医学
乳腺癌
PARP抑制剂
肿瘤科
转移性乳腺癌
合成致死
拉帕蒂尼
抗药性
癌症
内科学
癌症研究
聚ADP核糖聚合酶
DNA修复
聚合酶
曲妥珠单抗
生物
生物化学
基因
微生物学
作者
Stefania Morganti,Antonio Marra,Carmine De Angelis,Angela Toss,Luca Licata,Federica Giugliano,Beatrice Taurelli Salimbeni,Pier Paolo Maria Berton Giachetti,Angela Espósito,Antonio Giordano,Giampaolo Bianchini,Judy E. Garber,Giuseppe Curigliano,Filipa Lynce,Carmen Criscitiello
出处
期刊:JAMA Oncology
[American Medical Association]
日期:2024-03-21
标识
DOI:10.1001/jamaoncol.2023.7322
摘要
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of patients with germline BRCA1/2-associated breast cancer, representing the first targeted therapy capable of improving outcomes in patients with hereditary tumors. However, resistance to PARP inhibitors occurs in almost all patients.This narrative review summarizes the biological rationale behind the use of PARP inhibitors in breast cancer, as well as the available evidence, recent progress, and potential future applications of these agents. Recent studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations. Moreover, these agents proved to be effective both in the metastatic and adjuvant settings. However, patients with metastatic breast cancer usually do not achieve the long-term benefit from PARP inhibitors observed in other tumor types. Mechanisms of resistance have been identified, but how to effectively target them is largely unknown. Ongoing research is investigating both novel therapeutics and new combination strategies to overcome resistance. PARP1-selective inhibitors, by sparing the hematological toxic effects induced by the PARP2 blockade, are promising agents to be combined with chemotherapy, antibody-drug conjugates, and other targeted therapies.Although the efficacy of PARP inhibitors is well established, many questions persist. Future research should focus on identifying predictive biomarkers and therapeutic strategies to overcome resistance. Integrating well-designed translational efforts into all clinical studies is thereby crucial to laying the groundwork for future insights from ongoing research.
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