study effectively stratifies patients and identifies those who derive the greatest benefit, providing a basis for precision treatment in clinical practice.