Extended Endocrine Therapy Research Articles

Impact of extended endocrine therapy for patients with risk factors for late recurrence in estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after 5years of endocrine therapy.

Extended endocrine therapy shows promise for reducing the recurrence of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, its benefits in patients with high-risk factors for late recurrence remain unclear, particularly in premenopausal patients. In this study, we aimed to explore the impact of extended endocrine therapy in patients with risk factors for late recurrence of postmenopausal and premenopausal ER-positive, HER2-negative breast cancer. We retrospectively analyzed data from patients with ER-positive, HER2-negative breast cancer at Tohoku Kosai Hospital who were disease-free after 5years of adjuvant endocrine therapy. The patients were classified as high risk based on lymph node positivity, tumor size > 2cm, or high tumor grade. The high-risk group was further divided into extended therapy and stop groups. Propensity score matching was applied to balance baseline characteristics. Disease-free survival (DFS) was the primary endpoint. Among the 1474 eligible patients, 224 received extended endocrine therapy, and 1250 stopped therapy. After propensity score matching, the high-risk group comprised 348 patients (n = 174 patients/group). The extended therapy group had significantly higher 10-year DFS and distant DFS rates than the stop group. The multivariate Cox model indicated a 69% reduction in recurrence risk in the extended therapy group. Extended endocrine therapy can substantially improve DFS in patients with high-risk ER-positive, HER2-negative breast cancer, especially in those with large tumors, lymph node involvement, and high tumor grade. These findings support personalized treatment strategies for enhancing long-term outcomes.

Utility of the 70-Gene MammaPrint Assay for Prediction of Benefit From Extended Letrozole Therapy in the NRG Oncology/NSABP B-42 Trial.

MammaPrint (MP) determines distant metastatic risk and may improve patient selection for extended endocrine therapy (EET). This study examined MP in predicting extended letrozole therapy (ELT) benefit in patients with early-stage breast cancer (BC) from the NSABP B-42 trial. MP was tested in 1,866 patients randomly assigned to receive ELT or placebo. The primary end point was distant recurrence (DR). Secondary end points were disease-free survival (DFS) and BC-free interval (BCFI). Tumors were classified as MP high risk (MP-HR) or low risk (MP-LR). MP-LR tumors were further classified as ultralow risk (MP-UL) or low non-ultralow risk (MP-LNUL). There was no statistically significant difference in ELT benefit on DR between MP-HR and MP-LR (interaction P = .38). MP-LR tumors (n = 1,160) exhibited a statistically significant 10-year benefit of 3.7% for DR (hazard ratio [HR], 0.43 [95% CI, 0.25 to 0.74]; P = .002), whereas MP-HR tumors (n = 706) exhibited a nonsignificant 2.4% benefit (HR, 0.65 [95% CI, 0.34 to 1.24]; P = .19). The 10-year ELT benefit was significant for DFS (7.8%) and BCFI (7.0%) for MP-LR tumors, whereas MP-HR tumors did not significantly benefit (interaction DFS: P = .015, BCFI: P = .006). In exploratory analysis, the 10-year ELT benefit was significant and more pronounced in MP-LNUL (n = 908) tumors: 4.0% for DR, 9.5% for DFS, and 7.9% for BCFI; the benefit in MP-UL (n = 252) tumors was not significant: 3% for DR, 1.8% for DFS, and 4.1% for BCFI. The primary hypothesis of predictive ability of MP on DR was not confirmed. However, the secondary outcomes demonstrated MP was predictive of ELT response and identified a subset of patients with early-stage hormone receptor-positive BC (MP-LR) with improved outcomes from ELT. These data could have important clinical implications in patient selection beyond clinical risk assessment for EET.

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]

Use of Oncotype vs. Breast Cancer Index (BCI) for extended endocrine therapy decisions: A single center analysis in stage IA hormone receptor positive breast cancer.

e13083 Background: Extended Endocrine Therapy (EET) for hormone receptor positive HER-2 negative early-stage breast cancer reduces late recurrence risks but raises concerns about toxicity. Biomarker tests like the Breast Cancer Index (BCI) are vital for identifying patients who could benefit from continued ET, reassuring others against unnecessary extension. This study evaluates prognostic implications for both Oncotype Dx (Recurrence score, RS) and BCI amidst concerns about added testing costs in patients with early stage, estrogen receptor (ER) positive breast cancer. Methods: This is a single institution retrospective review of Stage IA ER positive HER-2 negative breast cancer patients who underwent both Oncotype Dx and BCI testing from January 2021 to December 2023. Pearson's correlation coefficient (r) was used to assess the linear relationship between the assays (p<0.05 for significance), analysis was performed with SAS software, version 9.4. Results: Fifty-eight patients with Stage IA ER positive HER-2 negative breast cancer who had both Oncotype and BCI results were identified (100% female; mean age 72.2 years [54-87]). After a median followed up of 72 months (63-75), no systemic or locoregional recurrences were reported. A low positive correlation between Oncotype and BCI was observed across the entire cohort (r=0.4058; p=0.0016). However, subgroup analysis showed no significant correlations: Oncotype <11 (n=17; r=0.2415; p=0.3504), Oncotype ≤18 (n=43; r=0.0914; p=0.5600), Oncotype <26 (n=51; r=0.2530; p=0.0733); Oncotype ≥26 (n=7; r=-0.5634; p=0.1878). Correlation was also not found in patients with Grade 1 tumor (n=16; r=0.3138; p=0.2365). Thirty-nine patients (67.24%) had their treatment recommendation changed based on BCI results. Side effects from ET affected 15 patients (25.86%) and included arthralgias (60%, n=9), hot flashes (26.67%, n=4), depression (13.33%, n=2), insomnia (6.67%, n=1), and others (53.3%, n=8). Twenty-two patients (37.93%) developed new osteopenia, and 6 (10.34%) new osteoporosis while on EET. Eight patients (13.79%) had ET interruption during their treatment course. Conclusions: Despite inclination towards cost-saving measures, Oncotype DX may be more useful to give prognosis in the early adjuvant period whereas BCI is more useful to evaluate late recurrence risk. Low or high Oncotype scores and tumor grade may not align with BCI findings. Considering the importance of managing toxicity against the risk of late recurrence, incorporating BCI testing can enhance EET recommendations, even for Stage I, node-negative, ER positive patients.

Comparative analysis of genomic tests for the prediction for late recurrence risk in hormone receptor–positive invasive breast cancer in a sample of Colombian patients.

e13092 Background: Approximately 70% of invasive breast cancers are hormone receptor-positive, requiring 5 years of endocrine therapy as the gold standard treatment. However, extended endocrine therapy (EET) may be needed, considering the late recurrence risk up to 15 years post-diagnosis. Different genomic tests predict the risk of recurrence. The 70-gene signature classifies patients as low or high risk during the first 5-years after diagnosis. The 12-gene test identifies high and low-risk patients for distant relapse up to 15 years, while a third test, based on 7-gene expression, assesses distant relapse risk up to 10 years. These tests assist clinicians in defining the need for EET. This study aims to compare the results of these genomic tests to determine late recurrence and distant relapse risks after 5 years, guiding EET indications. Methods: This is a retrospective descriptive transversal study involving 27 female patients diagnosed with hormone receptor-positive invasive breast cancer, treated in the same oncologic center in Colombia. All patients were first tested with the 70-gene genomic profile, with 15 patients undergoing the 12-gene test and 12 cases undergoing the 7-gene assay approximately 5 years later. Concordance between test results was assessed, and socio-demographic variables were descriptively analyzed. Results: The mean age was 54.4 years (SD=11.7). Invasive ductal carcinoma comprised 77.7% and invasive lobular carcinoma 22.22%. The 70-gene profile identified 21 cases (77.7%) as low-risk. Among those, 87.5% had a high-risk result with the 12-gene test, and 60% had a high-risk score with the 7-gene test. Conclusions: The findings support the utility observed in the sub-analysis of the NSABP-B42 study, showing that a low-risk result in the 70-genes signature, means high risk of late recurrence and the need for EET, emphasizing the importance of further evaluation and validation of genomic tests in predicting breast cancer recurrence risks. Larger sample sizes are necessary to confirm these results and establish their clinical relevance in oncology practice.

Clinical relevance of clinical treatment score post 5 years (CTS5) in HR-positive, HER2-positive breast cancer: An exploratory analysis from the HERA trial.

519 Background: The clinical treatment score post-5 years (CTS5) has proven valuable in assessing the necessity for extended endocrine therapy among patients with early-stage hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This study aimed to explore the potential of CTS5 as a predictive tool for long-term survival beyond five years in patients with specifically HR-positive, HER2-positive breast cancer. Methods: We collected patient-level data from the HERceptin Adjuvant (HERA) (BIG1-01; NCT00045032) trial. Our investigation focused on assessing the risk of late distant recurrence (DR) and overall survival (OS) according to the CTS5 risk score as continuous value and CTS5 stratification risk groups. Furthermore, we performed a Cox-regression analysis to determine the prognostic performance of CTS5, stratifying subgroups by age and administration of trastuzumab. Results: A total of 1,818 patients with HR-positive, HER2-positive breast cancer were included in this analysis. The CTS5 score, as a continuous variable, emerged as an independent prognostic factor for both late DR (adjusted HR, 2.04; 95% CI, 1.62-2.57; P < 0.001) and OS (adjusted HR, 2.02; 95% CI, 1.58-2.58; P < 0.001), respectively. In addition, multivariable analysis showed a significant association between the high-risk group and adverse outcomes in late DR (adjusted HR, 2.76; 95% CI, 1.84-4.15; P < 0.001) and OS (adjusted HR, 2.45; 95% CI, 1.60-3.74; P < 0.001) compared to low/intermediate group. Consistent results were observed, regardless of age or administration of HER2-targeted therapy. Conclusions: CTS5 is a useful prognostic tool for predicting late DR and OS in HR-positive, HER2-positive breast cancer patients. Extension of endocrine therapy should be actively considered in patients with CTS5 high-risk group.

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 PO5-01-11: Breast Cancer Index and comparative analysis of late distant recurrence risk with results from the TEAM trial

Abstract Background: Individualized risk assessment of distant recurrence (DR) is critical for early-stage HR+ breast cancer patients, as prolonged risk of recurrence continues even after completing 5 years of adjuvant endocrine therapy. The Breast Cancer Index (BCI) is a guideline-endorsed, validated gene expression assay that provides an individualized risk of overall (0-10y) and late (5-10y) DR and predicts the likelihood of benefit from extended endocrine therapy. The current BCI assay reports prognostic risk estimates based on tamoxifen-treated patients from the Stockholm (STO-3) cohort for node-negative (N0) patients, enrolled between 1976 through 1990 and a retrospective cohort from Massachusetts General Hospital (MGH) for patients with 1 to 3 positive nodes (N1), diagnosed between 1993 and 2007, of which approximately 50% were tamoxifen-treated. More recently, additional validation was completed in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial, in which patients were enrolled between 2001 and 2006. Here, individualized DR risk estimates from the TEAM trial were compared with those from Stockholm and MGH cohorts. Methods: For the TEAM translational study, BCI testing was performed blinded to clinical outcome and BCI and BCIN+ risk scores were calculated as previously described. A total of 2910 postmenopausal patients with HR+ breast cancer, including 1285 N0 and 1625 N1 patients, who remained DR-free for five years were analyzed to determine the risk of late DR. Cox proportional hazard models using Breslow estimates were used to calculate the risk of late DR as a function of continuous BCI risk scores. Results: Late DR risk estimates from both the TEAM trial and the Stockholm/MGH cohorts are summarized in the table below. In N0 patients, comparison of 5-10y risk estimates of late DR observed in TEAM patients were higher than those in the Stockholm cohort for BCI scores less than 8.0, but reduced for BCI scores greater than 8.0. Risk estimates differed by 1.5% for a BCI score of 0 and -4.3% for a BCI score of 10. A similar pattern was observed for N1 patients between the TEAM and MGH cohorts, with risk estimates from TEAM trial being higher for BCI scores less than 8.0 but reduced for BCI scores greater than 8.0 compared to those from the MGH cohort. Conclusions: BCI prognostic validation in the TEAM trial enabled the characterization of DR risk that is more compatible with the current standard of care in the US, as postmenopausal patients were all treated with at least 2-3 years or 5 years of primary adjuvant endocrine therapy with an aromatase inhibitor. Results from the TEAM study provide a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ early-stage breast cancer patients. Table. Citation Format: John MS Bartlett, Yi Zhang, Gregory Pond, Jenna Wong, Keying Xu, Melanie Spears, Elizabeth Mallon, Karen Taylor, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, Cornelis J.H. van de Velde, Daniel Rea, Adam Brufsky, Olle Stål, Dennis Sgroi, Catherine Schnabel, Kai Treuner, Jane Bayani. Breast Cancer Index and comparative analysis of late distant recurrence risk with results from the TEAM trial [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 PO5-01-11.

Abstract PO4-01-11: Ovarian function suppression (OFS) use beyond five years?: Young breast cancer patient preferences

Abstract Background. Breast cancer (BC) is the leading cause of cancer-related death in young women worldwide, and late recurrence of hormone receptor-positive disease plays a substantial role. Adjuvant endocrine therapy with 5 years of ovarian function suppression (OFS) and an aromatase inhibitor or tamoxifen is recommended for many young patients with high risk hormone receptor-positive BC. Data are limited regarding extended endocrine therapy among premenopausal BC survivors, and non-existent to inform treatment decisions regarding extending OFS beyond 5 years. We sought to evaluate young BC survivors’ perceptions and preferences regarding extending OFS beyond 5 years, and consideration of a potential future study to assess the role of extended OFS. Methods. From January-April 2023, email invites were sent to the Young Survival Coalition (YSC) listserv (N=14,291) specifically asking members with a history of invasive BC (≤45 years at diagnosis; stage I-III without metastatic recurrence) receiving OFS injections for adjuvant endocrine treatment to complete a one-time anonymous online survey. The survey was designed to capture information regarding current endocrine therapy use, patient-provider communication regarding extended endocrine therapy including OFS, OFS-related concerns (rating 0-5 [low: 0-1, moderate: 2-3, severe: 4-5]), and interest in a potential future clinical trial utilizing OFS beyond 5 years. Descriptive statistics were utilized to summarize responses, and two-sided Fishers exact tests and chi-square analyses were used for comparisons. Results. A total of 1,030 YSC members completed the survey, and 615 were analyzed due to eligibility and completeness of data. The majority were from the United States (n=579, 94.1%) or Canada (n=8, 1.3%), were non-Hispanic white (n=452, 73.5%), non-Hispanic Black (n=46, 7.5%), or Hispanic (n=43, 7.0%), and had been diagnosed with stage II BC (n=316, 51.4%). The average age at survey was 38.1 years (SD=5.15, range=22-54) and at initial BC diagnosis was 34.6 years (SD=4.96, range=20-49). Most (n=510, 83.0%) were within their first 5 years of OFS treatment while 14.5% (n=89) had already been receiving OFS for more than 5 years. Many respondents (n=344, 55.9%) reported discussing OFS use beyond 5 years with their provider, of whom 39.8% (n=245) reported their provider recommending they continue OFS for more than 5 years. Despite reporting moderate and severe concerns regarding OFS side effects (n=476, 77.4%), inconvenience of injection visits (n=272, 44.2%), and high cost of medication (n=223, 36.3%), most respondents (n=396, 64.4%) would consider continuing OFS beyond 5 years if it would reduce risk of BC recurrence. For nearly half of respondents (n=289, 47.0%) a risk reduction of at least 5% would be required for extended OFS to be worthwhile compared to the remaining 46.3% (n=285) who indicated interest for < 5% risk reduction. When asked hypothetically if they would take part in a clinical trial to determine efficacy of OFS use beyond 5 years, the majority were interested (n=357, 58.0%). Respondents who were interested were less likely to be concerned about the high cost of medication (p=0.003) however they were also less likely to take OFS beyond 5 years if it only led to 1-2% BC risk reduction (p=0.006) compared to those who were not interested. There were no other proportional differences on any other outcome. Conclusion. Many BC survivors and providers are already considering incorporation of OFS beyond 5 years into adjuvant endocrine therapy despite harboring concerns and lack of data. Efforts to determine the efficacy and benefits of extended OFS are necessary given the risk of late recurrence in this population as well as the potential for significant short- and long-term toxicities. The results from this survey study suggest that future clinical trials evaluating potential benefits and risks of long-term OFS use among young BC survivors are needed and likely feasible. Citation Format: Kate Dibble, Tal Sella, Kathryn Ruddy, Craig Snow, Amanda Nixon, Patricia Spears, Karla Ballman, Lisa Carey, Ann Partridge. Ovarian function suppression (OFS) use beyond five years?: Young breast cancer patient preferences [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 PO4-01-11.

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.

Validation of CTS5 Model in Large-scale Breast Cancer Population and Combination of CTS5 and Ki-67 Status to Develop a Novel Nomogram for Prognosis Prediction.

More than half of patients with early-stage estrogen receptor-positive (ER+) breast cancer relapse after completing 5 years of adjuvant endocrine therapy, so it is important to determine which patients are candidates for extended endocrine therapy. The clinical treatment score after 5 years (CTS5) is a prognostic tool developed based on postmenopausal ER+ breast cancer to assess the risk of late distant recurrence (LDR) after 5 years of adjuvant endocrine therapy for breast cancer. We aimed to externally validate the prognostic value of CTS5 in premenopausal and postmenopausal patients and combined with Ki-67 to develop a new model to improve the ability of prognosis prediction. We included a total of 516 patients with early-stage ER+ breast cancer who had received 5 years of adjuvant endocrine therapy and were recurrence-free for 5 years after surgery. According to menopausal status, we divided the study population into 2 groups: premenopausal and postmenopausal women. The CTS5 of each patient was calculated using a previously published formula, and the patients were divided into low, intermediate, and high CTS5 risk groups according to their CTS5 values. Based on the results of the univariate analysis ( P <0.01), a multivariate COX proportional hazards regression analysis was conducted to establish a nomogram with significant variables ( P <0.05). The discriminative power and accuracy of the nomograms were assessed using the concordance index (C-index), calibration curve, and area under the time-dependent receiver operating characteristic curve. Discrimination and calibration were evaluated by bootstrapping 1000 times. Finally, we utilized decision curve analysis to assess the performance of our novel predictive model in comparison to the CTS5 scoring system with regard to their respective benefits and advantages. The median follow-up time was 7 years (6 to 9 years). The 516 women were categorized by CTS5 as follows: 246(47.7%) low risk, 179(34.7%) intermediate risk, and 91(17.6%) high risk. Using the CTS5 score as a continuous variable, patients' risk score was significantly positively associated with recurrence risk in both premenopausal and postmenopausal subgroups. For HER2- premenopausal patients and HER2+ postmenopausal patients, the CTS5 score was positively correlated with LDR risk. Patients with a Ki-67≥20% had a higher risk of LDR regardless of menopausal status. Using the CTS5 score as a categorical variable, the high-risk group of HER2- premenopausal patients had a higher risk of LDR. However, the CTS5 model could not distinguish the risk of LDR in different risk groups for HER2+ postmenopausal patients. In the high-risk group, patients with Ki-67≥20% had a higher risk of LDR, regardless of menopausal status. We developed a new nomogram model by combining the CTS5 model with Ki-67 levels. The C-indexes premenopausal and postmenopausal cohorts were 0.731 and 0.713, respectively. The nomogram model was well calibrated, and the time-dependent ROC curves indicated good specificity and sensitivity. Furthermore, decision curve analysis demonstrated that the new model had a wider and practical range of threshold probabilities, resulting in an increased net benefit compared with the CTS5 model. Our study demonstrated that the CTS5 model can effectively predict the risk of LDR in early-stage ER+ breast cancer patients in both premenopausal and postmenopausal patients. Extended endocrine therapy is recommended for patients with Ki-67≥20% in the CTS5 high-risk group, as well as premenopausal patients with HER2-. Compared with CTS5, the new nomogram model has better identification and calibration capabilities, and further research is required to validate its efficacy in large-scale, multicenter, and prospective studies.

Young Women with Breast Cancer: The Current Role of Precision Oncology.

Young adults aged 40 years and younger with breast cancer represent less than 5% of all breast cancer cases, yet it is the leading cause of death among young women with cancer worldwide. Breast cancer that develops at a young age is more aggressive and has biological features that carry an increased risk of relapse and death. Young adults are more likely to have a genetic predisposition and key biomarkers, including endocrine receptors, the HER2 receptor, and proliferation biomarkers, that appear different compared to older adults. Despite being more aggressive, management strategies are largely the same irrespective of age. Given the higher rates of genetic predisposition, fast access to genetic counselling and testing is a necessity. In this review, the biological differences in young adult breast cancer and the current role precision medicine holds in the treatment of young adults with breast cancer are explored. Given the relatively high risk of relapse, developing novel genomic tools to refine the treatment options beyond the current standard is critical. Existing predictive genomic tests require careful interpretation with consideration of the patient's clinical and pathological features in the young patient cohort. Careful evaluation is also required when considering extended endocrine therapy options. Improved characterization of mutations occurring in tumors using next-generation sequencing could identify important driver mutations that arise in young women. Applying the advances of precision medicine equitably to patients in resource-rich and low- and middle-income countries will be critical to impacting the survival of young adults with breast cancer worldwide.

Risk factors for late recurrence and postrelapse survival in estrogen receptor (ER)-positive, human epidermal growth factor receptor (HER) 2-negative breast cancer after 5 years of endocrine therapy

It is unclear which patients with ER-positive, HER2-negative breast cancer benefit from extended endocrine therapy beyond 5 years. Prognostic factors for late-recurring breast cancer postrelapse survival have been reported. We retrospectively analyzed data from 892 patients with ER-positive and HER2-negative invasive breast cancer who were disease-free after completing a 5-year adjuvant endocrine therapy. Patients were then classified as high-risk (positive lymph nodes, large tumor size, high tumor grade) or low-risk. High-risk patients were divided into extended endocrine therapy and stop groups. Comparisons were made using propensity score matching, and the benefits of extended endocrine therapy for high-risk patients and prognostic factors for postrelapse survival were assessed. The high- and low-risk groups comprised 444 and 448 patients, respectively. The 10-year distant disease-free survival (DDFS) rates were 96.3 % (95 % confidence interval [CI] 0.912–0.985) and 86.5 % (95 % CI 0.798–0911) in the extended and stop groups, respectively (P = 0.00382). Cox proportional hazards model revealed that extended endocrine therapy promoted greater reduction in distant metastasis risk than 5-year endocrine therapy in high-risk populations (hazard ratio [HR] 0.27; 95 % CI 0.11–0.68; P = 0.0054). Postrelapse survival was significantly different in patients with DDFS ≥7 years (HR 0.24; 95 % CI 0.072–0.81; P = 0.021) and those with better response to first-line treatment (HR 0.072; 95 % CI, 0.058–0.90; P = 0.041). Patients with risk factors for late recurrence should be considered for extended endocrine therapy. Longer DDFS and response to first-line treatment may be a prognostic factor for postrelapse survival after late recurrence.

Persistence to extended adjuvant endocrine therapy following Breast Cancer Index (BCI) testing in women with early-stage hormone receptor-positive (HR +) breast cancer

PurposeExtending adjuvant endocrine therapy (ET) beyond the standard 5 years offers added protection against late breast cancer recurrences in women with early-stage hormone receptor-positive (HR +) breast cancer. Little is known about treatment persistence to extended ET (EET) and the role that genomic assays may play. In this study, we evaluated persistence to EET in women who had Breast Cancer Index (BCI) testing.MethodsWomen with stage I-III HR + breast cancer who had BCI testing after at least 3.5 years of adjuvant ET and ≥ 7 years of follow-up after diagnosis were included (n = 240). Data on medication persistence was based on prescriptions in the electronic health record.ResultsBCI predicted 146 (61%) patients to have low – BCI (H/I)-low – and 94 (39%) patients to have high likelihood of benefit from EET (BCI (H/I)-high). Continuation of ET after BCI occurred in 76 (81%) (H/I)-high and 39 (27%) (H/I)-low patients. Non-persistence rates were 19% in the (H/I)-high and 38% in the (H/I)-low group. The most common reason for non-persistence was intolerable side effects. Patients on EET underwent more DXA bone density scans than those who stopped ET at 5 years (mean 2.09 versus 1.27; p < 0.001). At a median follow-up of 10 years from diagnosis, there were 6 metastatic recurrences.ConclusionsIn patients who continued ET after BCI testing, the rates of persistence to EET were high, particularly in patients with predicted high likelihood of benefit from EET. Use of EET is associated with increased use of DXA scans.

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 P2-03-18: Clinical use of Breast Cancer Index for prediction of late breast cancer recurrence and prediction of benefit in extended endocrine therapy: A single institution experience

Abstract Background: The decision to extend adjuvant endocrine therapy beyond five years is often individualized. Breast Cancer Index (BCI) (Biotheranostics, Inc.) is a validated multigene-expression tissue-based analytic tool used in early hormone-positive breast cancer to predict the response to extended endocrine therapy, based on the HOXB13/IL17BR ratio (H/I ratio), and prognosis 5-10 years after diagnosis, based on the molecular grade index (MGI) and H/I ratio. It is presumed that if BCI shows a high likelihood of benefit from endocrine therapy (BCI-high), the treating clinician would recommend extended adjuvant endocrine therapy and if the primary prediction shows a low likelihood of benefit (BCI-low), the clinician would recommend discontinuation of therapy; however, this may not always be practiced. The Clinical Treatment Score post-5 years (CTS5) is a validated clinicopathologic tool that provides a calculated risk assessment of late distant recurrence (LDR). Clinicians may use the calculated CTS5 score in deciding whether to extend adjuvant endocrine therapy and forego additional prognostic testing, such as BCI. The aim of the study is to understand how clinicians integrate BCI results into medical decision making and to determine the correlation with CTS5 scores in making the decision to offer extended endocrine therapy. Methods: This is a single institution retrospective study. All patients within Henry Ford Health Systewho had BCI testing ordered, between April 2016 and January 2022, were included. Recommendations regarding extended endocrine therapy were collected. CTS5 scores were calculated based on patient’s age, tumor size, tumor grade, and number of involved lymph nodes. If available, the 21-gene recurrence scores (Oncotype-DX) and Ki-67 scores were collected for additional comparison. Results: A total of 165 female patients were included in this study. The average age at diagnosis was 58.5 ± 10.4 years old; 116 (70%) were Caucasian, 35 (21%) were African American; 132 patients (80%) were post-menopausal. The decision regarding extending endocrine therapy was concordant with BCI predictive results in 93.3% of patients; endocrine therapy was continued in 87% of patients in the BCI-high group and discontinued in 95% of patients in the BCI-low group (p&amp;lt; 0.001). In comparing the categorical results of BCI predictive scores (low vs. high) and the CTS5 results (low vs. intermediate vs. high) univariate analysis did not detect a statistically significant relationship. In comparing BCI prognostic LDR risk percentage with the CTS5 LDR (5–10 year) risk percentage, a statistically significant, but weak, positive correlation was observed (Pearson correlation coefficient of 0.38487, p-value= &amp;lt; 0.0001). The odds of a BCI-high primary prediction were 1.031 (95% CI: 1.005, 1.057) times higher for every-one percentage increase in Ki-67 (p-value=0.0172), 1.052 (95% CI: 1.003, 1.057) times higher for every one-unit increase in Oncotype-DX score (p-value=0.0353) and 1.232 (95% CI: 124, 1.351) times higher for every-one percentage increase in BCI prognostic LDR risk assessment (p-value &amp;lt; 0.0001). No statistically significant association was found between the BCI predictive score and age, race, stage, lymph node involvement, and HER2 receptor positivity. Conclusions: This single-institution study revealed that clinicians make decisions regarding extended endocrine therapy that are usually concordant with BCI predictive results. CTS5 results weakly correlate with BCI prognostic results but may not provide conclusive information to support a clinical decision. For patients with early hormone-receptor positive breast cancer the BCI tissue-based analysis may influence a decision regarding extending endocrine therapy. Citation Format: Rebecca Chacko, Manasi M. Godbole, Kylie Springer, Haythem Ali, Vrushali Dabak. Clinical use of Breast Cancer Index for prediction of late breast cancer recurrence and prediction of benefit in extended endocrine therapy: A single institution experience [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 P2-03-18.

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.

Abstract P2-03-13: Breast Cancer Index (BCI) identifies fewer patients with high risk of late recurrence and high likelihood of benefit from extended endocrine therapy with invasive lobular compared to invasive ductal carcinoma

Abstract Background: Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the first and second most common histologic subtypes of breast cancer. Both IDC and ILC present distinguishing clinicopathologic features that contribute to differences in response to treatment and long-term prognosis. BCI is a validated gene expression assay that provides the risk of overall (0-10y) and late (5-10y) distant recurrence (DR) and predicts the likelihood of benefit from extended endocrine therapy (EET). In this analysis, BCI results between groups of HR+ ILC and IDC breast cancer patients were compared. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database containing &amp;gt;50 clinicopathologic and molecular variables from cases submitted for BCI testing in clinical practice (N=19,126). Molecular variables include BCI Prognostic score, HOXB13/IL17BR ratio (H/I), and molecular grade index (MGI). Clinicopathologic variables were abstracted from pathology reports when available. Chi-squared tests and Kruskal-Wallis tests were used to compare categorical and numeric factors, respectively, between IDC and ILC subgroups. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to analyze BCI Predictive performance in the lobular patients from IDEAL study. Results: The current study included 3814 patients submitted for BCI testing during years 4-7 post-diagnosis with available histologic subtype data (80.5% IDC; 13.2% ILC; 3.0% mixed; 3.3% other). Among those with either ductal (n=3072) or lobular (n=504) carcinomas (71% node-negative and 29% node-positive), patients with ILC were older compared to IDC (&amp;gt;70 y: 17% vs 12%). Clinically, ILC was generally less aggressive than IDC (Grade 3: 7% vs 21%; lymphovascular invasion: 9% vs 20%; HER2+: 2% vs 13%; Ki67 % positive stained cells: 29% vs 46%; p&amp;lt; 0.001 for all comparisons), with the exception that ILC had larger tumors than IDC (T2/T3: 46% vs 24%) due to its unique histology. This was consistent with BCI Prognostic results showing fewer ILC patients at high risk for late DR compared to IDC (43% vs 55%, p&amp;lt; 0.001). BCI (H/I) showed a similar trend with fewer patients with High Likelihood to benefit from EET (39% vs 43%) although the difference was not statistically significant (p=0.169). The combination of BCI prognostic and predictive results revealed that more ILC patients were classified as Low Risk/Low Likelihood of benefit (43% vs 38%) and fewer were called High Risk/High Likelihood of benefit (25% vs 35%) (p&amp;lt; 0.001) compared to IDC. The IDEAL BCI translational study included 142 ILC patients with 9.3 years of median follow-up. Similar to the BCI Clinical Database results, ILC was associated with less aggressive disease than IDC (Grade 3: 18% vs 41%; HER2+: 11% vs 24%). 39% and 61% of ILC patients were classified as BCI (H/I)-High and -Low, respectively. Given the small sample size, BCI (H/I)-High showed a non-significant absolute benefit of 11.9% (HR=0.44, 95% CI 0.09-2.14; p=0.298) and BCI (H/I)-Low showed no benefit (HR=2.63, 95% CI 0.70-9.93; p=0.138). An analysis of the 3-way interaction among treatment, biomarker and histology showed a non-significant p-value of 0.28, suggesting BCI (H/I) provides similar predictive information in ILC as in the overall population. Conclusion: BCI identified a smaller proportion of patients with ILC at High Risk of late DR and High Likelihood of benefit from EET compared to IDC. Data from the IDEAL translational study showed that while fewer patients with ILC were identified as BCI (H/I)-High, they still derived similar absolute benefit compared to the overall cohort, while those classified as BCI (H/I)-Low derived no benefit from EET. Citation Format: Otto Metzger, Neeta Parimi, Natalia Siuliukina, Yi Zhang, Kai Treuner, Gerrit-Jan Liefers. Breast Cancer Index (BCI) identifies fewer patients with high risk of late recurrence and high likelihood of benefit from extended endocrine therapy with invasive lobular compared to invasive ductal carcinoma [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 P2-03-13.

Abstract P2-03-05: HOXB13/IL17RB-low breast cancers are predicted to respond to PIK3CA inhibitors independent of PIK3CA mutational status

Abstract Background: The Breast Cancer Index is a gene expression-based signature comprising two functional biomarker panels, the Molecular Grade Index (MGI) and the two-gene ratio, HOXB13/IL17BR (H/I). MGI measures tumor proliferation, while H/I measures estrogen signaling. Integration of MGI and H/I provides a single score that quantifies the risk distant recurrence, while H/I alone predicts benefit from extended endocrine therapy (EET). In multiple EET trials, we have shown that hormone receptor-positive (HR+) breast cancer (BC) patients with H/I-high biomarker expression benefit from EET, while those with H/I-low expression do not benefit from such therapy. Previous protein-protein interaction (PPI) dysregulation (dysreg) analysis of H/I-low BC tumors with drug-response-associated dysreg in BC cell lines revealed a significant correlation with response to two PIK3CA inhibitors, suggesting that PIK3CA pathway may represent an exploitable therapeutic vulnerability for H/I-low BC patients. However, given that PIK3CA is frequently mutated in ER+ tumors, the PPI dysreg analysis may merely reflect enrichment of PIK3CA genomic alterations within the H/I-Low BCs. Thus, to determine if a genetic abnormality within the H/I-low BCs accounts for the correlation with PIK3CA inhibitor drug response in BC cell lines, we performed targeted DNA sequencing of H/I-high and H/I-low BC tumors. Methods: DNA was extracted from 44 H/I-high and 30-H/I-low BC samples using a Qiaqen DNeasy Blood &amp; Tissue Kit. Samples were then prepared using the Archer VariantPlex kits according to a modified protocol and sequenced in batches on the Illumina NextSeq platform. To determine if a genetic abnormality within H/I-low BCs accounts for the PPI dysreg correlation with PIK3CA drug response, the magnitude of the sample’s drug associated PPI dysregs was compared to its mutational status. Geneset enrichment (GSEA) functional profiles between BC tissue PPI dysregs and BC cell line drug response-associated PPI dysregs, identified two PIK3CA inhibitors as potential therapeutic drugs for H/I-low tumors. For each PIK3CA drug, the set of leading-edge genes associated with the genesets important to the observed correlation were isolated. Z-score transformed PPI dysreg count data across the BC samples was used to calculate the average dysreg scores for each sample based on the drug-associated leading-edge genes. The samples were sorted based on scores associated with each drug and GSEA was run on each ranked list looking for an association between the dysreg magnitude and PIK3CA mutation status. Results: Targeted DNA sequencing identified copy number variants for in H/I-high and low tumors, the most common of which are: ERBB2 (3/44 H/I-high; 1/30 H/I-low; p: 0.642), FGF19 (3/44 H/I-high; 1/30; p: 0.642), CCND1 (3/44 H/I-high; 1/30 H/I-low; p: 0.642). Sequencing identified a similar distribution of single nucleotide variants (SNVs) between the H/I-high and H/I-low groups. The most common SNVs identified in order of prevalence are PIK3CA (18/44, H/I-high; 6/30, H/I-low; p: 0.078), TP53 (12/44 H/I-high; 6/30 H/I-low; p: 0.585), CDH1 (4/44 H/I-high; 5/30 H/I-low; p: 0.471), BRCA2 (4/44 H/I-high; 2/30 H/I-low; p: 1). No significant difference in mutational prevalence was identified between the H/I-high and H/I-low BCs. No-significant associations between the PPI dysreg magnitude of the drug-associated leading-edge genes and PIK3CA mutational status was observed (AZD6482 FDR=0.736 and A66 FDR=0.95). Conclusion: No significant genetic alteration, including PIK3CA mutational status, was identified between H/I-high and H/I-low groups. Thus, protein-protein interaction (PPI) dysregulation analysis identifies H/I-low BC tumors as those that are predicted to response to PIK3CA inhibitors independent of PIK3CA mutational status. Citation Format: Baris Boyraz, Grace Kirkpatrick, Stefan T. Kaluziak, Robert Morris, Johannes Kreuzer, Wilhelm Haas, Anthony John Iafrate, Dennis Sgroi. HOXB13/IL17RB-low breast cancers are predicted to respond to PIK3CA inhibitors independent of PIK3CA mutational status [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 P2-03-05.