Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population

Abstract

SUMMARY BACKGROUND Greater than 50% of recurrences in estrogen receptor-positive (ER+) breast cancer occur after 5 years of adjuvant endocrine therapy. Biomarkers capable of improving the risk-benefit of extended adjuvant endocrine therapy for these late recurrences would be clinically valuable. We compared the prognostic ability of the Breast Cancer Index (BCI), Oncotype DX Recurrence Score (RS) and IHC4 for both early and late recurrence among patients with ER+, node negative (N0) disease within the ATAC clinical trial. METHODS BCI was performed from 1102 primary tumor samples from ER+ patients and two versions (BCI-C (primary) and BCI-L (secondary), based on cubic and linear combinations of the variables) were evaluated. RS and IHC4 values were previously derived. Prognostic discrimination for early (<5y) and late recurrence (5–10y) was assessed. To evaluate the ability of the biomarkers to predict recurrence beyond standard clinicopathological parameters, the likelihood-ratio chi-square (LR-Δχ2) was calculated from Cox proportional hazards models. The primary endpoint was distant recurrence (DR). FINDINGS In the primary analysis of 665 ER+ N0 patients, categorical BCI-C demonstrated significant differences in risk of DR over 10 years (P<0·0001). In the secondary analysis, BCI-L proved to be a much stronger predictor, and BCI-L, IHC4 and RS had significant prognostic performance for early DR (BCI-L, p<0·0002), while only BCI-L was significant for late DR (LR-Δχ2: 7·97, p=0·0048). For risk of early DR at 5 years, BCI-L classified 59% (390/665), 25% (166/665) and 16% (109/665) of patients with 1.3% (0.5% – 3.1%), 5.6% (2.9% – 10.5%) and 18.1% (12.0% – 27.0%) for low, intermediate and high risk, respectively. For risk of late DR at 10 years, BCI-L classified 61% (366/596), 25% (146/596) and 14% (84/596) of patients with 3.5% (2.0% – 6.1%), 13.4% (8.5% – 20.8%) and 13.3% (7.4% – 23.4%) for low, intermediate and high, respectively. INTERPRETATION While all three biomarkers predicted for early DR, BCI-L was the only significant prognostic for risk of late DR. The three BCI-L groups identified two risk populations for both early and late DR with 84% (556/665) of patients having low risk for early DR, and a smaller population (39%, 230/596) having high risk for late DR who may benefit from extended endocrine or other therapy. FUNDING Avon Foundation, National Institutes of Health, Breast Cancer Foundation, DOD Breast Cancer Research Program, Susan G. Komen for the Cure, Breakthrough Breast Cancer through the Mary-Jean Mitchell Green Foundation, Astrazeneca, NIHR Biomedical Research Centre at the Royal Marsden.