Breast Cancer Index is a predictive biomarker of treatment benefit and outcome from extended tamoxifen therapy: final analysis of the Trans-aTTom study

PURPOSE: The Breast Cancer Index (BCI) HOXB13/IL17BR (H/I) ratio predicts benefit from extended endocrine therapy in hormone receptor–positive (HR(+)) early-stage breast cancer. Here, we report the final analysis of the Trans-aTTom study examining BCI (H/I)'s predictive performance. EXPERIMENTAL DESIGN: BCI results were available for 2,445 aTTom trial patients. The primary endpoint of recurrence-free interval (RFI) and secondary endpoints of disease-free interval (DFI) and disease-free survival (DFS) were examined using Cox proportional hazards regression and log-rank test. RESULTS: Final analysis of the overall study population (N = 2,445) did not show a significant improvement in RFI with extended tamoxifen [HR, 0.90; 95% confidence interval (CI), 0.69–1.16; P = 0.401]. Both the overall study population and N0 group were underpowered due to the low event rate in the N0 group. In a pre-planned analysis of the N(+) subset (N = 789), BCI (H/I)-High patients derived significant benefit from extended tamoxifen (9.7% absolute benefit: HR, 0.33; 95% CI, 0.14–0.75; P = 0.016), whereas BCI (H/I)-Low patients did not (−1.2% absolute benefit; HR, 1.11; 95% CI, 0.76–1.64; P = 0.581). A significant treatment-to-biomarker interaction was demonstrated on the basis of RFI, DFI, and DFS (P = 0.037, 0.040, and 0.025, respectively). BCI (H/I)-High patients remained predictive of benefit from extended tamoxifen in the N(+)/HER2(−) subgroup (9.4% absolute benefit: HR, 0.35; 95% CI, 0.15–0.81; P = 0.047). A three-way interaction evaluating BCI (H/I), treatment, and HER2 status was not statistically significant (P = 0.849). CONCLUSIONS: Novel findings demonstrate that BCI (H/I) significantly predicts benefit from extended tamoxifen in HR(+) N(+) patients with HER2(−) disease. Moreover, BCI (H/I) demonstrates significant treatment to biomarker interaction across survival outcomes

Validation of the prognostic performance of Breast Cancer Index (BCI) in hormone receptor-positive (HR+) postmenopausal breast cancer patients in the TEAM trial

Purpose: Early-stage HR+ breast cancer patients face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) is significantly prognostic for overall (0-10 years) and late (5-10 years) distant recurrence risk (DR) in N0 and N1 patients. Here, BCI prognostic performance was evaluated in HR+ postmenopausal women from the TEAM trial.Experimental Design: 3544 patients were included in the analysis (N=1519 N0, N=2025 N+). BCI risk groups were calculated using pre-specified cut-points. Kaplan-Meier analyses and logranktests were used to assess the prognostic significance of BCI risk groups based on DR. Hazard ratios (HR) and confidence intervals (CI) were calculated using Cox models with and without clinical covariates.Results: For overall 10-year DR, BCI was significantly prognostic in N0 (N=1196) and N1 (N=1234) patients who did not receive prior chemotherapy (p<0.001). In patients who were DRfree for 5 years, 10-year late DR rates for low- and high-risk groups were 5.4% and 9.3% (N0 cohort, N=1285) and 4.8% and 12.2% (N1 cohort, N=1625) with multivariate HRs of 2.25 (95% CI: 1.30-3.88; p=0.004) and 2.67 (95% CI: 1.53-4.63; p=<0.001), respectively. Late DR performance was substantially improved using previously optimized cut-points, identifying BCIlow-risk groups with even lower 10-year late DR rates of 3.8% and 2.7% in N0 and N1 patients, respectively.Conclusions: The TEAM trial represents the largest prognostic validation study for BCI to date and provides a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ early-stage breast cancer patients

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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-022-01589-x

Validation of the prognostic performance of Breast Cancer Index (BCI) in hormone receptor-positive (HR+) postmenopausal breast cancer patients in the TEAM trial

PURPOSE: Early-stage HR+ breast cancer patients face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) is significantly prognostic for overall (0-10 years) and late (5-10 years) distant recurrence risk (DR) in N0 and N1 patients. Here, BCI prognostic performance was evaluated in HR+ postmenopausal women from the TEAM trial.EXPERIMENTAL DESIGN: 3544 patients were included in the analysis (N=1519 N0, N=2025 N+). BCI risk groups were calculated using pre-specified cut-points. Kaplan-Meier analyses and log-rank tests were used to assess the prognostic significance of BCI risk groups based on DR. Hazard ratios (HR) and confidence intervals (CI) were calculated using Cox models with and without clinical covariates.RESULTS: For overall 10-year DR, BCI was significantly prognostic in N0 (N=1196) and N1 (N=1234) patients who did not receive prior chemotherapy (p&lt;0.001). In patients who were DR-free for 5 years, 10-year late DR rates for low- and high-risk groups were 5.4% and 9.3% (N0 cohort, N=1285) and 4.8% and 12.2% (N1 cohort, N=1625) with multivariate HRs of 2.25 (95% CI: 1.30-3.88; p=0.004) and 2.67 (95% CI: 1.53-4.63; p=&lt;0.001), respectively. Late DR performance was substantially improved using previously optimized cut-points, identifying BCI low-risk groups with even lower 10-year late DR rates of 3.8% and 2.7% in N0 and N1 patients, respectively.CONCLUSIONS: The TEAM trial represents the largest prognostic validation study for BCI to date and provides a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ early-stage breast cancer patients.</p