Purpose: Predictive biomarkers may help predicting adjuvant trastuzumab response and thus optimize the treatment of patients with HER2-positive breast cancer. The aim of the present study was to assess the prognostic/predictive value of various biomarkers involved in cell cycle regulation or proliferation.
Methods: Expression of p27, cyclin D1, TOP2a, and Ki67 was immunohistochemically determined in tissue micro arrays of specimens from 862 patients randomized to the trastuzumab (1 or 2 year; N=561) and observation (N=301) arms of the HERA trial. The primary endpoint of the analysis was disease-free survival (DFS). Biomarker expression status was determined as continuous variable or by pre-defined categories. The interaction terms between the four biomarkers and treatment were assessed in multivariate Cox proportional hazards regression models adjusted for variables of clinical interest. Associations were considered significant only if the false discovery rate (FDR) adjusted p-values remained significant.
Results: Baseline characteristics were well balanced between the two study arms. A total of 249 DFS events (28.9%) were observed in the TransHERA cohort, with an overall 8-year DFS of 70.5% (95% CI 67.2%-73.5%). None of the four biomarkers was significantly associated with DFS in the total study population. When biomarkers were categorized according to pre-defined cut-off levels, only p27 turned out to be highly predictive: Expression data for p27 were available in 753 TransHERA patients. A highly significant interaction was detected between p27 and treatment when adjusting for clinical parameters and the remaining three biomarkers (p=0.0039). For patients classified as p27 low (≤70% p27-positive tumor cells; N=318), a significant treatment effect was observed, with the hazard of a DFS event being greater for the observation group compared to patients treated with trastuzumab (HRTrast vs Obs=0.43, 95% CI 0.29-0.64, p<0.001). In contrast, no statistically significant effect of trastuzumab treatment was detected in the p27 high group (N=435; HRTrast vs Obs=0.97, 95% CI 0.66-1.44, p=0.89), indicating that p27 high patients derived little or no benefit from trastuzumab treatment. Cyclin D1, TOP2a, and Ki67 used as categorical variables were not predictive, while cyclin D1 used as continuous variable was predictive of adjuvant trastuzumab benefit.
Conclusion: HER2-positive early breast cancer patients with low p27 expression in their tumors appear to benefit from trastuzumab treatment, whereas patients with high p27 expression do not.
This study was funded by Roche.
Citation Format: Martin Filipits, Michael Gnant, Urania Dafni, Varvara Polydoropoulou, Margaret J Hills, Brian Leyland-Jones, Martine Piccart-Gebhart, Mitch Dowsett. TransHERA: The cell cycle regulator p27 predicts benefit from trastuzumab treatment in HER2-positive early breast cancer patients treated within the HERA trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-18-01.