A neoadjuvant phase II/III RCT for BRCA1/2-associated and familial triple negative breast cancer comparing carboplatin to docetaxel (neoFAM)

来自BRCA 1或BRCA 2基因突变的高危家族的乳腺癌患者，其乳腺癌的终生风险约为60%，卵巢癌的终生风险为20-40%。体外和回顾性体内研究（也来自我们自己的研究组）中有越来越多的证据表明，与抗微管蛋白药物（例如多西他赛）相比，BRCA相关乳腺癌对DNA嵌入物质（例如卡铂）表现出优先治疗反应。这在功能上可以解释为BRCA基因参与DNA双链修复，导致BRCA阴性细胞的同源重组缺陷和对DNA嵌入药物的脆弱性。三阴性乳腺癌（TNBC）具有BRCA 1样表型，通常与较短的无病生存期和总生存期相关，目前占所有乳腺癌的15-20%和乳腺癌相关死亡的25%。因此，大多数TNBC可能受益于DNA嵌入药物的治疗。在这一迄今为止的首次新辅助随机对照试验中，我们希望回答以下问题：对于BRCA相关乳腺癌和家族性TNBC，基于铂类的化疗是否上级基于紫杉烷的化疗？作为一个新的方面，我们想验证BRCAness和新辅助治疗疗效的五个生物标志物。本研究也可作为散发性乳腺癌（具有BRCAness表型）和其他靶向药物（例如PARP抑制剂）的概念验证研究。

Breast cancer patients from high risk families with mutations in the BRCA1 or BRCA2 gene have a lifetime risk of about 60% for breast cancer and 20-40% for ovarian cancer. There is accumulating evidence from in vitro and retrospective in vivo studies, also from our own group, that BRCA-associated breast cancer exhibit preferential treatment response to DNA-intercalating substances (e.g. carboplatin) compared to antimicrotubulin agents (e.g. docetaxel). This can be functionally explained by the involvement of the BRCA genes in DNA double-strand repair that lead to homologous recombination deficiency in BRCA-negative cells and vulnerability to DNA-intercalating drugs. Triple-negative breast cancers (TNBC) share a BRCA1-like phenotype and are generally associated with shorter disease free and overall survival and currently account for 15-20% of all breast cancers and 25% of breast cancer-related deaths. Therefore the majority of TNBC might benefit from treatment with DNA-intercalating drugs. In such a hitherto first neoadjuvant randomised controlled trial we want to answer the following question: Is a platinum-based chemotherapy superior over a taxane-based chemotherapy for BRCA-associated breast cancer and familial TNBC? As a novel aspect we want to validate five biomarkers for BRCAness and neoadjuvant treatment efficacy. This study may also serve as a proof of concept study for sporadic breast cancers that present with a BRCAness phenotype and other targeted agents (e.g. PARP inhibitors).