Premnath Naveen, O'Reilly Eileen M
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Chin Clin Oncol. 2020 Oct;9(5):64. doi: 10.21037/cco-2019-ddp-05. Epub 2020 Aug 10.
BReast CAncer (BRCA) genes 1 and 2 were discovered in the 1990's by Hall et al. and Wooster et al. respectively. BRCA genes have been shown to be associated with an increased risk of various gastrointestinal (GI) cancers beyond known risk of breast, ovary and prostate cancers. Studies have demonstrated the role of BRCA genes in the DNA repair pathway and modalities to exploit this pathway are being currently explored. Using the concept of synthetic lethality, poly-ADP ribose polymerase inhibitors (PARPi) have significant activity in BRCA deficient cells. Targeted therapy is gaining popularity worldwide and BRCA genes have received much attention since the development and approval of PARPis. Multiple studies have also identified the predictive value of BRCA genes related to platinum and other DNA-damaging cytotoxic agents. BRCA deficient cells are about 5-fold more sensitive to platinum-based agents and almost 1,000-fold more with PARPis. Genomic instability has been established as the hallmark of BRCA deficient tumors and the specific roles of BRCA genes in DNA damage repair is increasingly clear. Herein, we discuss the risks and incidence of individual GI cancers seen with BRCA mutations, highlight tumor biology and provide a comprehensive review of the available preclinical and clinical data and upcoming trials related to this topic. The "POLO" trial in metastatic pancreas cancer establishes a "proof of principle" regarding treatment of BRCA-related cancer and PARPi. In pancreatic cancer routine germline genetic testing is now recommended in most major guidelines. Newer studies are emerging, which will expand the concept of BRCAness and ways to effectively detect this phenotype in GI cancers and impact clinical practice.
乳腺癌（BRCA）1和2基因分别于20世纪90年代由霍尔等人和伍斯特等人发现。已表明BRCA基因除了与已知的乳腺癌、卵巢癌和前列腺癌风险增加相关外，还与各种胃肠道（GI）癌症风险增加有关。研究已经证明了BRCA基因在DNA修复途径中的作用，目前正在探索利用该途径的方式。利用合成致死的概念，聚-ADP核糖聚合酶抑制剂（PARPi）在BRCA缺陷细胞中具有显著活性。靶向治疗在全球范围内越来越受欢迎，自PARPis开发和批准以来，BRCA基因受到了广泛关注。多项研究还确定了BRCA基因与铂和其他DNA损伤细胞毒性药物相关的预测价值。BRCA缺陷细胞对铂类药物的敏感性大约高5倍，对PARPis的敏感性几乎高1000倍。基因组不稳定性已被确立为BRCA缺陷肿瘤的标志，BRCA基因在DNA损伤修复中的具体作用越来越清晰。在此，我们讨论了BRCA突变患者中各类胃肠道癌症的风险和发病率，强调了肿瘤生物学，并对现有的临床前和临床数据以及与此主题相关的即将开展的试验进行了全面综述。转移性胰腺癌的“POLO”试验确立了关于BRCA相关癌症和PARPi治疗的“原理证明”。在胰腺癌中，现在大多数主要指南都建议进行常规种系基因检测。新的研究正在涌现，这将扩展BRCAness的概念以及在胃肠道癌症中有效检测这种表型的方法，并影响临床实践。
