Time dependence of prognostic values of gene-expression signatures for breast cancer

Abstract

11085 Background: Gene-expression signatures were shown to be prognostic and predictive for breast cancer but their performances over time have not been investigated. Methods: Recurrence score (RS) of oncotype, 70-gene profile (SGP) of Mammaprint, intrinsic subtype (IS) and wound signature (WS) were analyzed using a single dataset of 295 samples from Fan et al. (Fan et al. N Engl J of Med 2006; 355:560–9). Time-varying coefficient Cox models were used to estimate the time-dependent hazard ratios (HR) for relapse-free survival (RFS). Annualized RFS hazard rates were estimated using cubic splines. Concordance between RS and SGP was calculated for different intrinsic subtypes in all 295 samples and was evaluated in a subset of 173 ER+ samples not in the training set of SGP for unbiased comparison. Results: For the high risk groups of RS, SGP, IS and WS, hazard rates peaked around the 2nd year from surgery and decreased rapidly over time. For the low risk groups, hazard rates also peaked around the 2nd yr but remained fairly constant over time. Hazard ratios of high vs. low risk groups of RS at yr 2, 5 and 10 were 17.0 (8.4–34.0), 4.0 (2.0–8.0), 1.7 (0.83–3.4). For intermediate vs. low risk groups of RS, the corresponding HRs were 2.7 (1.1–7.0), 5.0 (1.1–7.4), 1.6 (0.63–4.2). Poor vs. good groups of SVP had HRs of 7.4 (4.5–12.1), 3.6 (2.2–5.9), 2.0 (1.2–3.3) at yr 2, 5, 10. HRs of Luminal B (LB), Basal-like (BL), HER2/ER- (HER2), Normal-like (NL) vs. Luminal A (LA) of Intrinsic Subtypes were 6.8 (4.0–11.5), 5.7 (3.2–10.0), 7.6 (4.0–14.1) and 1.7 (0.9–3.3) at yr 2. HRs at yr 5 were 4.0 (2.3–6.8), 0.7 (0.4–1.2), 1.1 (0.6–2.0) and 2.3 (1.2–4.4) respectively. For WS, HRs at yr 2, 5, 10 were 6.3 (3.3–11.9), 2.9 (1.6–5.6) and 2.2 (1.2–4.1) respectively. Concordance rates of RS and SVP were 1.0, 0.91, 0.86, 0.72 and 0.62 for BL, HER2, LB, LA, NL of Intrinsic Subtypes. In 173 ER+ samples not present in the SGP training set, concordance rate between RS and SVP was 0.77 (Cramer's V = 0.56); the same as in the whole set of 225 ER+ patients (Fan et al. N Engl J of Med 2006; 355:560–9). Conclusions: Prognostic values of gene-expression signatures decrease over time. They can best predict breast cancer relapse during the first 5 years. Concordance between RS and SPV is highest in the basal-like tumors and lowest in the Luminal B and Normal-like subtypes. No significant financial relationships to disclose.