Esserman, Laura J.

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Abstract Introduction: Pathological complete response (pCR) is a strong prognostic marker, but survival outcomes comparing treatment to control do not reliably align with treatment-control differences in pCR rates in breast cancer. A novel Bayesian hierarchical framework models treatments within trials, allowing us to predict treatment effects on distant recurrence-free survival (DRFS) from pCR with greater accuracy. Methods: We analyzed 12 neoadjuvant breast cancer trials (6,000 patients, all HR/HER2 subtypes; including I-SPY2). The framework of Burzykowski, Molenberghs & Buyse (2005) is extended to a novel arm-based hierarchical structure providing a distribution of pCR and DRFS treatment effects controlling for subtype (HR/HER2), N and T stage, grade, and calendar year. Three held-out trials (877 patients; 26 regimens; med follow-up >4 years) validate predictions of DRFS treatment benefit from pCR. All data was used to estimate treatment-effect correlation and the surrogate threshold effect (STE). Analyses were repeated for Residual Cancer Burden Index (binary RCB01, continuous RCB). Results: Predicted probability of DRFS benefit closely matched actual DRFS follow-up (mean absolute error 0.06; Pearson r = 0.9). Across all trials, pCR showed moderate surrogacy (ρ = 0.82, R2 = 0.67). A 60% increase in pCR odds achieves ≥95% probability of DRFS benefit (STE = OR of 1.60). RCB outperforms pCR across all metrics, with 92% sensitivity and 93% specificity for detecting DRFS benefit in 26 validation regimens (Table 1). Conclusion: This novel Bayesian meta-analytic framework reveals that pCR, RCB01 and continuous RCB reliably predict survival benefit across heterogeneous trials, with RCB performing the best in an external validation. This provides a statistical foundation for accelerated approval decisions using robust early biomarkers in modern neoadjuvant trial designs by accurately predicting survival at the treatment arm level. Citation Format: Keli S. Santos-Parker, Jessica R. Santos-Parker, W. Fraser Symmans, Laura J. Esserman, Christina Yau, Angie DeMichele, Laura van't Veer, Doug Yee, Fabien Reyal, Helena Earl, Jean Abraham, David Cameron, Peter Hall, Judy Boughey, Matthew Goetz, Gabe Sonke, Miguel Martín, Sara López-Tarruella, Priyanka Sharma, Rachel Freiberg, Jane Perlmutter, Aditya Bardia, Martin Eklund, Rachel Freiberg, Lajos Pusztai. A novel statistical framework for surrogate endpoint prediction of survival in neoadjuvant breast cancer trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1401.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

604 Background: The addition of OFS to standard endocrine therapy (ET) improves iDFS for preM women with early-stage hormone receptor positive (HR+) breast cancer (BC). Incomplete OFS occurs in a subset of women, the long-term clinical significance of which is unclear. This study evaluates local sE2 levels in preM women receiving OFS with an oral SERD in the neoadjuvant (NA) setting. Methods: The EOP is a I-SPY2 sub-study investigating NA endocrine-based strategies in pts with HR+ HER2- Stage 2/3 BC predicted to have lower benefit from chemotherapy. Pts were randomized to oral amcenestrant 200 mg/d, alone or in combination with either letrozole 2.5 mg/d or abemaciclib 150 mg bid. Additional pts were randomized to a standard of care (SOC) arm consisting of an aromatase inhibitor. All PreM pts received OFS with monthly GnRHa up to 2 wks prior to C1D1 of study therapy. Pts were treated for 6 months prior to surgery. sE2 levels were collected locally prior to each GnRHa injection. Tumor Ki67 was assessed at 3 weeks and surgery, and associated with sE2 level. Statistical significance was determined using a two-sided Student’s t-test and a significance level 0.05. Results: Between 5/2021-8/2022, 74 pts were enrolled to an amcenestrant containing arm, 40 of whom were preM. 38/40 pts had at least one local sE2 level measured in follow up. Of these 38 pts (median age 45 years), 37 suppressed sE2 into the postmenopausal (postM) range at one or more follow-up timepoints. Of the 37 pts that completely suppressed into the postM range, 6 pts had sE2 levels rebound into the preM range (mean 319 pg/mL, range 20-848 pg/mL) with peak sE2 levels occurring at a median of 12 weeks from C1D1. One pt never suppressed to the postM range (peak sE2 1227 pg/mL) and was found to have an ovarian cyst after 3 months on amcenestrant, requiring surgery. One additional pt had multiple ovarian cysts (sE2 84 pg/mL). Median age of the 7 pts who had sE2 rebound was 43 years. There was no significant difference in Ki67 at 3 weeks and surgery between pts whose sE2 levels remained suppressed (median Ki67 2.0%) compared to those whose estradiol rebounded into the preM range or never suppressed (median Ki67 1.5%). In the 5 pts whose sE2 rebounded to > 200 pg/mL, all pts had tumor Ki67 < 10% at 3 weeks and surgery. Between 12/2022 and 8/2023, 20 pts were enrolled to AI +/- OFS and 11 pts were preM. Of the 11 preM pts, all pts suppressed sE2 to the postM range. No SOC patients had sE2 levels rebound into the preM range. Conclusions: In this study of neoadjuvant oral SERD with monthly OFS, 7/38 (18.4%) preM pts had sE2 levels remain or rebound into the preM range. sE2 levels did not appear to impact Ki67 suppression on NA ET. Work up for ovarian cysts should be considered in pts with symptoms, or significantly elevated or persistent sE2 levels. Clinical trial information: NCT01042379 .

612 Background: EOP, an I-SPY2 sub-study, evaluates the tolerability and activity of novel endocrine strategies in stage 2/3 breast cancer (BC) patients (pts) predicted to have lower chemotherapy benefit. Laso, a selective estrogen receptor modulator (SERM), has shown favorable toxicity profile and activity in HR+/HER2- endocrine-resistant metastatic BC. Methods: Pts with Stage 2/3 HR+/HER2-, MammaPrint (MP) low risk BC were enrolled. Pts with MP High1 BC were included if clinically node-negative. Pts received oral laso 5 mg daily for six 28-day cycles. Laso was continued until the day prior to surgery. Premenopausal pts received ovarian function suppression (OFS) starting C2D1. The primary endpoint was feasibility (>75% of patients completing >75% study therapy). Baseline (T0), 3-wk (T1) biopsies, and the surgical specimen (T3) was assessed centrally for Ki-67. Breast MRI functional tumor volume (FTV) was performed at T0, T1, 12 weeks (T2), and pre-operatively (T3). Blood was collected for tumor informed ctDNA at T0, T1, T2, T3. Advance event (AE) was assessed using CTCAE V5. Results: From 3/2023 to 5/2024, 20 pts were enrolled. Median age 50.5 years, 50% premenopausal, and 1 male pt. 60% cN0, 80% MP low-risk signature. 18 (90%) pts completed >75% study therapy. Two pts discontinued treatment due to pt preference. Median Ki67 at T0 was 14.7%. At T1, 87.5% of pts remained or suppressed Ki67 to <10% and 37.5% suppressed to <2.7%. Ki67 at T1 was similar between pre-and postmenopausal pts despite OFS (Table). The median MRI FTV was 8.4 cc at T0, and 3.4 cc at T3. Median % FTV reduction from T0 to T3 was -47.5%. 2/20 pts (10%) achieved a modified PEPI score of 0. No patients achieved completed pathological response. Of the 16 pts with RCB results, 2 (12.5%) RCB-1, 6 (37.5%) RCB-2, 8 (50%) RCB-3 disease. 14 pts had ctDNA available at T0. 4/14 were ctDNA+ at T0, 2 of whom became ctDNA negative, and 2 remained ctDNA+. 10/14 pts were ctDNA negative at T0, 8 of whom remained negative, 2 became positive at T1 then cleared. All AEs were grade(G) 1 except 1 pt with G2 hot flashes. Most common AEs include hot flashes (85%), constipation (50%), fatigue (50%), and nausea (35%). One pt had G3 hypersensitivity and hypertension, both unrelated to therapy. Conclusions: Neoadjuvant laso demonstrates a favorable AE profile and promising anti-tumor activity in suppressing 3-wk Ki67 and MRI FTV change in pts with HR+ HER2-negative early BC. Ki67 suppression in premenopausal pts was seen in the absence of OFS. Clinical trial information: NCT01042379 . Ki67 expression at pre-treatment, and 3-wk time point. All Patients(n=20) Premenopausal (n=10) Postmenopausal (n=9) Median Ki67 expression Baseline 10.0% 12.5% 10.0% 3-wk 5.1% 3.0% 6.0% Number of pts with Ki67 expression <10% at 3-wk 87.5% 1 87.5% 85.7% Number of pts with Ki67 expression <2.7% at 3-wk 37.5% 50% 28.6% 1 Include the one male pt.

610 Background: The adverse event (AE) landscape in oncology is changing due to the introduction of immunotherapy and antibody drug conjugates. These AEs come with both short and long-term symptoms that significantly impact patient quality of life. Monitoring for early onset of symptoms could optimize therapy for a particular patient, maximizing potential efficacy while mitigating toxicity. It is also possible that some toxicities are directly associated with drug sensitivity. We sought to identify symptoms associated with pathologic complete response (pCR) using patient-reported outcomes (PROs) in early-stage high-risk breast cancer patients. Methods: Our study population included 288 stage II/III high-risk breast cancer patients enrolled on the I-SPY2 trial from 2021-2024, who received novel neoadjuvant therapies ± standard paclitaxel. pCR was assigned if tumor was absent in breast and nodes at surgery following neoadjuvant treatment. Patients (n = 288, pCR rate = 29%, 89% administered immunotherapy) were sent electronic PROs. 33 patient-reported AEs were measured using NCI's Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE). Each symptom was evaluated using severity, frequency, and interference on a Likert Scale. Presence of early PRO symptoms (cycles 1-3 of treatment) were binarized (at least one of moderate or greater), and odds ratios were computed with pCR as outcome. To assess whether higher grade AEs were enriched in patients that achieved a pCR, we also performed the Wilcoxan rank sum test using maximum (worst) symptom severity. Results: Of 288 patients included in our analysis (median age = 48 years, range = 20-78), 203 (70.5%) were White, 17 (5.9%) were Asian, 33 (11.5%) were Black or African American, and 35 (12.2%) were Hispanic. PRO analysis revealed that patients that had moderate to severe muscle pain (27% vs 10% OR = 3.15, p < 0.05), joint pain (22% vs 8% OR = 3.23, p < 0.05), headache (27% vs 12.5% OR = 2.59, p < 0.05), or mouth/throat sores (16% vs 5% OR = 3.56, p < 0.05) within weeks 1-3 had higher odds of achieving a pCR. When we looked at maximum severity between weeks 1-3, patients that achieved a PCR had higher grade muscle pain (p = 0.04), heart palpitations (p = 0.035), and significantly lower grade numbness and tingling (p = 0.002). Beyond 6 weeks, associations were weaker or insignificant. Conclusions: Our study utilizes an analysis framework that was able to determine sentinel symptoms such as muscle and joint pain, mouth/throat sores and palpitations as early as weeks 1-3 associated with increased efficacy. This may suggest an early immune reaction in patients that eventually respond favorably to treatment. Our work can help provide earlier proactive monitoring to mitigate toxicities, treatment redirection if needed, and a potential symptom-based early understanding to personalize treatment efficacy. A similar analysis is underway to predict immune related AEs. Clinical trial information: NCT01042379 .

504 Background: Axillary surgery in breast cancer is used for staging and therapeutic purposes, but axillary lymph node dissection (ALND) confers high risk of complications including lymphedema. Accordingly, trials have focused on right-sizing axillary surgery, with options ranging from complete omission of surgery, sentinel lymph node (SLN) surgery, targeted axillary dissection (TAD), or ALND. Identifying a biomarker to reliably predict nodal burden would facilitate accurate selection of surgical management. We evaluated whether the presence or absence of ctDNA in the blood pre and post NAC is associated with residual nodal burden. Methods: I-SPY2 is a prospective, multicenter NAC trial for patients with clinical stage II-III high-risk breast cancer. Patients are randomized to novel NAC agents, with pathologic complete response being the primary endpoint. As part of the trial, serial ctDNA is assessed with a highly sensitive tumor-informed assay using up to 16 patient-specific tumor mutations (Signatera) at baseline, 3 weeks, 12 weeks, and post-NAC. We determined whether ctDNA positivity or negativity post-NAC, and the change in ctDNA status baseline/post-NAC (-/-, -/+, +/+, +/-) are associated with ypN category (N0, N1, N2). Results: ctDNA status was available post-NAC in 495 patients and change in ctDNA status from baseline was available in 493. At baseline, ctDNA was detected in 160/220 (72.3%) cN0 patients and 227/273 (83.2%) cN+ patients (p=0.006). Post-NAC, ctDNA was detected in 11/220 (5%) cN0 patients and 34/273 (12.5%) cN+ patients (p=0.004). While baseline ctDNA status was not associated with ypN category, there was a significant association between post-NAC ctDNA status and ypN category. For ctDNA + patients post-NAC, 33.3% were ypN0, 31.1% were ypN1, and 35.6% were ypN2 at surgery; in contrast, for ctDNA - patients post-NAC, 67.1% were ypN0, 23.1% were ypN1, and 9.8% were ypN2 (p<0.0001). Dynamic ctDNA changes were also associated with ypN category, with significantly more ypN0 patients among ctDNA -/- or ctDNA +/- cases, and more ypN2 patients in those who did not clear ctDNA (+/+) (p=0.0001, Table). Conclusions: To our knowledge this is the first study to demonstrate a significant relationship between ctDNA and ypN category, which has important surgical implications. CtDNA negativity was associated with low likelihood of ypN2 disease, making these patients excellent candidates for SLN surgery or TAD. Ongoing analyses will incorporate receptor subtype and timing of clearance of ctDNA. CtDNA in breast cancer may help tailor surgical management of the axilla, potentially reducing patient morbidity without compromising prognostic information. ctDNA baseline/post-NAC ypN0 (n=317) ypN1 (n=116) ypN2 (n=60) ctDNA -/- (n=105) 72.4% 19.1% 8.6% ctDNA -/+ (n=1) 0.0% 100.0% 0.0% ctDNA +/+ (n=44) 34.1% 29.6% 36.4% ctDNA +/- (n=343) 65.9% 23.9% 10.2%

3008 Background: Numerous studies have demonstrated the prognostic value of ctDNA analysis after neoadjuvant chemotherapy for early-stage high-risk breast cancer. Few studies have characterized ctDNA in pts receiving NET for early-stage hormone receptor positive (HR+)/HER2- BC that is predicted to benefit less from chemotherapy. Methods: Cell-free DNA (cfDNA) was isolated from 432 plasma samples from 108 pts enrolled in the I-SPY2 EOP trial. Pts had Stage 2/3 HR+/HER2-, MammaPrint low or high risk 1 BC. Pts were randomized to one of 7 neoadjuvant-based treatment arms including arms containing AI, Z-endoxifen, Lasofoxifene, vepdegestrant (ARV-471), and Abemaciclib. Pts were treated for 6 months prior to surgery. Blood was collected at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). A personalized ctDNA test (Signatera) was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The chi-square test was used to assess associations between categorical variables, and the Wilcoxon rank-sum test was used to evaluate differences in medians. Results: ctDNA information was available for 101 patients at baseline (T0) (Table 1). At T0, 36 (35.6%) patients were ctDNA-positive. 23/36 (63.9%) became ctDNA-negative and 13/36 (36.1%) remained ctDNA-positive. At T0, 65/101 patients (64.4%) were ctDNA-negative. Of these, 57 (87.7%) remained negative, while 8 (12.3%) became ctDNA-positive at T1 before reverting to ctDNA-negative. A higher percentage of ctDNA-positive patients at T0 were cN+ compared to ctDNA-negative pts (p = 0.036, 64% vs. 40%). Additionally, ctDNA-positivity at T0 was strongly associated with higher Ki67 (p = 0.03) and larger functional tumor volume by MRI at baseline (p = 0.03). T3/T4 and high-grade tumors at baseline were also associated with having ctDNA positivity at baseline, though this was not statistically significant (p = 0.34 and 0.058, respectively). Conclusions: In this study of pts with Stage 2/3 HR+ HER2- BC with largely MammaPrint low risk signatures, over one-third of pts had detectable ctDNA at baseline. Detectable ctDNA at baseline was associated with cN+ disease, larger FTV, and high baseline Ki67. The majority of pts with positive ctDNA at baseline cleared the ctDNA on NET. Clinical trial information: NCT01042379 . Clinicopathologic characteristics of EOP patients. All Patients(N=101) Age at screening 55 (27-80) years* Clinical N Stage Node+ (cN+) 49 (48.5%) Node- (cN-) 52 (51.5%) SET status High 84 (83.2%) Low 14 (13.9%) Missing 3 (2.97%) MammaPrint (MP) risk** High risk 1 (H1) 15 (14.9%) Low risk 86 (85.1%) *Mean(min-max). **H1: MP score between 0 and -0.57; low: MP score between 0 and 0.355.

Abstract Objectives We describe the development and implementation of a system for monitoring patient-reported adverse events and quality of life using electronic Patient Reported Outcome (ePRO) instruments in the I-SPY2 Trial, a phase II clinical trial for locally advanced breast cancer. We describe the administration of technological, workflow, and behavior change interventions and their associated impact on questionnaire completion. Materials and Methods Using the OpenClinica electronic data capture system, we developed rules-based logic to build automated ePRO surveys, customized to the I-SPY2 treatment schedule. We piloted ePROs at the University of California, San Francisco (UCSF) to optimize workflow in the context of trial treatment scenarios and staggered rollout of the ePRO system to 26 sites to ensure effective implementation of the technology. Results Increasing ePRO completion requires workflow solutions and research staff engagement. Over two years, we increased baseline survey completion from 25% to 80%. The majority of patients completed between 30% and 75% of the questionnaires they received, with no statistically significant variation in survey completion by age, race or ethnicity. Patients who completed the screening timepoint questionnaire were significantly more likely to complete more of the surveys they received at later timepoints (mean completion of 74.1% vs 35.5%, P &lt; .0001). Baseline PROMIS social functioning and grade 2 or more PRO-CTCAE interference of Abdominal Pain, Decreased Appetite, Dizziness and Shortness of Breath was associated with lower survey completion rates. Discussion and Conclusion By implementing ePROs, we have the potential to increase efficiency and accuracy of patient-reported clinical trial data collection, while improving quality of care, patient safety, and health outcomes. Our method is accessible across demographics and facilitates an ease of data collection and sharing across nationwide sites. We identify predictors of decreased completion that can optimize resource allocation by better targeting efforts such as in-person outreach, staff engagement, a robust technical workflow, and increased monitoring to improve overall completion rates. Trial Registration https://clinicaltrials.gov/study/NCT01042379.

601 Background: EOP is an I-SPY2 neoadjuvant sub-study designed to test the tolerability and impact of novel endocrine-based strategies in stage 2/3 BC pts predicted to have lower benefit from chemotherapy. Amcenestrant (A) is an oral selective estrogen receptor degrader (SERD) with activity in hormone receptor positive (HR+) HER2- metastatic BC. Methods: EOP eligibility included pts screened for the main I-SPY2 trial with HR+ HER2-, MammaPrint (MP) low risk Stage 2/3 BC. Pts with MP High risk tumor signatures were eligible if clinically node-negative (cN-). Pts were stratified by SET index and menopausal status. Pts were randomized to 3 arms: A 200 mg qd (A), A + abemaciclib 150 mg bid (AA), A + letrozole 2.5 mg qd (AL). Premenopausal pts received concurrent ovarian function suppression. Treatment was for 6 mos followed by surgery. Baseline (BL) and 3-wk biopsies were performed. Breast MRIs were conducted at BL (T0), 3 wks (T1), 12 wks (T2), 6 mos (T3). The primary endpoint was feasibility, defined as >75% of pts completing >75% study therapy. Results: Between May 2021 and Aug 2022, 74 pts were randomized: 31 A, 21 AA, 22 AL. Median age 50 years, 54% premenopausal, 38% clinically node-positive (cN+). 41% pts had ductal, 38% lobular, 11% mixed ductal/lobular histology. Mean BL tumor Ki67 (central testing) was 16.9%, 88% MP low, 76% SET index Hi. Pt and tumor characteristics were balanced across the 3 arms. Treatment in all 3 arms was feasible with 95% of pts completing >75% study therapy. Most common AEs include grade 1-2 hot flashes (69%) and fatigue (66%). Grade 3 AEs include neutropenia (2 pts) and diarrhea (1 pt) in AA. Table summarizes key response endpoints, which were similar between pre- and postmenopausal pts. Of 28 cN+ pts, 2 (7%) were pathologically node-negative (pN-). Mean MRI Functional Tumor Volume (cc) change between T0->T1, T1->T2, T2->T3, T0->T3 was -6.06 (-34.2%), -3.55 (-29.2%), -0.829 (-20.1%), -11.3 (-68.4%), respectively, similar across arms (p=0.396).ctDNA was detected in 10/59 (17%) pts at T0. ctDNA became undetectable in 6 pts, decreased in 4 pts, and went from ctDNA undetectable at baseline to detectable at T3 in 2 pts. Conclusions: Six months of neoadjuvant endocrine therapy (NET) with the oral SERD amcenestrant is feasible, well-tolerated, and demonstrates anti-proliferative and anti-tumor activity in pre- and postmenopausal pts. NET provides a rich platform for biomarker discovery and investigating response to endocrine therapy. Clinical trial information: NCT01042379 . [Table: see text]