Tumors arising in BRCA1/2 germline mutation carriers usually demonstrate somatic loss of the remaining BRCA1/2 allele and increased sensitivity to platinum compounds, anthracyclines, mitomycin C and poly (ADP-ribose) polymerase inhibitors (PARPi). Exposure to conventional platinum-based therapy or PARPi results in the restoration of BRCA1/2 function and development of resistance to systemic therapy, therefore, there is a need for other treatment options. Some studies suggested that the use of specific drug combinations or administration of high-dose chemotherapy may result in pronounced tumor responses. BRCA1/2-driven tumors are characterized by increased immunogenicity; promising efficacy of immune therapy has been demonstrated in a number of preclinical and clinical investigations. There are outstanding issues, which require further consideration. Platinum compounds and PARPi have very similar mode of antitumor action and are likely to render cross-resistance to each other, so their optimal position in cancer treatment schemes may be a subject of additional studies. Sporadic tumors with somatically acquired inactivation of BRCA1/2 or related genes resemble hereditary neoplasms with regard to the spectrum of drug sensitivity; the development of user-friendly BRCAness tests presents a challenge. Many therapeutic decisions are now based on the BRCA1/2 status, so the significant reduction of the turn-around time for predictive laboratory assays is of particular importance.

中文翻译：

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BRCA1/2 驱动癌症的细胞毒性和靶向治疗

在 BRCA1/2 种系突变携带者中出现的肿瘤通常表现出剩余 BRCA1/2 等位基因的体细胞丢失以及对铂化合物、蒽环类、丝裂霉素 C 和聚（ADP-核糖）聚合酶抑制剂 (PARPi) 的敏感性增加。暴露于传统的基于铂的治疗或 PARPi 会导致 BRCA1/2 功能的恢复和对全身治疗的抵抗力的发展，因此，需要其他治疗选择。一些研究表明，使用特定的药物组合或给予高剂量化疗可能会导致明显的肿瘤反应。BRCA1/2 驱动的肿瘤的特点是免疫原性增加；许多临床前和临床研究已经证明了免疫疗法的有希望的疗效。有悬而未决的问题，这需要进一步考虑。铂化合物和 PARPi 具有非常相似的抗肿瘤作用模式，并且可能相互产生交叉耐药性，因此它们在癌症治疗方案中的最佳位置可能是进一步研究的主题。BRCA1/2 或相关基因的体细胞获得性失活的散发性肿瘤在药物敏感性谱方面类似于遗传性肿瘤；开发用户友好的 BRCAness 测试提出了挑战。许多治疗决定现在基于 BRCA1/2 状态，因此显着减少预测性实验室检测的周转时间尤为重要。所以他们在癌症治疗方案中的最佳位置可能是额外研究的主题。BRCA1/2 或相关基因的体细胞获得性失活的散发性肿瘤在药物敏感性谱方面类似于遗传性肿瘤；开发用户友好的 BRCAness 测试提出了挑战。许多治疗决定现在基于 BRCA1/2 状态，因此显着减少预测性实验室检测的周转时间尤为重要。所以他们在癌症治疗方案中的最佳位置可能是额外研究的主题。BRCA1/2 或相关基因的体细胞获得性失活的散发性肿瘤在药物敏感性谱方面类似于遗传性肿瘤；开发用户友好的 BRCAness 测试提出了挑战。许多治疗决定现在基于 BRCA1/2 状态，因此显着减少预测性实验室检测的周转时间尤为重要。