Incorvaia L, Marchetti C, Brando C, Bazan Russo T D, Bono M, Perez A, Congedo L, Ergasti R, Castellana L, Insalaco L, Contino S, Gristina V, Galvano A, Fanale D, Badalamenti G, Russo A, Scambia G, Bazan V
Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), Section of Medical Oncology, University of Palermo, Palermo, Italy.
Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy.
ESMO Open. 2025 Feb;10(2):104076. doi: 10.1016/j.esmoop.2024.104076. Epub 2025 Jan 22.
Germline pathogenic variants (gPVs) in the breast cancer susceptibility gene 1/2 (BRCA1/2) genes confer high-penetrance susceptibility to breast cancer (BC) and ovarian cancer (OC). Although most female BRCA carriers develop only a single BRCA-associated tumor in their lifetime, a smaller subpopulation is diagnosed with multiple primary tumors (MPTs). The genetic factors influencing this risk remain unclear. Further, in patients with BRCA-mutated tumors, there appears to be a variability in the effectiveness of olaparib treatment.
This real-world, multicenter, observational study aimed to determine whether the location of BRCA gPVs within functional domains (FDs) is associated with the development of MPTs and the magnitude of olaparib benefit. The study population comprised consecutive patients with OC who underwent hereditary cancer genetic testing between May 2015 and March 2023. MPT history was assessed based on mutated genes (BRCA1 or BRCA2) and the location of the PVs within the FDs. Clinical outcomes of olaparib first-line maintenance therapy were evaluated according to BRCA1/2 FD location.
The frequency of MPT history in the overall population was 13.3% (118/882), and 20.4% in the BRCA-mutated subpopulation (68/333; P < 0.001). We observed a significant association between the DNA-binding domain (DBD) FD of BRCA2 and MPT. Specifically, 55.6% of BRCA2-mutated patients with PVs in the DBD had a history of BC as a second tumor. At a median follow-up of 48.5 months (95% confidence interval 10-70 months), the 48-month progression-free survival rates were 100.0% for patients with PVs in DBD, 91.7% for those with PVs in other FDs, and 36.4% for those with PVs in the RAD51-binding domain (RAD51-BD) of BRCA2 (P = 0.01). Results in the BRCA1 cohort were not statistically significant.
The results suggest that the location of PVs within BRCA FDs may influence the onset of multiple tumors and the benefit of olaparib in patients with BRCA-mutated OC. These findings could be relevant for cancer prevention efforts, particularly given the increasing number of cancer survivors. However, further understanding is needed before these results can inform clinical decisions.
乳腺癌易感基因1/2（BRCA1/2）中的胚系致病变异（gPVs）赋予了对乳腺癌（BC）和卵巢癌（OC）的高 penetrance 易感性。尽管大多数携带BRCA的女性在其一生中仅发生一种与BRCA相关的肿瘤，但仍有一小部分亚群被诊断为多发性原发性肿瘤（MPTs）。影响这种风险的遗传因素尚不清楚。此外，在患有BRCA突变肿瘤的患者中，奥拉帕尼治疗的有效性似乎存在差异。
这项真实世界、多中心、观察性研究旨在确定BRCA gPVs在功能域（FDs）内的位置是否与MPTs的发生以及奥拉帕尼获益程度相关。研究人群包括2015年5月至2023年3月期间接受遗传性癌症基因检测的连续性OC患者。根据突变基因（BRCA1或BRCA2）以及PVs在FDs内的位置评估MPT病史。根据BRCA1/2 FD位置评估奥拉帕尼一线维持治疗的临床结局。
总体人群中MPT病史的发生率为13.3%（118/882），在BRCA突变亚群中为20.4%（68/333；P<0.001）。我们观察到BRCA2的DNA结合域（DBD）FD与MPT之间存在显著关联。具体而言，55.6%的DBD中存在PVs的BRCA2突变患者有BC作为第二肿瘤的病史。在中位随访48.5个月（95%置信区间10 - 70个月）时，DBD中存在PVs的患者48个月无进展生存率为100.0%，其他FDs中存在PVs的患者为91.7%，BRCA2的RAD51结合域（RAD51 - BD）中存在PVs的患者为36.4%（P = 0.01）。BRCA1队列的结果无统计学意义。
结果表明，BRCA FDs内PVs的位置可能影响BRCA突变OC患者的多肿瘤发生及奥拉帕尼的获益。这些发现可能与癌症预防工作相关，特别是考虑到癌症幸存者数量不断增加。然而，在这些结果可为临床决策提供依据之前，还需要进一步了解。
