Rodriguez-Hernandez A, Martínez-Sáez O, Brasó-Maristany F, Conte B, Gómez R, García-Fructuoso I, Fratini B, Segui E, Potrony M, Sanfeliu E, Cobo S, Galvan P, Moreno L, Grau E, Aceituno M R, Puig-Butille J A, Oriola J, Goberna G, Blasco P, Castillo O, Sirenko V, Aguirre A, Vidal M, Muñoz M, Ramon Y Cajal T, Balaguer F, Prat A, Adamo B
Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain; Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Facultat de Medicina i Ciències de la Salud, Universitat de Barcelona (UB), Barcelona, Spain. Electronic address: https://twitter.com/AdelaRodrguezH1.
Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain; Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Facultat de Medicina i Ciències de la Salud, Universitat de Barcelona (UB), Barcelona, Spain; SOLTI Cooperative Group, Barcelona, Spain.
ESMO Open. 2025 Apr;10(4):104543. doi: 10.1016/j.esmoop.2025.104543. Epub 2025 Apr 9.
Germline (likely) pathogenic variants (PVs) are identified in 5%-10% of patients with breast cancer (BC) and play a critical role in guiding clinical management, including the use of targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). High-risk genes such as BRCA1, BRCA2, and PALB2, and moderate-risk genes such as CHEK2 and ATM, influence BC risk and treatment decisions. This study evaluates the prevalence and clinical impact of PVs in a large consecutive cohort.
A retrospective analysis was conducted on 912 individuals with BC who underwent germline testing at the Hospital Clinic of Barcelona from 2016 to 2023. Genetic testing for 14 BC and Lynch syndrome genes was carried out using the TruSight Hereditary Cancer Panel. Statistical analyses were carried out to assess associations between germline results and clinical characteristics, including eligibility for PARPi therapy.
Of the 912 individuals, 129 (14.1%) had a PV, with BRCA2 (31.8%) and BRCA1 (24%) being the most frequently altered genes. Additionally, 16.2% carried variants of uncertain significance, most commonly in ATM and BRCA2 genes. Patients with PV were younger compared with PV-negative individuals (median age: 43.5 versus 48.2 years, P = 0.006), more likely to have bilateral BC (13.3% versus 5.8%, P = 0.002), and more frequently diagnosed with triple-negative BC (TNBC; 28.7% versus 20.8%, P = 0.046). Of those with PVs, 39.1% completed a bilateral mastectomy, 36.7% had a risk-reducing salpingo-oophorectomy, and 22.7% had both surgeries. PV detection was associated with higher stages at diagnosis (stage IV: 13.0% versus 5.9%, P < 0.001). In the metastatic cohort, 12.9% received PARPi therapy, with 80.7% harboring BRCA1/2 PVs. In early BC, 13.1% met the criteria for adjuvant PARPi.
The identification of germline PVs significantly influences surgical decisions and systemic therapies. Genetic testing for patients with BC optimizes care, particularly in selecting candidates for PARPi in both early and advanced BC, improving management and prevention strategies.
在5%-10%的乳腺癌（BC）患者中可检测到种系（可能）致病变异（PVs），这些变异在指导临床管理方面发挥着关键作用，包括使用聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）等靶向治疗。BRCA1、BRCA2和PALB2等高风险基因，以及CHEK2和ATM等中度风险基因，会影响BC风险和治疗决策。本研究评估了一个大型连续队列中PVs的患病率及其临床影响。
对2016年至2023年在巴塞罗那医院诊所接受种系检测的912例BC患者进行回顾性分析。使用TruSight遗传性癌症检测板对14个BC和林奇综合征基因进行基因检测。进行统计分析以评估种系检测结果与临床特征之间的关联，包括PARPi治疗的适用性。
在912例患者中，129例（14.1%）存在PV，其中BRCA2（31.8%）和BRCA1（24%）是最常发生改变的基因。此外，16.2%携带意义未明的变异，最常见于ATM和BRCA2基因。与PV阴性个体相比，PV阳性患者更年轻（中位年龄：43.5岁对48.2岁，P = 0.006），更易发生双侧BC（13.3%对5.8%，P = 0.002），且更常被诊断为三阴性BC（TNBC；28.7%对20.8%，P = 0.046）。在PV阳性患者中，39.1%完成了双侧乳房切除术，36.7%进行了降低风险的输卵管卵巢切除术，22.7%进行了这两种手术。PV检测与诊断时更高的分期相关（IV期：13.0%对5.9%，P < 0.001）。在转移性队列中，12.9%接受了PARPi治疗，其中80.7%携带BRCA1/2 PVs。在早期BC中，13.1%符合辅助PARPi的标准。
种系PVs的鉴定对手术决策和全身治疗有显著影响。对BC患者进行基因检测可优化治疗，特别是在为早期和晚期BC患者选择PARPi候选者时，改善管理和预防策略。
