title: Correlation between progression-free survival and overall survival in metastatic breast cancer patients receiving anthracyclines, taxanes, or targeted therapies: a trial-level meta-analysis.
abstract: Over the past decade, several new drugs have received regulatory approval for metastatic breast cancer (MBC). However, some of these approvals were based on improvement in progression-free survival (PFS), without a concomitant increase in overall survival (OS). This has led some to question the utility of using PFS as a measure for drug approval. To address the uncertainty of using PFS as a surrogate for OS in MBC, a systematic literature review followed by a trial-level correlative analysis was conducted in patients receiving anthracyclines, taxanes, or targeted therapies. Electronic databases were searched to identify randomized trials published between January 1990 and August 2015. Data extraction included hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms as well as trial-level parameters. Weighted multivariate regression analysis was then used to test the strength of the association between HRPFS and HROS. 72 trials providing 84 comparative arms met the inclusion criteria. HRPFS was a significant predictor of HROS (model coefficient = 0.18, p = 0.04). However, only 31% (i.e., model R (2)) of the variability between the PFS-OS association was accounted for. When trials were limited to ≥2nd-line setting, the strength of the association improved (model coefficient = 0.40, p < 0.001) and the model R (2) increased to 55%. However, the HRPFS-HROS association was no longer significant when only 1st-line trials were considered (p = 0.90). HRPFS is a predictor for HROS in MBC randomized trials. However, the effect was driven by trials in the ≥2nd-line setting. Therefore, PFS can be a suitable surrogate for OS in trials evaluating new treatments in the 2nd setting and beyond. The use of PFS alone as a primary trial endpoint in the 1st-line setting is not recommended.
authors.affiliation: Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Adunlin
authors.affiliation: Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: John W W
authors.initials: JW
authors.lastname: Cyrus
authors.affiliation: Augmentium Pharma Consulting Inc., 283 Danforth Ave, Suite 448, Toronto, M4K 1N2, Canada. george@augmentium.com.
authors.forename: George
authors.initials: G
authors.lastname: Dranitsaris
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D043823:Taxoids
keywords: Breast cancer; Overall survival; Progression-free survival; Surrogate endpoints