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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 7  |  Page : 1672-1678

Efficacy and safety of poly (ADP-ribose) polymerase inhibitors therapy for BRCA-mutated breast cancer: A systematic review and meta-analysis


1 Department of Clinical Laboratory, Jiaxing Maternity and Child Health Care Hospital, Jiaxing, China
2 Department of Oncology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
3 Department of Prenatal Diagnostic, Jiaxing Maternity and Child Health Care Hospital, Jiaxing, China
4 Department of Clinical Laboratory, Jiaxing Maternity and Child Health Care Hospital, Jiaxing; Shandong Provincial Key Laboratory for Rheumatic Disease and Translational medicine, Jinan, China

Date of Submission17-Nov-2021
Date of Acceptance11-Dec-2021
Date of Web Publication10-Mar-2022

Correspondence Address:
Lili Cao
No. 16766 Jingshi Road, Jinan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_2085_21

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 > Abstract 


Background: To evaluate the efficacy, safety, and potential advantages of Poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA-mutated breast cancer, we performed a meta-analysis of published studies.
Materials and Methods: Four randomized controlled trials (RCTs) were included in the meta-analysis. Data analysis was conducted in Review Manager 5.4.
Results: The progression-free survival (PFS) of the patients with triple-negative (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.74–0.88; P < 0.00001) or hormone receptor-positive (HR 0.83; 95% CI 0.77-0.91; P < 0.0001) BRCA-mutated breast cancer was significantly extended in the containing PARPi therapy arm versus the chemotherapy arm. PFS of the patients who did not receive platinum-based therapy (HR 0.78; 95% CI 0.70–0.86; P < 0.0001) was significantly extended in the PARPi monotherapy arm versus the chemotherapy arm. The objective response rate of patients treated by PARPi monotherapy (risk ratio [RR] 2.51; 95% CI 1.81–3.47; P < 0.00001) was significantly higher than that of patients treated by chemotherapy. The incidence of thrombocytopenia in patients received PARPi combined therapy was obviously increased compared with chemotherapy group (RR 1.36; 95% CI 1.07–1.72; P = 0.01). PARPi monotherapy markedly increased the incidence of anemia (RR 5.83; 95% CI 2.64–12.88; P < 0.0001) versus chemotherapy. However, the risk of neutropenia (RR 0.48; 95% CI 0.29–0.81; P = 0.006) was reduced in the PARPi monotherapy arm. There were no statistical differences in other adverse events among these three groups.
Conclusions: PARPi combined therapy and monotherapy improved PFS of patients with BRCA-mutated breast cancer compared with standard chemotherapy, which was unrelated to type of BRCA mutation and status of hormone receptor. PARPi therapy has slightly higher hematological toxicity and better overall safety and tolerance.
Prospero registration number: CRD42020204385.

Keywords: BRCA-mutated breast cancer, chemotherapy, Poly (ADP-ribose) polymerase inhibitors combined therapy, Poly (ADP-ribose) polymerase inhibitors monotherapy


How to cite this article:
Zhang M, Yu X, Wang J, Li Y, Cao L. Efficacy and safety of poly (ADP-ribose) polymerase inhibitors therapy for BRCA-mutated breast cancer: A systematic review and meta-analysis. J Can Res Ther 2021;17:1672-8

How to cite this URL:
Zhang M, Yu X, Wang J, Li Y, Cao L. Efficacy and safety of poly (ADP-ribose) polymerase inhibitors therapy for BRCA-mutated breast cancer: A systematic review and meta-analysis. J Can Res Ther [serial online] 2021 [cited 2022 Sep 30];17:1672-8. Available from: https://www.cancerjournal.net/text.asp?2021/17/7/1672/339237




 > Introduction Top


The most common malignancy in women is breast cancer, which is also the main cause of death for women.[1],[2] Breast cancer includes 21 different histologic and 4 molecular types, which are classified by pathological and molecular characteristics of breast cancer.[3],[4] Every subtype of breast cancer needs a specific treatment and has a different prognosis.[5]

Deleterious mutations in BRCA susceptibility genes, including BRCA1 and BRCA2, are closely related to the occurrence and development of breast cancer, especially triple-negative breast cancer (TNBC). These studies showed that ≥75% of breast cancer patients carrying a BRCA mutation had TNBC.[6] However, the prognosis of TNBC is the poorest of all types of breast cancer, and this is related to the lack of target therapies.[4] Poly (ADP-ribose) polymerase inhibitors (PARPi) disrupt DNA repair through inhibition of PARP enzyme activity and poly-ADP-ribosylation reactions.[7] Studies have found that PARPi can induce synthetic lethality in BRCA1-or BRCA2-mutated cancer as early as 2005.[8],[9] The discoveries provide new target treatment forms for breast cancer with BRCA mutation, especially TNBC. Some studies have explored the effectiveness of PARPi for breast cancer with mutations in BRCA and their latest results are published.[10],[11],[12],[13] To provide newest and more reliable reference for the clinicians, we conducted this meta-analysis to evaluate the efficacy and safety of PARPi for BRCA-mutated breast cancer.


 > Materials and Methods Top


This article started to be written in October 2020. It has been registered in PROSPERO (No. CRD42020204385). This meta-analysis was conducted in light of the Cochrane Collaboration criteria. We investigated all randomized controlled trials (RCTs) published to date in our study. We searched the PubMed, Embase Medline, and Cochrane databases. Our search strategy included the following key words: “veliparib,” “talazoparib,” “olaparib,” “rucaparib,” “niraparib,” “breast cancer,” and “randomized controlled trial.” No language restrictions were used in our search strategy.

Study selection criteria

Eligible articles needed to meet the following criteria: (1) RCTs; (2) PARPi + chemotherapy combined therapy vs chemotherapy or PARPi monotherapy vs chemotherapy for BRCA-mutated breast cancer; (3) data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) of PARPi combined therapy or PARPi monotherapy; (4) any stage of breast cancer; and (5) human studies. Exclusion criteria included (1) dose-finding trials; (2) placebo-controlled trials; and (3) designs of trials.

Data extraction

Two investigators (MYZ and XSY) independently searched articles from the PubMed, Embase Medline, and Cochrane databases and subsequently extracted data according to the prespecified data form. Some important data that needed to be extracted from the studies included the name of the first author, time of publication, patient features, inventions, follow-up time, number of participants in every group, Kaplan–Meier curves, OS and PFS, ORR and grade 3 or higher AEs (i.e., anemia, leucopenia, neutropenia, thrombocytopenia, back pain, diarrhea, fatigue, nausea, and vomiting). The risk of bias, random sequence generation, allocation concealment, blinding method, and number of participants lost to follow-up were also extracted and evaluated.

Quality assessment

The risk of bias of all articles was assessed independently by two authors used the Cochrane risk of bias tool in Review Manager 5.4 (The Cochrane Collaboration, Oxford, UK).

Statistical analysis

The data of all patients who met the selection criteria were analyzed. The primary endpoints consisted of OS, PFS, and ORR. The secondary endpoints were AEs in this meta-analysis. The hazard ratio (HR) was used to evaluate the OS and PFS. The risk ratio (RR) was utilized to assess the ORR and AEs.

Both χ2 and I2 were used to estimate heterogeneity of the results of the trials. If total I2 ≥50%, the heterogeneity was judged as high level, and random-effect model was utilized. Otherwise, fixed-effect model was used. Subgroup analysis was conducted, according PARPi was used either alone or in combination with chemotherapy, the hormone receptor of patients was positive or triple-negative, participants had received previous platinum treatment or not, and patients had BRCA1 or BRCA2 mutations. All statistical analyses were performed through Review Manager 5.4.


 > Results Top


Study selection and characteristics

We collected 498 articles from three databases, and 64 full-text articles were evaluated for eligibility. Finally, 4 RCTs were included in this meta-analysis. The details of the article selection are presented in the PRISMA flowchart [Figure 1]. A total of 1438 patients from 4 RCTs were included in this meta-analysis. Characteristics of the eligible studies are listed in [Table 1].
Figure 1: Study selection flow chart

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Table 1: Characteristics of studies

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Quality assessment

Four studies included in our meta-analysis were RCTs, and quality assessment was conducted in Review Manager 5.4. Selection bias, detection bias, reporting bias, and other bias of most studies were regarded as having a “low risk of bias.” However, performance bias and attrition bias were judged as having a “high risk of bias” [Figure 2].
Figure 2: The results of quality assessment. Plus symbol, low risk of bias; question mark, unknown risk of bias; minus symbol, high risk of bias

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Overall survival

PARPi combined therapy (HR 0.95; 95% confidence interval [CI] 0.86–1.04; P = 0.27) and monotherapy (HR 0.92; 95% CI 0.84–1.02; P = 0.11) did not improve OS compared to chemotherapy [Supplementary Figure 1].



Progression-free survival

PARPi combined therapy (HR 0.87; 95% CI 0.80–0.95; P = 0.001) and monotherapy (HR 0.78; 95% CI 0.71–0.85; P < 0.00001) significantly prolong the PFS of patients with BRCA-mutated breast cancer compared to that of the chemotherapy group. Given the type of BRCA, our results showed that PARPi combined therapy apparently improved the PFS of patients with BRCA1 (HR 0.87; 95% CI 0.78–0.97; P = 0.01) or BRCA2 (HR 0.85; 95% CI 0.75–0.95; P = 0.006) mutation versus that of the chemotherapy. Moreover, PARPi monotherapy obviously extended the PFS of patients with BRCA1 (HR 0.78; 95% CI 0.69–0.88; P < 0.0001) or BRCA2 (HR 0.78; 95% CI 0.69–0.88; P = 0.0001) mutation vs that of the chemotherapy. In view of hormone-receptor status, we found that PARPi combined therapy and monotherapy significantly extended the PFS of TNBC (HR 0.88; 95% CI 0.79–1.00; P = 0.04 and HR 0.75; 95% CI 0.66–0.84; P < 0.00001) or hormone-receptor positive (HR 0.85; 95% CI 0.76–0.95; P = 0.004 and HR 0.81; 95% CI 0.72–0.92; P < 0.0001) patients compared to chemotherapy. Whether the patients received platinum-based treatment was taken into account, although the PFS of the patients who did not receive platinum-based therapy was prolonged by PARPi monotherapy (HR 0.78; 95% CI 0.70–0.86; P < 0.0001), and the PFS of the patients who had accepted platinum-based therapy was similar in both the PARPi monotherapy arm and the chemotherapy arm (HR 0.86; 95% CI 0.73–1.03; P = 0.10) [Figure 3].
Figure 3: Forest plot for progression-free survival. (a) progression-free survival of all patients, (b) progression-free survival of patients with a BRCA1, (c) progression-free survival of patients with a BRCA2 mutation, (d) progression-free survival of patients with triple-negative breast cancer, (e) progression-free survival of patients with hormone-positive breast cancer, (f) progression-free survival of patients who had or had not received platinum-based chemotherapy; yes, patients had or had not received platinum-based chemotherapy; no, patients had not received platinum-based chemotherapy

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Objective response rate

We found that the ORRs of the PARPi monotherapy arm were obviously higher than those of the chemotherapy arm (RR 2.51; 95% CI 1.81–3.47; P < 0.00001). Unfortunately, PARPi combined therapy did not increase the ORRs of patients vs the chemotherapy (RR 1.12; 95% CI 0.91–1.38; P = 0.30) [Figure 4]a.
Figure 4: Forest plot for objective response rate and grade 3 or higher adverse events.(a) ORR, (b) anemia, (c) neutropenia, (d) thrombocytopenia

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Grade 3 or higher adverse events

Hematotoxicity events

Four hematotoxicity events were evaluated in this meta-analysis. PARPi combined therapy obviously increased the incidence of thrombocytopenia compared to chemotherapy (RR 1.36; 95% CI 1.07–1.72; P = 0.01). However, the risks of anemia (RR 1.05; 95% CI 0.85–1.30; P = 0.64), neutropenia (RR 0.97; 95% CI 0.90–1.05; P = 0.49), and leukopenia (RR 0.70; 95% CI 0.28–1.73; P = 0.44) were not different between PARPi combined therapy and chemotherapy. PARPi monotherapy obviously reduced the risk of neutropenia vs the chemotherapy (RR 0.48; 95% CI 0.29–0.81; P = 0.006).The risk of leucopenia was similar between the PARPi monotherapy arm and the chemotherapy arm (RR 0.76; 95% CI 0.40–1.43; P = 0.39). However, PARPi monotherapy markedly increased the incidence of anemia compared to chemotherapy (RR 5.83; 95% CI 2.64–12.88; P < 0.0001) [Figure 4]b, [Figure 4]c, [Figure 4]d [Supplementary Figure 2]a.



Nonhematotoxicity events

Our meta-analysis also assessed 5 nonhematotoxicity events. The incidence of the following 5 AEs was not different between PARPi combined therapy and chemotherapy: Back pain (RR 1.39; 95% CI 0.40–4.78; P = 0.60), diarrhea (RR 1.04; 95% CI 0.39–2.79; P = 0.94), fatigue (RR 1.24; 95% CI 0.66–2.34; P = 0.51), nausea (RR 1.29; 95% CI 0.59–2.82; P = 0.52), vomiting (RR 1.97; 95% CI 0.64–6.07; P = 0.24). Moreover, the risks of the 5 AEs were similar between PARPi monotherapy and chemotherapy: Back pain (RR 1.62; 95% CI 0.46–5.75; P = 0.46), diarrhea (RR 0.27; 95% CI 0.03–2.33; P = 0.23), fatigue (RR 1.06; 95% CI 0.38–2.98; P = 0.91), nausea (RR 0.19; 95% CI 0.0.3-1.28; P = 0.09), and vomiting (RR 0.95; 95% CI 0.27–3.34; P = 0.93) [Supplementary Figure 2]b, [Supplementary Figure 2]c, [Supplementary Figure 2]d, [Supplementary Figure 2]e, [Supplementary Figure 2]f.


 > Discussion Top


Studies have explored the effectiveness of PARPi for breast cancer with mutations in BRCA and their latest results has been updated. To provide newest and more reliable reference for the clinicians, we conducted this meta-analysis to evaluate the efficacy and safety of PARPi for breast cancer. In general, our meta-analysis consisted of 4 RCTs, of which two compared PARPi combined therapy with chemotherapy for breast cancer, and the two other trials compared PARPi monotherapy with chemotherapy for BRCA-mutated breast cancer. We found that PARPi combined therapy and monotherapy did not prolong the OS vs chemotherapy arm. However, the PFS of PARPi combined therapy and monotherapy compared with chemotherapy was extended, which was unrelated to type of BRCA mutation and status of hormone receptor. Our results demonstrated that PARPi monotherapy increased the ORR compared to chemotherapy. The incidence of all grade 3 or higher AEs, except anemia, neutropenia and thrombocytopenia, was similar in both the containing PARPi therapy group and the chemotherapy group.

We discovered that the PFS of PARPi combined therapy and monotherapy compared with chemotherapy were extended, which were concerned with type of BRCA mutation and status of hormone receptor. The results indicated that it is essential to detect the status of BRCA mutation before using PARPi therapy. Moreover, the efficacy of PARPi therapy for BRCA-mutated breast cancer may be affected by status of hormone receptor. Notably, patients who did not receive platinum-based therapy may benefit from PARPi monotherapy, but patients who had received platinum-based therapy could not benefit from PARPi monotherapy. This may be because platinum and PARP inhibitors have the same resistance mechanism.[14] Patients who had received platinum-based therapy were more likely to have platinum resistance, which also enhanced the probability that patients possessed PARPi resistance. However, the standard single-agent chemotherapy which compared to PARPi monotherapy did not include the platinum chemotherapy. Moreover, one study showed that the PFS and ORR of patients with BRCA-mutated breast cancer who had received the carboplatin monotherapy was similar with PARPi monotherapy.[11],[12],[15] Combining PARPi monotherapy and platinum chemotherapy might have higher efficacy in BRCA-mutated breast cancer, which might avoid cross-resistance. The results of our article are consistent with the meta-analysis from Poggio et al.,[16] which compared PARPi monotherapy with chemotherapy for BRCA-mutated breast cancer.

PARPi monotherapy obviously improved the ORR compared with standard single-agent chemotherapy, but the ORR of PARPi combined therapy was not better than those of chemotherapy. One previous study, the I-SPY 2 trial, demonstrated that treatment with additional veliparib did not contribute to response rate compared to the treatment of only paclitaxel plus carboplatin followed by doxorubicin and cyclophosphamide.[17] These results demonstrated that platinum drugs play a crucial role in improving the ORR in combined therapy, not PARPi agents.

In terms of toxicity, PARPi monotherapy obviously decreased the risks of neutropenia compared to chemotherapy. However, PARPi monotherapy increased the incidence of anemia. Moreover, the risk of thrombocytopenia was increased in PARPi combined therapy vs chemotherapy. The results were similar with those of Zhou et al., who demonstrated that PARPi therapy increased the risk of Grade 3 or higher hematologic toxicity events.[18] The incidence of the other Grade 3 or higher AEs did not have difference between the PARPi therapy group and the chemotherapy group. Increased hematologic toxicity events might be associated with myelosuppression of PARPi therapy. Hence, dose of PARPi must be taken with caution.

It is noteworthy that our meta-analysis had some strengths. Our meta-analysis contained four trials that were all RCTs, and we conducted subgroup analyses. These were instrumental in decreasing heterogeneity. Furthermore, we excluded some RCTs that only designed PARPi therapy versus placebo control therapy. This made our data more reliable. However, there were some limitations in our study. First, the number of trials and patients contained in every subgroup were few. Second, the results did not reflect individual reactions to PARPi therapy.

It is obvious that more clinical trials will need to be carried out in the future to provide more reliable evidence. First, RCTs that explore whether additional high-dose veliparib can benefit patients with breast cancer are needed. Second, RCTs that explore the efficacy of PARPi and platinum-based chemotherapy are needed. Finally, and most importantly, the RCTs should have a large sample size and high quality.


 > Conclusions Top


PARPi combined therapy and monotherapy improved PFS of patients with BRCA-mutated breast cancer compared with standard chemotherapy, which was unrelated to type of BRCA mutation and status of hormone receptor. PARPi therapy has slightly higher hematological toxicity and better overall safety and tolerance.

Acknowledgment

This work was supported by grants from the Shandong Provincial Key Research and Development Program (SPKR&DP, 2019GSF108180), Jinan Science and Technology Development Plan (201907119), Cultivation Fund for the First Affiliated Hospital of Shandong First Medical University (QYPY2019NSFC1015).

Financial support and sponsorship

The study was financially supported by Shandong Provincial Key Research and Development (Program SPKR&DP, 2019GSF108180), Jinan Science and Technology Development Plan (201907119), Cultivation Fund for the First Affiliated Hospital of Shandong First Medical University (QYPY2019NSFC1015).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature 2005;434:913-7.  Back to cited text no. 9
    
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Han HS, Diéras V, Robson M, Palácová M, Marcom PK, Jager A, et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: Randomized phase II study. Ann Oncol 2018;29:154-61.  Back to cited text no. 10
    
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Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753-63.  Back to cited text no. 11
    
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Robson ME, Tung N, Conte P, Im SA, Senkus E, Xu B, 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;30:558-66.  Back to cited text no. 12
    
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Diéras V, Han HS, Kaufman B, Wildiers H, Friedlander M, Ayoub JP, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:1269-82.  Back to cited text no. 13
    
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Fojo T, Bates S. Mechanisms of resistance to PARP inhibitors-three and counting. Cancer Discov 2013;3:20-3.  Back to cited text no. 14
    
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Tutt A, Tovey H, Cheang MC, Kernaghan S, Kilburn L, Gazinska P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT Trial. Nat Med 2018;24:628-37.  Back to cited text no. 15
    
16.
Poggio F, Bruzzone M, Ceppi M, Conte B, Martel S, Maurer C, et al. Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: A systematic review and meta-analysis. ESMO Open 2018;3:e000361.  Back to cited text no. 16
    
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Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 2016;375:23-34.  Back to cited text no. 17
    
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Zhou JX, Feng LJ, Zhang X. Risk of severe hematologic toxicities in cancer patients treated with PARP inhibitors: A meta-analysis of randomized controlled trials. Drug Des Devel Ther 2017;11:3009-17.  Back to cited text no. 18
    


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