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. 2025 Jun 4:15:1556978.
doi: 10.3389/fonc.2025.1556978. eCollection 2025.

Efficacy and safety of PI3K inhibitors combined with fulvestrant for HR+/HER2- advanced breast cancer: a systematic review and meta-analysis

Xuefeng Li #  1 , Hongxian Wang #  2 , Shuhui Lin  3 , Tianwen Chen  2
Affiliations

Efficacy and safety of PI3K inhibitors combined with fulvestrant for HR+/HER2- advanced breast cancer: a systematic review and meta-analysis

Xuefeng Li et al. Front Oncol. .

Abstract

Objectives: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of combination of Phosphatidylinositol 3-kinase (PI3K) inhibitors and fulvestrant in patients with advanced breast cancer (ABC) who are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-).

Methods: A systematic search was conducted across the PubMed, Cochrane Library, EMBASE databases and major conference websites (ASCO, ESMO, SABCS) to identify randomized controlled trials (RCTs) evaluating the combination of PI3K inhibitors and fulvestrant in the treatment of advanced breast cancer. Two independent reviewers systematically screened the literature, extracted data, and assessed the risk of bias for the included studies based on predefined criteria. Meta-analysis was subsequently performed using R software in accordance with the PRISMA guidelines.

Results: A total of five randomized controlled trials (RCTs) involving 3,011 patients were included. The findings indicated that the combination of PI3K inhibitors and fulvestrant significantly improved progression-free survival (PFS) (HR = 0.74, 95% CI 0.67-0.80, P < 0.0001) and the objective response rate (ORR) (RR = 1.80, 95% CI: 1.39-2.35, P < 0.0001) compared to placebo plus fulvestrant. However, there was no statistically significant difference in clinical benefit rate (CBR) (RR = 1.10, 95% CI: 0.97-1.25, P = 0.1341). Subgroup analysis indicated that the predefined subgroup of PFS based on PIK3CA mutation status assessed by ctDNA was statistically significant (P = 0.0039), whereas the predefined subgroup of PFS based on PIK3CA mutation status assessed by tumor tissue was not statistically significant (P = 0.1514). In terms of adverse events, the incidence of grade ≥3 events was significantly increased in the PI3K inhibitors combined with fulvestrant group (RR=2.11, 95% CI: 1.73-2.58, P<0.0001), particularly hyperglycemia, rash, and transaminitis (ALT).

Conclusion: The combination of PI3K inhibitors and fulvestrant significantly improved PFS and ORR in patients with advanced breast cancer. However, substantial dose-limiting toxicities associated with this therapeutic regimen restrict its broader clinical application. In patients with PIK3CA mutations detected on ctDNA analysis, PFS was significantly improved compared to those with wild-type PIK3CA, suggesting that ctDNA-based PIK3CA mutation status may serve as a potential biomarker for treatment response.

Systematic review registration: PROSPERO, identifier CRD42023407466.

Keywords: PI3K inhibitors; PIK3CA mutations; advanced breast cancer; meta-analysis; progression-free survival.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flow chart for the identification of included studies.
Figure 2
Figure 2
Forest plot for progression-free survival (PFS). CI, confidence interval; HR, hazard ratio; PI3Ki, PI3K inhibitors; Ful, fulvestrant.
Figure 3
Figure 3
Forest plot for overall response rate (ORR).
Figure 4
Figure 4
Forest plot for clinical benefit rate (CBR).
Figure 5
Figure 5
Forest plot for grade ≥3 adverse events.
Figure 6
Figure 6
Forest plots for top five grade ≥3 adverse events: (A), Hyperglycemia; (B), Rash; (C), Transaminitis (ALT); (D), Fatigue; (E), Diarrhoea.
Figure 7
Figure 7
Forest plots of dose adjustment events for pi3k inhibitors vs. placebo: (A), Dose reductions; (B), Dose interruptions; (C), Dose discontinuations.
Figure 8
Figure 8
Subgroup analysis of progression-free survival (PFS) stratified by PIK3CA mutation status confirmed by ctDNA analysis.
Figure 9
Figure 9
Subgroup analysis of progression-free survival (PFS) stratified by PIK3CA mutation status confirmed by tumor tissue.
Figure 10
Figure 10
Subgroup analysis of progression-free survival (PFS) based on different types of PI3K inhibitors: selective vs pan-PI3K Inhibitors.
Figure 11
Figure 11
Subgroup analysis of grade ≥3 adverse events stratified by PIK3CA mutation status confirmed by tumor tissue.
Figure 12
Figure 12
Risk of bias. (A) Risk of bias graph of included RCTs. (B) Risk of bias summary of included RCTs. RCTs, randomized controlled trials.
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