The efficacy of angiogenesis inhibitors combined with chemotherapy in advanced breast cancer: a systematic review and meta-analysis
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Clinical trial registration Globally, breast cancer is the most common malignancy in women. Despite treatment advances, 20–30% of early-stage patients progress to advanced disease, which remains largely incurable with a 5-year survival rate of only ~20%. Chemotherapy, the current mainstay, has reached a therapeutic plateau, with limited efficacy and potential pro-metastatic effects. Anti-angiogenic agents targeting VEGF/VEGFR2 (e.g., bevacizumab, TKIs) are used clinically, but their benefit in advanced breast cancer is controversial: progression-free survival (PFS) gains are inconsistent, overall survival (OS) benefits are unclear, and resistance with class-specific toxicities (e.g., hypertension) is common. Furthermore, comparative efficacy across drug classes and optimal patient selection remain undefined. These unresolved issues highlight the urgent need for a comprehensive synthesis to guide clinical decisions and future research. Methods Systematic search of PubMed/Web of Science (up to July 16, 2025) identified 29 phase II/III RCTs (N = 8,480) comparing angiogenesis inhibitors + chemotherapy vs. chemotherapy alone (± placebo) in advanced breast cancer. Outcomes included PFS, OS, objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety. Two independent reviewers performed screening, extraction, and quality assessment. Pooled HRs (95% CI) for PFS/OS; ORs for binary outcomes. Random-effects model used if I² ≥ 50%; prespecified subg
Abstract
Clinical trial registration Globally, breast cancer is the most common malignancy in women. Despite treatment advances, 20–30% of early-stage patients progress to advanced disease, which remains largely incurable with a 5-year survival rate of only ~20%. Chemotherapy, the current mainstay, has reached a therapeutic plateau, with limited efficacy and potential pro-metastatic effects. Anti-angiogenic agents targeting VEGF/VEGFR2 (e.g., bevacizumab, TKIs) are used clinically, but their benefit in advanced breast cancer is controversial: progression-free survival (PFS) gains are inconsistent, overall survival (OS) benefits are unclear, and resistance with class-specific toxicities (e.g., hypertension) is common. Furthermore, comparative efficacy across drug classes and optimal patient selection remain undefined. These unresolved issues highlight the urgent need for a comprehensive synthesis to guide clinical decisions and future research. Methods Systematic search of PubMed/Web of Science (up to July 16, 2025) identified 29 phase II/III RCTs (N = 8,480) comparing angiogenesis inhibitors + chemotherapy vs. chemotherapy alone (± placebo) in advanced breast cancer. Outcomes included PFS, OS, objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety. Two independent reviewers performed screening, extraction, and quality assessment. Pooled HRs (95% CI) for PFS/OS; ORs for binary outcomes. Random-effects model used if I² ≥ 50%; prespecified subgroup/sensitivity analyses explored heterogeneity. Results This meta-analysis (29 RCTs, N = 11,068) showed that adding angiogenesis inhibitors in advanced breast cancer significantly improved PFS (HR 0.75), ORR, CBR, and DCR (all P<0.001), but not OS (HR 0.95, P = 0.171). PFS benefit varied by subtype: mAbs (e.g., bevacizumab) outperformed TKIs in TNBC (HR 0.59 vs. 0.75); TKIs trended better in HR+ disease (HR 0.67). Benefit was consistent across metastasis patterns but greater in patients without bone metastasis. Safety risks increased significantly, including hypertension (OR 4.59), thrombocytopenia (OR 4.54), proteinuria (OR 2.38), hand-foot syndrome (OR 2.14), and diarrhea (OR 1.97). Conclusions This meta-analysis (29 RCTs) finds that adding angiogenesis inhibitors to chemotherapy significantly improves PFS and response in advanced breast cancer—especially in TNBC with mAbs and HR+ disease with TKIs—but not OS. Benefit is independent of visceral metastasis but reduced in bone metastases. Increased toxicities (hypertension, proteinuria, hand-foot syndrome, diarrhea) warrant proactive management.