Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Laboratory of Methodology for Clinical Research, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Br J Cancer. 2022 Jan;126(1):120-128. doi: 10.1038/s41416-021-01609-1. Epub 2021 Nov 3.
The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies.
We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR.
Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity.
The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy.
寻找评估卵巢癌（OC）同源重组（HR）功能并预测治疗反应的生物标志物是一项迫切的临床需求，这有助于改善对可能受益于铂类和奥拉帕利（聚 ADP 核糖聚合酶抑制剂，PARPi）治疗的患者的选择。
我们使用了大量 OC 患者来源的异种移植（PDX）（n=47），并根据 BRCA1/2 突变、BRCA1 启动子甲基化和 HRDetect 评分评估其 HR 状态。通过免疫荧光法在福尔马林固定、石蜡包埋的未经处理的肿瘤标本中定量 RAD51 焦点，并通过实时 PCR 定量 21 个 DNA 修复基因的信使 RNA 表达。
肿瘤 HR 缺陷预测了铂类和奥拉帕利的反应。在 geminin 阳性/复制细胞中评估的基础 RAD51 焦点水平与奥拉帕利反应呈强烈负相关（p=0.011）；特别是，焦点评分越低，对奥拉帕利的敏感性越高，而低 RAD51 焦点评分似乎与铂类药物的活性有关。
基础 RAD51 焦点评分是 OC 患者奥拉帕利反应的候选预测生物标志物，因为它可以很容易地转化为临床环境。此外，这些发现证实了 OC-PDX 作为识别和验证治疗反应生物标志物的可靠工具的重要性。
