Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, 10 Center Dr. MSC1906 Building 10, Room 4B54, Bethesda, MD, 20892-1906, USA.
School of Medicine, Stony Brook University School of Medicine, 101 Nicolls Road Stony Brook, Bethesda, NY, 11794-8434, USA.
Curr Treat Options Oncol. 2018 Apr 11;19(5):21. doi: 10.1007/s11864-018-0540-2.
The single agent activity of PARP inhibitors (PARPi) in germline BRCA mutated (gBRCAm) breast and ovarian cancer suggests untapped potential for this new class of drug in breast cancer. The US Food and Drug Administration has approved three PARPi (olaparib, rucaparib, and niraparib) so far to treat certain ovarian cancers, including those with gBRCAm and olaparib for treatment of gBRCAm breast cancers. Several PARPi are now under clinical development for breast cancer in the various treatment settings. Recently, two phase III trials of olaparib (OlympiaD) and talazoparib (EMBRACA) demonstrated 3-month progression-free survival improvement with PARPi compared to physician's choice single agent chemotherapy in metastatic gBRCAm breast cancer. To date, PARPi seems less efficacious in metastatic breast cancer patients than those with BRCA mutated platinum-sensitive recurrent ovarian cancer, perhaps reflecting the biologic heterogeneity and low somatic BRCA mutation rate in breast cancer. The use of PARPi is gradually evolving, including combination strategies with chemotherapy, targeted agents, radiotherapy, or immunotherapy in women with and without gBRCAm. The role of predictive biomarkers, including molecular signatures and homologous recombination repair deficiency scores based on loss of heterozygosity and other structural genomic aberrations, will be crucial to identify a subgroup of patients who may have benefit from PARPi. An improved understanding of the mechanisms underlying PARPi clinical resistance will also be important to enable the development of new approaches to increase efficacy. This is a field rich in opportunity, and the coming years should see a better understanding of which breast cancer patients we should treat with PARPi and where these agents should come in over the course of treatment.
聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）在种系 BRCA 突变（gBRCAm）乳腺癌和卵巢癌中的单药活性表明，这种新药类在乳腺癌中有未被挖掘的潜力。美国食品和药物管理局迄今已批准三种 PARPi（奥拉帕利、鲁卡帕利和尼拉帕利）用于治疗某些卵巢癌，包括 gBRCAm 和奥拉帕利治疗 gBRCAm 乳腺癌。目前，几种 PARPi 正在各种治疗环境中用于乳腺癌的临床开发。最近，奥拉帕利（OlympiaD）和他拉唑帕利（EMBRACA）的两项 III 期试验显示，与医生选择的单药化疗相比，PARPi 可改善转移性 gBRCAm 乳腺癌患者的 3 个月无进展生存期。迄今为止，PARPi 在转移性乳腺癌患者中的疗效似乎不如 BRCA 突变铂类敏感复发性卵巢癌患者，这可能反映了乳腺癌的生物学异质性和低体细胞 BRCA 突变率。PARPi 的使用正在逐渐发展，包括在有或没有 gBRCAm 的女性中与化疗、靶向药物、放疗或免疫疗法联合使用的策略。预测生物标志物（包括基于杂合性丢失和其他结构基因组异常的分子特征和同源重组修复缺陷评分）的作用对于确定可能从 PARPi 中获益的患者亚组至关重要。深入了解 PARPi 临床耐药的机制也很重要，这将有助于开发新方法来提高疗效。这是一个充满机遇的领域，未来几年我们应该更好地了解哪些乳腺癌患者应该用 PARPi 治疗，以及这些药物应该在治疗过程中的哪个阶段使用。
