源于携带生殖系BRCA1和BRCA2致病性变异体（PV）的乳腺癌（BCs）长期以来被认为是无法区分的生物学和临床实体。然而，BRCA1或BRCA2蛋白的功能丧失对于肿瘤细胞对雌激素受体信号和肿瘤微环境组成具有不同的后果。在这里，我们回顾积累的临床前研究和临床数据表明，BRCA1或BRCA2失活可能不同程度地影响BC对标准全身治疗的敏感性。基于BRCA1或BRCA2与ER通路之间不同的相互作用，BRCA2突变的激素受体阳性、HER2阴性晚期BC可能对内分泌治疗（ET）加CDK 4/6抑制剂（CDK 4/6i）的敏感性较低，而BRCA2突变的三阴性乳腺癌（TNBC）可能对免疫检查点抑制剂特别敏感。如果在未来的前瞻性研究中得到验证，这些数据可能具有相关的临床意义，从而在携带BRCA1或BRCA2的患者中建立不同的治疗途径。版权所有 © 2023。Elsevier B.V.出版。

Breast cancers (BCs) arising in carriers of germline BRCA1 and BRCA2 pathogenic variants (PV) have long been considered as indistinguishable biological and clinical entities. However, the loss of function of BRCA1 or BRCA2 proteins has different consequences in terms of tumor cell reliance on estrogen receptor signaling and tumor microenvironment composition. Here, we review accumulating preclinical and clinical data indicating that BRCA1 or BRCA2 inactivation may differentially affect BC sensitivity to standard systemic therapies. Based on a different crosstalk between BRCA1 or BRCA2 and the ER pathway, BRCA2-mutated Hormone Receptor-positive, HER2-negative advanced BC may be less sensitive to endocrine therapy (ET) plus CDK 4/6 inhibitors (CDK 4/6i), whereas BRCA2-mutated triple-negative breast cancer (TNBC) may be especially sensitive to immune checkpoint inhibitors. If validated in future prospective studies, these data may have relevant clinical implications, thus establishing different treatment paths in patients with BRCA1 or BRCA2.Copyright © 2023. Published by Elsevier B.V.