Final results of a meta-analysis testing HER2 and topoisomerase IIα genes as predictors of incremental benefit from anthracyclines in breast cancer.

Abstract

519 Background: Five trials comparing anthracyclines (A) with CMF in the early setting tested HER2 and topoisomerase IIα (TOP2A) genes as predictors of benefit from A. An interim report of this meta-analysis suggested that both genes are clinically modest predictors (SABCS 2008 abs 705). Methods: HER2 and TOP2A were tested in four national laboratories by FISH (amplification: ratio ≥2; TOP2A deletion: ratio ≤ 0.8). National lab (NL) scores were validated by submitting randomly selected cases to a central lab (CL) for FISH (Abbott labs, USA). Individual patient data were centralized. Onsite visits were performed. Results: Final results are based on 3,452 and 3,102 pts for HER2 and TOP2A, respectively. HER2 NL scores were validated in 137 cases (discordance 8/137, 5.8%), TOP2A NL scores in 123 cases (discordance 38/123, 30.9%). Conclusions: HER2 and TOP2A genes have clinically modest and statistically borderline predictive value. Some HER2-negative pts derive benefit from A. Disease-free survival (DFS) hazard ratio A versus CMF (95% CI) HER2 TOP2A Study No. pts Amp (No. 843) NA (No. 2,609) No. pts Amp (No. 275) N (No. 2,511) D (No. 316) Belgium 353 0.72 (0.37, 1.39) 1.31 (0.90, 1.91) 89 0.37 (0.12, 1.17) 0.89 (0.42, 1.87) * Canada 626 0.60 (0.39, 0.92) 0.95 (0.73, 1.22) 437 0.71 (0.34, 1.50) 1.01 (0.76, 1.36) 0.26 (0.09, 0.76) Denmark 670 0.73 (0.52, 1.03) 0.83 (0.62, 1.10) 773 0.54 (0.30, 0.97) 0.92 (0.72, 1.17) 0.62 (0.36, 1.06) UK-NEAT 1,508 0.73 (0.51, 1.04) 0.88 (0.71, 1.08) 1,508 0.69 (0.31, 1.54) 0.87 (0.71, 1.06) 0.78 (0.47, 1.28) UK- BR9601 295 0.81 (0.42, 1.60) 0.54 (0.34, 0.85) 295 2.35 (0.39, 14.07) 0.60 (0.39, 0.92) 0.47 (0.19, 1.16) Meta-analysis [p value heterogeneity test] 3,452** 0.71 (0.58, 0.86) p.0004 [p.94] 0.89 (0.79, 1.01) p.07 [p.06] 3,102*** 0.62 (0.43, 0.90) p.01 [p.51] 0.88 (0.78, 1.00) p.052 [p.38] 0.63 (0.46, 0.87) p.004 [p.45] Abbreviations: Amp, amplified; NA, nonamplified; N, normal; D, deleted; No., number. * Only 8 cases; ** interaction test = p.048; *** interaction test = p.051. Overall survival and DFS results are similar. A planned analysis tested both genes in distinct groups: highly or moderately hormone sensitive (MHS), HER2+, triple negative (TN). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, Pfizer, Roche, sanofi-aventis GlaxoSmithKline, Pfizer, Roche, sanofi-aventis Pfizer, sanofi-aventis