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PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

TPS655 Background: Early (14-28 day) on-treatment suppression of tumor proliferation during neoadjuvant endocrine therapy (NET) is strongly associated with favorable long-term outcomes in estrogen receptor–positive (ER+) HER2– breast cancer. In premenopausal women, tamoxifen with or without ovarian function suppression (OFS) results in suboptimal Ki-67 suppression compared with aromatase inhibitor + OFS. (Z)-endoxifen (ENDX), the active metabolite of tamoxifen, dually inhibits ER signaling and PKCβ1-mediated AKT activation, supporting its evaluation as an alternative NET strategy in this population. Methods: EVANGELINE (NCT05607004) is an ongoing, multicenter, open-label Phase 2 study evaluating daily 40 mg ENDX plus goserelin administered every 28 days as neoadjuvant therapy in premenopausal women with ER+/HER2–, cT2–3, cN0–1 breast cancer. The primary objective is to determine the proportion of patients with baseline Ki-67 >10% who achieve Ki-67 ≤10% after 4 weeks of therapy. A Simon two-stage design is used to test whether the Week 4 Ki-67 ≤10% rate is at least 65%, with 20 patients enrolled into the first stage and, if promising, another 25 patients enrolled into the second stage (cohort A). A parallel cohort of 20 patients with baseline Ki-67 ≤10% (cohort B) is enrolled to assess objective response rate (ORR) at 24 weeks per RECIST v1.1. Secondary objectives include examining safety and tolerability, residual cancer burden, and PEPI score. Correlative analyses include examining effect of treatment on select tumor and plasma biomarkers. Clinical trial information: NCT05607004 .

Abstract Background: Endocrine therapy (ET) with aromatase inhibitors (AIs) plus ovarian function suppression (OFS) is a standard endocrine strategy for premenopausal women with ER+/HER2- breast cancer. However, poor tolerability to AI+OFS limits its use, leaving tamoxifen as the only alternative. Prospective studies demonstrated that premenopausal women treated with neoadjuvant ET whose tumors exhibit Ki-67 ≤ 10% following 4 weeks of therapy achieve 5-year distant disease-free survival > 96%. Problematically, only 41% of patients reach this threshold with tamoxifen compared to 78% with AI+OFS (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent selective estrogen receptor modulator that dually targets ERα and PKCβ1. At plasma concentrations of 3-5 ng/mL, it inhibits ERα; at ≥ 500 ng/mL, it targets PKCβ1, leading to AKT suppression. The EVANGELINE trial aims to examine endocrine sensitivity in terms of Week 4 Ki-67 in premenopausal women whose baseline Ki-67 > 10%, and objective response rate after 24 weeks of ENDX + goserelin in premenopausal women with baseline Ki-67≤ 10%. Methods: EVANGELINE (NCT05607004) is a multicenter, open-label, Phase 2 study comprised of three parts. Eligible patients are premenopausal women with Stage IIA/IIB ER+/HER2- breast cancer. • Part 1 (PK Run-in): assessed 40mg vs 80mg ENDX (+/- OFS) in 22 patients. • Part 2: patients with baseline Ki-67 >10% were randomized to 40 mg ENDX + goserelin or exemestane + goserelin for 6 months with the primary objective being 4-week ESD rate. Patients with a baseline Ki-67 ≤10% were assigned to a single-arm cohort of 40 mg ENDX monotherapy (no OFS) to evaluate the 24-week endocrine sensitivity disease rate. • Part 3 (replaces Part 2): all patients are treated with ENDX 40mg daily + goserelin every 28 days. A two stage Phase II design was chosen to assess outcomes as follows: Part 3a: Up to 45 patients with baseline Ki-67> 10% to assess Week 4 Ki-67≤ 10% rate is at least 65%. If 9 or more of these patients have a Week 4 Ki-67>10%, enrollment will be stopped due to futility. Otherwise, enrollment will continue. Part 3b: Up to 20 patients enrolled with baseline Ki-67≤ 10% to assess Week 24 objective response rate. Ki-67 levels are determined by central laboratory and images are centrally reviewed. Secondary objectives include safety, tolerability, surgical outcomes, and biomarker analysis using paired biopsies (baseline, week 4) and surgical specimens. Results: The PK run-in (completed Fall 2024) enrolled 22 patients and assessed ENDX doses (40 mg daily vs 80 mg daily (+/-OFS)). The Week 4 Ki-67 ≤ 10% rate with ENDX was 86% and did not differ according to dose. Early safety, PK, efficacy and compliance data supported the selection of 40 mg ENDX daily as the optimal dose. Enrollment in Part 2 began in May 2025. Part 3 will replace Part 2 with simplification of the trial design. Conclusions: EVANGELINE is the first trial to evaluate (Z)-endoxifen + OFS as neoadjuvant therapy in premenopausal ER+/HER2- breast cancer. By targeting both ER and PKC pathways, ENDX may offer a well-tolerated alternative to AI-based regimens and expand endocrine therapy options for this population. Clinical Trial Registration: NCT05607004 Citation Format: M. P. Goetz, V. J. Suman, C. Lopez, H. Erickson, L. Beaulieu, S. S. Hammer, L. Mina, R. Leon-Ferre, K. N. Hunt, M. Piltin, A. Degnim, J. N. Ingle, J. C. Boughey, B. A. Sarah, J. M. Reid, M. Schellenberg, J. R. Hawse, P. Advani, K. Giridhar, F. Batalini, D. Flora, J. M. Jones, N. A. Bagegni, J. Jakub, V. Abramson, V. Dabak, W. J. Irvin, E. Sima, K. Seema, S. C. Quay. A Phase 2 Trial of (Z)-endoxifen + Goserelin as Neoadjuvant Treatment for Premenopausal Women with ER+, HER2-, Breast Cancer (EVANGELINE) [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 PS5-12-16.

Abstract Background: The association of TILs with pathologic complete response (pCR) and survival in HER2+ breast cancer is not well established with several prior studies showing inconsistent results. In this secondary analysis of EA1181, we evaluated the association between stromal TILs (sTILs) and pCR rates. Methods: EA1181 (NCT04266249) enrolled patients (pts) with anatomic clinical stage II/III HER2+ breast cancer who preoperatively received 4 cycles of trastuzumab and pertuzumab with 12 weeks of paclitaxel or docetaxel q3w x 4 (THP), followed by surgery. sTILs density was assessed on full-face hematoxylin and eosin (H&E)-stained tumor biopsy sections. sTILs scores were analyzed per protocol as a continuous variable (every 10% increment) and as a categorical variable (<10% vs 10-60% vs >60% as per Denkert et al, 2018), and also with an exploratory 30% cutoff commonly used in TNBC. Cox proportional hazards models were used to examine the association between sTILs and pCR, adjusting for available baseline factors. The associations between sTILs (by category) and clinicopathologic characteristics were examined using Fishers’ exact test. Results: Among 2141 pts with HER2+ BC treated on EA1181, H&E slides were available for 1328 (62%). The study population evaluated for sTILs was comparable to the overall population. pCR rates were 44.5% overall, 64% for HER2+/ER- and 33% for HER2+/ER+ disease. sTILs distribution was: 623 (47%) <10%, 698 (52%) 10-60%, and 7 (0.5%) >60%, which led us to merge the latter two groups (705 [53%] had ≥10% sTILs). In univariable and multivariable analyses, increasing sTILs (as a continuous variable) were associated with increasing pCR rates in both HER2+/ER+ and HER2+/ER- disease (p<0.001; Table). sTILs analyzed as a categorical variable (<10% vs ≥10%) were significantly associated with pCR for all patients (combined) and for those with HER2+/ER+ disease. In exploratory analysis using a cutoff of <30% vs ≥30% sTILs, an association with pCR was also seen in univariable analysis for both HER2+/ER+ disease (p<0.001) and HER2+/ER- disease (p=0.045), though in multivariable analysis with clinical factors, sTILs >30% remained a significant predictor for pCR only in HER2+/ER+ disease. Additional exploratory analysis with other molecular biomarkers, intrinsic subtypes, and immune signatures will be presented. Conclusion: sTILs were associated with pCR after THP, further supporting the important role of immune mechanisms in HER2+ breast cancer, and highlighting a potentially robust predictive tool to assess pathologic response. Baseline sTILs could potentially inform the preoperative design of future trials of therapy optimalization. Association of baseline sTILs with recurrence free survival in EA1181 will be reported in the future. Citation Format: S. S. Badve, F. Zhao, N. Tung, Y. Gokmen-Polar, C. C. O'Sullivan, A. Prat, E. P. Winer, J. L. Wright, A. Recht, A. C. Weiss, J. A. Tjoe, S. M. Feldman, G. B. Rocque, M. Smith, N. Unni, S. Sardesai, S. Tang, S. Modi, W. J. Irvin, P. Villagrassa, C. Battelli, A. K. Krie, N. Bagegni, M. A. George, M. L. Telli, V. F. Borges, N. D’Abreo, P. Shah, K. D. Miller, A. H. Partridge, L. A. Carey, A. M. DeMichele, A. C. Wolff, ECOG-ACRIN.Tumor infiltrating lymphocytes (TILs) and pathologic complete response (pCR) in stage II/III HER2+ breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): secondary results from the ECOG-ACRIN EA1181/CompassHER2 pCR trial [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 GS1-04.

Background: Susceptibility to cardiometabolic diseases (CDs) is shaped by genetic, socio-environmental, and lifestyle factors. We evaluated the associations of disease-specific polysocial risk scores (PSSs)— derived from social determinants of health (SDOH) and lifestyle factors—and genetic risk factors with six CDs, across self-identified race/ethnicity (SIRE) groups in the eMERGE IV cohort. Methods: The six CDs included: atrial fibrillation, coronary heart disease, chronic kidney disease, hyperlipidemia, obesity, and type 2 diabetes. Disease-specific PSSs were developed using machine-learning models based on 65 SDOH and lifestyle factors. Participants were grouped based on their SIRE as Asian, Black, Hispanic/Latino, and White. We evaluated PSS distributions across SIRE groups. Genetic risk was assessed through disease-specific polygenic risk scores (PRSs), monogenic etiologies, and family history (FamHx). High PSS and high PRS were defined as the top 5th percentile. Associations were tested using multivariable logistic regression; model performance was assessed using the C-statistic. Results: Among 20178 participants (50±15 years, 68% female, 40% non-White), the most frequently associated PSS components were physical activity, sleep, self-perceived health, and income. PSS distributions varied across SIRE groups, with Whites having the lowest and Black and Hispanic/Latinos the highest scores for most CDs (Figure 1). All PSSs were significantly associated with their respective CDs, independent of confounders (OR per 1 SD increase: 1.19–2.68; Figure 2-A). No significant interactions were observed between PSSs and PRSs or monogenic etiologies. However, significant interactions were noted between PSSs and FamHx for CKD and obesity. PSS and PRS effects on the odds of CDs were independent (Figure 2-B) and additive (Figure 2-C). Incorporating PSSs into models that included clinical and genetic risk factors improved predictive performance of risk prediction models (Figure 3). Conclusion: PSSs, reflecting socio-environmental and lifestyle disadvantage, varied significantly across SIRE groups and were associated with risk of six CDs, independent of and additive to PRS. Given the substantial variation in socio-environmental and lifestyle risks across SIRE groups, integrating these factors into risk prediction models for CDs may help address health disparities and enhance preventive efforts, especially in marginalized populations.

Background: We investigated the impact of genetic risk factors for coronary heart disease (CHD) -polygenic risk score (PRS), familial hypercholesterolemia (FH), and family history (FamHx)- on CHD risk estimates, across the age spectrum, in two diverse cohorts of US adults -eMERGE IV (eIV) and All of Us (AoU). Methods: CHD was defined as myocardial infarction, unstable angina, and coronary revascularization. Self-identified race/ethnicity (SIRE) was used as a population descriptor. We calculated a PRS for CHD (PRS CHD , PGS004698), ascertained FH as the presence of pathogenic/likely pathogenic variants in FH genes, and defined FamHx as early-onset CHD in first-degree relatives. We employed Pooled Cohort Equations (PCE) to estimate the 10y risk of CHD for adults ≥40y and modeled the association of conventional risk factors with CHD in adults <40y. AoU served as the training set, and eIV as the testing set. We analyzed the impact of PRS CHD and FamHx on CHD risk estimates by a) using multivariable logistic regression and Cox proportional hazard models, assessing discrimination and the extent of risk reclassification; and b) net benefit analysis and decision curves to assess the performance of prediction models across actionable thresholds. Results: We analyzed data for 19348 participants from eIV (age 50±15, 68% female, 41% non-White) and 239645 participants from AoU (age 55±17, 61% female, 48% non-White). Genetic risk factors were significantly associated with CHD. PRS CHD performance varied by SIRE groups, while FamHx was consistent. The effects of PRS CHD and FamHx on CHD were independent and additive (Figure 1). In adults ≥40y, incorporating PRS CHD and FamHx into PCE improved discrimination (C-statistic increased from 0.719 to 0.753; P -diff=9.1×10 -3 , Figure 2) and reclassified risk in 19% and 20% of participants at the 7.5% and 10% 10y CHD risk thresholds, respectively. Between the 7.5% and 10% 10y CHD risk thresholds, incorporating PRS CHD and FamHx into the PCE improved the net benefit of the risk prediction models across White, Black, and Hispanic/Latino groups (Figure 3). Conclusion: PRS CHD and FamHx were independently and additively associated with CHD in two large diverse cohorts in the US. Incorporating PRS CHD and FamHx into PCE improved risk discrimination, reclassified risk in a significant portion of participants, and improved net benefit of the PCE across all three major SIRE groups, motivating the addition of these factors to clinical risk calculators.

Background: The cumulative effect of repetitive subconcussive head impacts on neurocognitive function during youth contact sports remains largely unknown. There is a paucity of literature evaluating cumulative helmet forces over a season and their correlation with preseason and postseason cognitive performance tasks such as the King-Devick test (KDT). Hypothesis: Higher helmet forces recorded throughout a 10-week, 10-game youth football season would correlate with slower performance on postseason KDT. Study Design: Prospective cohort study. Level of Evidence: Level 3. Methods: A cohort of 58 youth football players (ages 9-13 years) underwent pre- and postseason KDT. Players wore SpeedFlex helmets (Riddell) fitted with InSite Impact Response System helmet accelerometers (Riddell) which recorded impacts of ≥15 g . Head impacts were tallied over a season and assigned a score of 1, 2, or 3 based on magnitude of g forces. Suspected concussions were correlated with KDT times and recorded instances of head impact. Pre- and postseason KDT scores were compared. Results: During the season, 2013 head impacts were recorded. Median (range) total cumulative force score was 24 (5-476); 6 players sustained head impacts concerning for concussion, and 4 were clinically diagnosed with concussions. Overall, postseason KDT times improved compared with preseason, with a median (range) change of −4.8 seconds (−7.6, −1.1). Analysis showed no correlation between changes in KDT time and total cumulative force score over the season. Conclusion: KDT times in youth football players did not change significantly based on head impact exposure over a single youth football season; most players’ KDT times improved from preseason to postseason. Clinical Relevance: Although our study did not show significant cognitive impact as measured by KDT over a single youth football season, the long-term effects of concussion on the immature brain and how it can impact cognitive development remains largely unknown and should be an area of ongoing study.