Association of p27 and Cyclin D1 Expression and Benefit from Adjuvant Trastuzumab Treatment in HER2-Positive Early Breast Cancer: A TransHERA Study.
Date
2018-07ICR Author
Author
Filipits, M
Dafni, U
Gnant, M
Polydoropoulou, V
Hills, M
Kiermaier, A
de Azambuja, E
Larsimont, D
Rojo, F
Viale, G
Toi, M
Harbeck, N
Prichard, KI
Gelber, RD
Dinh, P
Zardavas, D
Leyland-Jones, B
Piccart-Gebhart, MJ
Dowsett, M
TransHERA investigators
Type
Journal Article
Metadata
Show full item recordAbstract
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 (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). 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. Clin Cancer Res; 24(13); 3079-86. ©2018 AACR.
Collections
Subject
TransHERA investigators
Humans
Breast Neoplasms
Neoplasm Metastasis
Receptor, erbB-2
Cyclin D1
Neoplasm Staging
Prognosis
Treatment Outcome
Chemotherapy, Adjuvant
Gene Expression Regulation, Neoplastic
Adult
Aged
Middle Aged
Female
Cyclin-Dependent Kinase Inhibitor p27
Young Adult
Neoplasm Grading
Biomarkers, Tumor
Trastuzumab
Antineoplastic Agents, Immunological
Research team
Endocrinology
Language
eng
Date accepted
2018-03-06
License start date
2018-07
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (13), pp. 3079 - 3086