Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China.
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China; Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China.
Life Sci. 2020 Nov 15;261:118434. doi: 10.1016/j.lfs.2020.118434. Epub 2020 Sep 14.
Defective DNA repair is one of the most important features of tumors. BRCA1/2 participates in homologous recombination repair as a key tumor suppressor gene. BRCA1/2 mutation is an important biomarker for predicting the sensitivity of platinum salts and Poly (ADP-ribose) polymerase (PARP) inhibitors in breast cancer, ovarian cancer, and other cancers. However, epigenetic modifications and other mutations in homologous recombination repair (HRR) genes can also cause homologous recombination deficiency (HRD). Patients with no BRCA1/2 mutations, but bearing similar molecular phenotypes (BRCAness) can still obtain clinical benefits from treatment with platinum salts or PARP inhibitors. Therefore, an accurate assessment of HRD is essential for the formulation of personalized treatments. However, methods to identify HRD in tumors vary and are controversial. Currently, genomic scar assays have been used in multiple clinical trials to assess patient clinical benefit. This review summarizes the therapeutic effects of platinum salts and PARP inhibitors in breast and ovarian cancer, clarifies the predictive value of genomic scar assays in evaluating the clinical benefit of different patient groups and treatment options, and proposes the limitations and optimization of current HRD scoring methods. Using and optimizing genomic scar assays can help to accurately screen the population with the most benefit, expand the scope of drug application, and make the most suitable clinical decision based on individual differences.
DNA 修复缺陷是肿瘤最重要的特征之一。BRCA1/2 作为关键的肿瘤抑制基因，参与同源重组修复。BRCA1/2 突变是预测乳腺癌、卵巢癌和其他癌症中铂盐和聚（ADP-核糖）聚合酶（PARP）抑制剂敏感性的重要生物标志物。然而，同源重组修复（HRR）基因中的表观遗传修饰和其他突变也可导致同源重组缺陷（HRD）。没有 BRCA1/2 突变但具有类似分子表型（BRCAness）的患者仍可从铂盐或 PARP 抑制剂治疗中获得临床获益。因此，准确评估 HRD 对于制定个体化治疗方案至关重要。然而，肿瘤中 HRD 的鉴定方法存在差异，且颇具争议。目前，基因组疤痕检测已在多项临床试验中用于评估患者的临床获益。本综述总结了铂盐和 PARP 抑制剂在乳腺癌和卵巢癌中的治疗效果，阐明了基因组疤痕检测在评估不同患者群体和治疗方案临床获益中的预测价值，并提出了当前 HRD 评分方法的局限性和优化方案。使用和优化基因组疤痕检测有助于准确筛选获益最大的人群，扩大药物应用范围，并根据个体差异做出最适合的临床决策。
