Breast Cancer Index and Prediction of Benefit From Extended Endocrine Therapy in Breast Cancer Patients Treated in the Adjuvant Tamoxifen—To Offer More? (aTTom) Trial

J. M. S. Bartlett; D. C. Sgroi; K. Treuner; Y. Zhang; I. Ahmed; T. Piper; R. Salunga; E. F. Brachtel; S. J. Pirrie; C. A. Schnabel; D. W. Rea


Ann Oncol. 2019;30(11):1776-1783. 

In This Article

Abstract and Introduction


Background: Extending the duration of adjuvant endocrine therapy reduces the risk of recurrence in a subset of women with early-stage hormone receptor-positive (HR+) breast cancer. Validated predictive biomarkers of endocrine response could significantly improve patient selection for extended therapy. Breast cancer index (BCI) [HOXB13/IL17BR ratio (H/I)] was evaluated for its ability to predict benefit from extended endocrine therapy in patients previously randomized in the Adjuvant Tamoxifen—To Offer More? (aTTom) trial.

Patients and methods: Trans-aTTom is a multi-institutional, prospective–retrospective study in patients with available formalin-fixed paraffin-embedded primary tumor blocks. BCI testing and central determination of estrogen receptor (ER) and progesterone receptor (PR) status by immunohistochemistry were carried out blinded to clinical outcome. Survival endpoints were evaluated using Kaplan–Meier analysis and Cox regression with recurrence-free interval (RFI) as the primary endpoint. Interaction between extended endocrine therapy and BCI (H/I) was assessed using the likelihood ratio test.

Results: Of 583 HR+, N+ patients analyzed, 49% classified as BCI (H/I)-High derived a significant benefit from 10 versus 5 years of tamoxifen treatment [hazard ratio (HR): 0.35; 95% confidence interval (CI) 0.15–0.86; 10.2% absolute risk reduction based on RFI, P = 0.027]. BCI (H/I)-low patients showed no significant benefit from extended endocrine therapy (HR: 1.07; 95% CI 0.69–1.65; −0.2% absolute risk reduction; P = 0.768). Continuous BCI (H/I) levels predicted the magnitude of benefit from extended tamoxifen, whereas centralized ER and PR did not. Interaction between extended tamoxifen treatment and BCI (H/I) was statistically significant (P = 0.012), adjusting for clinicopathological factors.

Conclusion: BCI by high H/I expression was predictive of endocrine response and identified a subset of HR+, N+ patients with significant benefit from 10 versus 5 years of tamoxifen therapy. These data provide further validation, consistent with previous MA.17 data, establishing level 1B evidence for BCI as a predictive biomarker of benefit from extended endocrine therapy.


Treatment of HR+ breast cancer with adjuvant antiestrogen therapies has been a mainstay of care for over 40 years. Selection of patients based on estrogen receptor (ER) and/or progesterone receptor (PR) expression marked a pivotal advancement toward modern precision oncology.[1] ER and PR expression is routinely measured in current clinical practice to indicate hormone-responsive disease, and their prognostic effect is well established; however, within the HR+ population they have limited predictive value for selecting patients who derive benefit from antiestrogen treatment.[2–5] To date, predictive biomarkers with robust clinical validation and utility to optimize patient selection and inform prolonged endocrine treatment have been lacking.

Gene expression analyses that provide information on tumor biology have been incorporated into several classifiers with a major impact on patient selection for chemotherapy treatment.[6–8] Since early-stage HR+ breast cancer is associated with a persistent risk of recurrence and death,[9] another important decision for patients is whether to extend endocrine therapy to reduce the ongoing risk of late (beyond 5 years of diagnosis) distant recurrence. Multiple trials have demonstrated consistent but modest absolute benefits with continuing endocrine therapy to 10 years in the range of 2%–5% absolute risk reduction in HR+ patients.[10–14] While extending endocrine therapy to 10 years is endorsed by several clinical practice guidelines,[15–17] clear guidance on individualized approaches to optimize patient selection for prolonged endocrine regimens remains limited.

The Breast Cancer Index (BCI) is an algorithmic gene expression-based signature comprised of two functional biomarker panels, the molecular grade index (MGI) and the two-gene ratio, HOXB13/IL17BR (H/I), that evaluate tumor proliferation and estrogen signaling, respectively. The BCI test reports both a prognostic as well as a predictive result. Integration of MGI and H/I generates a prognostic BCI score quantifying both the risk of overall (0–10 years) and late (5–10 years) distant recurrence.[18–20] The predictive component of BCI, the H/I ratio, has been shown to predict endocrine response across several different treatment scenarios.[18,20,21] In the extended endocrine therapy setting, BCI predicted benefit from an additional 5 years of letrozole after adjuvant tamoxifen in the MA.17 study.[18] The current study was aimed at strengthening the clinical evidence for BCI in the extended endocrine therapy setting through examination of its predictive performance in breast cancer patients treated in the Adjuvant Tamoxifen—To Offer More? (aTTom) trial.