REVIEW ARTICLE

Open Access

Poly (adenosine diphosphate-ribose) polymerase inhibitors in the treatment of triple-negative breast cancer with homologous repair deficiency

Peng Yuan

Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Search for more papers by this author

Nan Ma,

Nan Ma

Value & Implementation, Global Medical & Scientific Affairs, MSD China, Shanghai, China

Search for more papers by this author

Binghe Xu,

Corresponding Author

Binghe Xu

[email protected]

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Correspondence Binghe Xu, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Email: [email protected]

Search for more papers by this author

Peng Yuan,

Peng Yuan

Search for more papers by this author

Nan Ma,

Nan Ma

Value & Implementation, Global Medical & Scientific Affairs, MSD China, Shanghai, China

Search for more papers by this author

Binghe Xu,

Corresponding Author

Binghe Xu

[email protected]

Email: [email protected]

Search for more papers by this author

First published: 24 June 2024

https://doi.org/10.1002/med.22058

Citations: 5

Share a link

Email
Wechat
Bluesky

Abstract

Breast cancer (BC) is a highly heterogeneous disease, and the presence of germline breast cancer gene mutation (gBRCAm) is associated with a poor prognosis. Triple-negative breast cancer (TNBC) is a BC subtype, characterized by the absence of hormone and growth factor receptor expression, making therapeutic decisions difficult. Defects in the DNA damage response pathway due to mutation in breast cancer genes (BRCA 1/2) lead to homologous recombination deficiency (HRD). However, in HRD conditions, poly (adenosine diphosphate–ribose) polymerase (PARP) proteins repair DNA damage and lead to tumor cell survival. Biological understanding of HRD leads to the development of PARP inhibitors (PARPi), which trap PARP proteins and cause genomic instability and tumor cell lysis. HRD assessment can be an important biomarker in identifying gBRCAm patients with BC who could benefit from PARPi therapy. HRD can be identified by homologous recombination repair (HRR) gene-based assays, genomic-scarring assays and mutational signatures, transcription and protein expression profiles, and functional assays. However, gold standard methodologies that are robust and reliable to assess HRD are not available currently. Hence, there is a pressing need to develop accurate biomarkers identifying HRD tumors to guide targeted therapies such as PARPi in patients with BC. HRD assessment has shown fruitful outcomes in chemotherapy studies and preliminary evidence on PARPi intervention as monotherapy and combination therapy in HRD-stratified patients. Furthermore, ongoing trials are exploring the potential of PARPi in BC and clinically complex TNBC settings, where HRD testing is used as an adjunct to stratify patients based on BRCA mutations.

1 INTRODUCTION

Breast cancer (BC) is the most common global malignancy among women, accounting for one-fourth of the cancer burden, with an incidence of 2.3 million cases (11.7%).¹ Hereditary susceptibility due to autosomal dominant gene mutation is a major risk factor in acquiring BC.² BC is highly heterogeneous and is classified into various subtypes according to the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Patients with BC lacking the expression of ER, PR, and HER2 (14%–16%) are termed as triple-negative breast cancer (TNBC). TNBC is an aggressive subtype of BC, accounting for about 15%–20% of BC cases, and shows poor prognosis, high recurrence, and high mortality rates. Most of the TNBC patients develop distant metastatic recurrence which is linked to a rapidly progressing illness and early mortality (<12 months).³ Based on molecular heterogeneity, TNBC is further divided into 6 different subgroups: basal-like, mesenchymal-like, mesenchymal stem-like, luminal AR expression, immunomodulatory, and unstable type.⁴

The greatest risk factor for BC is the introduction of mutation in any one of the breast cancer genes (BRCA1 or BRCA2). BRCA1 and BRCA2 (BRCA1/2) tumor suppressor gene–encoding proteins that are essential for DNA damage repair, cell growth regulation, and cell division. Both proteins are known to function in homologous recombination (HR), a vital DNA repair process that uses the undamaged sister chromatid to perform high-fidelity repair of predominantly replication-associated DNA double-strand breaks (DSB). Genetic variations in essential HR genes such as BRCA1/2 lead to homologous recombination deficiency (HRD).⁵ Patients with TNBC mostly harbor germline BRCA1/2 mutation (gBRCAm) and are known to be deficient in HR and develop advanced or metastatic BC.⁶ HRD tumors are sensitive to DNA-damaging therapies such as poly (adenosine diphosphate–ribose) polymerase inhibitors (PARPi).⁷ Tumors with BRCA1/2 mutations are highly dependent on poly (adenosine diphosphate–ribose) polymerase (PARP) proteins, which are essential for single-strand DNA damage repair by base excision repair (BER) pathway. Hence, an interaction between 2 BRCA genes in which the mutation of either of these 2 genes alone is compatible with viability, whereas the simultaneous mutation of both genes causes death. Many novel therapies such as chemotherapy, hormonal therapy, anti-HER2 mAbs, and others for treating BC have emerged since the 1900s.

Among them, PARP inhibitors (PARPi) were developed and were the first clinically approved which showed promising activity in patients with BRCA-deficient tumors.^{4, 8} PARPi such as olaparib and talazoparib are Food and Drug Administration (FDA)-approved drugs for the treatment of BRCA-associated BC, and there is a growing interest in analyzing their effectiveness and safety, particularly in patients with TNBC, either as monotherapy or combination therapy. Recent evidence also shows PARPi effectivity in BRCA1/2 wild-type BC patients with HRD. Although the use of PARPi in patients with TNBC is imminent, challenges such as poor response in wild-type BRCA patients and lack of predictive biomarkers to guide PARPi therapy have to be addressed.^9-11 Very few previously published reviews focused on the PARPi in TNBCs, but they focused on PARPi on HR status, PD-L1, etc.^{8, 11} Considering these circumstances, our review mainly focuses on BRCA mutations and HRD testing and their relevance to the clinical application of PARPi in patients with BC and TNBC.

2 PREVALENCE AND IMPACT OF BRCA MUTATION AND HRD IN BC

Germline pathogenic mutations in the BRCA1/2 genes increase the likelihood of developing several malignancies, including BC and ovarian cancer. Risk estimates show that 50%–80% of people with germline BRCA1/2 mutation may develop BC at a young age.¹² BRCA1/2 mutations predispose high penetrance in hereditary carriers and are found in ~20% of germline BC. Other germline mutations such as TP53, PTEN, and STK11 are identified in <1% of BC families and are associated with cancer syndromes.¹³ BRCA1 mutation–associated BC was mostly diagnosed in younger women and was presented with a poor prognosis; high nuclear grade tumors; poorly differentiated, infiltrating ductal carcinomas; and stain negative for ER, PR, and HER2. BRCA2-mutated BC possesses a similar clinical prognosis in non-germline carriers and affects older women.¹⁴

TNBC patients with mutations were generally younger at first diagnosis, with a mean age of 44 and 47 years for patients with germline BRCA1 and BRCA2 mutations, respectively, and 51 years for patients without pathogenic germline mutations.¹⁵ The prevalence rate of germline BRCA1/2 mutation in BC was 5.3%, and high in patients with TNBC (11.2%; BRCA1, 8.5% and BRCA2, 2.7%).¹⁶ An earlier study showed that 68% and 16% of patients with BC were categorized to have TNBC and BRCA1 and BRCA2 mutations, respectively.¹⁷ Mutations in BRCA1/2 lead to HRD that attenuates the DNA repair mechanism ¹⁸ and are observed in ~67% of patients with TNBC.¹⁹ However, more than 20% of patients with TNBC harbor HRD without BRCA1/2 mutations (Figure 1A).²⁰ HRD increases the number of tumor mutations, reduces DNA repair capacity, and may induce tumorigenesis resulting in molecular lesions. In addition, mutations in other HR-related genes, such as BARD1, RAD50, RAD51, PALB2, ATM, MRN, MRE11, RPA, NBS1, CHEK2, TP53, PTEN, and BRIP1, might also lead to DNA repair deficiencies.⁵ As the rates of BRCA mutations and HRD are higher, consideration of these factors in clinical practice would greatly contribute to the implementation of newer targeted therapy strategies for patients with BC.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

(A) Probability and crossover of triple-negative breast cancer patients with BRCA1/2 mutations and HRD (B) Different HRD detection methods. BRCA, breast cancer genes; HRD, homologous recombination deficiency; HRR, homologous recombination repair; PARPi, poly (adenosine diphosphate–ribose) polymerase inhibitors. [Color figure can be viewed at wileyonlinelibrary.com]

3 CURRENT SITUATION OF HRD DETECTION AND ITS RESEARCH DIRECTION IN BC

Genetic variations in the BRCA1/2 gene destabilize the HR pathway and DNA repair targeting DNA-damaging PARPi therapy. However, the effectiveness of PARPi is largely dependant on the HRD status of the patients.²¹ A phase III clinical evaluation of iniparib did not show positive outcomes in patients with TNBC, which could be attributed to the non-stratification of patients based on their BRCA1/2 mutation status.²² According to the National Institute for Health and Care Excellence (NICE), genetic BRCA1/2 testing is recommended when the combined BRCA1 and BRCA2 mutation carrier probability is ≥10%.²³ These factors emphasize the need for a reliable and robust diagnostic tool for HRD testing. Also, the assessment of HRD serves as an important prognostic and predictive biomarker for patients on PARPi therapy. At present, HRD status is best assessed in ovarian cancer for its clinical utility in determining PARPi benefits.²⁴ However, HRD detection methods are varied and controversial, and gold-standard methodologies are not yet available. Hence, understanding the currently employed methodologies to assess HRD is vital for its use in clinical research and practice. HRD assays can be classified into 4 categories: homologous recombination repair (HRR) gene-based assays, genomic scarring assays and mutational signatures, and functional assays (Figure 1B).

3.1 HRR gene-based assays

Sequencing HR genes to detect germline mutations was used to categorize tumors as HRD. Clinical studies suggest that germline BRCA1/2 mutation detection remains the reliable clinical biomarker of HRD detection.²⁵ The GeparSixto trial showed that germline BRCA1/2 mutation status predicts higher pathological complete response (pCR) rates in patients with TNBC on neoadjuvant chemotherapy.²⁶ Similarly, the NeoSTOP trial demonstrated higher pCR correlating with event-free survival (EFS) and overall survival (OS) in germline BRCA1/2 mutation patients with TNBC on platinum-based neoadjuvant chemotherapy.²⁷ Many phase III studies (Study 19, NCT00753545; NOVA trial, NCT01847274; and OlympiAD trial, NCT02000622) have used BRCA analysis to establish germline BRCA1/2 mutation status in patients with BC and ovarian cancer.²⁵ Of the existing BRCA-sequencing assays, the FDA has approved the sequencing-based Myriad Genetics BRACAnalysis CDx platform (Myriad Genetics) to detect deleterious germline BRCA1/2 mutation variations in patients with ovarian cancer.²⁵

Besides germline BRCA1/2 mutation, the prevalence of somatic BRCA mutations in patients with ovarian cancer led to the FDA approval of the tissue-based FoundationFocus CDxBRCA assay (Foundation Medicine) based on the ARIEL trials, which detect both germline and somatic BRCA mutations.²⁸ A recently developed capture-based–targeted resequencing assay, Leuven HRD assay, was compared with Myriad myChoice PLUS, and the results showed robust correlations and positive outcomes.²⁹ However, negative predictive value, detection of variants of uncertain significance, genotype-phenotype correlations, and somatic reversion mutation leading to HR proficiency serve as important drawbacks of predicting HRD using gBRCAm testing.²⁵ Hence, constant efforts have been made to identify genomic, transcriptomic, proteomic, and functional markers to identify HRD in tumors.

3.2 Genomic scarring assays and mutational signatures

HRD can be detected by chromosomal aberrations arising from defective repair pathways due to gross genomic alterations (also referred to as “genomic scars”). The “myChoice” HR deficiency test (Myriad Genetics Inc.) is a next-generation sequencing (NGS) assay that evaluates genomic scarring by measuring the loss of heterozygosity (LOH), large-scale transitions, and telomeric allelic imbalances. A genomic instability score (GIS) of >42 is considered positive for HRD.³⁰ The NGS-based comprehensive genomic profiling assay “FoundationOne®CDx (F1CDx)” (Foundation Medicine) is capable of assessing 324 cancer genes, including deleterious BRCA1 and/or BRCA2 mutations, to diagnose HRD.³¹

In addition to genomic scarring assays, the presence of mutational signatures or patterns in the entire genome caused by mutagen exposure or genomic instability has been validated as a predictor of HRD tumors. “Signature 3” is one such mutational signature attributed to underlying HRD and detected in several cancers including BC.³² “HRDetect”, a whole genome sequencing (WGS)–based classifier, designed to detect HRD has a high sensitivity in predicting BRCA deficiency and is based on gene signatures arising due to base substitutions and rearrangements.³³ Similar to HRR gene-based assays, reversion or secondary mutation restores HR functionality, but the scar would remain detectable. Hence, assays mitigating the false positivity of HRD after treatment and mutation reversal would add more clinical value.

3.3 Transcription and protein expression profiles

Unlike irreversible genetic signals, it is hypothesized that RNA and proteins fluctuate dynamically in quantity and localization based on the current HRD status. Gene expression profiling (GEP) performs real-time indication of HRD by capturing the current transcriptional state of a tumor. GEP assays may not necessarily focus on HR but analyze genes that regulate apoptosis, cell cycle entry, and DNA repair. A retrospective GEP evaluation analyzing the 93-gene chemotherapy response profile (CRP) showed an excellent response to platinum therapy in patients with ovarian cancer.²⁵ The TAILORx trial involving HR-positive, HER2-negative, axillary node-negative invasive patients with BC who met the clinical recommendation for adjuvant chemotherapy was maintained on endocrine therapy based on a 21-gene assay (Oncotype DX Recurrence Score, Genomic Health). Adjuvant therapy showed a beneficial efficacy at 5 years in patients who had a midrange 21-gene recurrence score (OS, 98.0%; disease-free survival, 93.8%).³⁴ The dynamicity of GEP assays was evident in a 60-gene signature assay, which classified tumors as BRCA-like and non-BRCA-like. Furthermore, GEP assays identified the evolution of platinum resistance by reading the change in the BRCAness profile using gene signatures during the therapy.³⁵ In BC, a formalin-fixed paraffin-embedded (FFPE) compatible 44-gene microarray-based assay was developed to predict a complete pathologic response after neoadjuvant chemotherapy. A 77-gene expression profile known as BRCA1ness was developed based on a cohort of TNBC linked to a known BRCA1-like array-based comparative genomic hybridization (aCGH) profile, which helped to identify the subset of patients who are benefiting from adjuvant DSB-inducing chemotherapy.³⁶ A similar 77-gene BRCA1ness signature developed using a centroid model was evaluated in the phase II I-SPY 2 study. Here, HER2-negative patients with BC positive for BRCA1ness receiving paclitaxel with veliparib and carboplatin had significantly higher pCR rates.³⁷ At present, these GEP assays have not been specifically assessed for PARPi inhibition.

Similar to GEP assays, immunohistochemical analyses of tumor suppressor proteins can serve as evaluation tools for cancer treatment sensitivities. Owing to a low expression of BRCA proteins and non-BRCA DNA damage response proteins, many clinical studies on PARPi have examined ataxia-telangiectasia-mutated kinase (ATM). ATM loss has been noted in a variety of tumor types, including breast, colon, and gastric cancers.²⁵ Reduction of ATM is linked to PARPi sensitivity in vitro, and a loss of 20% in ATM levels was noted in gastric cancer.^{38, 39} A correlation between ATM loss and OS improvement was demonstrated by a randomized phase II study of paclitaxel + olaparib versus paclitaxel + placebo.⁴⁰ GEP and protein expression analysis is an indirect evaluation of HRD and is not included in the acceptable methodologies for HRD detection as per the European expert consensus.⁴¹ However, the focus of further research may make GEP and protein expression analysis an excellent and acceptable tool for determining prognosis and the likelihood of benefit from selected therapeutic agents such as PARPi in patients with BC.

3.4 Functional assays

Functional assays possess the ability to provide a dynamic readout of the actual HRR status by measuring the actual ability of tumors to accumulate RAD51 protein at DNA DSB.⁴² RAD51 is a downstream HR protein that gets employed in the sites of DNA damage to facilitate strand invasion into the sister chromatid in cooperation with the BRCA1/PALB2/BRCA2 complex. In the presence of HRD, there is a reduction or inability to form RAD51 foci. The presence of RAD51 occurs when the reversion mutation restores HRR. Limitations such as the inability of RAD51 assays to identify HRR defects, downstream of RAD51 loading onto DNA, and elicitation of RAD51 signals exogenous DNA damage have undermined its clinical utility.²⁴ However, RAD51 can be used in the absence of exogenous factors.⁴³ RAD51 can be assessed using DNA sequencing and immunostaining assays and is currently being investigated extensively as a biomarker to predict HRD and promote its clinical utility.⁴⁴

4 STUDIES ASSESSING HRD IN PATIENTS WITH BC

GeparOLA (NCT02789332), a phase 2, randomized, open-label ongoing trial, compares paclitaxel/olaparib 100 mg twice daily (BID) with paclitaxel/carboplatin in 107 patients with HER2-negative early BC. The preliminary report showed that the rate of pCR was not significantly different between the olaparib and carboplatin arms. In the subgroup analysis, the pCR rates in the olaparib and carboplatin arms were 52.6% and 20.0%; 56.0% and 59.3% in HRD patients and HR-proficient patients, respectively.⁴⁵ The phase II TBCRC 030 study evaluated HRD biomarker association with pathological response (RCB-0/1) to single-agent cisplatin or paclitaxel. HRD assay by Myriad Genetics, Inc. was performed in the NGS platform using FFPE tumor tissues. This study demonstrated that HRD is not a predictive biomarker of pathological response, as no significant association was observed between HRD score and RCB response.⁴⁶ A retrospective, blinded, biomarker analysis from the tissue samples of the GeparSixto trial in patients with TNBC showed a high concordance (87%) between RAD51 and genomic HRD. Functional HRD by RAD51 was detected in 61% of the tumor patients, and the RAD51 test identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases. Similar pCR rates were observed between Myocet®-non-pegylated liposomal doxorubicin (PM) and PM plus carboplatin (PMCb) treatment arms (PMCb vs PM, 31% vs 39%; OR, 0.71, 0.23–2.24; p = 0.56). PMCb was beneficial to patients with RAD51-low tumors (pCR, 66% vs 33%; OR, 3.96, 1.56–10.05, p = 0.004; interaction test p = 0.02). Disease-free survival was similar when carboplatin was added in the RAD51-high (hazard ratio [HR], 0.40; log-rank p = 0.11) and RAD51-low (0.45, p = 0.11) groups.⁴⁷ A similar benefit was not observed in the TNT trial conducted in a metastatic setting where no difference was observed in PFS or OS between the carboplatin and docetaxel arms when stratified according to HRD status.⁴⁸

The BrighTNESS trial evaluated HRD score as a biomarker to predict response to neoadjuvant platinum-based chemotherapy in TNBC and showed that patients with HRD were more likely to achieve pCR than HR-proficient patients (OR, 13.06; 95% CI, 1.52–11.241; p = 0.0028). Among BRCA1/2 wild-type patients, HR-deficient patients were more likely to achieve a pCR (OR, 16; 95% CI, 1.65–160.41; p = 0.0041) than HR-proficient patients. Furthermore, HRD scores were highly concordant with pre- and post-therapy outcomes (Spearman correlation >99%).⁴⁹ These factors indicate that HRD is an effective predictor of the pCR rates and therapy outcomes.

Studies assessed presented conflicting opinions on HRD testing. The findings clearly show that there is no robust, reliable, and accurate biomarker to identify HRD tumors that could guide PARPi treatment. The inconsistencies observed could have been caused by differences in the HRD scoring threshold used to correlate with pCR rates across studies. The TBCRC 030 and BrighTNESS trials employing a HRD scoring threshold of 33 did not correlate with favorable pCR rates in patients with TNBC, whereas the scoring threshold of ≥42 in the GeparSixto trial is associated with favorable pCR rates. Differences in outcomes based on the HRD scoring threshold suggest the need to achieve a common consensus on the HRD score to predict treatment responses in patients with TNBC. Furthermore, investigations performed have majorly predicted chemotherapy responses based on HRD, where PAPRi are only used as adjuvant therapy. Prospective clinical trials could, therefore, aid in determining whether HRD can be used as a prognostic predictor during PARPi therapy where it is used as the primary intervention in patients with BC and TNBC stratified based on HRD. In addition, limitations of HRR gene sequencing in identifying the epigenetic inactivation and restoration of HRR upon progression invite the need for additional or alternate methodologies such as functional RAD51 assay, which showed a high concordance with genomic HRD assays. Therefore, systematic validations and implementation of genomic scarring assays, functional assays, and protein expression profiles could assist in predicting the PARPi responses since PARPi activity is directly dependent on HRD positivity.

5 PARPI structure–activity RELATIONSHIP AND TREATMENT MECHANISM

5.1 Chemistry of PARP inhibitors – structure–activity relationship (Sar)

The development of PARPi has paved the way for treating various cancers including BC. Most PARPi compounds possess N heterocycle, benzene ring, halogen, and free amine (N-H) moieties.^{50, 51} The pharmacophore modelling of PARPi revealed the presence of nicotinamide moiety which interacts with the nicotinamide binding site of PARP enzymes. The presence of at least one free -NH group is essential which acts as a hydrogen bond donor. The improvement in the activity is more associated with the presence of an electron-rich aromatic ring or phenyl ring which is required for π-π stacking interaction. For instance, the six-membered ring showed better activity than the seven-membered ring.^50-52 The carboxamide moiety in the PARPi should be restricted to either cis or trans-, which is crucial in forming hydrogen bond formation. The presence of non-cleavable bonds at the 3rd position relative to carboxamide moiety is essential for improving the conjugations. The presence of one or more heterocyclic rings containing nitrogen/fluorine/carbonyl groups is preferable for imparting a hydrophobic nature at the adenosine binding region⁵² (Figure 2).

5.2 Mechanism of PARPi in the treatment of HRD tumors

Hormone therapies do not help patients with TNBC since there is no receptor overexpression, thus making TNBC clinical management challenging. gBRCAm is more sensitive to DNA-damaging therapies such as PARPi therapy.⁵³ PARPi have been postulated to kill tumor cells using synthetic lethality, wherein only tumor cells are affected and not normal cells. Hence, PARPi has evolved as an effective treatment agent for TNBC with BRCA mutation and HRD. The results of HRD in a variety of DNA lesions such as single-strand break (SSB), DSB, bulky adducts, base mismatches, insertions, deletions, and base alkylation are caused by continuous DNA damage. The repair mechanisms for DNA can vary based on the type of lesions that are present. PARP proteins are important repair regulators of SSB and repair DNA through the BER pathway. PARPi trap PARP proteins from binding to the sites of SSB, which inhibits the BER pathway thereby improving SSB to DSB conversion.⁵⁴

DSB repair usually occurs through HRR pathway where BRCA1/2 protein restores DSB accurately with a high precision. BRCA1 gets employed in the sites of DSB where it promotes 5′ to 3′ resection creating 3′ overhangs, thus playing an early and prominent role in the promotion and regulation of HRR. BRCA1 modulates PALB2-dependent loading of BRCA2-RAD51 repair machinery at the sites of DSB. Then RAD51 is loaded by BRCA2 in the overhang, forming nucleoprotein filament and D loop. RAD51 then promotes strand invasion using the sister chromatid leading to error-free repair. In cases of HRD, DNA replication fork collapses due to PARP trapping by PARPi leading to the accumulation of DSB and cell death. Further, DSB repair can be performed by nonhomologous end-joining (NHEJ) repair pathway. It does not require homologous template for DSB repair, rather ligates the DNA ends directly. However, NHEJ is an error-prone pathway and leads chromosomal aberrations, cell cycle arrest, and eventually apoptosis ⁵⁴ (Figure 3).

Preclinical studies have also shown PARPi efficacy in BC cells lacking BRCA mutations.⁵⁵ Furthermore, niraparib treated for ovarian cancer showed progression-free survival (PFS) benefits irrespective of BRCA mutation and HRD. Similar effects cannot be replicated in non-BRCA1/2–mutated BC, highlighting the complexity in using PARPi beyond gBRCAm.⁵⁶ Hence, further studies on PARPi in patients with BC stratified based on BRCA1/2 mutation status are required to extend their clinical benefit beyond BRCA.

6 PROGRESS OF PARPI IN BC WITH GBRCA MUTATION OR HRD

Over years, PARPi have gained interest among many researchers for its activity against TNBC. Several PARPi are currently being investigated in adjuvant, neo-adjuvant, and metastatic settings as monotherapy or combination therapy in BC patients with BRCA1/2 mutation and HRD (Table 1). The FDA has approved olaparib and talazoparib in 2018 as monotherapies for gBRCAm HER2-negative metastatic BC.^{65, 66} Many completed and on-going clinical trials (~140 clinical trials) involving different PARPi, such as niraparib, olaparib, rucaparib, talazoparib, and veliparib, for BC and TNBC have been registered.

Table 1. Clinical trial outcomes of poly (adenosine diphosphate–ribose) polymerase inhibitors (olaparib and talazoparib) intervention studies in BRCA1/2-mutated patients with breast cancer.^a

Study design	Clinical trial identification number	Clinical trial status	Intervention	No. of patients	ORR in %	PFS in months	OS in months	Comparator	No. of patients	ORR in %	PFS in months	OS in months
Phase I, nonrandomized study⁵⁷	NCT00516373	Completed	Olaparib	19	47.3	NA	NA	None	NA	NA	NA	NA
Phase II, nonrandomized, multicenter, sequential cohort study⁵⁸	NCT00494234	Completed	Olaparib 400 mg	27	41	5.7	NA	None	NA	NA	NA	NA
	NCT00494234	Completed	Olaparib 100 mg	27	22	3.8	NA	None	NA	NA	NA	NA
Phase II, prospective, multicenter, nonrandomized study⁵⁹	NCT01078662	Ongoing	Olaparib	62a	12.9	3.7	11	None	NA	NA	NA	NA
Phase I, open-label, multicenter study⁶⁰	NCT00782574	Completed	Olaparib continuously or intermittently with cisplatin	42a	71	NA	NA	None	NA	NA	NA	NA
Phase I/Ib, open-label, dose-escalation study⁶¹	NCT01445418	Completed	Olaparib in combination with carboplatin	28	22	NA	NA	None	NA	NA	NA	NA
Phase III, randomized controlled, open-label, multicenter trial⁶²	NCT02000622	Ongoing	Olaparib	205	59.9	7	19.3	Treatment of physician's choice (capecitabine, vinorelbine, or eribulin)	97	28.8	4.2	17.1
Phase Ib, multicenter, open-label, classic 3 + 3 dose-escalation clinical trial	SU2C-AACR-DT16–15		Olaparib in combination with alpelisib	28	36	7.2	21.3	None	NA	NA	NA	NA
Phase 2, open-label, single-arm study⁶³	NCT02657889	Completed	Niraparib in combination with pembrolizumab	55	21	2.3	NA	None	NA	NA	NA	NA
Phase III, randomized, open-label trial⁶⁴	NCT01945775	Completed	Talazoparib	287	62.6	8.6	22.3	Treatment of physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine)	144	27.2	5.6	19.5

Note: All the clinical trial data was obtained from http://clinicaltrials.gov/.
Abbreviations: BRCA, breast cancer genes; NA, not available; NCT, National Clinical Trial number; ORR, objective response rate; OS, overall survival; PARPi, poly (adenosine diphosphate–ribose) polymerase inhibitors; PFS, progression-free survival.
^a Data of patients with breast cancer are only included; $Data of patients with breast cancer with deleterious BRCA1/2 mutations.

6.1 Olaparib

6.1.1 Olaparib as monotherapy

Olaparib, the first PARP-1 inhibitor approved by the FDA to treat primary peritoneal, ovarian or fallopian tube cancers, was developed by Kudos in collaboration with Maybridge.⁶⁷ A phase I trial (NCT00516373) on olaparib demonstrated antitumor activity in patients with gBRCAm ovarian and BC and advanced solid tumors.⁵⁷ Agreeable therapeutic index was observed in a phase II trial (ICEBERG, NCT00494234) in patients with confirmed BRCA mutations. It provided proof of concept for the efficacy of olaparib by showing an objective response rate (ORR) of 41% (11/27) in patients administered with olaparib 400 mg BID.⁵⁸ In 2014, a multicenter, open label, noncomparative phase II clinical trial (NCT01078662) examined the efficacy of olaparib monotherapy in patients with advanced recurrent cancer with a gBRCA1/2 mutation. Among them, 60% of 62 patients with BC had BRCA1 mutation. Tumor response rate was observed in 12.9% of patients with BC, with 46.8% of patients achieving stable disease (SD) after ≥8 weeks of olaparib treatment. The median duration of response was 29 weeks, and the PFS was observed in 29% of patients at 6 months. The median OS was 11 months, and 44.7% of patients were alive at the end of 12 months.⁶⁸

6.1.2 Olaparib as combination therapy

The combination of PARPi and immunotherapy has yielded promising outcomes in breast cancer patients. Olaparib is also given in combination with other cytotoxic drugs. A phase I study (NCT00782574) published in 2014 showed a 71% response rate (12/17 patients) to olaparib (50 mg, BID) plus cisplatin (60 mg/m²) combination therapy in patients with BRCA1/2 BC. However, higher doses of olaparib (100 or 200 mg BID) and cisplatin (75 mg/m²) were intolerable due to frequent grade 3 toxicities.⁶⁰ In a phase I/Ib trial, women with sporadic TNBC (75% pretreated) were given olaparib in combination with carboplatin (NCT01445418). The study shows 1 complete response (CR; 69+ months) and 5/27 partial responses (19%; median: 4 months [4-7]), with an ORR of 22%.⁶⁹ The FDA approval of olaparib was based on the phase III OlympiAD clinical trial. OlympiAD is a randomized, controlled, open-label, multicenter phase III trial (NCT02000622) comparing olaparib with standard therapy (capecitabine, eribulin, or vinorelbine) in HER2-negative early BC patients with gBRCAm. The trial observed median PFS (mPFS) of the olaparib arm to be ~67%, which is longer than the standard therapy arm (olaparib, 7.0 months; standard therapy, 4.2 months). The response rate was 59.9% with the olaparib arm (100 patients of 167) and 28.8% with the standard-therapy arm (19 of the 66 patients). Adverse events (AEs) rated grade 3 or higher occurred in 36.6% of patients in the olaparib arm and 50.5% in the standard-therapy arm.⁷⁰ A randomized, multicenter, open-label, phase 1b, classic 3 + 3 dose-escalation clinical trial evaluated combination therapy of olaparib with the PI3K inhibitor alpelisib in epithelial ovarian cancer and BC patients with known gBRCAm status. Synergistic approach of the combination resulted in an ORR of 31.3% in gBRCAwt platinum–resistant patients and 33.3% in BRCAwt (germline and somatic) platinum–resistant patients in a setting where ORR of ~ 5% is usually expected in monotherapy of the evaluated drugs. Grade 3+ treatment-related non-hematologic and hematologic toxicities occurred in ≥10% of patients with no unexpected toxicities and no irreversible toxicities.³⁵ In a phase I study, Olaparib was co-administered with durvalumab (anti-PD-L1 antibody) in 12 patients (2 were TNBC and 10 were ovarian cancer) which exhibited an 83% disease control rate.⁷¹

6.2 Niraparib

Niraparib was developed by Merck & Co., Inc., Rahway, NJ, USA and approved by the FDA in 2017 for ovarian and breast cancer, inhibits PARP-1 and PARP-2 and is metabolized by carboxylesterase and glucuronidation to form an inactive metabolite.⁷² In the TOPACIO (NCT02657889) study, the safety and efficacy of niraparib in combination with pembrolizumab was evaluated in metastatic TNBC patients. This open-label, single-arm, phase 2 study demonstrated an ORR of 27% and an mPFS of 8.3 months in patients with tBRCA mutations. Patients with BRCA wild-type tumors had a reduced ORR of 11% and an mPFS of 2.1 months. The most common grade ≥3 treatment-related AEs were anemia (18%), thrombocytopenia (15%), and fatigue (7%). Immune-related AEs were also observed in 15% of the study patients.⁷³

6.3 Talazoparib

Talazoparib inhibits PARP catalytic activity and traps PARP-1/2 on damaged DNA, used for breast cancer and prostate cancer, developed by Lead Therapeutics and BioMarin.⁷⁴ A dose-escalation phase I trial administered talazoparib either at 9 different dosage levels, ranging from 0.025 to 1.1 mg/day (arm 1), or at 1.0 mg/day (arm 2). In arm 1, higher ORR was observed in patients with BRCA 2 mutation (55%) compared with those with BRCA 1 mutation (38%). A higher clinical benefit rate (CBR) was also seen in patients with BRCA 2 mutation (91%) than those with BRCA1 mutation (50%). In arm 2 patients, an ORR of 50% was observed with a CBR of 86%. Five patients had SD for 24 weeks, and 1 patient had CR. Results from this study demonstrated the potency and tolerability of talazoparib.⁷⁵ The FDA approval for talazoparib for the treatment of patients with BRCA-mutated, HER2-negative, advanced or metastatic BC was based on the EMBRACA trial (NCT01945775). It is a phase III, open-label, randomized trial compared talazoparib with physician's choice of therapy (PCT) in patients with BC with advanced disease and gBRCAm. Talazoparib was administered to 288 patients, and 144 patients were treated with PCT. The mPFS for talazoparib patients and PCT patients was 8.6 months and 5.6 months, respectively. The OS was also higher in talazoparib patients (22.3 months) than that in PCT patients (19.5 months). The ORR was significantly higher in talazoparib patients (62.6%) than that in PCT patients (27.2%).⁷⁶ Apart from olaparib and talazoparib, other PARPi drugs, such as veliparib, niraparib, and rucaparib, were also evaluated as monotherapies and combination therapies, which showed promising results.

Although the results of PARPi in BC are promising, acquired resistance is conferred by various mechanism such as secondary mutation, HRR restoration, replication fork stabilization, and additionally other causes including altered cell cycle regulation, altered miRNA-622, miRNA-182 expression, altered PARP expression, and drug efflux is a cause of concern. Further challenges include dose-limiting toxicities and similar resistance mechanisms to combination drugs, which share a similar mechanism of action to that of PARPi.^77-83 This necessitates further research in identifying the subset of patients with BC for the maximum benefit from PARPi combination therapy and planning treatment strategies to overcome PARPi resistance.

7 LIMITATIONS OF HRD ASSAYS

Current HRD assays have certain limitations due to tumor heterogeneity, the presence of secondary variations in HR genes, the inability to detect non-HRR gene-related PARPi resistance, inability to report specific DNA abnormalities, the quality of tumor tissue samples and others.^{84, 85} Multiple reasons for the inconsistency between clinical PARPi responses and HRD assay results, including the timing, quality and quantity of samples, tumor heterogeneity, reversion mutations, and PARPi resistance mechanisms that are not related to HRD.^{84, 85} The assays determine HRD based on genomic scars, but they are unable to reflect dynamic changes in the homologous recombination function of the cells. For instance, in the ARIEL2 study, 117 patients had both pretreatment and archival tumor biopsies used for genomic LOH assays. 34% of patients with LOH-low in the initial biopsy turned out to be LOH-high in the later biopsy, and 30% of these patients had partial responses to rucaparib. Fresh tumor samples provide more accurate results due to tumor heterogeneity and clonal evolution.⁸⁶

8 FURTHER PROSPECTS OF PARP INHIBITORS IN THE TREATMENT OF BREAST CANCER WITH HRD APPROACH

Clinical trials for the elucidation of PARPi response based on HRD stratification are ongoing. Results from these trials are sought to investigate the applicability of HRD as a predictive maker for therapy decisions in patients with BC and that could add value to the modest evidence currently available. At present, the ongoing phase III BrighTNess trial, comparing veliparib plus carboplatin with carboplatin alone, may provide useful insights on the predictive value of HRD testing in patients with BC.³¹ This could expand the scope of HRD testing and benefit patients with BC in terms of treatment options. Several phase II clinical trials are in progress evaluating the efficacy of PARPi based on HR status. These include PARPi such as olaparib in the NOBROLA trial, rucaparib in the RUBY trial, and talazoparib in the TBB trial.^87-89 The efficacy of Olaparib is currently assessed in the NOBROLA trial where Olaparib monotherapy is administered to pretreated metastatic BC patients with HR mutation nonrelated to BRCA. HRD identification is performed in the NOBROLA trial by tumor tissue analysis using FMI Lynparza HRR assay.⁸⁷ The phase II RUBY trial evaluates rucaparib in patients with gBRCA wild-type metastatic BC. Early reports showed that the genome-wide assessment of LOH showed correlations with high LOH and antitumor activity. The final analysis using WGS will throw more light on HRD mutation signatures and their effects on treatment responses.⁸⁸ The preliminary reports of the phase II TBB trial show antitumor activity of talazoparib in HER2-negative metastatic in patients with BC having HR pathway mutation beyond BRCA.⁸⁹ In addition, another phase II trial is assessing the safety and efficacy of olaparib monotherapy and olaparib combination therapy with 2 different agents (olaparib + ceralasertib and olaparib + adavosertib) in patients with TNBC stratified based on mutation leading to HRD.⁹⁰ In the phase 2 clinical study (QUADRA), patients with HRD-BRCA positive tumors sensitive were selected using the Myriad HRD assay and were treated with niraparib treatment.⁹¹ The above studies might conclude the benefit of HRD testing in PARPi treatment in patients with BC.

HRD contributes to BC development, progression, and loss of response to therapy. HRD testing provides an opportunity to identify patients with BC who might benefit from a targeted therapy such as PARPi. Studies have shown clinical activity of therapeutic agents targeting HRD, such as PARPi, in ovarian cancer and BC. However, significant challenges are observed in the precision of treatment in such cancers. Clear evidence of HRD is required for drugs such as PARPi targeting HRD to be effective. At present, there is no robust, reliable, accurate biomarker available to identify HRD tumors. Although the gene-based assay, such as Myriad HRD assay, has shown promising challenges, reversion mutation in HRR genes could render it as ineffective. In addition, 15% of the tests are not informative, and PARPi response was also observed among HRD-negative patients. Furthermore, conflicting results in pCR rates based on HRD scoring threshold were observed due to the absence of global consensus for gene-based assays. However, the majority of studies employ gene-based assays for the detection of HRD to guide PARPi therapy in patients with BC. Hence, it is important to evaluate the clinical utility of the various functional HRD assays along with gene-based assays. Thus, HRD assays can be used to maximize the accuracy in predicting PARPi response in BRCA mutant in patients with BC and TNBC.

9 CONCLUSION

Homologous recombination deficiency testing may identify the subset of breast cancer patients who are likely to benefit from PARP inhibitor therapy in the future, but its predictive potential is debatable. Although an increasing number of studies validate the applicability of homologous recombination deficiency in treatment decisions, additional biomarkers such as RAD51 are highly necessary to optimize the effective use of PARP inhibitors in breast cancer patients. In the absence of a gold standard methodology to identify homologous recombination deficiency, this should remain an experimental benefit limited to the boundaries of clinical studies until concrete outcomes from ongoing trials are available.

AUTHOR CONTRIBUTIONS

All authors substantially contributed to planning, gathering, and interpreting the information or ideas used in the paper. During the process, they substantially contributed in providing suggestions for revision or critically reviewing subsequent iterations of the manuscript and ensured that questions regarding the accuracy or integrity of any part of the work were appropriately investigated and resolved. Finally, they all reviewed and approved the final version of the paper.

ACKNOWLEDGMENTS

The authors acknowledge Swathirajan CR, PhD and Roopa Subbaiah, PhD of Indegene Pvt Ltd for providing medical writing and editorial assistance.

CONFLICT OF INTEREST STATEMENT

Nan Ma is employed by MSD China. The remaining authors declare no conflict of interest.

Biographies

Peng Yuan is the chief physician and doctoral supervisor of Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College. She has been working in medical oncology department for more than 25 years and is devoted to the comprehensive treatment of breast cancer. She has rich experience in chemotherapy, immunotherapy and targeted therapy for solid tumors. She has been engaged in clinical and translational research of breast cancer for a long time and presided over several pre-marketing, marketing and clinical studies of new drugs. Her research interests focus on the molecular regulation mechanism of tumor metastasis and the clinical application of artificial intelligence to accurately predict tumor metastasis. Relevant research has been published in top international journals such as JAMA and she has been invited to give oral presentation and present poster in international conferences such as ESMO BC and ASCO. Dr. Peng Yuan participated in the compilation of 15 tumor treatment guidelines, including “Chinese Guidelines for Diagnosis and Treatment of Advanced Breast Cancer”, “Guidelines and Norms for Diagnosis and Treatment of Breast Cancer of Chinese Anti-Cancer Association”, and “Manual of Clinical Oncology Internal Medicine”. She is the director of the Chinese Anti-Cancer Association and the chairman of the International Medical and Cooperation Branch. She is also a member of the Standing Committee of Breast Cancer Professional Committee, and Breast Cancer Expert Committee of Chinese Society of Clinical Oncology (CSCO).
Nan Ma academic degree is Master of Oncology and worked as a medical oncologist for 7 years. Since then, she served in AZ as a Medical Science Liaison (MSL), and currently works as a Medical Advisor (MA) in MSD China. Her main field is the treatment of breast cancer. She has many years of experience in the field of tumor treatment, and she is good at the treatment and academic support of breast cancer and lung cancer.
Binghe Xu is the academician of Chinese Academy of Engineering, Director, National Clinical Research Center for New Anticancer Drugs, Former Director, Department of Medical Oncology at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS), and Tenured Professor of Peking Union Medical College (PUMC). He received his Doctorate of Philosophy and Master of Science degree in oncology from PUMC, and his Doctorate of Medicine from Wuhan University Medical College, China. His major interests are in basic and clinical research of solid tumors, especially breast cancer, as well as clinical trials of new anticancer agents. He has participated as principal investigator (PI) for more than 100 clinical trials. Currently, he is leading PI, executive steering committee (EC) as well as steering committee (SC) members of several regional and global multicenter clinical trials. Dr. Xu has published 430 papers in peer reviewed oncology journals, this includes papers published in journals such as Nature Medicine, Lancet Oncology, Annals of Oncology, Journal of Clinical Oncology, JAMA Oncology, Cancer Cell, Cancer Research, Clinical Cancer Research, and NEJM. Dr. Xu is a faculty member of European School of Medical Oncology. He is also a panel member of the St Gallen International Consensus on the Primary Therapy of Early Breast Cancer, ESMO Clinical Practice Guideline on eBC and International Consensus Guidelines for Advanced Breast Cancer. Dr. Xu has served on the editorial boards of 20 journals including The Breast, and the International Advisory Board Member of Lancet Oncology.

Open Research

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this review article as no new data were generated or analyzed.

REFERENCES

1Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71: 209-249.
10.3322/caac.21660
PubMed Web of Science® Google Scholar
2Mahdavi M, Nassiri M, Kooshyar MM, et al. Hereditary breast cancer; genetic penetrance and current status with BRCA. J Cell Physiol. 2019; 234: 5741-5750.
10.1002/jcp.27464
CAS PubMed Web of Science® Google Scholar
3Borri F, Granaglia A. Pathology of triple negative breast cancer. Sem Cancer Biol. 2021; 72: 136-145.
10.1016/j.semcancer.2020.06.005
CAS PubMed Web of Science® Google Scholar
4Barchiesi G, Roberto M, Verrico M, Vici P, Tomao S, Tomao F. Emerging role of PARP inhibitors in metastatic triple negative breast cancer. Current scenario and future perspectives. Front Oncol. 2021; 11: 1-16.
10.3389/fonc.2021.769280
Web of Science® Google Scholar
5Stoppa-Lyonnet D. The biological effects and clinical implications of BRCA mutations: where do we go from here? Eur J Human Genet. 2016; 24: S3-S9.
10.1038/ejhg.2016.93
CAS PubMed Web of Science® Google Scholar
6Pascual T, Gonzalez-Farre B, Teixidó C, et al. Significant clinical activity of olaparib in a somatic BRCA1-mutated triple-negative breast cancer with brain metastasis. JCO Precis Oncol. 2019; 3: 1-6.
10.1200/PO.19.00012
PubMed Web of Science® Google Scholar
7Keung M, Wu Y, Vadgama J. PARP inhibitors as a therapeutic agent for homologous recombination deficiency in breast cancers. J Clin Med. 2019; 8: 435.
10.3390/jcm8040435
CAS PubMed Web of Science® Google Scholar
8Wooten J, Mavingire N, Damar K, Loaiza-Perez A, Brantley E. Triumphs and challenges in exploiting poly(ADP-ribose) polymerase inhibition to combat triple-negative breast cancer. J Cell Physiol. 2023; 238: 1625-1640.
10.1002/jcp.31015
CAS PubMed Web of Science® Google Scholar
9Lee A, Djamgoz MBA. Triple negative breast cancer: emerging therapeutic modalities and novel combination therapies. Cancer Treat Rev. 2018; 62: 110-122.
10.1016/j.ctrv.2017.11.003
CAS PubMed Web of Science® Google Scholar
10Daly GR, AlRawashdeh MM, McGrath J, et al. PARP inhibitors in breast cancer: a short communication. Curr Oncol Rep. 2024; 26: 103-113.
10.1007/s11912-023-01488-0
CAS PubMed Web of Science® Google Scholar
11Gupta T, Vinayak S, Telli M. Emerging strategies: PARP inhibitors in combination with immune checkpoint blockade in BRCA1 and BRCA2 mutation-associated and triple-negative breast cancer. Breast Cancer Res Treat. 2023; 197: 51-56.
10.1007/s10549-022-06780-4
CAS PubMed Web of Science® Google Scholar
12Bordeleau L, Panchal S, Goodwin P. Prognosis of BRCA-associated breast cancer: a summary of evidence. Breast Cancer Res Treat. 2010; 119: 13-24.
10.1007/s10549-009-0566-z
CAS PubMed Web of Science® Google Scholar
13Balmaña J, Díez O, Rubio IT, Cardoso F. BRCA in breast cancer: ESMO clinical practice guidelines. Ann Oncol. 2011; 22: vi31-vi34.
10.1093/annonc/mdr373
PubMed Web of Science® Google Scholar
14Xu J, Wang B, Zhang Y, Li R, Wang Y, Zhang S. Clinical implications for BRCA gene mutation in breast cancer. Mol Biol Rep. 2012; 39: 3097-3102.
10.1007/s11033-011-1073-y
CAS PubMed Web of Science® Google Scholar
15Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015; 33: 304-311.
10.1200/JCO.2014.57.1414
CAS PubMed Web of Science® Google Scholar
16Hahnen E, Hauke J, Engel C, Neidhardt G, Rhiem K, Schmutzler RK. Germline mutations in triple-negative breast cancer. Breast Care. 2017; 12: 15-19.
10.1159/000455999
PubMed Web of Science® Google Scholar
17Mavaddat N, Barrowdale D, Andrulis IL, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012; 21: 134-147.
10.1158/1055-9965.EPI-11-0775
CAS PubMed Web of Science® Google Scholar
18Denkert C, Liedtke C, Tutt A, von Minckwitz G. Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. The Lancet. 2017; 389: 2430-2442.
10.1016/S0140-6736(16)32454-0
CAS PubMed Web of Science® Google Scholar
19Liao G, Yang Y, Xie A, et al. Applicability of anticancer drugs for the triple-negative breast cancer based on homologous recombination repair deficiency. Front Cell Dev Biol. 2022; 10: 1-14.
10.3389/fcell.2022.845950
Web of Science® Google Scholar
20Furlanetto J, Möbus V, Schneeweiss A, et al. Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy. Eur J Cancer. 2021; 145: 44-52.
10.1016/j.ejca.2020.12.007
CAS PubMed Web of Science® Google Scholar
21Creeden JF, Nanavaty NS, Einloth KR, et al. Homologous recombination proficiency in ovarian and breast cancer patients. BMC Cancer. 2021; 21: 1154.
10.1186/s12885-021-08863-9
CAS PubMed Web of Science® Google Scholar
22O'Shaughnessy J, Schwartzberg L, Danso MA, et al. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014; 32: 3840-3847.
10.1200/JCO.2014.55.2984
CAS PubMed Web of Science® Google Scholar
23Sharma P, Klemp JR, Kimler BF, et al. Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer Res Treat. 2014; 145: 707-714.
10.1007/s10549-014-2980-0
CAS PubMed Web of Science® Google Scholar
24Miller RE, Leary A, Scott CL, et al. ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer. Ann Oncol. 2020; 31: 1606-1622.
10.1016/j.annonc.2020.08.2102
CAS PubMed Web of Science® Google Scholar
25Hoppe MM, Sundar R, Tan DSP, Jeyasekharan AD. Biomarkers for homologous recombination deficiency in cancer. J Natl Cancer Inst. 2018; 110: 704-713.
10.1093/jnci/djy085
PubMed Google Scholar
26Loibl S, Weber KE, Timms KM, et al. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto. Ann Oncol. 2018; 29: 2341-2347.
10.1093/annonc/mdy460
CAS PubMed Web of Science® Google Scholar
27Chai Y, Chen Y, Zhang D, et al. Homologous recombination deficiency (HRD) and BRCA 1/2 gene mutation for predicting the effect of platinum-based neoadjuvant chemotherapy of early-stage triple-negative breast cancer (TNBC): a systematic review and meta-analysis. J Pers Med. 2022; 12: 323.
10.3390/jpm12020323
PubMed Web of Science® Google Scholar
28Pellegrino B, Musolino A, Llop-Guevara A, et al. Homologous recombination repair deficiency and the immune response in breast cancer: a literature review. Transl Oncol. 2020; 13: 410-422.
10.1016/j.tranon.2019.10.010
CAS PubMed Web of Science® Google Scholar
29Loverix L, Vergote I, Busschaert P, et al. Predictive value of the leuven HRD test compared with myriad mychoice PLUS on 468 ovarian cancer samples from the PAOLA-1/ENGOT-ov25 trial (LBA 6). Gynecol Oncol. 2022; 166: S51-S52.
10.1016/S0090-8258(22)01299-9
Web of Science® Google Scholar
30Telli ML, Timms KM, Reid J, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res. 2016; 22: 3764-3773.
10.1158/1078-0432.CCR-15-2477
CAS PubMed Web of Science® Google Scholar
31Loibl S, O'Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018; 19: 497-509.
10.1016/S1470-2045(18)30111-6
CAS PubMed Web of Science® Google Scholar
32Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013; 500: 415-421.
10.1038/nature12477
CAS PubMed Web of Science® Google Scholar
33Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nature Med. 2017; 23: 517-525.
10.1038/nm.4292
CAS PubMed Web of Science® Google Scholar
34Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015; 373: 2005-2014.
10.1056/NEJMoa1510764
CAS PubMed Web of Science® Google Scholar
35Konstantinopoulos PA, Spentzos D, Karlan BY, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010; 28: 3555-3561.
10.1200/JCO.2009.27.5719
CAS PubMed Web of Science® Google Scholar
36Vollebergh MA, Lips EH, Nederlof PM, et al. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann Oncol. 2011; 22: 1561-1570.
10.1093/annonc/mdq624
CAS PubMed Web of Science® Google Scholar
37Severson TM, Wolf DM, Yau C, et al. The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. Breast Cancer Res. 2017; 19: 99.
10.1186/s13058-017-0861-2
PubMed Web of Science® Google Scholar
38Subhash VV, Tan SH, Yeo MS, et al. ATM expression predicts veliparib and irinotecan sensitivity in gastric cancer by mediating P53-Independent regulation of cell cycle and apoptosis. Mol Cancer Ther. 2016; 15: 3087-3096.
10.1158/1535-7163.MCT-15-1002
CAS PubMed Web of Science® Google Scholar
39Kim HS, Kim MA, Hodgson D, et al. Concordance of ATM (Ataxia Telangiectasia Mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients. Pathobiology. 2013; 80: 127-137.
10.1159/000346034
CAS PubMed Web of Science® Google Scholar
40Bang Y-J, Im SA, Lee KW, et al. Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol. 2015; 33: 3858-3865.
10.1200/JCO.2014.60.0320
CAS PubMed Web of Science® Google Scholar
41Vergote I, González-Martín A, Ray-Coquard I, et al. European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer. Ann Oncol. 2022; 33: 276-287.
10.1016/j.annonc.2021.11.013
CAS PubMed Web of Science® Google Scholar
42van Wijk LM, Nilas AB, Vrieling H, Vreeswijk MPG. RAD51 as a functional biomarker for homologous recombination deficiency in cancer: a promising addition to the HRD toolbox? Expert Rev Mol Diagn. 2022; 22: 185-199.
10.1080/14737159.2022.2020102
PubMed Web of Science® Google Scholar
43Castroviejo-Bermejo M, Cruz C, Llop-Guevara A, et al. A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. EMBO Mol Med. 2018; 10:e9172.
10.15252/emmm.201809172
PubMed Web of Science® Google Scholar
44Ladan MM, van Gent DC, Jager A. Homologous recombination deficiency testing for BRCA-Like tumors: the road to clinical validation. Cancers. 2021; 13: 1004.
10.3390/cancers13051004
CAS PubMed Web of Science® Google Scholar
45Fasching PA, Jackisch C, Rhiem K, et al. GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD). J Clin Oncol. 2019; 37:506506.
Web of Science® Google Scholar
46Mayer EL, Abramson V, Jankowitz R, et al. TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker. Ann Oncol. 2020; 31: 1518-1525.
10.1016/j.annonc.2020.08.2064
CAS PubMed Web of Science® Google Scholar
47Llop-Guevara A, Loibl S, Villacampa G, et al. Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. Ann Oncol. 2021; 32: 1590-1596.
10.1016/j.annonc.2021.09.003
CAS PubMed Web of Science® Google Scholar
48Tutt A, Tovey H, Cheang MCU, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nature Med. 2018; 24: 628-637.
10.1038/s41591-018-0009-7
CAS PubMed Web of Science® Google Scholar
49Telli ML, Hellyer J, Audeh W, et al. Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer. Breast Cancer Res Treat. 2018; 168: 625-630.
10.1007/s10549-017-4624-7
CAS PubMed Web of Science® Google Scholar
50Yu L, Yan Z, Wang Y, et al. Recent advances in structural types and medicinal chemistry of PARP-1 inhibitors. Med Chem Res. 2022; 31: 1265-1276.
10.1007/s00044-022-02919-6
CAS Web of Science® Google Scholar
51Wahlberg E, Karlberg T, Kouznetsova E, et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nature Biotechnol. 2012; 30: 283-288.
10.1038/nbt.2121
CAS PubMed Web of Science® Google Scholar
52Jain PG, Patel BD. Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents—a recent update. Eur J Med Chem. 2019; 165: 198-215.
10.1016/j.ejmech.2019.01.024
CAS PubMed Web of Science® Google Scholar
53Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434: 917-921.
10.1038/nature03445
CAS PubMed Web of Science® Google Scholar
54Rose M, Burgess JT, O'Byrne K, Richard DJ, Bolderson E. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol. 2020; 8: 1-22.
10.3389/fcell.2020.564601
PubMed Web of Science® Google Scholar
55Keung MY, Wu Y, Badar F, Vadgama JV. Response of breast cancer cells to PARP inhibitors is independent of BRCA status. J Clin Med. 2020; 9: 940.
10.3390/jcm9040940
CAS PubMed Web of Science® Google Scholar
56den Brok WD, Schrader KA, Sun S, et al. Homologous recombination deficiency in breast cancer: a clinical review. JCO Precis Oncol. 2017; 1: 1-13.
10.1200/PO.16.00031
Web of Science® Google Scholar
57Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009; 361: 123-134.
10.1056/NEJMoa0900212
CAS PubMed Web of Science® Google Scholar
58Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. The Lancet. 2010; 376: 235-244.
10.1016/S0140-6736(10)60892-6
CAS PubMed Web of Science® Google Scholar
59Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016; 140: 199-203.
10.1016/j.ygyno.2015.12.020
CAS PubMed Web of Science® Google Scholar
60Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol. 2014; 25: 1656-1663.
10.1093/annonc/mdu187
CAS PubMed Web of Science® Google Scholar
61Lee J-M, Hays JL, Annunziata CM, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. JNCI: J Natl Cancer Inst. 2014; 106:dju089.
10.1093/jnci/dju089
Web of Science® Google Scholar
62Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019; 30: 558-566.
10.1093/annonc/mdz012
CAS PubMed Web of Science® Google Scholar
63Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019; 5: 1141-1149.
10.1001/jamaoncol.2019.1048
PubMed Web of Science® Google Scholar
64Hurvitz SA, Gonçalves A, Rugo HS, et al. Talazoparib in patients with a germline BRCA-mutated advanced breast cancer: detailed safety analyses from the phase III EMBRACA trial. Oncologist. 2020; 25: e439-e450.
10.1634/theoncologist.2019-0493
CAS PubMed Web of Science® Google Scholar
65 US Food and Drug Administration. FDA approves first treatment for breast cancer with a certain inherited genetic mutation. 2018. Accessed May 31, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-breast-cancer-certain-inherited-genetic-mutation
Google Scholar
66 US Food and Drug Administration. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. 2022. Accessed March 31, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-gbrcam-her2-negative-locally-advanced-or-metastatic-breast-cancer#:~:text=On%20October%2016%2C%202018%2C%20the,advanced%20or%20metastatic%20breast%20cancer
Google Scholar
67Liu FW, Tewari KS. New targeted agents in gynecologic cancers: synthetic lethality, homologous recombination deficiency, and PARP inhibitors. Curr Treat Options Oncol. 2016; 17: 12.
10.1007/s11864-015-0378-9
PubMed Web of Science® Google Scholar
68Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015; 33: 244-250.
10.1200/JCO.2014.56.2728
CAS PubMed Web of Science® Google Scholar
69Lee J-M, Hays JL, Chiou VL, et al. Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer. Oncotarget. 2017; 8: 79175-79187.
10.18632/oncotarget.16577
PubMed Google Scholar
70Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017; 377: 523-533.
10.1056/NEJMoa1706450
CAS PubMed Web of Science® Google Scholar
71Lee J-M, Cimino-Mathews A, Peer CJ, et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-Ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women's cancers: a dose-escalation, phase I study. J Clin Oncol. 2017; 35: 2193-2202.
10.1200/JCO.2016.72.1340
CAS PubMed Web of Science® Google Scholar
72Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016; 375: 2154-2164.
10.1056/NEJMoa1611310
CAS PubMed Web of Science® Google Scholar
73Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019; 5: 1132-1140.
10.1001/jamaoncol.2019.1029
PubMed Web of Science® Google Scholar
74Shen Y, Rehman FL, Feng Y, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013; 19: 5003-5015.
10.1158/1078-0432.CCR-13-1391
CAS PubMed Web of Science® Google Scholar
75de Bono J, Ramanathan RK, Mina L, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov. 2017; 7: 620-629.
10.1158/2159-8290.CD-16-1250
PubMed Web of Science® Google Scholar
76Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018; 379: 753-763.
10.1056/NEJMoa1802905
CAS PubMed Web of Science® Google Scholar
77Kim Y, Kim A, Sharip A, et al. Reverse the resistance to PARP inhibitors. Int J Biol Sci. 2017; 13: 198-208.
10.7150/ijbs.17240
CAS PubMed Web of Science® Google Scholar
78Bitler BG, Watson ZL, Wheeler LJ, Behbakht K. PARP inhibitors: clinical utility and possibilities of overcoming resistance. Gynecol Oncol. 2017; 147: 695-704.
10.1016/j.ygyno.2017.10.003
CAS PubMed Web of Science® Google Scholar
79Barber LJ, Sandhu S, Chen L, et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J Pathol. 2013; 229: 422-429.
10.1002/path.4140
CAS PubMed Web of Science® Google Scholar
80Makvandi M, Xu K, Lieberman BP, et al. A radiotracer strategy to quantify PARP-1 expression in vivo provides a biomarker that can enable patient selection for PARP inhibitor therapy. Cancer Res. 2016; 76: 4516-4524.
10.1158/0008-5472.CAN-16-0416
CAS PubMed Web of Science® Google Scholar
81Ray Chaudhuri A, Callen E, Ding X, et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature. 2016; 535: 382-387.
10.1038/nature18325
CAS PubMed Web of Science® Google Scholar
82Tapodi A, Debreceni B, Hanto K, et al. Pivotal role of Akt activation in mitochondrial protection and cell survival by poly(ADP-ribose)polymerase-1 inhibition in oxidative stress. J Biol Chem. 2005; 280: 35767-35775.
10.1074/jbc.M507075200
CAS PubMed Web of Science® Google Scholar
83Veres B, Gallyas F, Varbiro G, et al. Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock. Biochem Pharmacol. 2003; 65: 1373-1382.
10.1016/S0006-2952(03)00077-7
CAS PubMed Web of Science® Google Scholar
84Chiang Y-C, Lin P-H, Cheng W-F. Homologous recombination deficiency assays in epithelial ovarian cancer: current status and future direction. Front Oncol. 2021; 11:675972.
10.3389/fonc.2021.675972
CAS PubMed Web of Science® Google Scholar
85Mangogna A, Munari G, Pepe F, et al. Homologous recombination deficiency in ovarian cancer: from the biological rationale to current diagnostic approaches. J Pers Med. 2023; 13: 284.
10.3390/jpm13020284
PubMed Web of Science® Google Scholar
86Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017; 18: 75-87.
10.1016/S1470-2045(16)30559-9
CAS PubMed Web of Science® Google Scholar
87Aguirre E, Amillano K, Cortés A, et al. Abstract CT165: a two-stage simon design phase II study for NOn-BRCA metastatic BReast cancer (MBC) patients with homologous recombination deficiency treated with OLAparib single agent.(NOBROLA study). Cancer Res. 2018; 78:CT165CT165.
10.1158/1538-7445.AM2018-CT165
Web of Science® Google Scholar
88Patsouris A, Tredan O, Nenciu D, et al. RUBY: a phase II study testing rucaparib in germline (g) BRCA wild-type patients presenting metastatic breast cancer (mBC) with homologous recombination deficiency (HRD). J Clin Oncol. 2019; 37:10921092.
10.1200/JCO.2019.37.15_suppl.1092
Web of Science® Google Scholar
89Gruber JJ, Afghahi A, Hatton A, et al. Talazoparib beyond BRCA: a phase II trial of talazoparib monotherapy in BRCA1 and BRCA2 wild-type patients with advanced HER2-negative breast cancer or other solid tumors with a mutation in homologous recombination (HR) pathway genes. J Clin Oncol. 2019; 37:30063006.
10.1200/JCO.2019.37.15_suppl.3006
Web of Science® Google Scholar
90Tutt A, Stephens C, Frewer P, et al. VIOLETTE: a randomized phase II study to assess DNA damage response inhibitors in combination with olaparib (Ola) vs ola monotherapy in patients (pts) with metastatic, triple-negative breast cancer (TNBC) stratified by alterations in homologous recombination repair (HRR)-related genes. J Clin Oncol. 2018; 36:TPS1116.
10.1200/JCO.2018.36.15_suppl.TPS1116
Web of Science® Google Scholar
91Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019; 20: 636-648.
10.1016/S1470-2045(19)30029-4
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume44, Issue6

November 2024

Pages 2774-2792

Poly (adenosine diphosphate-ribose) polymerase inhibitors in the treatment of triple-negative breast cancer with homologous repair deficiency

Abstract

1 INTRODUCTION

2 PREVALENCE AND IMPACT OF BRCA MUTATION AND HRD IN BC