Zielli Teresa, Labidi-Galy Intidhar, Del Grande Maria, Sessa Cristiana, Colombo Ilaria
Service of Medical Oncology, Oncology Institute of Southern Switzerland (IOSI), EOC, Bellinzona 6500, Switzerland.
Department of Oncology, Geneva University Hospitals, Geneva 1205, Switzerland.
Cancer Drug Resist. 2023 Jul 28;6(3):499-516. doi: 10.20517/cdr.2023.08. eCollection 2023.
Ovarian cancer is the most lethal gynecologic cancer. Optimal cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab is the conventional therapeutic strategy. Since 2016, the pharmacological treatment of epithelial ovarian cancer has significantly changed following the introduction of the poly (ADP-ribose) polymerase inhibitors (PARPi). mutations and homologous recombination deficiency (HRD) have been established as predictive biomarkers of the benefit from platinum-based chemotherapy and PARPi. While in the absence of HRD (the so-called homologous recombination proficiency, HRp), patients derive minimal benefit from PARPi, the use of the antiangiogenic agent bevacizumab in first line did not result in different efficacy according to the presence of homologous recombination repair (HRR) genes mutations. No clinical trials have currently compared PARPi and bevacizumab as maintenance therapy in the HRp population. Different strategies are under investigation to overcome primary and acquired resistance to PARPi and to increase the sensitivity of HRp tumors to these agents. These tumors are characterized by frequent amplifications of Cyclin E and MYC, resulting in high replication stress. Different agents targeting DNA replication stress, such as ATR, WEE1 and CHK1 inhibitors, are currently being explored in preclinical models and clinical trials and have shown promising preliminary signs of activity. In this review, we will summarize the available evidence on the activity of PARPi in HRp tumors and the ongoing research to develop new treatment options in this hard-to-treat population.
卵巢癌是最致命的妇科癌症。最佳细胞减灭术，随后联合或不联合贝伐单抗进行铂类化疗是传统的治疗策略。自2016年以来，随着聚（ADP-核糖）聚合酶抑制剂（PARPi）的引入，上皮性卵巢癌的药物治疗发生了显著变化。突变和同源重组缺陷（HRD）已被确立为铂类化疗和PARPi获益的预测生物标志物。在不存在HRD（即所谓的同源重组熟练，HRp）的情况下，患者从PARPi中获益甚微，而一线使用抗血管生成药物贝伐单抗，根据同源重组修复（HRR）基因突变的存在情况，疗效并无差异。目前尚无临床试验比较PARPi和贝伐单抗作为HRp人群维持治疗的效果。正在研究不同的策略来克服对PARPi的原发性和获得性耐药，并提高HRp肿瘤对这些药物的敏感性。这些肿瘤的特征是细胞周期蛋白E和MYC频繁扩增，导致高复制应激。目前正在临床前模型和临床试验中探索不同的针对DNA复制应激的药物，如ATR、WEE1和CHK1抑制剂，并且已经显示出有前景的初步活性迹象。在这篇综述中，我们将总结关于PARPi在HRp肿瘤中活性的现有证据，以及为这个难以治疗的人群开发新治疗方案的正在进行的研究。
