Association of p27 and Cyclin D1 Expression and Benefit from Adjuvant Trastuzumab Treatment in HER2-Positive Early Breast Cancer: A TransHERA Study

Purpose: To assess the prognostic and predictive value of selected biomarkers involved in cell-cycle regulation or proliferation in patients with HER2-positive early breast cancer. Methods: Protein expression of TOP2A, Ki67, cyclin D1, and p27 was immunohistochemically determined in tissue microarraysof surgical specimens from 862 patients randomized to trastuzumab(1 or 2 years; N = 561) and observation ( N = 301) arms of the HERAtrial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables(predefined cutoffs). Interaction terms between biomarkers and treatment were assessed in multivariate Cox models adjusted for variables of clinical interest. Results: A significant interaction was detected between p27 and treatment (adjusted P = 0.0049). Trastuzumabeffect was significant in the p27-low subgroup (≤70% p27-positive tumor cells; N = 318). HR Comb Trast vs. Obs 0.44, 95% CI, 0.29–0.65 ( P N = 435; HR Comb Trast vs. Obs 0.97, 95% CI, 0.66–1.44, P = 0.89), indicating that these patients derived little or no benefit from trastuzumabtreatment. A prognostic effect of p27 on DFS was observed, with p27-high patients experiencing half the hazard of a DFS event compared with low ones (HR p27 High vs. Low 0.49, 95% CI, 0.32–0.75). TOP2A, Ki67, and cyclin D1, as categorical variableswere not predictive, whereas cyclin D1as continuous variable was predictive of trastuzumabbenefit. Conclusions: In TransHERA, patients with HER2-positive early breast cancer with low p27 expression in their tumors benefited from trastuzumabtreatment, whereas patients with high p27 expression did not. Clin Cancer Res; 1–8. ©2018 AACR.