Years Of Adjuvant Endocrine Therapy Research Articles

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 PO5-06-14: Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma

Abstract Background: Triple-negative (TN) invasive lobular carcinoma (ILC) of the breast is a rare entity, comprising roughly 2% of primary ILC. Clinicopathologic studies have shown that TN ILC is associated with more pleomorphism, higher nuclear grade, older patient age, and worse disease-related outcomes compared to estrogen receptor-positive (ER+) ILC. Intrinsic subtyping indicates that TN ILC less frequently expresses basal markers than TN invasive ductal carcinoma (IDC). This prompted investigation of the genomic landscape and clinical management of TN ILC to provide insight into potential therapeutic approaches. Methods: Twenty patients with TN ILC were included in this study. Three patients were treated at a single academic center and underwent comprehensive genomic profiling (CGP) of breast or metastatic tissue; clinicopathologic details were obtained from their electronic health records. Seventeen patients with TN ILC who underwent CGP of breast or metastatic biopsies were included from the Foundation Medicine, Inc. database. PD-L1 testing for all patients was determined by immunohistochemistry (IHC) using the VENTANA SP142 or Dako 22C3 commercial assays. HER2 expression was determined by IHC. Negative HER2 expression was defined as an IHC score of 0, or IHC 1+ or 2+ with non-amplified fluorescence in situ hybridization (FISH). Results: In the Foundation Medicine database of patients with TN ILC, the most frequent genomic alterations were in CDH1 (15/17 patients [88.2%]), TP53 (10/17 patients [58.8%]), and PIK3CA (10/17 patients [58.8%]). Short variant mutations in ERBB2 were found in 3/17 patients (17.6%). Fourteen patients were HER2-low (HER2 IHC 1+ or 2+ with non-amplified FISH). No cases were MSI high or expressed PD-L1 (8 of 17 cases underwent PD-L1 assessment by SP142). Median tumor mutational burden (TMB) was 5 muts/Mb. Among the three patients with TN ILC treated at a single center, the most common somatic mutations were in CDH1 and TP53, and no cases were MSI high or expressed PD-L1 (by SP142 or 22C3). All three patients had pleomorphic ILC, histologic grade 2 or 3, and HER2 IHC 0. One patient with mpT1cN1a(sn) ER+/HER2- ILC of the right breast in 2011 received adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide), breast/axillary radiation, and ten years of adjuvant endocrine therapy. She was diagnosed with TN ILC of the left supraclavicular nodes in 2022; she did not exhibit a response to docetaxel and carboplatin with pembrolizumab, and she subsequently received palliative radiation followed by capecitabine. Another patient with locally advanced TN ILC progressed on the KEYNOTE-522 regimen, immediately developed metastases, and is currently receiving palliative sacituzumab govitecan. The third patient with cT3N1 TN ILC progressed on neoadjuvant therapy (through the I-SPY 2 trial) with oral paclitaxel, encequidar, and dostarlimab, followed by dostarlimab with dose-dense doxorubicin and cyclophosphamide. Her surgical pathology demonstrated ypT3N3a disease with 10 × 7 cm of tumor, and she developed skin metastases on the chest wall within weeks post-operatively. She received comprehensive chest wall and nodal radiation and is currently receiving palliative capecitabine with neratinib given a high variant allele frequency driver somatic ERBB2 mutation. Conclusions: The most common somatic mutations among TN ILC patients included in this study were in CDH1, TP53, and PIK3CA. Currently the management of TN ILC is extrapolated from that of TN IDC, however our patients did not respond to chemoimmunotherapy. The presence of HER2-low status or somatic ERBB2 mutations may provide opportunities for treatment with an anti-HER2 antibody-drug conjugate or tyrosine kinase inhibitor. Studies with larger sample sizes of TN ILC are needed for molecular profiling and assessment of outcomes with specific therapeutic approaches. Citation Format: Hemali Batra-Sharma, Smruthy Sivakumar, Prashanth Ashok Kumar, Ethan Sokol, Rebecca Shatsky, Jeffrey Ross. Genomic Landscape and Clinical Outcomes of Triple-Negative Invasive Lobular Carcinoma [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 PO5-06-14.

Abstract PO4-11-11: Provider perceptions of the POSITIVE trial, endocrine therapy interruption, and fertility preservation

Abstract Background: Fertility preservation and family planning are pressing survivorship concerns for many young, reproductive-aged women with hormone receptor-positive (HR+) early-stage breast cancer. Following primary treatment, patients typically receive 5-10 years of adjuvant endocrine therapy (ET), during which pregnancy is contraindicated and fertility may decrease. The first-of-its-kind POSITIVE trial (NCT02308085) sought to challenge this archetype by prospectively evaluating the impact of temporary ET interruption to allow patients to attempt conception. Participants (n=516) received 18-30 months of ET followed by a 3-month washout period prior to initiating a 2-year break from therapy to attempt pregnancy. Results demonstrated that short-term disease outcomes were not impacted by temporarily pausing therapy to allow women who desire conception to attempt pregnancy. This survey-based study aimed to evaluate community oncologists’ perceptions of the POSITIVE trial data, ET interruption, and fertility preservation efforts. Methods: US-based oncologists convened at three live meetings in March and April 2023 to review clinical updates presented at SABCS 2022. Participant characteristics and demographic data were collected via an online survey prior to the respective meetings. Perceptions/reactions to clinical updates were captured using audience response system technology. Data were summarized using descriptive statistics. Results: Among 157 respondents, 82.8% identified as community providers, with 17.9 mean years of clinical experience. On average, participants reported that 85.4% of their time is allocated towards direct patient care, with approximately 21 patients seen per clinic day. Most respondents (85.8%) indicated that they only refer patients to a fertility specialist if the patient initiates fertility preservation discussions and nearly half (45.7%) reported that within the last year, 20% or less of their patients have discussed fertility concerns with them prior to initiating therapy. Additionally, over three-quarters of respondents (79.9%) indicated that 10% or less of their patients with breast cancer underwent fertility preservation within the last year. Prior to reviewing the POSITIVE trial data, 51.3% of respondents reported that they would be most likely to offer therapy interruption to patients with low- or intermediate-risk disease, while 19.8% would do so for all patients regardless of risk status. After reviewing the POSITIVE trial data, 59.3% of respondents would offer therapy interruption to patients with low- or intermediate-risk disease, while 30% would do so for all patients regardless of risk status. Notably, a majority of respondents (54.8%) indicated that they would recommend a therapy interruption of 12 months or less, while 11.1% would opt for 19-24 months. Conclusions: Findings demonstrate that the onus of initiating discussions surrounding fertility and reproductive topics is often placed on patients, and many patients do not proactively address these matters or undergo fertility preservation prior to initiating treatment. Overall, respondents viewed the POSITIVE trial favorably, as evidenced by their increased willingness to consider temporary ET interruption for all patients following their review of the study data. Although the POSITIVE trial allowed up to 2 years of therapy interruption, respondents preferred a treatment break of 12 months or less. With the adoption of the POSITIVE strategy into routine clinical practice, younger women with HR+ breast cancer may no longer be faced with the difficult choice of pursuing potentially life-saving therapy or starting/expanding a family, thereby addressing a current unmet survivorship need among this patient population. However, it remains to be seen how many physicians will offer this approach, who is the ideal candidate, and what the appropriate ET interruption length will be. Citation Format: Brooke Leon, Robert Bone, Yolaine Jeune-Smith, Sigrun Hallmeyer, Bruce Feinberg. Provider perceptions of the POSITIVE trial, endocrine therapy interruption, and fertility preservation [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 PO4-11-11.

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.

Clinical factors associated with patterns of endocrine therapy adherence in premenopausal breast cancer patients

IntroductionPatients with hormone receptor positive breast cancer are recommended at least five years of adjuvant endocrine therapy, but adherence to this treatment is often suboptimal. We investigated longitudinal trends in adjuvant endocrine therapy (AET) adherence among premenopausal breast cancer patients and identified clinical characteristics, including baseline comorbidities and non-cancer chronic medication use, associated with AET adherence.MethodsWe included stage I–III premenopausal breast cancer patients diagnosed during 2002–2011 and registered in the Danish Breast Cancer Group clinical database who initiated AET. We used group-based trajectory modeling to describe AET adherence patterns. We also linked patients to Danish population-based registries and fit multinomial logistic models to compute odds ratios (ORs) and 95% confidence intervals (95% CIs) associating clinical characteristics with AET adherence patterns.ResultsWe identified three adherence patterns among 4,353 women—high adherers (57%), slow decliners (36%), and rapid decliners (6.9%). Women with stage I disease (vs. stage II; OR: 1.9, 95% CI 1.5, 2.5), without chemotherapy (vs. chemotherapy; OR: 4.3, 95% CI 3.0, 6.1), with prevalent comorbid disease (Charlson Comorbidity Index score ≥ 1 vs. 0; OR: 1.6, 95% CI 1.1, 2.3), and with a history of chronic non-cancer medication use (vs. none; OR: 1.3, 95% CI 1.0, 1.8) were more likely to be rapid decliners compared with high adherers.ConclusionsWomen with stage I cancer, no chemotherapy, higher comorbidity burden, and history of chronic non-cancer medication use were less likely to adhere to AET. Taking steps to promote adherence in these groups of women may reduce their risk of recurrence.

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.

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.

Factors associated with the decision to continue adjuvant endocrine therapy for five more years in a diverse sample of breast cancer survivors.

319 Background: Guidelines suggest that breast cancer survivors consider taking adjuvant endocrine therapy for 10 years post diagnosis to maximize recurrence prevention. Little is known about how patients decide to continue endocrine therapy beyond 5 years. Methods: iCanCare is a longitudinal study of women diagnosed with breast cancer in 2014-15 and reported to the Los Angeles County and Georgia Surveillance, Epidemiology and End Results (SEER) registries. Women were surveyed during initial treatment and again 6 years later (2021-22) (Expected final N=1430, 60% current response rate). The proportion of respondents who completed 5 years of endocrine therapy was determined from SEER and patient report (N=793). This group was queried regarding their decision to continue for an additional 5 years (yes/no/undecided). Patients were asked about the importance of personal values in making this decision (all categorized into very/quite/somewhat important vs. a little/not important), and perceived benefit of continuing (none, small/moderate, large/huge). They were also asked to report on how the decision was made (decision style, involvement of oncologist and primary care physician, PCP). We conducted bivariate analyses to assess associations between the decision to continue (yes vs. no/undecided) and decision-making factors. Results: In the sample of 793 women who completed 5 years of endocrine therapy, 40% decided to take it for more than 5 years, 54% decided not to, and 5% were undecided. Overall, 44% reported that it was a shared decision between them and their physician(s). The values survivors reported as most important in their decision to continue were doing what their oncologist wanted them to do (77%) and worry about recurrence (61%). Medication costs (11%) was the least important factor. Among survivors who chose to continue, most important were doing what their oncologist wanted them to do, worry about recurrence, and desiring the most extensive treatment possible (all p &lt;0.001). A greater proportion of those who perceived a large/huge benefit (vs. less benefit) of continued therapy chose to continue (87% vs. 13%, P&lt;0.001). Having received a strong oncologist recommendation was strongly associated with the decision to continue, as was PCP involvement in the decision (both p&lt;0.001). Conclusions: In this population-based sample of breast cancer survivors who completed 5 years of adjuvant endocrine therapy, less than half decided to extend therapy for 5 more years. Personal values and role of physicians weighed heavily into the decision to continue. Further work to understand how to incorporate and address patient values in endocrine therapy decision making is needed.

THU554 Unconventional Estrogen Receptor Antagonists Reveal Cryptic Therapeutic Anti-breast Cancer Transcriptional Pathways

Abstract Disclosure: G. Hancock: None. K. Young: None. G.L. Greene: None. S.W. Fanning: Advisory Board Member; Self; Olema Oncology. Grant Recipient; Self; Olema Oncology. Breast cancer is the most diagnosed cancer and 2nd leading cause of cancer-related death in women worldwide. The luminal subtype accounts for ∼70% of this heterogeneous disease. Standard of care for these estrogen receptor alpha (ERα) positive diseases includes 5 years of adjuvant endocrine therapy in the form of aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs). Despite therapeutic advances, approximately half of ERα+ patients develop resistance to these endocrine therapies. In this study, x-ray crystallography of SERMs and SERDs link structural characteristics to transcriptional activity in order to understand mechanisms of antiestrogen efficacy in ER+ drug resistant breast cancers. A new class of antiestrogen based on a tetrahydro-6-isoquinoline (T6I) scaffold was developed to antagonize ERα by adopting unique binding poses to inhibit coactivator binding to the ligand binding domain (LBD). Optimization of structure-activity relationships produced unique antiestrogenic activities and a lead compound that induces transcriptional programs similar to fulvestrant despite its SERM-like accumulation of ERα in the breast cancer cell. Like fulvestrant, this T6I uniquely induces the expression of small ubiquitin-like modifier-1 (SUMO1), in opposition to 17β-estradiol. Together, this study uses structurally unique antiestrogens to further the understanding of key functional components of estrogen therapies. Presentation: Thursday, June 15, 2023

Ki-67, 21-Gene Recurrence Score, Endocrine Resistance, and Survival in Patients With Breast Cancer.

Both high 21-gene recurrence score (RS) and high Ki-67 level are poor prognostic factors in patients with estrogen receptor (ER)-positive ERBB2-negative (ER+/ERBB-) breast cancer; however, a discrepancy between the 2 has been noted. Survival differences according to these 2 biomarkers are not well known. To assess the associations between RS and Ki-67 expression and between Ki-67 expression and recurrence-free survival in patients with ER+/ERBB- breast cancer with low RS. This cohort study included women treated for ER+/ERBB2- breast cancer who underwent the 21-gene RS test from March 2010 to December 2020 in 2 hospitals in Korea. Recurrence score and Ki-67 level. A Cox proportional hazards regression model was used to examine the association of Ki-67 with recurrence-free survival (RFS), while a binary logistic regression model was used to examine the association between Ki-67 and secondary endocrine resistance. High Ki-67 expression was defined as 20% or greater, and low genomic risk as an RS of 25 or less. Secondary endocrine resistance was defined as breast cancer recurrence that occurred after at least 2 years of endocrine therapy and during or within the first year after completing 5 years of adjuvant endocrine therapy. A total of 2295 female patients were included (mean [SD] age, 49.8 [9.3] years), of whom 1948 (84.9%) were in the low genomic risk group and 1425 (62.1%) had low Ki-67 level. The median follow-up period was 40 months (range, 0-140 months). The RS and Ki-67 level had a moderate correlation (R = 0.455; P < .001). Of the patients with low Ki-67 level, 1341 (94.1%) had low RS, whereas 607 of 870 patients with high Ki-67 level (69.8%) had low RS. In patients with low RS, the RFS differed significantly according to Ki-67 level (low Ki-67, 98.5% vs high Ki-67, 96.5%; P = .002). Among the 1807 patients with low genomic risk who did not receive chemotherapy, high Ki-67 level was independently associated with recurrence (hazard ratio, 2.51; 95% CI, 1.27-4.96; P = .008). Recurrence after 3 years differed significantly according to Ki-67 level (low Ki-67, 98.7% vs high Ki-67, 95.7%; P = .003), whereas recurrence within 3 years did not differ (low Ki-67, 99.3% vs high Ki-67, 99.3%; P = .90). In addition, Ki-67 was associated with secondary endocrine resistance in patients with low RS who did not receive chemotherapy (odds ratio, 2.49; 95% CI, 1.13-5.50; P = .02). In this cohort study of patients with ER+/ERBB2- breast cancer, a moderate correlation was observed between Ki-67 and RS, and high Ki-67 level in patients with low genomic risk was associated with increased risk of secondary endocrine resistance.

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.

Impact of endocrine therapy adherence on racial disparities in breast cancer survival.

541 Background: Black women have worse breast cancer outcomes compared to their White counterparts, even for hormone receptor positive (HR+) HER2 negative (HER2-) breast cancer (BC). This tumor type is usually treated with 5-10 years of adjuvant endocrine therapy (ET) to reduce risk of BC recurrence and improve survival. We investigated the impact of adherence to ET on racial differences in survival for HR+ HER2- BC survivors. Methods: We conducted a population-based, retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, which links demographic and clinical data with cause of death for persons with cancer and Medicare claims for covered health services. We examined 9,039 women with HR+ HER2- stage I-III BC diagnosed between 2007 and 2016, who received primary breast surgery and initiated ET. Adherence to ET was measured using the medication possession ratio (MPR), which assesses the proportion of time a patient has medication available via filled prescriptions. As in established literature, we defined ET adherence as MPR &gt; = 80%. Causal mediation analysis was performed to measure to impact of adherence on survival disparities between Black and White BC survivors. Results: Mean age at diagnosis was 72 years, 6.5% were Black, and 20.9% were dual eligible for Medicaid (a surrogate for socioeconomic hardship). Most had stage I or II breast cancer (69.3%) and mastectomy as primary surgery (69.7%). Nineteen percent received chemotherapy and 62.5% received radiation. In univariate analyses, factors associated with ET adherence were Black race (OR 0.62, 95% CI 0.54-0.75), insured by Medicaid (OR 0.72, 95% CI 0.65-0.81), being married (OR 1.14, 95% CI 1.03-1.25), and increased comorbidities (Charlson score &gt; = 2) (OR 0.88, 95% CI 0.78-0.99). Age, BC stage, type of surgery, and receipt of chemotherapy or radiation were not associated with ET adherence. In multivariable models adjusting for age, race, marital status, Medicaid eligibility, and Charlson score, Black race and Medicaid eligibility remained inversely associated with ET adherence (OR 0.70, 95% CI 0.59-0.83 and OR 0.77, 95% CI 0.69-0.87 respectively). Among those who were adherent to ET, Black women had 43% higher risk of mortality compared to White women (HR 1.43, 95% CI 1.17-1.76). In mediation analysis, 4.25% of the observed survival disparity between Black and White women can be explained by differences in ET adherence. Conclusions: We identified racial disparities in ET adherence and overall survival among women with BC. Adherence to ET accounted for a small percentage of racial disparities in survival. Further research is needed to delineate other factors contributing to ET non-adherence among Black women and to investigate additional factors contributing to known disparities in BC survival.

Side effects and impacts of extended adjuvant endocrine therapy: A qualitative study among women with HR+/HER2- breast cancer.

e12509 Background: Extended (≥5-year) adjuvant endocrine therapy (ET) is generally the preferred treatment approach for patients with hormone receptor–positive (HR+) breast cancer at high risk of recurrence. However, due to side effect burden and other challenges, patient adherence to extended adjuvant ET is often suboptimal, presenting challenges for patients and healthcare providers alike. To further understand potential barriers to adherence, the objective of this study was to explore the side effects and impacts of extended adjuvant ET among women with HR+ breast cancer through in-depth qualitative interviews. Methods: Individual qualitative interviews were conducted with 20 US women with a self-reported clinical diagnosis of nonmetastatic HR+/HER2− breast cancer who had undergone ≥4 years of adjuvant ET and were currently taking ET or had concluded their regimen within the past 12 months. Using thematic analysis methods, interview transcripts and interviewers’ field notes were analyzed to identify important concepts and dominant trends. Results: Interview participants averaged 52.8 years in age and were diverse in race, education level, and employment status. The most commonly reported ET side effects among the 20 participants were hot flashes (n = 16), joint pain (n = 15), difficulty sleeping (n = 15), difficulty with weight management (n = 15), fatigue (n = 15), reduced interest in sex (n = 14), and feeling irritable (n = 14). Participants most frequently identified joint pain (n = 8), reduced interest in sex (n = 4), and discomfort with intercourse (n = 4) as the most bothersome ET side effects. Participants generally reported that the frequency and severity of side effects that they experienced remained constant throughout the extended adjuvant period; only 3 reported having switched ET regimens to manage side effects. Participants reported numerous impacts from ET side effects, including to cognitive and physical functioning (most common), social interactions, and work/productivity. Several participants spoke about the tradeoffs they make in enduring ET side effects and impacts to reduce risk of recurrence. For most participants, the primary benefit of extended adjuvant ET was the perceived reduction of risk of recurrence; some reported “peace of mind” from taking ET, knowing they were doing everything possible to reduce their risk of recurrence. Several participants expressed reluctance to stop taking ET despite the side effects because adherence to their medication made them feel less anxious or worried about recurrence. Conclusions: Patients receiving ET for HR+/HER2− breast cancer continue to experience significant side effects during extended adjuvant ET, and these side effects impact quality of life in many ways. Some patients are nonetheless motivated to continue with long-term ET to reduce risk of recurrence and/or because of the emotional benefit it affords.

Abstract OT1-01-02: EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET

Abstract Background: Adjuvant ET has been the standard of care for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) EBC. A significant proportion of patients with increased risk still experience disease relapse despite available ET and more optimum ET is needed to prevent patients developing incurable metastatic cancer. Distant recurrence risk ranges from 20% to 40% after 5 years of adjuvant ET, depending on clinicopathological (clin-path) features at diagnosis. Consequently, there is a need to further optimize adjuvant treatment, particularly in those patients who are at increased risk of recurrence. Imlunestrant is an orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties and the potential to overcome ET resistance. In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2- advanced breast cancer patients (EMBER, Jhaveri 2022) along with robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2, Neven). Trial Design: EMBER-4 is a randomized, open-label, global phase 3 study comparing imlunestrant versus physicians’ choice of ET, in patients who are at an increased risk of recurrence based on clin-path features and who have received 2 to 5 years of standard adjuvant ET. Approximately 6,000 patients will be randomized 1:1 to receive imlunestrant (400 mg daily) for 5 years or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor, AI, dosed per label). Study treatment duration is 5 years. Males and pre-/peri-menopausal women will receive concomitant treatment with a GnRH agonist if receiving imlunestrant or an AI. Stratification factors include time from initial adjuvant ET, use of prior adjuvant cyclin dependent kinase 4/6 inhibitors, nodal status, menopausal status, and geographic region. Eligibility criteria: Eligible patients are adult males and females (pre-, peri- or postmenopausal) with ER+, HER2- EBC who have completed definitive locoregional therapy and have received 2 to 5 years of prior adjuvant ET without disease recurrence, but who are at increased risk of recurrence based on clin-path features at diagnosis. Prior (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor is permitted. Study endpoints: The primary endpoint is invasive disease-free survival (IDFS), excluding second non-breast primary invasive cancers. Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK and patient reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022. Citation Format: Komal Jhaveri, Joyce O’Shaughnessy, Fabrice Andre, Matthew P. Goetz, Nadia Harbeck, Miguel Martín, Francois-Clement Bidard, Zachary M. Thomas, Suzanne Young, Roohi Ismail-Khan, Lillian M. Smyth, Michael Gnant. EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET [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 OT1-01-02.

Abstract P3-03-12: Risk of recurrence with adjuvant endocrine therapy in real world patients with hormone receptor positive/human epidermal growth factor receptor-negative early breast cancer: a US database analysis

Abstract Background The recommended 5-10 years of adjuvant endocrine therapy (ET) as standard of care has improved outcomes in patients with HR+/HER2− early breast cancer (EBC); however, risk of recurrence persists. The monarchE study demonstrated improvement in invasive disease-free survival (iDFS) with abemaciclib in node-positive, high-risk EBC, the majority of which were stage III (Johnston SRD, et al. J Clin Oncol. 2021;38:3987); however, monarchE’s relatively short follow-up time to date only allowed for observation of early recurrences—longer follow-up is needed to evaluate late recurrences. Risk of recurrence is a concern for patients with all stages of EBC (Pan H, et al. N Engl J Med. 2017;377:1836). We assessed the risk of recurrence in a real-world setting among patients with stage II-III HR+/HER2− EBC after initiation of adjuvant ET. Methods This was a retrospective analysis of ConcertAI’s deidentified electronic medical records data set among patients treated from January 1, 1995, to April 30, 2021. The cohort included stage II-III patients with HR+/HER2− EBC who underwent surgery and initiated adjuvant ET (if IIIB or IIIC, confirmation was required on residual tumor status). Patients were from academic and community oncology clinics across the US. Data were missing from the database for some variables; thus, percentages may not add up to 100%. iDFS was assessed to determine the risk of disease recurrence, death, or second primary tumor and was defined as the time interval between start of ET and first iDFS event. Kaplan-Meier methods were used to estimate cumulative probabilities of experiencing an iDFS event at 5 and 10 years from the start of ET. Results A total of 3133 patients (98.8% female) with stage II-III HR+/HER2− EBC were included in the analysis. The median follow-up time was 68.1 months. The median age was 59 years; 22.2% of female patients were pre/perimenopausal and 44.7% were postmenopausal; 80.9% of all patients had stage II disease, while 19.1% had stage III disease. In total, 42.1% and 3.7% of those with stage II and III disease had no nodal involvement, respectively. Overall, 51.2% of patients did not receive radiotherapy, and 59.5% of patients did not receive (neo)adjuvant chemotherapy. In the total sample, the 5- and 10-year risk of an iDFS event was 26.1% and 45.0%, respectively. In patients with stage II disease, the 5- and 10-year risks were 22.7% and 40.5%, respectively, and 40.4% and 62.9% among stage III. Conclusions These real-world data demonstrate that the risk of recurrence with adjuvant ET, particularly in those with stage II EBC, is higher than reported in many randomized controlled trials. Importantly, our data show that, in the real-world setting, the stage II population represents a significant proportion of patients (nearly 4 times more than stage III). These findings confirm and underscore the clear unmet need in this population and highlight the need for improved treatment options in this broader EBC population. The NATALEE study will investigate ribociclib + ET in a broad population of patients including stage II and stage III HR+/HER2− EBC with high-risk features, regardless of nodal status. Citation Format: Joyce O’Shaughnessy, Denise Yardley, Lowell Hart, Pedram Razavi, Stephanie L. Graff, Jenifer Wogen, Courtney McDermott, Pierre-Alexandre Dionne, Sina Haftchenary, Purnima Pathak, Sara Tolaney. Risk of recurrence with adjuvant endocrine therapy in real world patients with hormone receptor positive/human epidermal growth factor receptor-negative early breast cancer: a US database analysis [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 P3-03-12.

Abstract P3-05-28: Impact of increased adiposity on extended aromatase inhibitor treatment in postmenopausal patients with estrogen receptor positive (ER+) breast cancer: a retrospective analysis of the SOLE trial

Abstract Background: The risk of late distant recurrence (≥ 5 years) in post-menopausal patients with ER+ BC remains significant even after standard adjuvant endocrine therapy (ET). Obesity, which has reached high proportions in Western Countries, is one of the modifiable factors that can contribute to BC recurrences. While body mass index (BMI) is an easily available surrogate measure of adiposity, it might not reflect accurately patient adiposity, especially in post-menopausal patients. We therefore hypothesize that mammary adipocyte measurements might better capture the adiposity of the patient. In this study, we retrospectively evaluated the prognostic role of both BMI and adipocyte measurements in the SOLE trial. Patients &amp; Methods: The SOLE trial (NCT00553410) consisted of 4,884 postmenopausal women with hormone receptor positive, lymph node-positive BC treated with 5 years of letrozole after having completed 4-6 years of adjuvant ET. BMI was available for 3,606 patients with ER+/HER2- BC and categorized according to the WHO classification (underweight: &amp;lt; 18.5, normal weight 18.5 – 24.9, overweight 25 – 29.9, obesity ≥ 30 kg/m2). Considering the small sample size, patients with underweight (n=35) were grouped together with patients with normal weight for the subsequent analyses. We evaluated the association between clinico-pathological characteristics and BMI using Fisher exact test and Kruskal-Wallis test. Given the previously reported association of BMI with distant recurrences (PMID: 21115856), we considered distant-relapse free interval (DRFI) as the main study endpoint. Cox regression analyses were adjusted for histology, chemotherapy (yes/no), type of local therapy, in addition to previously reported clinico-pathological variables (PMID: 29158011). Then, we conducted a stratified case-cohort study consisting of 311 patients (97 with distant relapse-cases) with successful digital assessment of adipocytes on normal mammary adipose tissue sample collected at surgery, as previously described (PMID: 33120083). Stratification factors were treatment arm and type of prior ET. Weighted Cox regression models (PMID: 17554753, 18712477) were used to evaluate prognostic association with adipocyte size (area in µm²) categorized in quartile of the 75th percentile (Q4 vs Q1-3), as done previously (PMID: 33753731). Results: 1392 (39%) patients were normal weight, 1315 (36%) were overweight and 899 (25%) were obese. Older age at diagnosis, lymph node involvement (≥4), large tumor size and menopausal status were associated with overweight and obesity. After a median follow-up of 84 months, no associations were found between DRFI and BMI in the univariable and multivariable analysis (adjusted HR overweight vs normal=0.99, 95%CI: 0.76 – 1.29, p=0.977 and HR obese vs normal=1.11, 95%CI: 0.84 - 1.47, p=0.425). In the case-cohort study, patients with larger adipocytes had an increased hazard of distant recurrence in the univariable and multivariable analysis (see table 1). Conclusion: In this study, we did not detect any association between BMI and survival outcomes. We however found that larger mammary adipocytes were independently associated with an increased hazard of distant recurrence. These results suggest that mammary adipocytes, which can be easily evaluated on H&amp;E slides using digital pathology, should be considered as a novel marker to evaluate the risk of late recurrence in patients with breast cancer. Citation Format: Edoardo Isnaldi, François Richard, Giuseppe Marano, Patrizia Boracchi, Marion Maetens, Giuseppe Floris, Guy Jerusalem, Andrea Gombos, Alastair M. Thompson, Erika Hitre, Stefan Aebi, Marco Colleoni, Patrizia Dell’Orto, Roswitha Kammler, Patrick Neven, Giuseppe Viale, Meredith Regan, Elia Biganzoli, Christine Desmedt. Impact of increased adiposity on extended aromatase inhibitor treatment in postmenopausal patients with estrogen receptor positive (ER+) breast cancer: a retrospective analysis of the SOLE 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 P3-05-28.

Abstract P2-11-10: Validation of the Breast Cancer Index (BCI) prognostic models optimized for late distant recurrence in postmenopausal women with early-stage HR+ breast cancer in the TEAM trial

Abstract Background: Women with HR+ breast cancer experience a persistent risk of distant recurrence (DR) even after completion of 5 years of adjuvant endocrine therapy, with more than 50% of DR occurring after 5 years (late DR). The prognostic genomic signatures currently being used in the clinic were not developed or optimized specifically for late DR. We have previously shown that the Breast Cancer Index (BCI) and BCIN+ prognostic models were significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence (DR) in N0 and N1 HR+ patients in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Here, the prognostic performance of the BCI and BCIN+ models with alternative cut-points optimized for late DR were evaluated in patients from the TEAM trial, who were free from DR for at least 5 years. Methods: BCI testing was performed blinded to clinical outcome. The pre-specified alternative cut-points 4.4 and 1.8 for BCI and BCIN+ models were determined previously from Trans-aTTom and IDEAL studies, respectively (ESMO 2021). Kaplan-Meier analysis and log-rank test were used to evaluate the prognostic significance of BCI/BCIN+ risk groups based on DR. Univariate and multivariate Cox models were used to estimate hazard ratios (HRs) and the associated 95% confidence intervals (CIs). Results: 1285 HR+ N0 (median age 69.2, 54.2% T1, 92.5% G2-3, 21.3% chemotherapy) and 1762 N1 (median age 68.5, 49.7% T1, 80.8% G2-3, 42.6% chemotherapy) patients who remained free from DR at 5 years post randomization were included in the current analysis. For N0 patients, BCI identified 439 (34%) and 846 (66%) patients as low and high-risk with late 10-year DR rates of 3.8% (95% CI: 1.5-6.0%) and 9.1% (95% CI: 6.8-11.4%), respectively (HR: 2.6, 95% CI: 1.4-5.0; p=0.0025). For N1 patients, BCIN+ identified 287 (16%) and 1475 (84%) patients as low and high-risk with late 10-year DR rates of 3.4% (95% CI: 1.2-5.5%) and 12.3% (95% CI: 10.4-14.2%), respectively (HR: 3.5, 95% CI: 1.8-6.9; p&amp;lt; 0.0001). Similar results were observed in the HER2- patients. Notably, BCI/BCIN+ remained a statistically significant prognostic factor in the multivariate analysis after controlling for age, tumor size, grade, treatment. (Table). Conclusions: Compared to the original BCI/BCIN+ models, the optimized BCI and BCIN+ models showed improved prognostic performance for identifying low-risk patients with a very low risk of late DR (&amp;lt; 4%), for both N0 and N1 patients. These results provide further validation of BCI clinical utility as an aid in the decision-making for extended endocrine therapies for HR+ breast cancer, particularly in patients with N1 disease that may be spared extended endocrine treatment. Table Citation Format: John MS Bartlett, Keying Xu, Jenna Wong, Gregory R. Pond, Yi Zhang, Melanie Spears, Ranelle Salunga, Elizabeth Mallon, Karen J. Taylor, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, Cornelis J.H. van de Velde, Daniel Rea, Catherine A. Schnabel, Kai Treuner, Jane Bayani. Validation of the Breast Cancer Index (BCI) prognostic models optimized for late distant recurrence in postmenopausal women with early-stage HR+ breast cancer in the TEAM 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 P2-11-10.

Abstract P1-02-01: Comparing the efficacy of aromatase inhibitors vs tamoxifen in hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: a systematic review and trial-level meta-analysis

Abstract Background: Five years of adjuvant endocrine therapy (ET) including aromatase inhibitors (AIs) and tamoxifen (TAM) is considered the standard of care in hormone receptor–positive, human epidermal growth factor–negative (HR+/HER2−) early breast cancer (eBC). Clinical practice guidelines recommend the use of an AI or TAM depending on menopausal status and clinical risk stratification. Although TAM is generally recommended and more commonly used in premenopausal women, there is mixed evidence for different clinical outcomes. Patient-level meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed significantly lower rates of BC recurrence with AIs vs TAM. However, this was not specific to patients with HR+/HER2− eBC. This trial-level meta-analysis was conducted to compare AIs ± ovarian function suppression (OFS) vs TAM ± OFS in HR+/HER2−, pre- and postmenopausal patients with eBC. Methods: A systematic literature review (SLR) was conducted using key literature databases, ie, Embase, PubMed, and MEDLINE In-Process (from database inception to March 2022) and key conferences (2019-2021). Studies selected for the SLR were those that included either ≥80% of patients with HR+/HER2− eBC in the mixed patient population or subgroup data provided specifically for patients with HR+/HER2− eBC. Of these, randomized controlled trials (RCTs) investigating AI ± OFS vs TAM ± OFS and assessing disease-free survival (DFS) were included in the trial-level meta-analysis. This meta-analysis was conducted using the generic invariance method to obtain a pooled effect estimate (hazard ratio [HR]) together with its CI for DFS. This pooled estimate was calculated as a weighted average of the intervention effects estimated in the individual trials. Both fixed- and random-effect models (FEM, REM) were used to estimate the effect size. A base-case analysis was performed including all eligible trials. Three other scenario analyses were conducted: trials investigating only nonsteroidal AIs (NSAIs), assessing only premenopausal women, and assessing only postmenopausal women. Heterogeneity across the trials was assessed using I2 statistic. Results: A total of 5 RCTs comparing AI ± OFS vs TAM ± OFS were eligible for the meta-analysis (SOFT, HOBOE, BIG 1-98, N-SAS BC 03, Li 2019; additional information on rationale for exclusion of specific trials will be reported). Two studies assessing NSAI vs TAM included postmenopausal women, while 3 studies assessing AIs + OFS vs TAM ± OFS included premenopausal women. A total of 6623 patients were followed up for 34-97.2 months across these five trials. Heterogeneity was found to be low (I2 &amp;lt; 40%) across all scenarios. The base-case results (including all studies) using FEM significantly favored AIs ± OFS over TAM ± OFS, with a 29% reduction in risk of recurrence or death (pooled HR, 0.71 [95%CI, 0.64-0.80]). Similar results were observed with NSAIs ± OFS vs TAM ± OFS (HR, 0.73 [95% CI, 0.64-0.83]). Among premenopausal patients, the pooled HR for AIs + OFS vs TAM ± OFS was 0.66 (95% CI, 0.54-0.79). For postmenopausal women, the HR was 0.75 (95% CI, 0.65-0.87), favoring AIs over TAM. The findings for the base-case and different scenarios remained consistent when REM was used. Conclusions: This trial-level meta-analysis suggests significantly greater benefit with AIs than with TAM for HR+/HER2− eBC. Notably, AIs in combination with OFS are associated with a 34% reduction in risk of recurrence or death vs TAM ± OFS in premenopausal women; these results are aligned with the patient-level data findings of the EBCTCG. The findings indicate that AIs ± OFS are associated with a better DFS in the HR+/HER2− population, especially premenopausal women, than TAM ± OFS. Citation Format: Wolfgang Janni, Michael Untch, Nadia Harbeck, Joseph Gilgorov, William Jacot, Stephen K. Chia, Jean-Francois Boileau, Sina Haftchenary, Rhea Gupta, Namita Mishra, Purnima Pathak, Giuseppe Curigliano. Comparing the efficacy of aromatase inhibitors vs tamoxifen in hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: a systematic review and trial-level meta-analysis [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 P1-02-01.

Impact of clinicopathological factors on extended endocrine therapy decision making in estrogen receptor-positive breast cancer.

In our study, we aim to analyze the impact of clinicopathological factors on the recommendation of extended endocrine therapy (EET) in patients with ER+ breast cancer and to retrospectively validate the value of CTS5 in EET decision making. The retrospective analysis was performed in patients with ER+ breast cancer who have finished 4.5-5 years of adjuvant endocrine therapy and undergone MDT discussion from October 2017 to November 2019. Multivariate logistic regression was used to identify the independent factors for treatment recommendation. CTS5 was calculated for retrospective validation of the EET decision making. Two hundred thirty-five patients were received; 4.5-5 years of adjuvant endocrine therapy were included in the study. Multivariate analysis suggested that age (OR 0.460, 95% CI 0.219-0.965, p = 0.04), pN (OR 39.350, 95% CI 9.831-157.341, P < 0.001), and receipt of chemotherapy (OR 3.478, 95% CI 1.336-9.055, p = 0.011) were independent predictors for the recommendation of EET. In the previously selective estrogen receptor modulator (SERM)-treated subgroup, pN and receipt of chemotherapy were independent predictors for the recommendation of EET. In the previously AI-treated subgroup, age, pN, and receipt of chemotherapy were independent predictors. Adverse events did not affect the recommendation in patients previously treated with adjuvant endocrine treatment nor in the previously SERM or AI-treated subgroups. CTS5 (OR 21.887, 95% CI 2.846-168.309, p = 0.003) remained an independent predictor for the recommendation of EET. Our study indicated that age, lymph nodal status, and receipt of chemotherapy were independent predictors for the recommendation of EET. The application of the CTS5 on EET decision making might be valuable among ER+ breast cancer patients.

Optimizing Adjuvant Treatment Recommendations for Older Women with Biologically Favorable Breast Cancer: Short-Course Radiation or Long-Course Endocrine Therapy?

Omission of radiotherapy among older women taking 5 years of adjuvant endocrine therapy following breast conserving surgery for early-stage, hormone sensitive breast cancers is well-studied. However, endocrine therapy toxicities are significant, and many women have difficulty tolerating endocrine therapy, particularly elderly patients with comorbidities. Omission of endocrine therapy among women receiving adjuvant radiation is less well-studied, but available randomized and non-randomized data suggest that this approach may confer equivalent local control and survival for select patients. Herein we review available randomized and non-randomized outcome data for women treated with radiation monotherapy and emphasize the need for future prospective, randomized studies of endocrine therapy omission.