PARP Inhibitors: A Major Therapeutic Option in Endocrine-Receptor Positive Breast Cancers

Abstract

Recently, OlympiAD and EMBRACA trials demonstrated the favorable efficacy/toxicity ratio of PARPi, compared to chemotherapy, in patients with HER2-negative metastatic breast cancers (mBC) carrying a germline BRCA mutation. PARPi have been largely adopted in triple-negative metastatic breast cancer, but their place has been less clearly defined in endocrine-receptor positive, HER2 negative (ER+/ HER2-) mBC. The present narrative review aims at addressing this question by identifying the patients that are more likely benefit from PARPi. Frequencies of BRCA pathogenic variant (PV) carriers among ER+/HER2- breast cancer patients have been underestimated, and many experts assume than 50% of all BRCA1/2 mutated breast cancers are of ER+/HER2- subtype. Patients with ER+/HER2- BRCA-mutated mBC seemed to have a higher risk of early disease progression while on CDK4/6 inhibitors and PARPi are effective especially when prescribed before exposure to chemotherapy. The OLYMPIA trial also highlighted the utility of PARPi in patients with early breast cancers at high risk of relapse and carrying PV of BRCA. PARPi might also be effective in patients with HRD diseases, representing up to 20% of ER+/HER2- breast cancers. Consequently, the future implementation of early genotyping strategies for identifying the patients with high-risk ER+/HER2- HRD breast cancers likely to benefit from PARPi is of high importance.

Clinical effectiveness and safety of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: final analysis of LUCY

“…Questions remain regarding the optimal sequencing of treatment with olaparib and CDK4/6 inhibitors. Real-world evidence indicates that patients with gBRCAm who receive CDK4/6 inhibitors as first-line therapy for mBC have poorer treatment outcomes than patients with wild-type BRCA [ 4 , 35 ]. Accordingly, treatment with olaparib earlier in the disease course may be particularly important in patients with gBRCAm, HER2-negative mBC.…”

“…Other limitations include the limited diversity of the patient population enrolled, suggesting that increased efforts are required to broaden inclusion in clinical trials overall and to better represent the populations at risk. The short period between the protocol amendment permitting the inclusion of patients with an sBRCA mutation (April 27, 2018) and the date of the last patient enrollment (March 21, 2019), as well as the lack of routine screening for sBRCA mutations at the time of the study likely contributed to the low number of patients enrolled into the sBRCAm cohort [ 35 ]. As well, the small sample size and missing data limited assessment of the clinical effectiveness of olaparib in patients with an sBRCA mutation.…”

Progress and prospects in research and clinical practice of hormone receptor-positive, HER-2-negative breast cancer with BRCA1/2 mutations

“…Therefore, the frequencies of BRCAm have been underestimated in patients with HR+/HER2-BC. Meanwhile, approximately 50% of all BCs with BRCA1/2m are of the HR+/HER2 subtype [ 38 , 39 ]. PARPis were approved by the Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of HER2- advanced BC with BRCA1/2m in 2018.…”

DNA Methylation Malleability and Dysregulation in Cancer Progression: Understanding the Role of PARP1

“…In AML and breast cancer cells, DNA demethylating agents (DNMT inhibitors) improve the lethal action of PARP1 inhibitors [240][241][242][243]. Both inhibitors' synergistic impact enhances DNA damage and, as a result, tumor cytotoxicity [244,245]. Notably, this combined treatment method improves the PARP1 inhibitor potency in cancer cells.…”