Correlative studies of the Breast Cancer Index (HOXB13/IL17BR) and ER, PR, AR, AR/ER ratio and Ki67 for prediction of extended endocrine therapy benefit: a Trans-aTTom study

Abstract

Background: Multiple clinical trials demonstrate consistent but modest benefit of adjuvant extended endocrine therapy (EET) in HR + breast cancer patients. Predictive biomarkers to identify patients that benefit from EET are critical to balance modest reductions in risk against potential side effects of EET. This study compares the performance of the Breast Cancer Index, BCI (HOXB13/IL17BR, H/I), with expression of estrogen (ER), progesterone (PR), and androgen receptors (AR), and Ki67, for prediction of EET benefit. Methods: Node-positive (N+) patients from the Trans-aTTom study with available tissue specimen and BCI results (N = 789) were included. Expression of ER, PR, AR, and Ki67 was assessed by quantitative immunohistochemistry. BCI (H/I) gene expression analysis was conducted by quantitative RT-PCR. Statistical significance of the treatment by biomarker interaction was evaluated by likelihood ratio tests based on multivariate Cox proportional models, adjusting for age, tumor size, grade, and HER2 status. Pearson’s correlation coefficients were calculated to evaluate correlations between BCI (H/I) versus ER, PR, AR, Ki67 and AR/ER ratio. Results: EET benefit, measured by the difference in risk of recurrence between patients treated with tamoxifen for 10 versus 5 years, is significantly associated with increasing values of BCI (H/I) (interaction P = 0.01). In contrast, expression of ER (P = 0.83), PR (P = 0.66), AR (P = 0.78), Ki67 (P = 0.87) and AR/ER ratio (P = 0.84) exhibited no significant relationship with EET benefit. BCI (H/I) showed a very weak negative correlation with ER (r = − 0.18), PR (r = − 0.25), and AR (r = − 0.14) expression, but no correlation with either Ki67 (r = 0.04) or AR/ER ratio (r = 0.02). Conclusion: These findings are consistent with the growing body of evidence that BCI (H/I) is significantly predictive of response to EET and outcome. Results from this direct comparison demonstrate that expression of ER, PR, AR, Ki67 or AR/ER ratio are not predictive of benefit from EET. BCI (H/I) is the only clinically validated biomarker that predicts EET benefit.