Extended Endocrine Therapy Benefit Research Articles

Breast Cancer Index re-stratifies 21-gene assay risk groups for late distant recurrence and extended endocrine therapy benefit: Results from the BCI Registry Study.

529 Background: Patients with hormone receptor-positive (HR+) breast cancer face a prolonged risk for late distant recurrence (DR), even after 5 years of adjuvant endocrine therapy. The BCI (Breast Cancer Index, Biotheranostics) is a genomic assay that provides the risk of late DR and predicts the likelihood of benefit from extended endocrine therapy (EET) based on the H/I (HOXB13/IL-17BR) ratio. The 21-gene RS (Recurrence Score; Oncotype DX, Exact Biosciences) test provides the 9-year risk of DR and the benefit from adjuvant chemotherapy (CT) in HR+/HER2− breast cancer. However, the RxPONDER trial showed that RS was not predictive of CT benefit in premenopausal women with N1 disease. Here, we investigated the concordance between BCI prognostic score and H/I versus RS in HR+/HER2- patients from the BCI Registry study. Methods: The BCI Registry study is a prospective, multi-institutional study to evaluate the long-term clinical outcome, decision impact and medication adherence in early-stage HR+ breast cancer patients. Based on TAILORx and RxPONDER results, RS stratified patients into four risk groups: Age ≤ 50, No CT benefit (RS ≤ 15); Age ≤ 50, CT benefit (RS>15); Age > 50, No CT benefit (RS ≤ 25); and Age > 50, CT benefit (RS > 25). Kendall’s correlation coefficient (R) was used to estimate the correlation between BCI prognostic score, BCI (H/I) and RS as continuous variables. Results: BCI and RS results were reported for 847 patients (76% T1; 59% grade II; 85% N0). H/I classified 559 patients (66%) as H/I-Low and 288 (34%) as H/I-High, respectively, while BCI prognostic risk scores classified 434 patients (51%) as low-risk and 413 (49%) as high-risk for late DR. RS classified 30 patients (4%) as Age ≤ 50, No CT benefit, 38 (5%) as Age ≤ 50, CT benefit, 665 (78%) as Age > 50, No CT benefit and 114 (13%) as Age > 50, CT benefit. When analyzed as continuous variables, BCI H/I and prognostic score showed a weak correlation with RS with R=0.18 and R=0.2, respectively. Based on categorical groups, H/I had low concordance with RS for younger women (Age ≤ 50) but showed some correlation with RS for older women (Age > 50). Among those older than Age 50, H/I identified 31% of those with no CT benefit as likely to benefit from EET while 39% of those with CT benefit as not likely to benefit from EET. Conclusions: BCI H/I and prognostic risk scores exhibited low concordance with RS risk categories. H/I consistently re-stratified RS risk categories into distinct H/I-Low and -High groups, further substantiating that prediction of CT benefit does not equate to prediction of EET benefit. [Table: see text]

Abstract PO1-02-03: Correlative analysis of Breast Cancer Index with CTS5 for prediction of extended endocrine benefit in the BCI Registry study

Abstract Background Hormone receptor-positive (HR+) breast cancer patients face a prolonged risk of late distant recurrence even after 5 years of primary adjuvant endocrine therapy and derive only a modest benefit from extended endocrine therapy (EET). The Breast Cancer Index (BCI) is a validated genomic assay that provides the risk of late (post 5 years) and overall (0-10 years) distant recurrence and predicts EET benefit in patients with HR+ disease. The predictive component of BCI, HOXB13/IL17BR ratio [BCI (H/I)], stratifies patients as Low- and High-Likelihood to benefit from EET and has been validated in the MA.17, Trans-aTTom, IDEAL, and B-42 trials. The Clinical Treatment Score post-5 years (CTS5) is a prognostic tool incorporating standard clinical risk factors such as age at diagnosis, tumor size, tumor grade, and nodal involvement to inform prognosis of late distant recurrence. A previous analysis in the IDEAL trial showed that CTS5 was not predictive of EET benefit. Here, we examine the relationship between BCI (H/I) and CTS5 in a large cohort from the BCI Registry study. Methods The BCI Registry study is an ongoing prospective study to evaluate the long-term clinical outcome, decision impact and medication adherence in HR+ early-stage breast cancer patients receiving BCI testing as part of routine clinical care. BCI (H/I)-Low and BCI (H/I)-High groups were determined using pre-specified cut-points. CTS5 scores were calculated using clinical information from the ClinCapture electronic data capture system and stratified into Low-, Intermediate-, and High-risk groups using published cut-points. Pearson’s correlation coefficient (r) was used to estimate the correlation between BCI (H/I) and CTS5 as continuous variables. Descriptive statistics were used to summarize the distribution of BCI (H/I) groups across all CTS5 risk categories. Results BCI and CTS5 results were reported for 1520 patients (75.1% T1; 53.4% grade II; 80.3% N0). BCI (H/I) classified 934 patients (61.4%) as BCI (H/I)-Low and 586 patients (38.6%) as BCI (H/I)-High. BCI Prognostic classified 705 patients (46.4%) as BCI-Low risk for late distant recurrence and 815 patients (53.6%) as BCI-High risk. CTS5 classified 945 patients (62.2%) as CST5-Low, 400 patients (26.3%) as CTS5-Intermediate, and 175 patients (11.5%) as CTS5-High. When analyzed as continuous variables, BCI (H/I) showed a weak correlation with CTS5 (r=0.18). When stratifying CTS5 risk categories by BCI (H/I) groups, 65.2% (N=616) of CTS5-Low patients were classified as BCI (H/I)-Low, while 34.8% (N=329) of CTS5-High Low patients were classified as BCI (H/I)-High. In addition, 57.8% (N=231) and 42.2% (N=169) of CTS5-Intermediate patients were classified as BCI (H/I)-Low and BCI (H/I)-High, respectively. Finally, 49.7% (N=87) and 50.3% (N=88) of CTS5-High patients were classified as BCI (H/I)-Low and BCI (H/I)-High, respectively. Conclusion BCI (H/I) consistently stratified CTS5 risk categories into separate BCI (H/I)-Low and BCI (H/I)-High groups, indicating that risk prognostication does not equate to prediction of benefit from EET. These results confirm previous findings in the IDEAL study demonstrating that CTS5 is not predictive of EET benefit and further substantiate the clinical utility of BCI as the only predictive biomarker for extended endocrine therapy benefit in patients with HR+ early-stage breast cancer. Citation Format: Naomi Dempsey, Jenna Wong, Natalia Siuliukina, Yi Zhang, Kai Treuner, Reshma Mahtani. Correlative analysis of Breast Cancer Index with CTS5 for prediction of extended endocrine benefit in the BCI Registry study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-03.

Abstract PO5-13-04: Breast Cancer Index (BCI) results from a HER2 low breast cancer community cohort of operable stage I-II hormone receptor positive (HR+) breast cancer

Abstract Background Hormone receptor positive (HR+) breast cancer (BC) traditionally included HER2-negative or HER2-positive classifications. The BCI test is a quantitative RNA profile assay applied to HR+ early-stage breast cancers from archival pretreatment surgical specimens. The BCI assay estimates the likelihood of distant recurrence (DR) during years 5-10 (prognostic result) and predicts extended endocrine therapy benefit (ETT)(i.e., BCI (H/I)-High, yes benefit) or no benefit (i.e., BCI (H/I)- Low) for patients who have completed 5 years of adjuvant endocrine therapy (AET). Based on the Destiny Breast 04 trial, an antibody drug conjugate (ADC) anti-HER2 therapy was recently approved for treating metastatic HR+HER2 low BCs, which are currently defined as tumors with either HER2 immunohistochemical (IHC) staining of 1+ or IHC 2+ without HER2 gene amplification. Primary archival specimens were eligible for enrollment on the Destiny Breast 04 trial (35%). Quality control of IHC result categories is needed due to new clinical implications in the metastatic setting. To date, BCI results for tumors classified as HER2 low has not been reported. Objectives Determine the average BCI distant DR risk (prognostic result) and the proportion of tumors with BCI (H/I)-High, yes benefit versus BCI (H/I)-Low, no benefit (predictive result) from a small community-based retrospective study of pretreatment samples from a cohort of HER2 low, HR+ breast tumors. Methods Around completion of 5 years of AET, BCI testing was applied to 110 surgically excised archived stage I and 2 HR+ untreated tumors that were collected between 2017 and 2022. Specimens had paired HER2 local pathology IHC and in-situ hybridization (ISH) results. Results 32 tumors were identified as HER2-low including 26 specimens with HER2 IHC 1+ results and six HER2 IHC 2+ tumors with non-amplified HER2 ISH results. Given this was a small exploratory analysis, statistical significance was deliberately not evaluated. Prognostic Results: The average estimated DR risk during years 5-10 was 8% for tumors classified as HER2-low (Range 1.3-17.5%). For 26/32 patients with HER2 IHC1+, the average DR risk was 7.4% (Range 1.3-17.5%). For 6/32 patients with HER2 IHC 2+ and non-amplified HER2 ISH results, the average DR risk was 4.6% (Range 1.6-8.6%). Predictive Results: Of the 32 HER2-low tumors, 15/32 (47%) were BCI (H/I)-High (yes benefit) compared to 17/32 (53%) which were BCI (H/I)-Low (no benefit). Conclusions The prevalence of HER2 low tumors appears to be as high as 67% in reports to date. In this small series, the prevalence of HR+ HER2 low tumors was 29% (32/110). The average DR risk in these HR+ HER2 low cases was roughly 8% which represents a DR risk that is very similar to the average DR risk of 7.4% for HR+ HER2 negative tumors reported from one of the large BCI validation studies (TransATAC). In this series of HER2 low BCs, the proportions of BCI (H/I)-High (yes benefit) and BCI (H/I)-Low (no benefit) tumors were 47% and 53%, compared with 46% and 54%, respectively, in three large BCI validation studies (Trans-aTTom, B42, IDEAL) for HER2 negative tumors. Although this is a small retrospective series, these results suggest that HER2 low tumor are, by BCI testing, very similar to HER2 negative tumors in DR risk (prognostic results). Also, it appears that BCI (H/I)-High (yes benefit) and BCI (H/I)-Low (no benefit) proportions (predictive results) for HER2 low tumors appear similar to reported results for HER2 negative tumors. Follow-up data from larger series are needed to determine if BCI testing is prognostic and predictive for HER-2 low BCs. Citation Format: Milana Dolezal, Mark Pegram. Breast Cancer Index (BCI) results from a HER2 low breast cancer community cohort of operable stage I-II hormone receptor positive (HR+) breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-04.

Impact of the Breast Cancer Index for Extended Endocrine Decision-Making: First Results of the Prospective BCI Registry Study.

The Breast Cancer Index (BCI) test assay provides an individualized risk of late distant recurrence (5-10 years) and predicts the likelihood of benefitting from extended endocrine therapy (EET) in hormone receptor-positive early-stage breast cancer. This analysis aimed to assess the impact of BCI on EET decision-making in current clinical practice. The BCI Registry study evaluates long-term outcomes, decision impact, and medication adherence in patients receiving BCI testing as part of routine clinical care. Physicians and patients completed pre-BCI and post-BCI test questionnaires to assess a range of questions, including physician decision-making and confidence regarding EET; patient preferences and concerns about the cost, side effects, drug safety, and benefit of EET; and patient satisfaction regarding treatment recommendations. Pre-BCI and post-BCI test responses were compared using McNemar's test and Wilcoxon signed rank test. Pre-BCI and post-BCI questionnaires were completed for 843 physicians and 823 patients. The mean age at enrollment was 65 years, and 88.4% of patients were postmenopausal. Of the tumors, 74.7% were T1, 53.4% were grade 2, 76.0% were N0, and 13.8% were HER2-positive. Following BCI testing, physicians changed EET recommendations in 40.1% of patients (P<.0001), and 45.1% of patients changed their preferences for EET (P<.0001). In addition, 38.8% of physicians felt more confident in their recommendation (P<.0001), and 41.4% of patients felt more comfortable with their EET decision (P<.0001). Compared with baseline, significantly more patients were less concerned about the cost (20.9%; P<.0001), drug safety (25.4%; P=.0014), and benefit of EET (29.3%; P=.0002). This analysis in a large patient cohort of the BCI Registry confirms and extends previous findings on the significant decision-making impact of BCI on EET. Incorporating BCI into clinical practice resulted in changes in physician recommendations, increased physician confidence, improved patient satisfaction, and reduced patient concerns regarding the cost, drug safety, and benefit of EET.

115P Longterm prognostic utility of 70-gene signature by clinical and genomic risks, including Ultralow (gUL) risk patients (pts)

In the MINDACT trial, 4 risk categories (RC) by clinical (c) and genomic (g) risks were defined. In cHigh/gLow risk patients (pts) with no adjuvant chemotherapy (CT), 8y-Distant Metastases Free Survival (DMFS) was 89.4 % [95% CI 86.2-91.5]. MP also identified a third subgroup of gUL pts (score 0.355 – 1.0, 15% in MINDACT), with an excellent prognosis and no benefit from extended endocrine therapy (EET). We aimed to study: DFS/ DMFS by the 6 RC resulting from combining the 2 (c) categories with the 3 (g) groups; the timing of recurrences; and the putative benefit of EET for each genomic group. All ER+/HER2- BC pts with MP data diagnosed between 2012-2017 at Vall d'Hebron University Hospital were selected. cLow risk was defined as in MINDACT trial. To study the benefit of EET, a landmark analysis at 5y from ET initiation was conducted. 140 pts were identified. Baseline features: 47.8% premenopausal; stage I/II: 74%/26%; histological grade 1/2/3: 19.6%/74.9%/6.5%. cLow/cHigh: 67%/33%; gUL/gLow-Non-Ultralow (LNUL)/gHigh: 11.4%/53.6%/35%. PgR and Ki67 tended to correlate with MP g risks, but only the IHC-subtype reached statistically significance. Systemic adjuvant treatments [N/%]: ET 138/98.5%; ovarian function suppression for premenopausal pts 23/35%; CT: 45/32%; EET: 49/35.8%. After 8y-median FU, 15 DFS events and 11 DMFS were observed. DMFS in cHigh/gLow (UL+LNUL) without CT was 90.6% [81.1%; 100%]. DFS/DMFS rates by each c/g category are depicted in the table. Only 4 DMFS events occurred after 5 years, precluding to explore EET role by RCTable: 115PcLow-gULcLow-gLNULcLow-gHighcHigh-gULcHigh-gLNULcHigh-gHighN (%)13 (9.4)45 (32)35 (25)3 (2.2)30 (22)13 (9.4)8y-DFS (%)1009184.81009076.9CI 95%-83.2-99.871.6-100-79.9-10057.1-1008y-DMFS (%)10095.589.11009084.6CI 95%-89.6-10077.7-100-79.9-10067.1-1008y-DMFS (%)cHigh-gLow (UL+LNUL) No CT90.6% (CI 95% 81.1-100)8y-DMFS (%) in Mindact TrialcHigh-gLow (UL+LNUL) No CT89.4% (CI 95% 86.2-91.5) Open table in a new tab . In our series, DMFS rate in cHigh-gLow pts without CT was similar to that reported in MINDACT trial. In line with prior reports, gUL pts had excellent survival, while cHigh-gHigh group showed significantly poorer outcome. Albeit limited by small sample size, classification in 6 RCs instead of 4 seems useful to redefine prognosis. Additional FU is warranted to determine the EET benefit in each RC.

Abstract P2-03-02: Prospective assessment of the decision-making impact of the Breast Cancer Index in the BCI Registry Study

Abstract Background: The Breast Cancer Index (BCI) is a validated gene expression assay that provides a quantitative individualized risk of late recurrence and predicts the likelihood of benefit from extended endocrine therapy (EET) in HR+ early-stage breast cancer. The objective of this analysis was to assess the impact of BCI on clinical decision-making regarding EET in the BCI Registry Study. Methods: The BCI Registry Study is an ongoing, prospective, large-scale study to investigate the long-term clinical outcome, decision impact, and medication adherence in HR+ early-stage breast cancer patients receiving BCI testing as part of routine clinical care. Per protocol, physicians and patients completed pre- and post-BCI test questionnaires to assess the following: physician decision-making regarding EET; physician confidence with decision-making; patient preferences for EET; patient concerns about the cost, side effects, drug safety and benefit of EET; and patient satisfaction regarding treatment recommendation. Pre- and post-BCI responses were compared using McNemar’s test and Wilcoxon signed rank test. Results: Pre- and post-BCI test physician and patient questionnaires were completed for 843 and 823 patients, respectively. For the patients included in this analysis, mean age at enrollment was 65y and 88.4% of patients were postmenopausal. 74.7% of tumors were T1, 53.4% were G2, 75.3% N0, and 13.8% HER2-positive. Following BCI testing, physicians changed treatment recommendations for EET in 40.1% (338/843) of patients (p&amp;lt; 0.0001). In cases in which physicians recommended EET prior to BCI testing, 44.7% (214/479) changed their recommendation not to extend endocrine therapy. Of these cases, 98.1% (210/214) were BCI Prognostic low risk and/or BCI (H/I) Predictive low likelihood of benefit from EET. In cases in which physicians did not recommend EET prior to BCI testing, 34.6% (124/358) changed their recommendation in favor of EET. In such cases, 87.1% (108/124) of cases were BCI Prognostic high risk and/or BCI (H/I) Predictive high likelihood of benefit from EET. Further, following BCI testing, 38.8% (327/843) of physicians felt more confident in their recommendation (p&amp;lt; 0.0001). The percentage of physicians having high confidence levels (confident or strongly confident) increased from 58.1% (490/843) before BCI testing to 80.5% (679/843) after BCI testing. The percentage of physicians having low confidence levels (not at all confident, not confident, or ambivalent) decreased from 39.1% (330/843) before BCI testing to 18.7% (158/843) after BCI testing. In addition, 40.5% (341/843) of patients felt more comfortable with their EET decision (p&amp;lt; 0.0001) following BCI testing. Notably, changes in patient preferences for EET correlated with BCI test results. In BCI (H/I)-Low patients, 46.9% (241/514) showed a decreased preference for EET (p&amp;lt; 0.0001) while in BCI (H/I)-High patients, 28.2% (87/309) showed an increased preference for EET (p&amp;lt; 0.0001). Compared with baseline, after BCI testing, significantly more patients were less concerned about cost (20.9%, p&amp;lt; 0.0001), drug safety (25.4%, p=0.0014), and the benefits of EET (29.3%, p=0.0002). No significant change in concern regarding side-effects was observed (p=0.1486). Conclusions: This first analysis in a large patient cohort of the BCI Registry confirms previous findings on the significant clinical decision-making impact of BCI for extending adjuvant endocrine therapy. Incorporating BCI into clinical practice resulted in changes in physician recommendations for EET in over 40% of cases, while at the same time increasing physician confidence in their recommendations. Knowledge of the BCI result also improved patient satisfaction and reduced patient concerns regarding cost, drug safety and benefit of EET. Citation Format: Tara B. Sanft, Jenna Wong, Brandon O’Neal, Natalia Siuliukina, Rachel C. Jankowitz, Mark Pegram, Jenny Fox, Yi Zhang, Kai Treuner, Joyce O’Shaughnessy. Prospective assessment of the decision-making impact of the Breast Cancer Index in the BCI Registry Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-02.

Abstract GS5-10: Utility of the 70-gene MammaPrint test for prediction of extended endocrine therapy benefit in patients with early-stage breast cancer in the IDEAL Trial

Abstract Background: The IDEAL trial showed no significant benefit of 5 years extended endocrine therapy (EET) using letrozole in postmenopausal patients with hormone receptor positive (HR+) breast cancer (BC) versus 2.5 years. Genomic classifiers may assist with treatment decisions by predicting EET benefit. The 70-gene MammaPrint (MP) test classifies tumors as having a higher or lower risk of distant metastasis in HR+ early-stage BC. A MP lower risk result can be further classified as either Ultra-Low risk or Low risk of distant metastasis. In the NSABP B42 trial, MP predicted a statistically significant absolute benefit from EET in patients with a MP Low Risk result. Here, we aimed to determine the utility of MP in identifying a subgroup of patients enrolled in the IDEAL trial for which 5 years of EET is beneficial compared to 2.5 years. Methods: A total of 869 patients had available primary tumor tissue for testing. MP results were available for 545/869 patients, of which 515 did not have an event at 2.5 year after randomization and were used for our analyses. The MP result for each patient was calculated by Agendia while blinded to patient clinical outcomes. The primary endpoint was distant recurrence (DR). Secondary endpoints were recurrence free interval (RFI) and breast cancer free interval (BCFI) as defined by STEEP criteria. Patients were classified as higher risk (score -1.000 - 0) or lower risk (score 0.001 - 1.000). Lower risk tumors were further classified as either MP Ultra-Low (score &amp;gt; 0.355) or MP Low Risk (score ≥ 0.001, ≤ 0.355). Likelihood ratio test based on stratified Cox proportional hazards (PH) model were used to evaluate treatment by risk group interaction. Differences in endpoints between treatment groups were assessed by stratified log-rank tests. Hazard ratios (HR) and 95% Confidence Intervals (CI) were computed based on the stratified Cox PH model. Results: The clinical characteristics of the 515 IDEAL samples with a MP result were comparable to the whole IDEAL cohort (n=1820). Within the 2.5 year EET group, 50.6% (n=134) were MP higher risk and 49.4% (n=131) MP lower risk, of which 14.5% (n=19/131) were MP Ultra-Low. Within the 5 year EET group, 50.0% (n=125) were MP higher risk and 50.0% (n=125) MP lower risk, of which 11.2% (n=14/125) were MP Ultra-Low. Among patients with MP lower risk tumors, 5 years vs. 2.5 years of EET resulted in a significant absolute benefit of 9.8% for DR (HR=0.42, [95% CI 0.174-0.996]), 9.8% for RFI (HR=0.43, [95% CI 0.198-0.934]), and 8.8% (HR=0.53, [95% CI 0.264-1.055]) for BCFI, whereas patients with MP higher risk tumors did not derive significant benefit (Table 1). Within the MP lower risk group, 5 year vs 2.5 year EET benefit was more pronounced in MP Low tumors, which exhibited a significant benefit of 10.1% for DR (HR=0.32, [95% CI 0.116-0.866]), 11.7% for RFI (HR=0.35, [95% CI 0.147-0.824]), and 9.7% for BCFI (HR=0.48, [95% CI 0.225-1.015]); MP Ultra Low tumors did not derive significant benefit. Treatment-by-risk group interaction was statistically significant for RFI. Conclusion: A significant EET benefit was observed for MammaPrint lower risk tumors but not for MP higher risk tumors. MammaPrint Low tumors exhibited the largest absolute benefit of 5 years of EET compared to 2.5 years. Consistent with the findings in the NSABP B42 trial, the results from this second randomized trial provide clinically meaningful implications in patient selection for extended endocrine therapy. Table 1. IDEAL: 10-year outcome analysis comparing 5 years vs. 2.5 years of EET using letrozole stratified by MP risk. **MammaPrint Lower Risk &amp; Higher Risk (n=515) and *** MammaPrint Low Risk &amp; High Risk (n=482) Citation Format: Gerrit-Jan Liefers, Elma Meershoek-Klein Kranenbarg, Marjolijn Duijm-de Carpentier, Cornelis J.H. van de Velde, Miranda Kleijn, Christa Dreezen, Andrea Menicucci, Laura van’t Veer, William Audeh. Utility of the 70-gene MammaPrint test for prediction of extended endocrine therapy benefit in patients with early-stage breast cancer in the IDEAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-10.

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

BackgroundMultiple 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.MethodsNode-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.ResultsEET 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).ConclusionThese 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.

Adherence to EndoPredict test scores for extended endocrine therapy management in the prospective EndoPredict Extended Endocrine Trial (EXET).

537 Background: Current guidelines advise that individuals with estrogen receptor-positive (ER+) breast cancer (BC) undergo 5 years of endocrine therapy with consideration of up to 10 years of extended endocrine therapy (EET). The relative benefit of EET beyond 5 years is minimal for many patients, yet a significant group of patients at higher risk of late recurrence may benefit. EndoPredict is a gene expression assay to stratify those with high versus low BC recurrence risk and is validated to predict early and late distant metastasis up to 15 years using an EPclin score. In the prospective EXET study we evaluated adherence to EndoPredict test results when making decisions regarding EET. Methods: Patients with prior ER+, human epidermal growth factor 2 negative (HER2-) BC diagnosis and 4-6.5 years of endocrine therapy underwent EndoPredict testing. To evaluate the impact on decision making for EET, chart review was performed at or after test results were clinically disclosed. Univariable analysis was used for EPclin risk classification (high, low), multivariable analysis was used to evaluate the EPclin score with clinical variables and Firth logistic regression was used to assess the association of a given variable with the therapy decision. Results: The cohort consisted of 411 patients with an average age of 62 years (range 27, 90), 107 received adjuvant chemotherapy (26%), and 71 were lymph node positive (17.3%). The rate of EET was significantly different for those with low-risk scores (EPclin Score ≤ 3.3) compared to high-risk scores (EPclin Score &gt; 3.3; OR 8.5×10-4 [95% CI 6.8×10-6, 6.0×10-3], p-value 5.7×10-68). All patients with high-risk scores received EET. Within the low-risk group, those treated with adjuvant chemotherapy and those who were lymph node positive chose to extend endocrine therapy at higher rates. The EPclin score provided significant information in predicting EET status, even when accounting for clinical variables such as node status, tumor grade, age at diagnosis, adjuvant chemotherapy status and tumor stage (EPclin Score OR 20.2 [10.1, 44.0]; p-value=3.1 × 10-25). Conclusions: Even after adjusting for other clinical factors, EndoPredict is a significant predictor of clinical decision on EET. High adherence to EndoPredict test results in EET decision making was noted in our study. Clinical trial information: NCT04016935. [Table: see text]

Abstract PD15-04: Breast Cancer Index and assessment of the Net Treatment Benefit (NTB) of extended endocrine therapy in HR+ breast cancer

Abstract Background: Extended endocrine therapy (EET) has shown modest gains in absolute benefit to reduce the long-term risk of recurrence in hormone receptor-positive (HR+) breast cancer but is accompanied by serious adverse events (AEs), such as bone and cardiovascular toxicities, endometrial cancer and other side effects that impair quality of life (QOL). Novel approaches that quantify the benefit-risk balance integrating both survival benefit and harm to determine a net health outcome would advance EET decision making. BCI is a gene expression-based assay that predicts benefit from endocrine therapy. Here, the ability of BCI by HOXB13/IL17BR (H/I) to predict the net benefit from 2.5 vs 5y of extended letrozole in patients treated in the IDEAL trial was examined by integrating both efficacy and toxicity outcomes into a single analysis. Methods: All IDEAL patients with available tumor specimens were eligible for this analysis. The Net Treatment Benefit (NTB) and the Win Ratio (WR) were examined using generalized pairwise comparisons to analyze both efficacy and safety wherein all possible patient pairs, one from each treatment arm, were compared based on several prioritized outcome measures scored as favorable, unfavorable, neutral or uninformative. The first prioritized outcome was recurrence-free survival (RFI) with a clinical threshold of ≥3 months; the second prioritized outcome was toxicity based on the highest grade of treatment related AEs. NTB was estimated as the difference in the proportions of favorable vs unfavorable pairs, representing the net probability of an improved health outcome with EET. WR was calculated as the ratio of favorable vs unfavorable pairs, representing the relative risk of an improvement in health outcomes with EET. AEs were evaluated in annual follow-up visits during the active treatment period. Bone-related AEs of ≥ grade 3 included arthralgia, osteoporosis, decreased joint range of motion, back pain and fracture. The most prevalent QOL-related AEs of ≥ grade 3 included hot flashes, fatigue, depression, insomnia and vaginal dryness. Results: 908 HR+ patients (73% pN+, median age 59y, 45% pT1, 48% pT2) were included, with 88% and 68% receiving prior treatment with an aromatase inhibitor (AI) or chemotherapy, respectively. When toxicity was assessed with treatment related AEs ≥ grade 2, no significant improvement in the benefit-risk was observed for EET in either BCI (H/I)-High or BCI (H/I)-Low group. However, when severe toxicity was assessed with AEs ≥ grade 3, significant benefit-risk improvements were observed for EET in BCI (H/I)-High patients (NTB=7.2%, WR=1.76, p=0.044), but not in BCI (H/I)-Low patients (NTB=-0.7%, WR=0.96, p=0.869). BCI (H/I)-High patients demonstrated significant NTB=7.7%/7.4%, WR=2.24/1.92 when analyzing bone-related and QOL-related toxicities, respectively (p=0.024, 0.024), while no significant results were observed in the BCI (H/I)-Low patients (p=0.902, 0.780, respectively). Prioritizing toxicity over efficacy produced similar results. Conclusion: Novel findings demonstrate that BCI not only significantly predicts preferential survival benefit from longer durations of endocrine therapy, but also significantly predicts the overall benefit/risk and likelihood of an improved health outcome from EET in HR+ patients treated with primary adjuvant AI, when severe AEs are considered. It should be noted that the results of our analysis could be biased due to a shorter AE recording period in the 2.5y arm, hence the true benefit/risk of EET could be larger than reported here. Quantification of a net treatment benefit when considering the impact of both efficacy and toxicity may represent a new paradigm for evaluation of the overall EET benefit and aid in patient selection for EET. Citation Format: Marc Buyse, Jenna Wong, Samuel Salvaggio, Jean-Christophe Chiem, Yi Zhang, Kai Treuner, Elma Meershoek-Klein Kranenbarg, Mickaël De Backer, Gerrit-Jan Liefers, Catherine A Schnabel. Breast Cancer Index and assessment of the Net Treatment Benefit (NTB) of extended endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD15-04.

Breast Cancer Index and prediction of benefit from extended endocrine therapy based on treatment compliance: An IDEAL study.

531 Background: The IDEAL trial randomized hormone receptor-positive (HR+) breast cancer patients to 5 vs 2.5y of extended letrozole after completion of 5y of adjuvant endocrine therapy. In the parent trial, approximately 60% of patients overall were compliant with endocrine treatment (59% vs 74% compliance in 5y and 2.5y arms, respectively), with patient experiences as the most significant factors leading to treatment discontinuation. Breast Cancer Index is a gene expression-based signature that predicts which HR+ patients are likely to benefit from extended endocrine therapy (EET) vs those unlikely to benefit [BCI (H/I)-High and -Low, respectively]. The current study examined EET compliance and outcome by BCI (H/I) status in patients treated in the IDEAL trial. Methods: Patients with available primary tumor specimens were eligible for this blinded study. Primary endpoint was recurrence-free interval (RFI), including locoregional and distant recurrences. Kaplan-Meier and Cox proportional hazards regression analysis were used to analyze the benefit of EET. Non-compliance was defined as completion of ≤60% of treatment duration (≤3y for 5y arm; ≤1.5y for 2.5y arm) for any reason other than disease events. Overtreatment was defined as % compliant BCI (H/I)-Low patients in the 5y arm; undertreatment was % noncompliant BCI (H/I)-High patients in the 5y arm. Results: 908 HR+ patients (73% pN+, 59y, 45% pT1, 48% pT2) were included. 78% (n = 708) of patients were compliant, of which 48% (n = 338) were BCI (H/I)-High and 52% (n = 370) were BCI (H/I)-Low. In non-compliant patients (22%, n = 200), 45% (n = 91) were BCI (H/I)-High and 55% (n = 109) were BCI (H/I)-Low. BCI (H/I)-Low patients irrespective of compliance status did not derive significant benefit from EET (P = 0.922, compliant subset; 0.894 non-compliant subset). Compliant BCI (H/I)-High patients showed significant benefit from EET (HR 0.35, 95% CI 0.16-0.79; absolute benefit 11.7%; P = 0.008) whereas non-compliant BCI (H/I)-High patients did not (HR 0.75, 95% CI 0.17-3.35; absolute benefit 2.1%, P = 0.704). In this study, 38% of patients in the 5y EET arm were BCI (H/I)-Low and compliant and thus were overtreated, while 13% of patients in the 5y EET arm were BCI (H/I)-High and non-compliant and thus were undertreated. Conclusions: Patients that were BCI (H/I)-Low did not derive significant benefit from 5 vs 2.5y of EET even when compliant, and thus may be considered for treatment de-escalation. Importantly, BCI (H/I)-High patients with endocrine responsive disease showed significant improvements in outcome when compliant and should be guided to continue treatment. BCI may serve as an important genomic tool to increase EET compliance and identify patients that may be candidates for increased side effect management and support to potentially improve outcomes. Clinical trial information: NTR3077; BOOG 2006-05; Eudra-CT 2006-003958-16.

HER2 status and prediction of extended endocrine benefit with breast cancer index (BCI) in HR+ patients in the adjuvant tamoxifen: To offer more? (aTTom) trial.

522 Background: BCI is a validated gene expression-based assay that stratifies patients based on risk of overall (0-10y) and late (post-5y) distant recurrence (DR) and predicts likelihood of benefit from extended endocrine therapy (EET). The Trans-aTTom study established Level1B validation for BCI (H/I) to predict benefit from EET.1 In this updated Trans-aTTom analysis including HER2 status, BCI (H/I) and prediction of endocrine benefit were further characterized. Methods: Centralized HER2 was determined for all cases according to current ASCO/CAP guidelines. Kaplan-Meier and Cox proportional hazards regression were conducted to assess primary and secondary endpoints of Recurrence-Free Interval (RFI) and Disease-Free Interval (DFI), respectively. A three-way interaction using likelihood ratio testing, which included treatment, BCI (H/I) and HER2, was performed to assess the effect of HER2 on BCI (H/I) prediction of EET benefit. Results: Of 789 N+ patients, 90% (N = 711) and 9% (N = 72) were HR+/HER2- and HR+/HER2+, respectively. In the HER2- subset, BCI (H/I)-High (48%) showed significant benefit from 10y vs. 5y of tamoxifen (9.4% RFI: HR = 0.35 [95% CI 0.15-0.81]; P = 0.047) while BCI (H/I)-Low patients did not (-2.1% RFI; HR = 1.15 [95% CI 0.78-1.69]; P = 0.491). For DFI, BCI (H/I)-High patients also showed significant benefit (10.3% DFI; HR = 0.41 [95% CI 0.18-0.91]; P = 0.047) while BCI (H/I)-Low patients did not (-1.7% DFI; HR = 1.10 [95% CI 0.75-1.62] P = 0.612). As demonstrated in the overall N+ cohort, significant interaction between BCI (H/I) and treatment was shown in the HER2- subset (RFI P = 0.045; DFI P = 0.044). Notably, three-way interaction evaluating BCI (H/I), treatment and HER2 status was not statistically significant (P = 0.85), indicating the ability of BCI (H/I) to predict benefit of EET activity was not significantly affected by HER2 status. Conclusions: In this updated Trans-aTTom analysis with HER2 data, BCI (H/I) showed similar predictive performance for EET response in the HER2- subset when compared to the overall N+ cohort. These data further support the clinical utility of BCI (H/I) as a predictive biomarker for informing EET benefit in HR+/HER2- and HR+/HER2+ disease. Clinical trial information: NCT00003678 . [Table: see text]

Breast cancer index (BCI) predicts benefit of two-and-a-half versus five years of extended endocrine therapy in HR+ breast cancer patients treated in the ideal trial.

512 Background: For postmenopausal women with hormone receptor positive (HR+) breast cancer, the optimal duration of extended endocrine therapy (EET), after completing 5 years of initial aromatase inhibitor (AI)–based adjuvant therapy, remains unclear. BCI [HOXB13/IL17BR (H/I)] is a gene expression-based biomarker that has been demonstrated to predict EET benefit in the MA.17 and Trans-aTTom studies in patients treated with adjuvant tamoxifen. The current study examined the ability of BCI (H/I) to predict endocrine benefit from 2.5 vs. 5 years of extended letrozole in the IDEAL trial. Methods: All patients with available tumor specimens were eligible for this blinded prospective-retrospective study. The primary endpoint was Recurrence-Free Interval (RFI). Median follow-up was 9.1 years from randomization. Kaplan-Meier and Cox proportional hazards regression analysis were used to analyze the differential benefit of EET with statistical significance of the interaction between BCI (H/I) and treatment assessed by likelihood ratio test. Results: 908 HR+ patients (73% pN+, median 59y, 45% pT1, 48% pT2, disease free at 2.5 years) were included, with 88% and 68% receiving prior treatment with an AI or chemotherapy, respectively. BCI by H/I status (High vs. Low) was significantly predictive of response from extended letrozole in the overall (N = 908) and pN+ (N = 664) cohorts. Notably, BCI (H/I) predicted EET benefit in patients that received any primary adjuvant therapy with an AI (N = 794). Treatment to biomarker interaction was significant in the overall (p = 0.045), pN+ (p = 0.029) and any prior AI (p = 0.025) cohorts, adjusted for age, pT stage, grade, nodal status, prior endocrine therapy and prior chemotherapy. Conclusions: Novel findings from this study demonstrate that BCI predicts endocrine benefit from extended letrozole in postmenopausal patients treated with primary adjuvant AI. These results support the growing body of evidence that BCI by H/I status predicts preferential endocrine response in distinct subgroups of patients, and further support its role as an important genomic tool to inform the risk-benefit regarding duration of extended endocrine therapy. Clinical trial information: NTR3077, BOOG 2006-05, Eudra-CT 2006-003958-16 . [Table: see text]

Abstract P2-11-02: Breast Cancer Index predicts benefit from extended endocrine therapy in HR+ breast cancer

Abstract Background: Optimizing the duration of adjuvant endocrine therapy in patients diagnosed with early stage hormone receptor-positive (HR+) breast cancer requires improved approaches to individualize disease profile and to reduce any unnecessary treatment burden for patients. Current clinical practice guidelines recommend 10 years of adjuvant endocrine therapy for most patients unless there are characteristics of low risk disease. However, approximately 2/3rds of patients have favorable long-term outcomes after completing 5 years of adjuvant therapy. Therefore, consideration of the risk-benefit profile for each patient is critical to identify who may be spared extended endocrine therapy (EET) and its associated toxicities, and which patients will benefit from an additional 5 years of endocrine therapy. The Breast Cancer Index (BCI) is a gene expression-based signature that stratifies patients based on the risk of overall (0-10y) and late (post-5y) distant recurrence (DR) and predicted the likelihood of benefit from extended endocrine therapy in MA.17. The translational-aTTom (Trans-aTTom) study is a multi-institutional, prospective-retrospective study to validate the predictive ability of BCI by HOXB13/IL17BR (H/I) status for EET benefit in early stage HR+, N0 and N+ breast cancer. Methods: Patients treated in the aTTom (Adjuvant Tamoxifen - To Offer More?) trial with available primary tumor tissue were eligible. Biospecimens were retrospectively collected from aTTom study sites and centrally assessed for ER, PR and HER2 status. Median follow-up was 12.6 years. Primary and secondary endpoints were recurrence-free interval (RFI) and disease-free interval (DFI), respectively. Statistical significance level was set at 0.0336 as per statistical analysis plan. Weighted Kaplan-Meier and Cox proportional hazards regression analysis with time-varying coefficients were used to test the predictive activity of BCI by HOXB13/IL17BR (H/I) status (High vs Low). Likelihood ratio test based on Cox regression was used to evaluate treatment by biomarker interaction. Results: Archived tumor specimens from 3328 patients were collected across 62 aTTom trial sites, representing 48% of the parent trial population. Central testing and assessment of ER, PR, HER2, and BCI resulted in 2445 HR+ patients (1367 N0, 789 N+, 289 nodal status unknown) in the overall cohort. At final analysis, the study remained underpowered for evaluating BCI predictive performance in the overall cohort due to an observed limited effect size that was smaller than planned and did not recapitulate the parent aTTom trial. However, evaluation of BCI predictive performance in the updated N+ subset (N=789) showed that patients classified as BCI(H/I)-High (N=404, 51%) experienced a statistically significant benefit from 10y vs 5y of tamoxifen (9.7% RFI: HR=0.33 [95% CI 0.14-0.75]; P=0.016), whereas those classified as BCI(H/I)-Low showed no significant benefit (-1.2% RFI; HR=1.11 [95% CI 0.76-1.64]; P=0.58). A statistically significant interaction between continuous BCI(H/I) and treatment was demonstrated (P = 0.036) adjusted for age, tumor size and grade, whereas no significant interaction was observed between treatment and quantitative ER (P=0.939) or PR (P=0.138) expression. 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 vs. 5 years of tamoxifen therapy. These data provide further validation, consistent with previous MA.17 data, for BCI as a predictive biomarker of benefit from extended endocrine therapy. Findings from the Trans-aTTom strengthen the clinical validity of BCI for prediction of endocrine response and its clinical utility in optimizing duration of endocrine therapy. Citation Format: John Bartlett, Dennis Sgori, Kai Treuner, Yi Zhang, Tammy Piper, Ranelle Shalunga, Ikhlaaq Ahmed, Lucy Doos, Sarah Thornber, Elena Brachtel, Sarah Pirrie, Catherine Schnabel, Daniel Rea. Breast Cancer Index predicts benefit from extended endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-02.

A comparison of genomic assays in determining risk of late recurrence and benefit of extended endocrine therapy (EET).

e12045 Background: Breast cancer patients who are ER positive, lymph node negative have the best overall prognosis. However 50% of recurrences occur after 5 years. The Breast Cancer Index (BCI) is a gene expression-based biomarker that provides an individual risk of distant recurrence and benefit of EET based on a continuous risk model. (1) The BCI may help with clinical decisions regarding EET since prolonged therapy may have an increase in side effects including uterine cancer, DVT, myalgias and bone loss. The OncotypeDX is a 21 gene assay that predicts recurrence with a recurrence score. A recent study by Wolmark et al. evaluated the use of quantitative Estrogen Receptor Index (ESRI) combined with RS and found that RS was prognostic in patients with higher quantitative ESRI, suggesting EET be used for patients with intermediate and high RS with ESR1 expression &gt; 9.1. (2) Methods: 20 patients, ER positive, node negative who had the BCI and ONC-DX performed were evaluated in this retrospective IRB approved review. Results: Using ESRI alone 85% of patients would be recommended to continue an additional 5 years of EET. Using BCI this number was reduced to 35%. Conclusions: Comparing both the risk of recurrence and benefit of ETT, ESRI and BCI were concordant only 37.5% of the time. The cost of extended adjuvant therapy with Anastrazole ($190/mos x 60 mos = $11,400) or Tamoxifen ($50/mos x 60 mos = $ 3,000) would have resulted in a cost savings of $79,800 (Anastrazole) or $21,000 (Tamoxifen) for this small group of patients. Utilization of the BCI (cost $ 3416.00) may be a cost effective and accurate genomic approach in determining the use of EET and avoiding concomitant side effects.

Abstract B031: Prediction of the clinical benefit of adjuvant tamoxifen therapy using Breast Cancer Index (HOXB13:IL17BR)

Abstract Background: Breast Cancer Index (BCI) is a gene expression-based biomarker with a novel mechanism of action that provides individual risk assessment of both early (0-5 years) and late (5-10 years) distant recurrence in ER+, node negative (LN-) breast cancer patients. BCI is an algorithmic combination of two complementary biomarkers: Molecular Grade Index (MGI), which recapitulates tumor grade/proliferation status; and HOXB13:IL17BR ratio (H/I), which interrogates estrogen signaling pathways. In a previous analysis of the randomized MA.17 trial, H/I was predictive of extended endocrine therapy benefit (Sgroi et al., JNCI 2013). The current study examined whether H/I predicts benefit of adjuvant tamoxifen (TAM) versus untreated (UNT) in ER+ LN- patients from the prospective, randomized, placebo-controlled Stockholm trial. Materials and Methods: Formalin fixed paraffin embedded (FFPE) tumor blocks from 808 LN- patients were analyzed with 37 cases excluded due to insufficient tumor content (N=771). The primary endpoint was distant recurrence, with 15-year clinical follow-up data. H/I was calculated and risk groups determined using a pre-specified cutpoint. Kaplan-Meier analysis and Cox proportional hazards regression with an interaction term between the treatments and pre-defined H/I risk groups were examined for prediction of benefit of TAM vs UNT. The strength of the relationship between magnitude of TAM benefit and H/I as a continuous variable was assessed by the likelihood ratio test. Results: Of 771 specimens assayed, RT-PCR was successful for 769 cases, among which 600 were from ER+ tumors (317 TAM, 283 untreated). Using the pre-specified cutpoint, 230 patients (38%) were classified as having high H/I ratio while 370 (62%) had a low H/I ratio. High H/I was predictive for benefit from TAM therapy, with a decrease of 17.4% in absolute risk of distant recurrence (90.6% [95% CI: 85.1-96.3%] for the TAM arm versus 73.1% [95% CI: 65.0-82.2%] for UNT arm) and a relative risk of 0.33 (95% CI: 0.17-0.63; p &amp;lt; 0.0001) as measured by hazard ratio (HR). No significant reduction in distant recurrence was observed in patients with low H/I [91.6% (95% CI: 87.7-95.6%) for the TAM arm versus 88.2% (95% CI: 83.3-93.5%) for the untreated arm] and a HR of 0.67 (95% CI: 0.35-1.28; p = 0.204). Multivariate analysis demonstrated that the benefit of TAM was significant in patients with high H/I (HR 0.33; 95% CI 0.17-0.62; p = 0.0007) after adjusting for age, tumor size, grade, PR and HER2 status. A multivariate analysis of Cox models with and without an interaction term between H/I and TAM treatment by likelihood ratio test showed that the interaction was significant (p = 0.003). Consistent with the significant interaction, the 10-year rate of distant recurrence as a function of continuous H/I for the 2 treatment arms demonstrated that the reduction in the rate of distant recurrence by TAM increases as the H/I ratio increases. Conclusions: This prospective-retrospective study of ER+ LN- breast cancer patients from the Stockholm trial demonstrated that H/I was predictive of benefit from adjuvant TAM treatment. The results from this study and the recent data demonstrating that H/I predicts benefit from extended letrozole therapy in the MA.17 trial, indicates that H/I is a predictive biomarker for both adjuvant and extended adjuvant endocrine therapies and further supports the clinical utility of BCI (H/I) for predicting patient benefit of extended endocrine therapy. Citation Format: Yi Zhang, Brock E. Schroeder, Piiha-Lotta Jerevall, Olle Stal, Dennis C. Sgroi, Mark G. Erlander, Catherine A. Schnabel. Prediction of the clinical benefit of adjuvant tamoxifen therapy using Breast Cancer Index (HOXB13:IL17BR). [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B031.