Barchiesi Giacomo, Roberto Michela, Verrico Monica, Vici Patrizia, Tomao Silverio, Tomao Federica
Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomo Patologiche, Università di Roma Sapienza, Rome, Italy.
UOSD Sperimentazioni Di Fase IV, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Regina Elena National Cancer Institute, Rome, Italy.
Front Oncol. 2021 Nov 25;11:769280. doi: 10.3389/fonc.2021.769280. eCollection 2021.
Triple negative tumors represent 15% of breast cancer and are characterized by the lack of estrogen receptors, progesterone receptor, and HER2 amplification or overexpression. Approximately 25% of patients diagnosed with triple negative breast cancer carry a germline BRCA1 or BRCA2 mutation. They have an aggressive biology, and chemotherapy has been the mainstay of treatment for a long time. Despite intensive therapies, prognosis is still poor, and many patients will eventually relapse or die due to cancer. Therefore, novel targeted agents that can increase the treatment options for this disease are urgently needed. Recently, a new class of molecules has emerged as a standard of care for patients with triple negative breast cancer and germline BRCA1 or BRCA2 mutation: poly (ADP-ribose) (PARP) inhibitors. In the first part of the review, we summarize and discuss evidence supporting the use of PARP inhibitors. Currently, two PARP inhibitors have been approved for triple negative metastatic breast cancer-olaparib and talazoparib-based on two phase III trials, which showed a progression-free survival benefit when compared to chemotherapy. Safety profile was manageable with supportive therapies and dose reductions/interruptions. In addition, other PARP inhibitors are currently under investigation, such as talazoparib, rucaparib, and veliparib. Subsequently, we will discuss the potential role of PARP inhibitors in the future. Clinical research areas are investigating PARP inhibitors in combination with other agents and are including patients without germline BRCA mutations: ongoing phase II/III studies are combining PARP inhibitors with immunotherapy, while phases I and II trials are combining PARP inhibitors with other targeted agents such as ATM and PIK3CA inhibitors. Moreover, several clinical trials are enrolling patients with somatic BRCA mutation or patients carrying mutations in genes, other than BRCA1/2, involved in the homologous recombination repair pathway (.., CHECK2, PALB2, RAD51, ).
三阴性肿瘤占乳腺癌的15%，其特征是缺乏雌激素受体、孕激素受体，且HER2无扩增或过表达。约25%被诊断为三阴性乳腺癌的患者携带种系BRCA1或BRCA2突变。它们具有侵袭性生物学行为，长期以来化疗一直是主要治疗手段。尽管进行了强化治疗，预后仍然很差，许多患者最终会因癌症复发或死亡。因此，迫切需要能够增加这种疾病治疗选择的新型靶向药物。最近，一类新的分子已成为三阴性乳腺癌和种系BRCA1或BRCA2突变患者的标准治疗药物：聚（ADP - 核糖）（PARP）抑制剂。在综述的第一部分，我们总结并讨论支持使用PARP抑制剂的证据。目前，基于两项III期试验，两种PARP抑制剂奥拉帕利和他拉唑帕利已被批准用于三阴性转移性乳腺癌，与化疗相比，这两项试验显示出无进展生存获益。通过支持性治疗和剂量减少/中断，安全性可控。此外，其他PARP抑制剂目前正在研究中，如他拉唑帕利、芦卡帕利和维利帕利。随后，我们将讨论PARP抑制剂在未来的潜在作用。临床研究领域正在研究PARP抑制剂与其他药物联合使用，并且纳入了没有种系BRCA突变的患者：正在进行的II/III期研究将PARP抑制剂与免疫疗法联合使用，而I期和II期试验则将PARP抑制剂与其他靶向药物如ATM和PIK3CA抑制剂联合使用。此外，几项临床试验正在招募具有体细胞BRCA突变的患者或携带除BRCA1/2之外参与同源重组修复途径的基因（如CHECK2、PALB... 2、RAD51）突变的患者。
