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 HER2-positive early breast cancer patients. Methods: Protein expression of TOP2A, Ki67, cyclin D1 and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 year; N=561) and observation (N=301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables (pre-defined 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). Trastuzumab effect was significant in the p27 low subgroup (≤70% p27-positive tumor cells; N=318). HR _{CombTrast vs. Obs} 0.44, 95% CI: 0.29-0.65 (p<0.001). No trastuzumab effect was observed in the p27 high subgroup 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 trastuzumab treatment. A prognostic effect of p27 on DFS was observed, with p27 high patients experiencing half the hazard of a DFS event compared to low ones (HR _{p27 High vs. Low} 0.49, 95% CI: 0.32-0.75). TOP2A, Ki67 and cyclin D1, as categorical variables were not predictive, whereas cyclin D1 as continuous variable was predictive of trastuzumab benefit. Conclusions: In TransHERA, HER2-positive early breast cancer patients with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not.

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