Combination Therapy, Drug Interactions, and Survival Outcomes in Metastatic Breast Cancer: A Pooled Analysis of Phase II Trials
Abstract
BACKGROUND: The relationship between regimen complexity, treatment sequencing, and survival outcomes in metastatic breast cancer (MBC) remains poorly characterized.
OBJECTIVES: To quantify how treatment complexity, line of therapy, and baseline performance status (PS) differentially affect progression-free survival (PFS) and overall survival (OS), and to identify synergistic and antagonistic drug combinations across MBC phase II trials.
METHODS: A systematic PubMed search (1992-2022) identified 892 eligible studies comprising 1,088 treatment arms and 53,672 patients. Objective response rate (ORR), median PFS, and median OS were extracted per arm along with molecular subtype, treatment size, therapy type, line of therapy, and weighted ECOG PS. Drug-drug interactions were inferred using a null model of non-interacting agents.
RESULTS: Adding agents improved both PFS and OS, but the PFS benefit was approximately twice the OS benefit (effect size, ε2 = 0.24 vs. 0.11; both p < 0.0001). Combination therapy progressively reduced the survival disadvantage associated with prior treatment, with PFS effect sizes declining from rrb = 0.55 (95% confidence interval [CI], 0.44-0.64) for single agents to 0.27 (0.09-0.44) for triplets. OS followed a similar pattern, decreasing from rrb = 0.58 (0.48-0.66) to 0.32 (0.14-0.48). ECOG PS showed an escalating correlation, from negligible for ORR (rs = -0.09, 95% CI -0.15 to -0.03) to medium for PFS (-0.23, -0.29 to -0.16) and very large for OS…
How strong is the evidence?
Evidence Hub reads this as a secondary / pooled analysis, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 53,672 participants or records.
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