ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer
ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer
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DOI：
10.1016/j.annonc.2020.08.2102
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发表时间：
2020-12-01
影响因子：
50.5
通讯作者：
Yates, L. R.
中科院分区：
文献类型：
--
作者：
Miller, R. E.;Leary, A.;Yates, L. R.
背景资料：同源重组修复缺陷（HRD）是高级别浆液性卵巢癌、输卵管癌和腹膜癌（HGSC）的常见特征，与PARP抑制剂（PARPi）治疗敏感性相关。HRD测试提供了一个机会，以优化PARPi的使用HGSC，但方法是多样的，临床应用仍然存在争议。材料和方法：为了定义HGSC的ESMO转化研究和精准医学工作组的HRD测试的最佳实践发起了一个合作项目，纳入了系统的审查方法。主要目的是（一）定义术语“HRD测试”;（二）提供一个概述的生物学原理和证据支持目前可用的HRD测试的水平;（三）提供建议的HRD测试在临床管理HGSC.Results的临床效用：广泛的修复基因，基因组疤痕，突变签名和功能测定与历史的HRD。目前，HRD测试在卵巢癌中的临床有效性最好评估，而不是生物学HRD状态本身，而是PARPi益处。临床试验证据支持使用BRCA突变检测和两种市售检测方法，这些检测方法还结合了基因组不稳定性，用于识别从PARPi治疗中获得不同程度获益的HGSC亚组，尽管临床情况存在一些差异。这些测试可用于告知治疗选择和时间表，但它们的使用受到限制，因为在大多数研究中无法一致地识别无法从PARPis中获益的患者亚组。现有的测试缺乏阴性预测值和不充分解决的复杂性和动态性质的HRD phenotype.Conclusions：目前可用的HRD测试是有用的预测可能的幅度从PARPis受益，但更好的生物标志物，迫切需要更好地确定当前的同源重组能力状态和分层HGSC管理。
Background: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial.Materials and methods: To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC.Results: A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype.Conclusions: Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.