Citations

Background/Objectives: We performed a systematic review of the current clinical and preclinical literature on the use of particle therapy, DDRi, and/or immunotherapy, specifically for pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, carbon) either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICI), or X-ray radiotherapy (XRT) in combination with DDRi/ICI. Results: In total, 133 studies met the inclusion criteria, including 62 clinical studies. Clinically, particle therapies show excellent local control and normal tissue sparing, with manageable toxicity profiles. Trials with any form of radiation and DDRi are few, potentially owing to toxicity concerns. ICI combinations showed promising efficacy with XRT, with no randomized trials comparing them to particle radiation. Conclusions: Particle radiation and/or DDRi have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increase response rates to immunotherapy (presented in the companion manuscript). Despite strong preclinical evidence and rationale, clinical trials including all three modalities are scarce. Existing evidence suggests a potential benefit based on extrapolation from photon-based studies and supports prospective evaluation with careful attention to treatment-related toxicity, which remains a concern.

Background Increased chronological age correlates with reduced relapse rates and increased disability in multiple sclerosis (MS). Biological age may better capture ageing’s impact on MS and might accelerate due to MS itself. Establishing accelerated biological ageing in adults is complicated by normal ageing and comorbidities. Telomere length, a well-recognised biological ageing marker, is shortened in adults with MS and associated with disability. Demonstrating accelerated biological ageing in paediatric-onset MS (POMS) would strengthen the hypothesis that MS drives premature biological ageing. This study aimed to determine if telomere length differs in POMS compared to age-similar healthy controls. Methods We performed a cross-sectional case-control study of whole blood samples and clinical data from The US Network of Pediatric MS Centers. Real-time quantitative PCR measured telomere length, expressed as a telomere to somatic DNA ratio (T/S ratio). T/S ratio was compared between cases and age-similar healthy controls using multivariate regression analysis adjusting for chronological age, sex, race, ethnicity, tobacco exposure, socioeconomic status and body mass index. Results We analysed 300 POMS cases and 200 controls. The unadjusted mean T/S ratios were 1.66 (SD 0.32) for cases and 1.71 (SD 0.29) for controls (mean difference –0.05, 95% CI –0.10 to 0.01, p=0.08). After adjusting for key covariables with face validity, POMS participants had a mean 0.086 shorter T/S ratio than controls (95% CI 0.015 to 0.157, p=0.018). Conclusions POMS participants demonstrated shorter telomeres than age-similar controls in a multivariable model adjusting for sociodemographic variables, suggesting that MS may contribute to accelerated biological ageing.

Abstract Background: Fatty Acid Synthase (FASN) is a key lipogenic enzyme co-regulated with HER2 and highly expressed in ER+ and HER2+ BC. Its targeting downregulates HER2 expression. Our preclinical studies revealed that FASN inhibition can sensitize or restore sensitivity to trastuzumab, paclitaxel and ET in HER2+ BC models. Denifanstat (deni, formerly TVB-2640) is a novel FASN inhibitor that demonstrated promising clinical activity and safety in a prior phase I trial as either monotherapy or in combination with paclitaxel. The primary objective of this study was to evaluate the objective tumor response rate (ORR) of deni plus trastuzumab (H) in combination with paclitaxel (T) or ET. Methods: Two independent, phase II clinical trials were initiated to assess the efficacy and safety of deni plus H in combination with T (Cohort A) or ET (Cohort B). Key inclusion criteria included HER2+ MBC resistant to HER2-directed therapy, measurable disease, unlimited ET, ≤6 prior chemotherapy or antibody drug conjugate regimens, and confirmation of HER2+ MBC on a pre-registration biopsy. Deni was administered 100 mg/m2 orally once daily. HP or H plus ET (fulvestrant or aromatase inhibitor) was administered at standard dose and schedule. Blood was collected on Cycle 1 Day 1 (C1D1), C1D8 and C2D1 for serum FASN analysis. An additional MBC tumor biopsy was collected on C2D1 for correlative studies. A 2-stage Simon design with a safety-run in was used to test the null hypothesis that the true ORR is at most 5% against the alternative it is at least 20%. With a sample size of 32 patients (pts) per cohort, if ≥4 responses are seen, this design has a 90% chance of rejecting the true ORR is <5% when the true ORR is ≥20% at a 0.10 level of significance. The decision to close both trials to enrollment early was multifactorial. Results: From August 2017 - February 2024, 33 pts with HER2+ MBC pre-registered, among which 17 were eligible and 16 were evaluable (15 pts in Cohort A and 1 pt in Cohort B). The most common reason for ineligibility was HER2-negative status on central review of the pre-registration biopsy. Median age was 57 years (range 35-80). All pts were non-Hispanic and 13 (81.3%) were White. Median prior lines of therapy was 5 (range 0 - 11). In Cohort A, there were 5 partial responses; thus, the primary endpoint was met with the ORR estimated to be 33.3% (90% CI: 14.2-57.7%). The median PFS time was 7.0 months (95 %CI: 3.7 - 11.3), and median OS was 25.7 months (95%CI: 10.2 - NE). No dose limiting toxicities were observed during the C1 safety run-in (6 pts). In Cohort A, 7 (46.7%) developed a grade 3 or 4 adverse event (AE) attributed to combination therapy. Grade ≥2 AEs regardless of attribution occurring in ≥20% of all pts included anemia, fatigue, neutropenia, palmar plantar erythrodysesthesia (PPE), and peripheral neuropathy. Treatment was discontinued due to progression (12; 80%) or AE (3; 20% - pneumonitis; neuropathy; PPE). In Cohort B, the pt maintained stable disease through 8 cycles with grade 3 ALT increase, and she remained alive 31.2 months post-registration. Median C1D1 FASN level was 32.7 ng/mL (IQR: 18.7 - 49.6 ng/mL). There was minimal association between C1D8 and C2D1 FASN levels and time to disease progression (C1D8 n=9, Spearman rank correlation coefficient (r s) = 0.040; C2D1 n=13, r s = -0.019). Analyses of changes in MBC tumor expression of FASN, phospho-AKT, and phospho-S6 are in progress. Conclusion: Deni combined with HP provided clinical antitumor activity in pts with HER2+ MBC resistant to trastuzumab. Expected paclitaxel-associated AEs were observed. Nearly half of pts experienced a grade 3 or 4 AE attributed to the combination therapy, and 20% stopped treatment due to AE. Further study of deni, H plus ET is necessary to draw safety and efficacy conclusions. Citation Format: T. C. Haddad, V. J. Suman, R. R. Roa, B. J. Ernst, R. Lupu, T. Vander Steen, M. H. Solanki, M. Keeney, D. W. Northfelt, K. S. Anderson, T. J. Hobday, S. Chumsri, J. E. Hoppenworth, J. L. Carroll, K. V. Giridhar, C. C. O’Sullivan, R. A. Leon-Ferre, M. P. Goetz. Phase II Trial of the FASN Inhibitor, Denifanstat (TVB-2640), Plus Trastuzumab in Combination with Paclitaxel or Endocrine Therapy (ET) in Patients with HER2+ Metastatic Breast Cancer (MBC) Resistant to Trastuzumab [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 PS5-01-16.

Abstract Background: Two years of adjuvant abemaciclib plus endocrine therapy is approved and guideline-recommended in patients (pts) with HR+, HER2-, node-positive, early breast cancer (EBC) at high risk of recurrence. In initial real-world studies, the high rate (>85%) of treatment (tx) persistence beyond 3 months suggests that adjuvant abemaciclib is well-tolerated in routine clinical practice.1,2 Dose reductions were associated with higher persistence in prior studies and clinical trial data have shown that efficacy of abemaciclib was maintained with dose reductions. This study describes 6-month tx persistence and dosing patterns in pts with HR+, HER2-, node-positive EBC initiating abemaciclib 150 mg twice daily (BID). Methods: Retrospective data were accessed from the US de-identified Flatiron Health Research Database. Adults with HR+, HER2-, node-positive, EBC, who initiated abemaciclib 150 mg BID from Jan 2022-Jun 2024 were eligible and further characterized by ≥1 vs no dose reduction. Data cut-off was Dec 2024. Persistence rate was the proportion of pts on abemaciclib >6 months, allowing for ≤60-day medication gap within this period. Time to dose modifications and reasons for discontinuation (DC) were summarized. Subgroup analyses were conducted in pts confirmed as meeting the monarchE high-risk criteria (N2, N3, or N1 plus Grade 3 and/or tumor >5 cm). All analyses were descriptive. Results: Of 1063 eligible pts, median age was 56 years (IQR 47, 65). Most had N1 (48%) or N2 (34%) disease. Median follow-up was 17.5 months (IQR 11, 25). Tx persistence at 6 months was 75%. DC was mostly due to adverse events (AEs; 19%) and <1% due to recurrence. Approximately 50% of pts had ≥1 dose reduction. Persistence was 85% in pts with ≥1 dose reduction and 64% in pts with no dose reductions. 70% of pts who DC’d by 6 months did not have a dose reduction. Median time from start of abemaciclib to first dose change and/or hold was 49 days (IQR 23, 111). During the first 30 days of tx and Days 31-90, DCs due to AEs were lower in pts with dose reductions vs pts with no dose reductions (Table). Persistence and use of dose reductions were similar in pts confirmed as meeting the monarchE high-risk criteria. Conclusion: In US clinical practice, a majority (75%) who initiated adjuvant abemaciclib continued abemaciclib beyond 6 months. Tx persistence was higher among pts with dose reductions relative to those with no dose reductions, and rates of early DCs due to AEs were low in pts with dose reductions. Given that dose reductions in monarchE were not associated with reduced efficacy, these additional real-world data support the use of early dose modifications to improve tolerability and tx persistence for adjuvant abemaciclib in pts with high risk of recurrence. Citation Format: H. Soliman, S. Dent, A. Liepa, V. Stefaniak, M. Huang, T. Sugihara, K. Moreira, K. Hudson, M. Goetz. Treatment Persistence and Dose Modifications in US Patients with HR+, HER2-, Node-Positive, Early Breast Cancer Treated with Adjuvant Abemaciclib [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 PS5-05-09.

Abstract As shown by the TAILORx and RxPONDER trials, recurrence score (RS) identifies many postmenopausal pts who do not benefit from addition of ACT to endocrine therapy (ET); however, it also identifies certain subsets of premenopausal pts who do benefit (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25). Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, we question whether the noted ACT benefit in TAILORx/RxPONDER may have been the result of chemotherapy-induced OFS. To address this, we developed OFSET, a phase III clinical trial comparing OFS+ET v ACT+OFS+ET. We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI) per physician discretion; or tamoxifen if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per protocol guidelines. The HRQOL substudy will assess differences between arms in severe menopausal symptoms (measured by FACT ESS-19) and pain severity (PROMIS). Blood and tumor specimens will be collected for future research. We anticipate accrual of 3,960 pts in 7 yrs, 7 mos. Per NSABP B-28/RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ∼95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with 1-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ∼11 yrs after study initiation. Accrual is 292/3,960 (from 8/2023 to 5/2025). Among 148 pts with OFS data available, 79 (53.4%) were prescribed goserelin and 69 (46.6%) leuprolide. A monthly dosing schedule was prescribed for 86.1% of pts receiving goserelin and 73.5% of those receiving leuprolide; the remaining received a 3-monthly schedule. NCT05879926 Support: U10 CA180868, -80822, UG1 CA189867, U24 CA196067 Citation Format: S. Swain, G. Tang, S. L. Puhalla, P. A. Ganz, N. L. Henry, R. S. Cecchini, S. A. Reid, P. Rastogi, C. E. Geyer, Jr., J. R. White, A. S. Clark, T. C. Haddad, G. A. Vidal, N. Wolmark, E. P. Mamounas. NRG-BR009: A phase III trial evaluating addition of adjuvant chemotherapy to Ovarian Function Suppression + Endocrine Therapy in premenopausal women with pN0-1, HR+/HER2- breast cancer and recurrence score ≤25 (OFSET) [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 PS5-07-04.

Abstract Background: Most patients with estrogen receptor-positive (ER+), metastatic breast cancer (mBC) treated with endocrine therapy (ET) will ultimately develop resistance. A large unmet need exists especially when resistance occurs following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), which is potentially driven by a mutation in the ERα-coding gene, ESR1. Lasofoxifene (LAS), an oral, next-generation ET and ER breast antagonist, was evaluated in two phase 2 studies of women with ER+/HER2- mBC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. In the ELAINE 1 trial, LAS monotherapy provided numerically greater progression-free survival (PFS, median 5.6 mos vs 3.7 mos; HR: 0.669 [95% CI, 0.445‒1.125], P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) compared with the ER degrader fulvestrant (fulv), with a favorable safety profile (Goetz MP et al. Ann Oncol 2023;34:1141‒51). The single-arm, ELAINE 2 trial showed that LAS combined with abemaciclib (Abema) was well tolerated with a median PFS of ∼13 mos, ORR of 56%, and CBR of 66% (Damodaran S et al. Ann Oncol 2023;34:1131‒40). The phase 3, registrational, ELAINE 3 trial was initiated based on these promising earlier-phase data. Recent results from postMONARCH confirmed superior efficacy of fulv/Abema over fulv/placebo (mPFS 6.0 mos vs 5.3 mos, HR 0.73 [0.57‒0.95], nominal P-value 0.017) in non-biomarker‒selected, mBC patients after progression on a prior CDK4/6i and aromatase inhibitor (AI), with similar HR in an ESR1-mutated cohort (Kalinsky K et al. J Clin Oncol 2025;43:1101‒12). Additionally, recent data from EMBER-3 demonstrated meaningful PFS with a novel ET combined with abemaciclib after progression on AI/CDK4/6i (Jhaveri KL et al. N Engl J Med 2025;392:1189‒202). The ELAINE 3, global trial will compare LAS/Abema with fulv/Abema in a post-CDK4/6i, ESR1-mutation‒selected, mBC population. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of LAS plus Abema versus fulv plus Abema. Patients are being enrolled at approximately 152 sites in 13 countries (Australia, Belgium, Canada, China, France, Italy, Israel, Poland, Romania, Spain, Taiwan, United Kingdom, United States). Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an AI plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive LAS 5 mg/day plus Abema 150 mg BID, or fulv 500 mg IM (days 1, 15, and 29, then once monthly) plus Abema 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS per RESIST 1.1 by blinded independent central review (BICR); key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Safety, time to cytotoxic chemotherapy, and quality of life (including vaginal health) will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected for genomic analyses at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit. Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test with an expected PFS hazard ratio of 0.68 at final analysis. Enrollment is currently ongoing to meet the target sample size of 500 patients. Citation Format: M. P. Goetz, S. A. Wander, T. Bachelot, G. Curigliano, A. de Nonneville, E. N. Gal-Yam, K. Jhaveri, S. L. Sammons, S. Shen, C. J. Twelves, G. Gasper, P. V. Plourde, D. J. Portman, S. Damodaran. Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation [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 PS5-07-30.

Abstract Background: Despite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in breast cancer and other solid tumors due to lack of targets that distinguish tumor from normal cells. Epithelial growth factor receptor (EGFR) plays a critical role in oncogenesis across several cancers and is often upregulated [1]. While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin and gastrointestinal toxicity, which constrains dose escalation and efficacy [2]. A2B395 is an allogeneic, logic-gated, EGFR-targeted, TmodTM CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR and a blocker targeting human leukocyte antigen (HLA)-A*02. The activator recognizes EGFR on both tumor and normal cells, whereas the blocker inhibits CAR T activity against normal cells (with preserved HLA expression) while allowing activation against tumor cells (with HLA-A*02 loss of heterozygosity [LOH]). This approach is designed to avoid on-target, off-tumor toxicity, a significant limitation to CAR T treatment of solid tumors [3]. To address potential graft-vs-host response, a short-hairpin RNA expression module targeting beta-2 microglobulin is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response [4]. Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy [5]. A2B395 represents a novel approach for targeting EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity. Methods: DENALI-1 is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA loss of heterozygosity at any time in the course of their disease via next-generation sequencing. Key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including triple-negative breast, colorectal, non-small cell lung, squamous cell head and neck, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of the phase 1 portion is to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D) using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm the RP2D and collect and analyze biomarker data. The Phase 2 portion will assess overall response rate per RECIST v1.1. As of 03 July 2025, the first patient dosed with A2B395, who has breast cancer, completed the 28-day safety review period. Dose-escalation is ongoing. Citation Format: J. M. Specht, S. R. Punekar, M. Ulrickson, D. J. Wong, J. R. Hecht, M. Maus, P. M. Grierson, J. B. Sunwoo, J. R. Molina, D. G. Maloney, K. Spencer, H. E. Fuentes Bayne, M. Davila, S. P. Patel, B. Creelan, D. B. Zhen, J. Niu, D. C. Prasad, R. L. Marar, N. A. Bagegni, G. Palluconi, J. Lee, A. Mardiros, W. Bretzlaff, W. J. Langeberg, J. S. Welch, E. Ng, W. Y. Go, K. Kirtane, R. A. Shatsky. Denali-1: a seamless phase 1/2 study of A2B395, a logic-gated, allogeneic, Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with triple-negative breast cancer and other EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity (LOH) [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 PS5-08-03.

Abstract Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy (ET), freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after breast-conserving surgery (BCS) and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for IBR and breast preservation in women intending ET for stage 1 invasive breast cancer (ER and/or PR-positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (≤11, >11-18/MammaPrint Low). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (moderate or ultra hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER and/or PR-positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS ≤18 (diagnostic core biopsy or resected specimen). A “low risk” MammaPrint is permissible if completed as part of usual care prior to screening. Primary endpoint is IBR (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% v 91.6% for the omission-of-RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1%/yr. Some T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. As of July 9, 2025, 1,490 pts have been screened and 1,349 randomly assigned. NCT #: NCT04852887 Support: U10 CA180868, -180822, U24 CA196067, UG1 CA189867 Citation Format: J. R. White, R. S. Cecchini, E. E. Harris, E. P. Mamounas, J. G. Bazan, D. G. Stover, P. A. Ganz, R. Jagsi, S. J. Anderson, C. Bergom, V. Théberge, M. B. El-Tamer, R. C. Zellars, D. A. Shumway, G. Chen, T. B. Julian, N. Wolmark. A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007 [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 PS5-08-20.

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: Breast cancer (BC) chemoprevention with selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) remains underutilized among high-risk women. Improving knowledge about BC risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this BC risk reduction strategy. Methods: We conducted a cluster randomized controlled trial to evaluate the effectiveness of web-based patient and provider decision support, RealRisks and BNAV, to improve chemoprevention informed choice among women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS). Thirty-one sites, including academic and community practices across the U.S., were randomized to standard patient educational materials alone or combined with RealRisks and BNAV. A total of 412 patients and 210 healthcare providers were enrolled. Patient surveys were administered at baseline, 6 and 12 months. The primary outcome at 6 months was chemoprevention informed choice, defined as adequate chemoprevention knowledge and attitudes congruent with decision. Secondary endpoints included BC risk perceptions, worry, chemoprevention knowledge, decision conflict and chemoprevention decision. Assuming 10% loss to follow up (LTFU), roughly equal accrual across sites, and an intraclass coefficient (ICC) of 0.02, we had 90% power to detect a 15% absolute difference in informed choice if the event rate in the control arm was 10%. Results: Among 24 evaluable sites, 14 were randomized to the intervention arm and 10 to the control arm. Among 210 enrolled providers, median age was 46 (range, 28-83) and 78% were female; 75% physicians and 25% advanced practice providers/nurses; 53% medical oncologists, 29% surgeons, and 10% gynecologists/family practitioners/internists; and 83% had previously prescribed chemoprevention. Among 412 enrolled patients, median age was 53 (range, 35-74), including 77% White, 8% Black, and 10% Asian race, and 14% Hispanic ethnicity. In terms of BC risk factors, 77% had AH and 23% LCIS, 34% had a first-degree family history of BC, and 65% had heterogeneously or extremely dense breasts on mammography. Thirty percent were unevaluable for the primary endpoint (1% ineligible, 26% LTFU, 3% missing data). Among 288 evaluable patients (148 at intervention sites, 140 at control sites), the proportion of patients exercising informed choice at 6 months in the intervention and control arms was 35% vs. 27%, respectively (odds ratio [OR]=1.44, 95% confidence interval [CI]=0.84-2.46, p=0.19; observed ICC=0.006). Compared to patients in the control arm at 6 months, those in the intervention arm were more likely to have accurate BC risk perceptions (OR=1.80, 95% CI=1.11-2.91) and adequate chemoprevention knowledge (OR=1.62, 95% CI=1.00-2.61). We observed no significant differences in BC worry, decision conflict, or chemoprevention decision between study arms. At 6 months, 49% of women in the control arm and 51% in the intervention arm decided to take a SERM or AI for BC chemoprevention (p=0.58), a rate higher than anticipated. Conclusions: We did not observe a significant increase in informed choice among patients and providers assigned to chemoprevention decision support compared to standard educational materials alone. Among women with AH or LCIS seen mainly by breast specialists who prescribed chemoprevention, about half decided to take a SERM or AI. Therefore, relatively high chemoprevention uptake may be achieved among women with high-risk breast lesions managed by breast specialists. Chemoprevention decision support may improve decision antecedents, such as accurate BC risk perceptions and chemoprevention knowledge, but may have a limited role in changing health behaviors. Citation Format: K. D. Crew, G. L. Anderson, K. B. Arnold, A. Michel, M. T. DeLucie, C. W. Law, S. Pruthi, A. C. Sandoval Leon, R. Shirley, M. T. Grosse Perdekamp, S. V. Colonna, S. L. Krisher, T. King, L. D. Yee, T. J. Ballinger, C. Braun-Inglis, D. A. Mangino, K. B. Wisinski, C. A. DeYoung, M. Ross, J. D. Floyd, A. Kaster, L. VanderWalde, T. Saphner, C. Zarwan, S. Lo, C. Graham, A. K. Conlin, K. J. Yost, D. M. Agnese, C. Jernigan, D. L. Hershman, M. L. Neuhouser, J. A. Zell, B. Arun, R. Kukafka. Making informed choices on incorporating chemoprevention into care (MiCHOICE): Cluster randomized controlled trial of decision support for breast cancer chemoprevention, SWOG 1904 [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 PS3-01-15.