Citations

525 Background: Adjuvant endocrine therapy (ET) decreases breast cancer (BC) recurrence and improves overall survival (OS) for patients (pts) with estrogen receptor positive (ER+) BC. Omission of adjuvant ET and nonadherence are major issues contributing to worse clinical outcomes. Recent data suggest that the number of pts who omit adjuvant ET may be increasing in Europe [1]. These data have yet to be evaluated in the U.S. We previously reported data from the National Cancer Database (NCDB) that ET omission was more likely in pts with ER+/HER2+ disease who achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) [2]. Herein we report an updated analysis with a larger cohort designed to examine trends in ET omission over time and the impact on OS in a group of pts at high risk of recurrence. Methods: The NCDB was queried from 2010-2022 for pts with stage I-III ER+BC treated with NAC and surgery. pCR was defined as ypT0, ypN0. Use of adjuvant ET and the impact of adjuvant ET omission on OS in pts with and without pCR were assessed separately based on HER2 status. Adjuvant ET initiation by 1 year was summarized using the cumulative incidence estimate to account for the competing risk of death. OS was analyzed with ET as a time-dependent covariate using multivariable Cox proportional hazards regression. Results: We identified 130,438 pts with ER+BC (78,778 ER+/HER2-, 51,660 ER+/HER2+) who received NAC. Median follow-up was 5 years. Overall, pCR was achieved in 10.0% of ER+/HER2- and 35.9% of ER+/HER2+. On multivariable analysis, ET omission was significantly associated with worse OS in pts with residual disease (RD) [ER+/HER2- (HR 1.80 p<0.001) ER+/HER2+ (HR 1.66 p<0.001] and in those with a pCR [ER+/HER2- (HR 1.38 p=0.002) ER+/HER2+ (HR 1.42 p<0.001)]. Between 2010-2017, adjuvant ET omission was stable, with approximately 10.0% of pts not having initiated ET by 1 year after surgery. The proportion of pts omitting ET overall increased thereafter to 12.9% in 2018, rising to 24.4% in 2022. A sharp increase in ET omission was observed 2021-2022 in ER+/HER2- BC who achieved pCR, with 42.4% omitting ET compared to 25.1% for 2018-2020 and 18.8% for 2010-2017 (p<0.001). Adjuvant ET omission showed more modest but significant increases for other subgroups (p<0.001): ER+/HER2- with RD (8.5% 2010-2017, 12.3% 2018-2020, 18.7% 2021-2022), ER+/HER2+ with pCR (15.1% 2010-2017, 14.0% 2018-2020, 24.4% 2021-2022), and ER+/HER2+ with RD (9.5% 2010-2017, 12.5% 2018-2020, 22.2% 2021-2022). Conclusions: In ER+BC treated with NAC, omission of ET is increasing over time and associated with a higher risk of death, regardless of HER2, RD, or pCR status. These findings have substantial public health implications as they may result in a reversal of the 4-decade improvements in breast cancer mortality. Additional intervention is critical to improve adherence to guidelines. [1] Verreck et al. Breast 2025 [2] Choong et al. SABCS 2022.

Abstract Background: The increasing volume and diversity of clinical genomic reports pose a significant challenge across healthcare institutions for the interpretation and proper implementation of precision oncology research. Reports from multiple different vendors (e.g., Invitae, Ambry Genetics, Foundation Medicine) are typically PDFs and exhibit substantial heterogeneity in panel design, gene coverage, and reporting standards, which hinders efficient retrospective data mining and patient cohort identification within the electronic medical records. We sought to develop a framework to interrogate all of these reports. Methods: We extracted genomic reports from patients with breast cancer treated with neoadjuvant chemotherapy and developed MolHarmonizer, a novel, scalable framework leveraging Python and Gemini LLMs, designed to process and harmonize genomic data from disparate multi-vendor reports. Gemini LLMs are employed explicitly for robust information extraction, normalization, and structuring of key genomic features, transforming unstructured data into a unified, queryable dataset. Results: Our MolHarmonizer framework successfully processed 1,147 genomic reports from 1703 breast cancer patients (2006-2023) from 23 different companies, demonstrating robust capability to extract and standardize critical actionable biomarkers. Data sources included Invitae (n=554), Ambry Genetics (n=189), Natera (n=95), Mayo Clinic (n=88), Tempus (n=63), Guardant Health (n=47), and Foundation Medicine (n=37), with others contributing less than 20 reports. Of the samples, 827/1147 (72.1%) were germline (blood/saliva). A majority of the patients were tested using the panels due to a personal/family history (n=925). Overall, 413/1147 (36.0%) reports identified at least one mutation. For breast cancer, 75 reports showed BRCA1/2 mutations (37 BRCA1, 37 BRCA2, and one patient with both BRCA1 and 2). Other mutations identified included: PIK3CA (n=40), TP53 (n=96), PTEN (n=21), ESR1 (n=13) and AKT1/2 (n=8). Conclusion: MolHarmonizer, a powerful framework leveraging Gemini LLMs, effectively addresses genomic data heterogeneity by automating biomarker extraction and harmonization. This enables rapid cohort identification and deep retrospective analyses for clinical insights, biomarker discovery, understanding disease history, facilitating novel pattern discovery, e.g., predicting BRCA1 mutations from WSI, and accelerating research within our neoadjuvant BC cohort. Future plans include expanding to include over 20,000 breast cancer patients, developing a user-friendly chatbot, and ensuring inter-institutional adaptability for a variety of complex diseases. Citation Format: Krishna Rani Kalari, Xiaojia Tang, Thanmayee Boyapati, Tanya L. Hoskin, Sumathilatha Myla, Sumedha G. Penheiter, Richard M. Weinshilboum, Liewei Wang, Hamid R. Tizhoosh, Karthik Vikram Giridhar, Matthew P. Goetz, Judy C. Boughey. Development of an LLM framework for analysis of heterogeneous breast cancer patients genomic reports [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 2756.

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 &gt;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.

Abstract Background: MHC class II molecules are normally restricted to professional antigen-presenting cells. Prior TNBC studies have focused on immune-compartment MHC-II. Using spatial transcriptomics, we recently identified aberrant tumor-cell MHC-II expression. Here, we characterized the immune architecture surrounding HLA-DRA-expressing tumor cells. Methods: High-plex single-cell spatial transcriptomics (CosMxTM SMI) was performed on treatment-naïve TNBC (Mayo TMA, n=65) and two neoadjuvant pembrolizumab cohorts (Mayo n=8; Emory n=4). Spatial neighborhoods were mapped relative to HLA-DRA-high tumor cells. Differential expression and adaptive immune gene-set scores were evaluated. Clinical relevance was assessed using FinXX (n=114), I-SPY2 (n=364), and Caris CODEai (n=3,662). Results: HLA-DRA-high tumor regions showed significant enrichment of adaptive immune subsets within ≤50 μm, including B cells, CD8+ T cells, NK cells, macrophages, and plasmacytoid dendritic cells. In pembrolizumab-treated cohorts, responders exhibited higher proportions of HLA-DRA-high tumor cells and greater numbers of B cells, plasmablasts, CD4+ and CD8+ T cells, and macrophages near tumor cells. Responders’ tumors showed upregulation of antigen-presentation machinery, B-cell/plasma-cell programs, CXCL13, and NOTCH3/DLL1. Across I-SPY2 and FinXX, higher HLA-DRA correlated with pathologic complete response and improved survival. In CODEai TNBC, high HLA-DRA expression correlated with higher CXCL13 (median TPM 7.5 vs. 1.1, q&lt;0.05) and longer overall survival (24.2 vs. 18.5 months, HR 0.77, 95% CI 0.71-0.83, p&lt;0.0001). This association was TNBC-specific. High CXCL13 also predicted improved survival (26.6 vs. 16.5 months, HR 0.64, 95% CI 0.59-0.69, p&lt;0.0001). Conclusions: Tumor-cell HLA-DRA expression defines a highly organized adaptive immune niche enriched with B cells and activated T-cell populations in close proximity. Adaptive immune programs—including enhanced antigen presentation and CXCL13-mediated B-cell/plasma-cell pathways—consistently associate with improved outcomes across TNBC cohorts treated with chemotherapy and immune checkpoint blockade. Aberrant tumor-cell MHC-II expression may contribute to antitumor immunity and warrants further investigation as a potential therapeutic target. Citation Format: Yi Liu, Sachin Kumar Deshmukh, Thiti Susiriwatananont, Panuch Eiamprapaporn, Bogang Wu, Heikki Joensuu, Roberto A. Leon-Ferre, David Zahrieh, Judy C. Boughey, James Newell Ingle, Fergus J. Couch, Sharon Wu, Shipra Gandhi, Maryam Lustberg, George W. Sledge, Matthew P. Goetz, Keith L. Knutson, E Aubrey Thompson, Jodi Carter, Saranya Chumsri. Spatially resolved tumor-cell MHC class II shapes adaptive immunity and therapeutic response in triple-negative breast cancer [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 1200.

Importance The management of infectious and inflammatory lesions of the breast remains controversial. The expert panel focused on management recommendations for 3 of the most common infectious breast conditions, as very few evidence-based guidelines for the management of these conditions exist. Observations Clinicians should distinguish between infectious and noninfectious lactational mastitis (LM) because the former often requires interventions whereas the latter requires supportive care only. Patients with infectious LM often have thick fluid collections that are not amenable to aspiration and usually require a stab incision with drain placement (but no packing) to resolve the infection. Operative drainage is only required if the patient cannot tolerate an office procedure. If a phlegmon is present, antibiotics should be prescribed for at least 10 days. The diagnosis of granulomatous mastitis (GM) requires pathology confirmation with characteristic findings on core biopsy. Cystic neutrophilic granulomatous mastitis (CNGM) is a specific form of GM associated with a granulomatous reaction to Corynebacterium infection and should be empirically treated with doxycycline. For patients without findings characteristic of CNGM and no other associated bacterium identified, there is no role for empiric antibiotic use. Granulomatous mastitis cases often recur and can take up to 18 months to resolve. Patients who have GM cases with worsening symptoms should be treated with repeated intralesional steroid injections; surgical excision or repeated aspirations should be avoided. Cases refractory to intralesional steroid injection may require oral steroids or even advanced biologic agents such as methotrexate or azathioprine. Periductal mastitis with squamous metaplasia of lactiferous ducts (PDM-SMOLD) is a distinct entity from other periductal mastitis cases that can present with recurrent abscesses and should be treated with antibiotics and aspiration for fluid collections. Operative excision for PDM-SMOLD is required for those patients who present with a fistula or recurrent episodes typically using a radial incision to remove the diseased ducts within and below the nipple. Conclusions and Relevance Evidence-informed, consensus-, and expert opinion–based guidelines for the management of infectious and inflammatory conditions of the breast were developed. Clinicians can use these guidelines to appropriately manage these conditions for which clinical care often varied in the past.

ABSTRACT The normal adult male breast has not been characterized at single-cell resolution, leaving the cellular basis of male breast cancer (MBC) biology undefined. Here we present an integrated single-cell RNA sequencing atlas of the adult human breast comprising 174,471 cells from 17 donors (3 male, 14 female), including 18,117 male-derived cells. This revealed that the male breast retains all three epithelial populations, basal (BC), luminal progenitor (LP), and luminal committed cells (LC), but with an increase in LC at the expense of BC and LP across all three male donors. Male LC were distinguished from female by elevated ESR1 and PGR mRNA, enrichment of RNA processing and ribosome biogenesis programs, reduced inflammatory cytokine and growth factor signaling, elevated estradiol gene set enrichment scores, and higher inferred activity of developmental patterning transcription factors. This pattern was observed across differential expression, gene ontology, ligand profiling, and regulon-based analyses, and was not restricted to sex chromosome-linked gene expression. This is consistent with the near-universal estrogen receptor (ER) positivity that characterizes MBC clinically. This atlas provides the first cellular and transcriptional reference for the normal male breast and a resource for investigating sex differences in mammary biology, germline susceptibility variant interpretation, and modeling breast malignancies.

BACKGROUND: Social determinants of health (SDOH) are associated with adverse cancer outcomes, yet the prevalence and impact of SDOH screening across Commission on Cancer (CoC)-accredited programs are unknown. We evaluated national SDOH screening practices and their association with adherence to CoC quality measures. STUDY DESIGN: A cross-sectional survey of 1,445 CoC-accredited programs (October to December 2024) was linked to National Cancer Database data (2020 to 2022). Adult patients treated at 435 responding hospitals (30.1%) were included. Programs were categorized by routine outpatient SDOH screening status. Multivariable logistic regression assessed associations between screening and receipt of quality measure–concordant care, adjusting for screening duration, age, race, ethnicity, Charlson Comorbidity Index, insurance status, rurality, and program type or case count. RESULTS: Of 435 programs, 165 (37.9%) reported routine SDOH screening. Screening programs more frequently treated ≥10% Medicaid or uninsured patients (29.1% vs 19.6%, p = 0.023). Mean performance was higher at screening hospitals for breast radiation within 60 days (66.6% vs 64.6%, p = 0.046), colon adjuvant chemotherapy within 120 days (84.6% vs 81.9%, p = 0.018), and lung systemic therapy within 90 days (77.2% vs 75.4%, p = 0.043). On adjusted analysis, screening for more than 3 years was independently associated with timely colon adjuvant chemotherapy (odds ratio 1.05; 95% CI 1.01 to 1.07; p = 0.033). Findings persisted after excluding safety net hospitals. CONCLUSIONS: Only one-third of responding CoC programs routinely screen for SDOH. Sustained screening was independently associated with improved adherence to time-sensitive colon cancer chemotherapy, supporting integration of patient-level SDOH assessment into oncology care delivery.

BACKGROUND: The National Cancer Database (NCDB) captures 73.7% of newly diagnosed cancers in the USs and underpins thousands of outcomes studies informing oncologic practice. To remain relevant amid rapid therapeutic and policy changes, the NCDB has undergone substantial structural and variable-level revisions. We characterized major updates during the past decade and their implications for research. STUDY DESIGN: We performed a narrative review of annual NCDB data dictionary revisions, American College of Surgeons bulletins, and internal program updates in collaboration with NCDB leadership. Structural modifications, variable additions, and policy changes affecting data capture, follow-up, staging, and accessibility were systematically summarized. RESULTS: The NCDB now includes data from 1,413 Commission on Cancer–accredited hospitals and more than 55 million records. Since 2020, the Rapid Cancer Reporting System enables near–real-time monthly submissions. Embargo periods were reduced from 5 to 3 years for survival data and 2 years for other variables, increasing analytic timeliness. Follow-up was limited to 15 years beginning January 1, 2022. Variable refinements include continuous tumor size in millimeters (since 2016), separation of tumor grade into clinical, pathologic, and posttherapy fields (since 2018), phased radiation treatment reporting (since 2018), and American Joint Committee on Cancer eighth edition staging implementation in January 2018 with nineth edition rollout ongoing. New data elements include Medicaid expansion status (2020), COVID-19 variables (2020 to 2021; 12.4% reduction in cases in 2020), smoking status (2023), and planned programmed death-ligand 1 reporting for non–small cell lung cancer beginning in 2025. CONCLUSIONS: The NCDB has evolved toward more granular, contemporary, and policy-relevant data capture while maintaining broad national coverage. Investigators must account for staging transitions, variable maturation, follow-up limits, and registry-specific biases to ensure valid interpretation of NCDB-based research.

Abstract Introduction Cancer clinical trials have historically faced challenges in achieving fully representative trial population, particularly in terms of including patients from diverse ethnic and racial groups, those with low socioeconomic status, and those living in rural regions. This has contributed to inequities in access to novel therapeutic options. Background The I-SPY adaptive platform trials have prioritized diversity since inception, consistently enrolling in &gt;10% of trial patients being Black and/or Hispanic individuals. The majority of participating institutions in the I-SPY 2.2 study are academic or large well-resourced health systems. In 2023, the I-SPY ACCESS (Achieving Cancer Clinical Trial Equity in Socioeconomically Diverse Sites) Initiative was launched to enhance representation by engaging and involving nontraditional trial sites- such as safety-net hospitals, community cancer centers, and rural cancer centers- that serve historically excluded patient populations. Methods The I-SPY ACCESS Initiative offers customized and personalized tailored support to under-resourced sites. This includes comprehensive feasibility and readiness assessments, onboarding guidance, enhanced site-specific training, centralized institutional review board (IRB) navigation, site peer mentorship, and educational materials for both patient and provider. Additionally, patients gain access to I-SPY advocate peer trial navigators. Sites are provided culturally responsive patient education tools- including multilingual brochures, a dedicated patient website, and content co-developed with community partners. A Clinical Trial Navigator supports both patients and sites, helping to locate logistical, social, and trial specific resources.Tools such as virtual Clinical Research Coordinators (vCRC's) and OneSource technology are deployed strategically based on assessed site need and resource availability. OneSource is an innovative platform that enables direct extraction of clinical data from electronic health records into trial databases, reducing site workload and improving data quality. Funding models are currently being explored to extend OneSource and vCRC services across more ACCESS sites. In the future, there are plans to pilot financial navigation services and integrative care resources for all patients enrolled in I-SPY with particular focus on those enrolled at ACCESS sites. Results and Progress As of June 2025, seven sites have been assessed as ACCESS sites for I-SPY 2.2, with two sites having successfully completed activation and currently enrolling participants. Beginning in mid-2024, one DCIS RECAST ACCESS site has been activated and 11 additional sites are in the onboarding process. The modest pace of I-SPY 2.2 activation reflects the complexity and operational demands associated with resource-intensive platform trial. In contrast, the DCIS RECAST protocol was designed with a lower burden, facilitating easier implementation by under-resourced sites, reflected by increased interest in the study among ACCESS sites. The ACCESS framework is being explored for potential future application in the Pre I-SPY Phase 1 platform trial, particularly considering the historical underrepresentation of such sites in the early-phase clinical research. Conclusion and Future Goals The I-SPY ACCESS initiative demonstrates that investing in thoughtful, innovative, and effective means for trial delivery, as well as incorporating community-based support, can strengthen representation in complex, adaptive breast cancer trials. The initiative offers a flexible, equity-driven framework that is impactful now and scalable for future innovation in oncology research. Citation Format: S. L. Horton, D. A. Idossa, K. C. Hewitt, J. Perlmutter, L. Van't Veer, N. Hylton, A. Borowsky, F. Symmans, D. Yee, C. Yau, P. Pohlmann, J. Boughey, L. Esserman. Expanding Diversity through Innovation: Development of the I-SPY ACCESS Initiative for the I-SPY2.2 and DCIS RECAST Clinical Trials [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-09-08.

Abstract Background: (Z)-endoxifen (ENDX) is an oral SERM that dually targets ERα (&gt; 5 ng/ml) and PKCβ1 (&gt;500 ng/ml). It has been tested in the endocrine resistant setting at doses of 20-360 mg/day; however, the optimal dose in an endocrine naïve population is not defined. We explored 10 mg/day dose of neoadjuvant ENDX in the Endocrine Optimization Pilot (EOP) of I-SPY2. Methods: EOP eligibility included pts with Stage II/III HR+ HER2- breast cancer, MammaPrint (MP) low. Pts with MP High1 scores were eligible if clinically node-negative. Pts received ENDX 10 mg orally once daily for 6 cycles (each cycle = 28 days). Premenopausal pts started ovarian function suppression on cycle 2, day 1. ENDX was continued until the day prior to surgery. The primary study endpoint was feasibility, defined as &gt;75% of pts completing &gt;75% of ENDX. Baseline (T0), 3-wk (T1) biopsies, and the surgical specimen (T3) were assessed centrally for Ki-67. Rates of modified preoperative endocrine prognostic index (mPEPI) 0 were reported, defined as pT1-2 pN0, Ki67&lt; 2.7%, or pathologic complete response. A genomic index for sensitivity to endocrine therapy (SET) index was done at T0. Breast MRI measurement of 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 and for pharmacokinetic (PK) steady state concentrations (Css) at T1. Safety data using CTCAE V5 is reported. Results: Between March 2023 and May 2024, 20 pts were enrolled in this arm. The median age was 52.5 years (range 32 -73), 13 (65%) were premenopausal, and 55% had clinically positive lymph nodes. Tumors were MPHigh1 in 3 pts (15%) and SET2,3 index high in 16 pts (80%). The primary endpoint was met with 95% of study participants completing ≥75% of therapy. The T0 median Ki-67 was 10.5% (range 2-60%). At T1 (n=19) and T3 (n=18), median Ki-67 was 5% (range 0-35%) and 5% (range 0-45%), respectively. The 3-week rate of Ki-67 ≤10% at T1 was 61.5% in premenopausal and 71.4% in postmenopausal women. The rate of Ki-67 ≤10% at surgery was 81.8% in premenopausal and 57.1% in postmenopausal women. An mPEPI score of 0 was observed in 1 (5%) of participants. The median T0 FTV was 8.9 ccs (range 0.9 to 251.1). The median T3 FTV was 1.3 ccs (range 0 to 11.2) and the median change in FTV from T0 to T3 was -72.0% (range -88.5% to -61.6%). ctDNA analysis was performed in 17 pts longitudinally across 64 blood samples.10 pts had positive ctDNA at T0, with 7 converting to ctDNA undetectable during treatment with ENDX. 1/7 pts who was ctDNA negative at T0 became positive at T1 and then reverted to undetectable ctDNA. The other 6 pts remained ctDNA negative at all timepoints. The median ENDX T1 Css was 79.3 ng/mL (range 73.6 - 906.4 ng /mL). The most common side effects reported were Grade 1 hot flush (70%), nausea (40%), fatigue (40%), and insomnia (35%). Grade 2 side effects included fatigue (15%) and night sweats (5%). No dose reductions or discontinuations due to toxicity occurred. Conclusions: ENDX at 10 mg was well tolerated and demonstrated reductions in Ki-67, MRI FTV, and ctDNA. The ISPY2 EOP is currently enrolling patients to ENDX 40 mg/day (intended to dually target ERα and PKCβ1) in combination with abemaciclib (with and without OFS). Citation Format: K. V. Giridhar, M. P. Goetz, C. Yau, A. M. Wallace, C. Falkson, J. Boughey, M. Arora, E. Stringer-Reasor, C. Nangia, C. Gallagher, A. Elias, A. Zimmer, M. S. Trivedi, C. Omene, L. van 't Veer, L. Brown Swigart, G. L. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, C. Vakalvas, M. Wei, J. M. Reid, S. Alhafaji, N. Chen, R. M. Mukhtar, L. Huppert, O. Opopade, L. J. Esserman, A. Chein. Low dose (Z)-endoxifen in the I-SPY2 Endocrine Optimization Pilot [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-10.