P1-06-07: TIMP-1 in Combination with HER2 and TOP2A for Prediction of Benefit from Adjuvant Anthracyclines in High Risk Breast Cancer Patients.

Abstract

Abstract Purpose: HER2 amplification, TOP2A aberrations and absence of TIMP-1 (Tissue Inhibitor of Metalloproteinase-1) expression in breast carcinomas have been associated with incremental benefit from anthracycline-containing adjuvant chemotherapy in several reports. In the DBCG 89D trial, we demonstrated that the predictive value of these markers improved when they were combined in a profile and the present study was undertaken to validate these findings in NCIC CTG MA.5, a similar but independent clinical trial. Design: TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to CEF or CMF in the MA.5 trial. Patients were classified according to 2 predefined marker profiles — the HT profile (HER2, TIMP-1) and the 2T profile (TOP2A, TIMP-1) and the statistical analyses were performed as closely as possible to the analytical approach used previously in the MA.5 trial and when analysing the biomarker profiles in the DBCG 89D trial. Results: 98 (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. 44% of patients were classified as HT responsive (HER2-positive and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT responsive patients, CEF was superior to CMF with improved RFS (adjusted HR, 0.64; 95% CI, 0.42 to 0.98) and a borderline-significant improvement in OS (adjusted HR, 0.66; 95% CI, 0.42 to 1.04). A significant HT profile versus treatment interaction was detected for OS (P=0.03). In 2T responsive patients, CEF was superior to CMF with borderline significant improvement in RFS (adjusted HR, 0.67; 95% CI, 0.43 to 1.03), and with improvement in OS (adjusted HR, 0.58; 95% CI, 0.36 to 0.93). A significant 2T profile versus treatment interaction was detected for OS (P=0.01). Conclusion: In the MA.5 trial, we have validated the HT and 2T profiles as predictors of incremental benefit from anthracycline-containing chemotherapy. The proportion of patients categorized as anthracycline responsive increases from 18–27% using individual markers to 37–44% when combining TIMP-1 with either HER2 or TOP2A. Patients with responsive profiles had a 34–42% relative reduction in mortality when treated with CEF. In contrast, patients with non-responsive profiles (56-63% of patients) had no incremental benefit from CEF compared with CMF. All 3 biomarkers are easily applied in the pathology lab and as such could be used in daily clinical practice to select patients for anthracycline or non-anthracycline containing adjuvant chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-07.