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

Laetitia Collet,Jonathan Lopez,Gilles Freyer,Frédérique Penault-Llorca,Julien Péron,Benoît You,Pascal Pujol

doi:10.3390/cancers14030599

Abstract

Simple SummaryOlympiAD and EMBRACA trials demonstrated the efficacy of PARPi, compared to chemotherapy, in patients with HER2-negative metastatic breast cancers (mBC) carrying a germline BRCA mutation. Patients with ER+/HER2-BRCA-mutated mBC seemed to have a higher risk of early disease progression while on CDK4/6 inhibitors and benefit from PARPi, especially when prescribed before chemotherapy. Importantly, the frequency of BRCA pathogenic variant (PV) carriers among ER+/HER2- breast cancer patients has been underestimated, and 50% of all BRCA1/2 mutated breast cancers are actually of ER+/HER2- subtype. Recent studies also highlight the benefit of PARPi in BRCA wild type mBC with HRD representing up to 20% of ER+/HER2- breast cancers. The OLYMPIA trial also demonstrated PARPi utility in patients with ER+/HER2- early breast cancers with BRCA PV at high risk of relapse. Consequently, implementation of early genotyping and new strategies for identifying patients with high-risk ER+/HER2- HRD breast cancers likely to benefit from PARPi is of high importance.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.

Highlights

Targeting deoxyribonucleic acid (DNA) damage repair (DDR) pathways has recently emerged as a major opportunity for managing cancers of different origins [1]
In the present narrative review, we review the frequency of homologous recombination (HR)-related gene mutations in breast cancer and the data on PARPi efficacy in patients with ER+/HER2- breast cancers, especially HR+/HER2- breast cancers with high-risk features
We present the different genomic tests able to identify the patients the more likely to benefit from PARPi, to discuss their place in the management of ER+/HER2-breast cancers

Summary

Introduction

Targeting deoxyribonucleic acid (DNA) damage repair (DDR) pathways has recently emerged as a major opportunity for managing cancers of different origins [1]. It is considered that most cancer cells exhibit deficiency in one of the five main DDR systems [2], making their survival dependent on the other DDR pathways [3] The blockage of these latter pathways induces the “synthetic lethality” due to the precipitation of unrepaired DNA damage. This concept spurred on the development of polyadenosine diphosphate–ribose polymerase (PARP) inhibitors (PARPi) in tumors characterized by deficiencies of the homologous recombination (HR), such as ovarian cancers, breast cancers, prostate cancers, and pancreatic cancers [1]. The inhibition of PARP concomitant in patients with diseases associated with HR deficiency results in genomic instability leading to cancer cell death [4] This strategy was effective in patients with ovarian cancers carrying germline or somatic BRCA1/2 mutations [5–10]. Beyond BRCA1/2 mutations, this concept was subsequently extended to alterations of other elements of the pathway, grouped into homologous recombination deficiencies (HRD) [11]

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