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

Abstract

BackgroundExtending 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 methodsTrans-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.ResultsOf 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.ConclusionBCI 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.Trial registrationISRCTN17222211; NCT00003678.

Breast Cancer Index Predicts Extended Endocrine Benefit to Individualize Selection of Patients with HR+ Early-stage Breast Cancer for 10 Years of Endocrine Therapy

“…High vs Low likelihood of benefit from extended endocrine therapy that is reported separately from the prognostic results (19,21,22).…”

“…Author Manuscript Published OnlineFirst on October 27, 2020; DOI: 10.1158/1078-0432.CCR- Previous clinical validation studies for prediction of extended endocrine benefit and outcome have demonstrated significant interaction between BCI (H/I) and extended endocrine therapy with letrozole or tamoxifen following initial tamoxifen treatment (19,22). A key question regarding BCI clinical utility is the biomarker effect in postmenopausal patients treated with a contemporary standard of care that includes an AI component as part of primary adjuvant treatment.…”

“…The IDEAL translational cohort (N=908) showed a 4.9% absolute benefit in the reduction of 10-year risk of RFI events with 10 years vs 7.5 years of endocrine therapy (HR 0.69, 95% CI 0.47-1.03; P=0.07). Powering assumptions included a 5% sample testing failure rate and that 40% of patients would be classified as BCI (H/I)-High based on previous studies (19,22). At 80% power, it was estimated that a total of 768 patients would be required to detect the benefit in BCI (H/I)-High patients at the 5% significance level.…”

Clinical Implications of Serum 25-Hydroxyvitamin D Status after 5-Year Adjuvant Endocrine Therapy for Late Recurrence of Hormone Receptor-positive Breast Cancer

“…After demonstrating the effectiveness of an extended endocrine therapy [ 26 ], it became crucial to determine the risk factors for late recurrence in HR-positive breast cancer to guide individualized extended endocrine therapy. Although the optimal predictive factor to select patients who will benefit from extended endocrine therapy remains unclear, it is commonly suggested that the prognostic benefit of extended endocrine therapy can be maximized among patients with a high disease relapse risk [ 27 ]. Based on our results, patients with 25(OH)D deficiency after the 5-year adjuvant endocrine therapy may be considered appropriate candidates for extended endocrine therapy.…”

Extended endocrine therapy in premenopausal breast cancer patients: Where are we now?

“…Globally, a significant benefit from extended tamoxifen was demonstrated for patients that were classified as BCI (H/I)‐High (HR = 0.35; 95% CI 0.15‐0.86): The risk of recurrence was 27.0% and 37.2% for patients treated with 10‐ and 5‐year tamoxifen, respectively, demonstrating a significant absolute benefit of 10.2% for the reduction in the risk of recurrence. In contrast, there was no significant benefit from an additional 5 years of tamoxifen in patients that were classified as BCI (H/I)‐Low (HR = 1.07; 95% CI 0.69‐1.65) 7 . These results highlight the clinical validity of BCI for the prediction of endocrine response and its clinical utility in tailoring the prescription of extended endocrine therapy.…”