Dataset Information

BRCA1 Versus BRCA2 and PARP Inhibitors Efficacy in Solid Tumors:A Meta-Analysis of Randomized Controlled Trials

ABSTRACT:

Background

BRCA2 mutation has a more substantial impact on the homologous recombination and superior therapeutic response to platinum-based chemotherapy than BRCA1 mutation. Whether BRCA2-mutated patients could benefit more from PARPi than BRCA1-mutated patients remains unclear. We performed a meta-analysis to assess the efficacy difference of PARPi between BRCA1 mutation carriers and BRCA2 mutation carriers.

Methods

Pubmed, Embase, and Cochrane Library were comprehensively searched for randomized controlled trials (RCTs) of PARPi that had available hazard ratios (HRs) of progression-free survival (PFS) in both BRCA1-mutated population and BRCA2-mutated population. We calculated the pooled PFS HRs and 95%CI using randomized-effect models, and the difference between the two estimates was compared by interaction test.

Results

A total of 11 eligible RCTs of high quality were identified through search. Overall, 1544 BRCA1 mutation carriers and 1191 BRCA2 mutation carriers were included in the final analysis. The pooled PFS HR was 0.42 (95% CI: 0.35-0.50) in BRCA1-mutated patients who were treated with PARPi compared with patients in the control group. In BRCA2-mutated patients treated with PARPi, the pooled PFS HR compared with the control groups was 0.35 (95% CI: 0.24-0.51). The difference in efficacy of PARPi was not significant between the two subgroups (Pheterogeneity = 0.40, for interaction).

Conclusion

BRCA1-mutated patients and BRCA2-mutated patients could benefit from PARPi, and the efficacy is comparable. Currently, there is no evidence that BRCA2-mutated patients would benefit more from PARPi than BRCA1-mutated patients.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42020214582.

SUBMITTER: Li S

PROVIDER: S-EPMC8580941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPoly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) provided significant antitumor activity in various tumors, mainly carrying deleterious mutations of BRCA1/BRCA2 genes. Only few data are available regarding the cardiac and vascular safety profile of this drug class. We carried out a meta-analysis for assessing the incidence and relative risk (RR) of major adverse cardiovascular events (MACEs), hypertension, and thromboembolic events in patients with solid tumors treated with PARPi-based therapy.MethodsProspective studies were identified by searching the Medline/PubMed, Cochrane Library, and ASCO Meeting abstracts. Data extraction was conducted according to the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) statement. Combined odds ratios (ORs), RRs, and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods, depending on studies heterogeneity. RevMan software for meta-analysis (v.5.2.3) was used to carry out statistical analyses.ResultsThirty-two studies were selected for the final analysis. The incidence of PARPi-related MACEs of any and high grade was 5.0% and 0.9%, respectively, compared with 3.6% and 0.9% in the control arms, corresponding to a significant increased risk of MACEs of any grade (Peto OR 1.62; P = 0.0009) but not of high grade (P = 0.49). The incidence of hypertension of any grade and high grade was 17.5% and 6.0% with PARPi, respectively, compared with 12.6% and 4.4% in the controls. Treatment with PARPi significantly increased the risk of hypertension of any grade (random-effects, RR = 1.53; P = 0.03) but not of high grade (random-effects, RR = 1.47; P = 0.09) compared with controls. Finally, PARPi-based therapies significantly increased the risk of thromboembolic events of any grade (Peto OR = 1.49, P = 0.004) and not of high grade (Peto OR = 1.31; P = 0.13) compared with controls.ConclusionsPARPi-based therapy is associated with a significantly increased risk of MACEs, hypertension, and thromboembolic events of any grade compared with controls. The lack of a significant increased risk of high-grade events together with the absolute low incidence of these adverse events led not to consider routine cardiovascular monitoring as recommended in asymptomatic patients.