Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Br J Cancer. 2024 Nov;131(9):1400-1414. doi: 10.1038/s41416-024-02827-z. Epub 2024 Aug 30.
Mutations in the BRCA1 and/or BRCA2 genes (BRCAm) increase the risk of developing breast cancer (BC) and are found in ~5% of unselected patients with the disease. BC resulting from a germline BRCAm (gBRCAm) has distinct clinical characteristics along with increased sensitivity to DNA-damaging agents such as poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies, and potentially decreased sensitivity to cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. Given the evolving treatment landscape for gBRCAm BC in early and advanced disease settings, timely determination of gBRCAm status is fundamental to facilitate the most effective treatment strategy for patients. However, many patients with gBRCAm are not identified due to suboptimal referral rates and/or a low uptake of genetic testing. We discuss current evidence for a differential response to treatment in patients with gBRCAm in early and advanced BC settings, including outcomes with PARP inhibitors, platinum-based chemotherapies, and CDK4/6 inhibitors, as well as ongoing treatment innovations and the potential of these treatment approaches. Current genetic testing strategies are also examined, including the latest guidelines on who and when to test for gBRCAm, as well as challenges to testing and how these may be overcome.
BRCA1 和/或 BRCA2 基因（BRCAm）的突变会增加患乳腺癌（BC）的风险，在未经选择的患者中，约有 5%存在该疾病。源自种系 BRCAm（gBRCAm）的 BC 具有独特的临床特征，并且对 DNA 损伤剂（如聚（ADP-核糖）聚合酶（PARP）抑制剂和铂类化疗药物）的敏感性增加，对细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂的敏感性降低。鉴于 gBRCAm BC 在早期和晚期疾病治疗中的治疗格局不断发展，及时确定 gBRCAm 状态对于为患者提供最有效的治疗策略至关重要。然而，由于转诊率不理想和/或遗传检测的接受率低，许多 gBRCAm 患者未被识别。我们讨论了 gBRCAm 在早期和晚期 BC 环境中治疗反应的差异的现有证据，包括 PARP 抑制剂、铂类化疗药物和 CDK4/6 抑制剂的治疗结果，以及正在进行的治疗创新和这些治疗方法的潜力。还检查了当前的遗传检测策略，包括关于谁以及何时进行 gBRCAm 检测的最新指南，以及检测的挑战以及如何克服这些挑战。
