Turnbull C, Achatz M I, Balmaña J, Castro E, Curigliano G, Cybulski C, Domchek S M, Evans D G, Hanson H, Hoogerbrugge N, James P A, Krause A, Nathanson K L, Ngeow Yuen Yie J, Robson M, Tischkowitz M, Westphalen B, Foulkes W D
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil.
Ann Oncol. 2025 Aug;36(8):853-865. doi: 10.1016/j.annonc.2025.04.012. Epub 2025 Jun 15.
With widening therapeutic indications, germline genetic testing is offered to an increasing proportion of patients with breast cancer (BC) via mainstream oncology services. However, the gene set tested varies widely from just BRCA1/BRCA2 through to 'pan-cancer' panels of nearly 100 genes. If a germline pathogenic variant (GPV) is detected, the BC proband and other family GPV-carriers may be offered interventions such as risk-reducing surgery and intensive surveillance over decades for the various cancers linked to that gene.
The European Society for Medical Oncology (ESMO) Precision Oncology Working Group established an international expert working group (EWG) in BC germline genetics. This EWG firstly established a framework of criteria by which to evaluate each breast cancer susceptibility gene (BCSG) for potential inclusion on a breast cancer multigene panel test (BC-MGPT) for universal mainstream testing for BC cases. Next, the EWG scored BCSGs for impact regarding (i) BC risk estimation, (ii) clinical actionability and (iii) cancer-related mortality.
The group agreed that they would constitute a BC-MGPT based on net clinical-public health utility, as quantified by likelihood of impact on cancer-related mortality. Judged as of high or moderate impact on this basis were six BCSGs: BRCA1, BRCA2, PALB2, RAD51C, RAD51D and TP53 (for BC diagnosed <40 years of age), with possible addition of BRIP1. While potentially informative for BC risk estimation, CHEK2 and ATM were judged to offer insufficient evidence for improving cancer-related mortality. The EWG recommended strongly against inclusion of 'syndromic' genes such as STK11, PTEN, NF1 and CDH1.
With expanded germline testing in patients with BC (and cascade testing into families), the number and nature of resultant GPV-carriers identified will be dictated by the genes included on the upfront BC-MGPT. The potential harms, opportunity and economic costs of decades of surveillance of multiple organs and risk-reducing surgeries for GPV-carriers should be justified by strong evidence of meaningful improvement in cancer-related mortality (or health-related quality of life).
随着治疗适应证的不断扩大，通过主流肿瘤服务为越来越多的乳腺癌（BC）患者提供种系基因检测。然而，检测的基因组合差异很大，从仅检测BRCA1/BRCA2到检测近100个基因的“泛癌”基因 panel。如果检测到种系致病变异（GPV），BC先证者和其他家族GPV携带者可能会接受诸如降低风险手术和针对与该基因相关的各种癌症进行数十年的强化监测等干预措施。
欧洲医学肿瘤学会（ESMO）精准肿瘤学工作组成立了一个BC种系遗传学国际专家工作组（EWG）。该EWG首先建立了一个标准框架，用于评估每个乳腺癌易感基因（BCSG）是否有可能纳入乳腺癌多基因panel检测（BC-MGPT），以用于BC病例的通用主流检测。接下来，EWG对BCSG在以下方面的影响进行评分：（i）BC风险估计，（ii）临床可操作性，以及（iii）癌症相关死亡率。
该小组一致认为，他们将根据对癌症相关死亡率的影响可能性所量化的净临床-公共卫生效用，构建一个BC-MGPT。在此基础上，六个BCSG被判定具有高或中度影响：BRCA1、BRCA2、PALB2、RAD51C、RAD51D和TP53（对于40岁之前诊断的BC），可能还会加入BRIP1。虽然CHEK2和ATM对BC风险估计可能有参考价值，但被判定为提供的改善癌症相关死亡率的证据不足。EWG强烈建议不要纳入诸如STK11、PTEN、NF1和CDH1等“综合征”基因。
随着BC患者种系检测的扩大（以及向家族的级联检测），所识别的GPV携带者的数量和性质将由前期BC-MGPT中包含的基因决定。对于GPV携带者进行数十年多器官监测和降低风险手术的潜在危害、机会和经济成本，应有确凿证据证明对癌症相关死亡率（或健康相关生活质量）有有意义的改善才能说得通。
