Guffanti Federica, Mengoli Ilaria, Alvisi Maria Francesca, Dellavedova Giulia, Giavazzi Raffaella, Fruscio Robert, Rulli Eliana, Damia Giovanna
Laboratory of Preclinical Gynaecological Oncology, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Laboratory of Methodology for Clinical Research, Clinical Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Front Pharmacol. 2024 Jun 25;15:1390116. doi: 10.3389/fphar.2024.1390116. eCollection 2024.
Standard therapy for high-grade ovarian carcinoma includes surgery followed by platinum-based chemotherapy and poly-ADP ribose polymerase inhibitors (PARPis). Deficiency in homologous recombination repair (HRD) characterizes almost half of high-grade ovarian carcinomas and is due to genetic and epigenetic alterations in genes involved in HR repair, mainly and predicts response to PARPi. The academic and commercial tests set up to define the HRD status of the tumor rely on DNA sequencing analysis, while functional tests such as the RAD51 foci assay are currently under study, but have not been validated yet and are available for patients. In a well-characterized ovarian carcinoma patient-derived xenograft platform whose response to cisplatin and olaparib, a PARPi, is known, we assessed the association between the BRCA1 foci score, determined in formalin-fixed paraffin-embedded tumor slices with an immunofluorescence technique, and other HRD biomarkers and explored the potential of the BRCA1 foci test to predict tumors' response to cisplatin and olaparib. The BRCA1 foci score was associated with both tumors' HRD status and RAD51 foci score. A low BRCA1 foci score predicted response to olaparib and cisplatin, while a high score was associated with resistance to therapy. As we recently published that a low RAD51 foci score predicted olaparib sensitivity in our xenobank, we combined the two scores and showed that the predictive value was better than with the single tests. This study reports for the first time the capacity of the BRCA1 foci test to identify HRD ovarian carcinomas and possibly predict response to olaparib.
高级别卵巢癌的标准治疗包括手术，随后进行铂类化疗和聚二磷酸腺苷核糖聚合酶抑制剂（PARPi）治疗。同源重组修复（HRD）缺陷在几乎一半的高级别卵巢癌中表现明显，这是由于参与HR修复的基因发生了遗传和表观遗传改变，主要是……并预测对PARPi的反应。用于定义肿瘤HRD状态的学术和商业检测依赖于DNA测序分析，而诸如RAD51灶分析等功能检测目前正在研究中，但尚未得到验证，也未应用于患者。在一个特征明确的卵巢癌患者来源异种移植平台中，已知其对顺铂和PARPi奥拉帕尼的反应，我们评估了用免疫荧光技术在福尔马林固定石蜡包埋肿瘤切片中测定的BRCA1灶评分与其他HRD生物标志物之间的关联，并探讨了BRCA1灶检测预测肿瘤对顺铂和奥拉帕尼反应的潜力。BRCA1灶评分与肿瘤的HRD状态和RAD51灶评分均相关。低BRCA1灶评分预测对奥拉帕尼和顺铂有反应，而高评分与治疗耐药相关。正如我们最近发表的，低RAD51灶评分在我们的异种移植库中预测奥拉帕尼敏感性，我们将这两个评分结合起来，结果显示联合预测价值优于单一检测。本研究首次报道了BRCA1灶检测识别HRD卵巢癌并可能预测对奥拉帕尼反应的能力。
