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Filipits, Martin; Dafni, Urania; Gnant, Michael; Polydoropoulou, Varvara; Hills, Margaret; Kiermaier, Astrid; Azambuja, Evandro de; Larsimont, Denis; Rojo, Federico; Viale, Giuseppe; Toi, Masakazu; Harbeck, Nadia; Prichard, Kathleen I.; Gelber, Richard D.; Dinh, Phuong; Zardavas, Dimitrios; Leyland-Jones, Brian; Piccart-Gebhart, Martine J.; Dowsett, Mitch (2018): Association of p27 and Cyclin D1 Expression and Benefit from Adjuvant Trastuzumab Treatment in HER2-Positive Early Breast Cancer: A TransHERA Study. In: Clinical Cancer Research, Vol. 24, No. 13: pp. 3079-3086
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Abstract

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. Experimental Design: 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 years;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 (Comb Trast 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 with 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, patients with HER2-positive early breast cancer with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not.