Everolimus plus Exemestane for Hormone Receptor‐Positive Advanced Breast Cancer: A PAM50 Intrinsic Subtype Analysis of BOLERO‐2

AbstractBackground.The prognostic and predictive value of the two nonluminal (human epidermal growth factor receptor 2 [HER2]‐enriched and basal‐like) subtypes within advanced hormone receptor‐positive (HR+) breast cancer is currently unknown.Materials and Methods.This study retrospectively analyzed 261 tumors (80.7% primary; 19.3% metastatic) from the BOLERO‐2 study; BOLERO‐2 randomized 724 patients with advanced HR+/HER2‐negative breast cancer to everolimus plus exemestane or placebo plus exemestane. Tumors were classified using a PAM50 subtype predictor. Multivariable Cox regression analyses tested the independent prognostic significance of PAM50, and associations between PAM50 subtypes and treatment upon progression‐free survival (PFS) were evaluated.Results.Subtype distribution was 46.7% luminal A (n = 122), 21.5% HER2‐enriched (n = 56), 15.7% luminal B (n = 41), 14.2% normal‐like (n = 37), and 1.9% basal‐like (n = 5); HER2‐enriched subtypes were more common in metastatic versus primary tumors (32.0% vs. 18.7%; p = .038). Median PFS differences between luminal and nonluminal (6.7 vs. 5.2 months; adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.47–0.94; p = .020) and HER2‐enriched and non‐HER2‐enriched subtypes (5.2 vs. 6.2 months; adjusted hazard ratio, 1.53; 95% CI, 1.07–2.19; p = .019) were significant. Everolimus plus exemestane significantly improved median PFS versus placebo plus exemestane among patients with HER2‐enriched tumors (5.8 vs. 4.1 months; adjusted hazard ratio, 0.49; 95% CI, 0.26–0.90; p = .034); however, the association between HER2‐enriched tumors and everolimus benefit was nonsignificant (p = .433).Conclusion.The HER2‐enriched subtype was identified in a substantial proportion of advanced HR+/HER2‐negative breast tumors, and was a consistent biomarker of poor prognosis. Tailored therapies are therefore needed for HER2‐enriched tumors in the advanced HR+/HER2‐negative breast cancer setting.Implications for Practice.Using 261 tumor samples from the BOLERO‐2 phase III clinical trial, this study shows that a substantial proportion (20%–30%) of hormone receptor‐positive (HR+)/human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancers do not have a luminal A or B gene expression profile. This group of patients with nonluminal disease has a poor survival outcome regardless of the addition of everolimus to exemestane. This is the second study that confirms the prognostic value of this biomarker. Overall, these findings indicate a necessity to design novel clinical trials targeting nonluminal disease within HR+/HER2‐negative breast cancer.

http://bit.ly/2WiK7a7