Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study

IF 7.1 2区医学 Q1 ONCOLOGY

ESMO Open Pub Date : 2025-04-01 DOI:10.1016/j.esmoop.2025.104533

C. Marchetti , A. Fagotti , R. Fruscio , C. Cassani , L. Incorvaia , M.T. Perri , C.M. Sassu , C.A. Camnasio , E. Giudice , A. Minucci , M. Seca , E. Arbustini , L. Vertechy , M. De Bonis , S.M. Boccia , D. Giannarelli , V. Salutari , M. Distefano , M.G. Ferrandina , C. Nero , D. Lorusso

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Abstract

Background

Knowledge about the association between the BRCA1/2 mutation type and location and response to poly (ADP-ribose) polymerase inhibitors (PARPis) as single agent in ovarian cancer is limited. This study aimed to investigate the effectiveness of PARPi based on functional domains (FD) [RING, BRCT, DNA-binding (BD), RAD51-BD] and types (frameshift, missense, nonsense, splicing) of BRCA1/2 gene mutations in ovarian cancer.

Materials and methods

This multicenter real-world study retrospectively enrolled BRCA1/2-mutated ovarian cancer patients receiving olaparib maintenance between January 2010 and December 2022. Data were compared with historical series of patients who did not receive olaparib and analyzed based on the FD involved in BRCA1/2 mutations. Progression-free survival was calculated from the date of the last platinum-based treatment until recurrence or last follow-up.

Results

After a median follow-up of 46 months (range 32-60 months), 140 patients who underwent olaparib maintenance were compared with 128 who did not. PARPi showed efficacy in the overall population. The no-exon 11 patients benefitted more from olaparib than exon 11 patients [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.25-0.93]. In the BRCA1 group, patients with mutations in RING and BRCT domains had significant benefits from PARPi (HR 0.08, 95% CI 0.01-0.75; HR 0.10, 95% CI 0.02-0.38, respectively). Among BRCA2-mutated patients, RAD51-BD mutations were associated with higher response to olaparib (HR 0.23, 95% CI 0.10-0.52). According to the mutation type, the major effect of PARPi was in the missense group (HR 0.04, 95% CI 0.01-0.31). No patients with p.(Ala1708Glu) in the BRCT domain (BRCA1) receiving PARPi experienced recurring disease in the study period.

Conclusions

BRCA1/2-mutated patients benefit from olaparib, but with variations according to the mutation type and FDs. BRCA1-mutated patients in the RING or BRCT and BRCA2-mutated in the RAD51-BD have the greatest benefit. Patients with missense mutations, especially those with p.(Ala1708Glu), have the most significant advantage from maintenance with PARPi.

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根据BRCA1/2突变类型和位点，新诊断的卵巢癌患者维持PARP抑制剂的获益：一项多中心现实世界研究

关于BRCA1/2突变类型和位置与卵巢癌患者对聚（adp -核糖）聚合酶抑制剂（PARPis）作为单一药物的反应之间的关系的知识是有限的。本研究旨在基于功能域（FD） [RING、BRCT、dna结合（BD）、RAD51-BD]和BRCA1/2基因突变类型（移码、错义、无义、剪接）来探讨PARPi在卵巢癌中的有效性。材料和方法本多中心真实世界研究回顾性纳入2010年1月至2022年12月期间接受奥拉帕尼维持治疗的brca1 /2突变卵巢癌患者。将数据与未接受奥拉帕尼治疗的患者的历史序列进行比较，并根据BRCA1/2突变相关的FD进行分析。无进展生存期从最后一次铂类药物治疗到复发或最后一次随访计算。结果中位随访46个月（32-60个月）后，140名患者接受了奥拉帕尼维持治疗，128名患者未接受奥拉帕尼维持治疗。PARPi在总体人群中显示出疗效。无外显子11的患者比外显子11的患者从奥拉帕尼中获益更多[风险比（HR） 0.48, 95%可信区间（CI） 0.25-0.93]。在BRCA1组中，RING和BRCT结构域突变的患者从PARPi中获益显著(HR 0.08, 95% CI 0.01-0.75；HR 0.10, 95% CI 0.02-0.38)。在brca2突变的患者中，RAD51-BD突变与对奥拉帕尼的更高反应相关（HR 0.23, 95% CI 0.10-0.52）。根据突变类型，PARPi的主要影响在错义组（HR 0.04, 95% CI 0.01 ~ 0.31）。接受PARPi治疗的BRCT结构域p.(Ala1708Glu) （BRCA1）患者在研究期间没有复发。结论brca1 /2突变患者受益于奥拉帕尼，但根据突变类型和fd存在差异。brca1突变的RING或BRCT和brca2突变的RAD51-BD患者获益最大。带有错义突变的患者，尤其是带有p.（Ala1708Glu）的患者，使用PARPi维持治疗具有最显著的优势。

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来源期刊

ESMO Open Medicine-Oncology

CiteScore

11.70

自引率

2.70%

发文量

255

审稿时长

10 weeks

期刊介绍： ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research. ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO. Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.