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

来自BRCA1或BRCA2基因突变的高危家族的乳腺癌患者一生患乳腺癌的风险约为60%，患卵巢癌的风险约为20%-40%。越来越多的体外和体内回顾性研究表明，与抗微管蛋白药物(如多西紫杉醇)相比，BRCA相关乳腺癌对DNA嵌入物(如卡铂)的治疗反应更好。这可以通过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嵌入药物的易感性来解释。三阴性乳腺癌(TNBC)具有类似BRCA1的表型，通常与较短的无病和总生存期有关，目前占所有乳腺癌的15%-20%，占乳腺癌相关死亡的25%。因此，大多数TNBC可能受益于DNA嵌入药物的治疗。在这项迄今为止首个新辅助随机对照试验中，我们想要回答以下问题：对于BRCA相关乳腺癌和家族性TNBC，以铂为基础的化疗是否优于以紫杉烷为基础的化疗？作为一个新的方面，我们想要验证五个生物标记物的BRCACESS和新辅助治疗的疗效。这项研究还可以作为散发性乳腺癌的概念验证研究，这些乳腺癌表现为BRCAness表型和其他靶向药物(例如PARP抑制剂)。

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).