A Functional Homologous Recombination Assay Predicts Primary Chemotherapy Response and Long-Term Survival in Ovarian Cancer Patients
A Functional Homologous Recombination Assay Predicts Primary Chemotherapy Response and Long-Term Survival in Ovarian Cancer Patients
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DOI：
10.1158/1078-0432.ccr-17-3770
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发表时间：
2018-09-15
影响因子：
11.5
通讯作者：
Kauppi, Liisa
中科院分区：
文献类型：
--
作者：
Tumiati, Manuela;Hietanen, Sakari;Kauppi, Liisa
目的：同源重组缺陷（HRD）与卵巢癌患者的铂敏感性相关，这在临床上是对PARPi敏感性的最有用的预测因素。到目前为止，还没有可靠的诊断工具来预测对铂类化疗的反应，因此我们的目的是开发一种离体功能性HRD检测测试，可以预测铂类敏感性和患者对靶向药物治疗的资格。我们通过定量原发性卵巢癌样本（n = 10）电离辐射诱导的DNA损伤后的同源重组（HR）修复，获得了功能性HR评分。32）。样本分为3类：HR缺乏、HR低和HR熟练。我们分析了HR评分与铂敏感性和治疗反应、无铂间期（PFI）和总生存期（OS）的相关性，并将其与其他临床参数进行了比较。在平行，我们进行了DNA测序的HR基因，以评估是否功能HRD可以预测目前提供的geneticscreening.Results：低HR评分预测原发铂敏感性具有较高的统计学意义（P = 0.0103），与较长的PFI（HR缺乏与HR熟练：531与53天），并显着相关的OS改善（HR评分< 35 vs. >= 35，风险比= 0.08，P = 0.0116）。在基因组水平上，我们发现了一些不清楚的HR基因突变和与HRD相关的突变特征，但总的来说，遗传筛查未能预测功能性HRD。我们开发了一种检测肿瘤功能性HRD和能够预测铂敏感性的HR评分的离体测定，其具有成为卵巢癌患者管理中的常规伴随诊断的临床相关潜力。临床癌症研究;（C）2018年AACR。
Purpose: Homologous recombination deficiency (HRD) correlates with platinum sensitivity in patients with ovarian cancer, which clinically is the most useful predictor of sensitivity to PARPi. To date, there are no reliable diagnostic tools to anticipate response to platinum-based chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments.Experimental Design: We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples (n = 32). Samples clustered in 3 categories: HR-deficient, HR-low, and HR-proficient. We analyzed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters. In parallel, we performed DNA-sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening.Results: Low HR scores predicted primary platinum sensitivity with high statistical significance (P = 0.0103), associated with longer PFI (HR-deficient vs. HR-proficient: 531 vs. 53 days), and significantly correlated with improved OS (HR score < 35 vs. >= 35, hazard ratio = 0.08, P = 0.0116). At the genomic level, we identified a few unclear mutations in HR genes and the mutational signature associated with HRD, but, overall, genetic screening failed to predict functional HRD.Conclusions: We developed an ex vivo assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of patients with ovarian cancer. Clin Cancer Res; (C) 2018 AACR.