Leon-Ferre, R. A.

Abstract Background PARP inhibitors (PARPi) are active in patients (pts) with germline BRCA1/2 or PALB2 mutated (gBRCA1/2; gPALB2m) breast cancer (BC). Preclinical data suggest PARPi leads to intratumoral activation of the proinflammatory cGAS/STING pathway, recruiting CD8+ T cells, and sensitizing gBRCAm cancers to immune-targeted therapy. Prolonged preoperative treatment with PARPi monotherapy has demonstrated notable pathologic complete response (pCR) rates. The randomized phase II TBCRC 056 study evaluates the PARPi niraparib (N) with the anti-PD-1 antibody dostarlimab (D) as neoadjuvant treatment of gBRCAm or gPALB2mHER2-negative BC, with cohorts for both triple negative BC (TNBC, Arms A and B) and estrogen receptor positive (ER+) BC (Arm C). Results from Arms A and B are being presented. Methods Eligible pts (gBRCA1/2m/gPALB2m BC, T >1.0 cm, ER- (<10%), HER2-) were randomized to either Arm A: upfront combination N 200 mg orally QD and D 500 mg IV every 3 weeks (wks) for 18 wks (1 cycle = 3 wks), or Arm B: N monotherapy for 3 wks, followed by combination N plus D for 15 wks, with baseline (BL) and wk 3 tumor biopsies. After 18 wks, pts either underwent surgery or received additional preoperative systemic therapy (per MD choice) after an end of treatment biopsy if residual disease present. The primary study objectives are to evaluate pCR in Arms A and B combined, as well as change in stromal tumor infiltrating lymphocytes (sTILs) from BL to 3 wks in each Arm separately; 46 pts and a target pCR rate of 50% provides 85% power to reject the null hypothesis of pCR < 30%. Results A total of 46 pts with TNBC enrolled to Arms A and B (38 gBRCA1m (82.6%), 8 gBRCA2m (17.4%), 0 gPALB2m). Median age was 39.3 years (range 24.8-72.8); 84.8% self-reported White, 6.5% Black, 4.3% Asian, and 8.7% Hispanic. Clinical stage distribution was 37.0% stage I, 45.7% stage II, and 17.4% stage III; most had ER- BC (42 ER <1%, and 4 ER 1-10%). Among all pts, 38 (82.6%) completed the target number of cycles of D, with mean cycles received 5.1. Five pts discontinued D early (3 inadequate response/progression, 2 unacceptable AE: LFTs, rash). A total of 38 pts (82.6%) completed 6 cycles of N, with mean cycles received 5.7. Seven pts discontinued N early (3 inadequate response/progression, 4 unacceptable AE: LFTs, anemia, rash (2)). Most common AEs (> grade 2) with D+N were anemia (26.1%), fatigue (21.7%), hypertension (15.2%), hypothyroidism (15.2%), and neutropenia (15.2%). Most common Grade >3 AEs with D+N were anemia (17%) and neutropenia (6.5%). Among all pts, 23 (50%) had a pCR at surgery (90% CI 37.1% - 62.9%), 12 (26.1%) had residual disease (4 RCB-I, 5 RCB-II, 2 RCB-III, 1 RCB not calculable), and 11 (23.9%) crossed over to additional preoperative therapy. The pCR rate exceeded the protocol efficacy criterion of >43%, a significant increase over null hypothesis. pCR rates were the same on Arms A (50%, 90% CI 31.1% - 68.9%) and B (50%, 90% CI 31.9% - 68.1%). Among 15 pts on Arm A with evaluable sTILs at BL and 3 wks, mean sTILs at BL was 16% (range 1% - 40%), and at 3 wks was 27.4% (range 0.5% - 60%), for an average increase of 11.4% (p=0.009). Among 22 pts on Arm B with evaluable sTILs at BL and 3 wks, mean sTILs at BL was 19.5% (range 1% - 75%), and at 3 wks was 42.1% (range 1% - 85%), for an average increase of 22.7% (p=0.0003). Among all pts, BL sTILs (continuous) were significantly higher among those who achieved pCR than those who did not (median 15% vs. 5%, p=0.03). There was no relationship between pCR and BL PD-L1 score, or pCR and ER-0 vs. ER-low. Conclusions In pts with gBRCAm early TNBC, 18 wks of targeted therapy using PARPi and anti-PD1 agents, with or without 3-week PARPi lead-in, resulted in a pCR rate of 50%, and a statistically significant increase in sTILs from BL to 3 wks. Further ongoing correlative work may identify best candidates for this non-chemotherapy-based approach. Citation Format: E. L. Mayer, N. Graham, R. A. Leon-Ferre, M. Rozenblit, C. A. Santa-Maria, S. Isakoff, J. Specht, N. Tung, V. Abramson, J. Desrosiers, A. Schubert, B. Koca, S. M. Tolaney, E. P. Winer, I. E. Krop, A. C. Wolff, G. I. Shapiro, N. Tayob, J. L. Guerriero. Tbcrc 056: a phase 2 study of neoadjuvant niraparib with dostarlimab for patients with BRCA- or PALB2-mutated breast cancer: results from the TNBC cohorts [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 RF5-02.

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 Introduction: An Our Practice Advisory (OPA), formerly known as Best Practice Advisory (BPA), is an electronic health record (EHR) tool. OPAs identify key parameters to alert providers of potential interventions that could enhance quality of care. Such functionality is increasingly relevant given the rapid pace of new drug approvals. Within the Mayo Clinic system, we previously identified that amongst Mayo Clinic patients (pts) meeting the MonarchE criteria, 28% of pts did not undergo a documented discussion with their provider regarding the role of adjuvant abemaciclib (Premji, SABCS 2024). Further, a Flatiron study identified that only 40% of eligible pts received abemaciclib (Sandoval, Miami Breast 2025). To address this practice gap, in 2024 we began to implement EHR clinical decision support by creating an OPA trigger for pts eligible for an adjuvant CDK 4/6 inhibitor (CDK 4/6i). Here we report on ‘action taken’ versus not for the OPA and the most common reasons for re-prompts. Methods: The Mayo Breast Disease Group designed an OPA including pts who are within 14 months of a clinical or pathologic diagnosis of high-risk early-stage breast cancer. We leveraged structured data captured in the Epic staging forms (Epic Systems) to identify pts with clinical or pathologic T-stage, N-stage, grade, ± Ki-67/ multigene signature to identify ER+/HER2- pts eligible for adjuvant ribociclib or abemaciclib based on FDA approvals. The OPA was triggered by a patient encounter in oncology when endocrine therapy (but not CDK4/6i) was on the active medication list resulting in a hard stop. The OPA gathered limited details about whether adjuvant CDK4/6 inhibitors were discussed and whether the provider followed a link that resulted in prescribing one—considered an indicator of action taken. In this IRB-exempt quality improvement project, we describe the responses captured in the OPA trigger utilizing Epic tools. Results: The OPA went live on 1/10/2025. Over a 5-month period post OPA initiation, we identified 517 OPA alerts among 332 unique pts. Their median age was 62.5 years, and the majority were female (97%). The median time to resolve the OPA was 17.5 seconds (range 2-567 seconds). 12.6% (65/517) of the time there was ‘action taken’ by selecting the hyperlink to potentially start a treatment plan. Providers selected the following OPA pre-set responses: ‘re-prompt in one month’ 248 (48%), ‘patient not a candidate for therapy’ 48 (9%), ‘patient declines’ 69 (13%), ‘outside oncologist will prescribe’ 36 (7%), ‘not discussed’ 44 (9%), and unknown 72 (14%). The most common free text comments among the 517 OPA alerts (summarized) included: ‘revisit in future’ 108 (21%), ‘too early’ 65 (13%), ‘patient declines’ 66 (13%), ‘outside oncologist will start’ 31 (6%), ‘not a candidate’ 26 (5%), and ‘co-morbidities’ 18 (3%). Erroneous OPA prompting occurred in 14 (3%) who previously failed a CDK4/6i due to toxicity and in 18 (3%) for pts currently on a CDK4/6i. 30 (6%) OPA comments noted that they discussed or started therapy that day. Conclusion: The OPA offered clinical decision support and ensured that clinicians considered prescribing CDK 4/6i in all pts identified as eligible, and captured deferrals. Refinements are needed to ensure appropriate timing of OPA and minimize erroneous firing. The OPA remains active and captures the reason for deferral of adjuvant CDK 4/6i prescription. This data pairs real world decision making to better understand clinically meaningful application of improved invasive disease-free survival (iDFS). Citation Format: S. Premji, P. Advani, S. Chumsri, L. Mina, J. Taraba, J. Carroll, J. Hoppenworth, E. Cathcart-Rake, T. Haddad, B. Rudder, G. Choong, D. Idossa, C. O’Sullivan, S. Yadav, K. Ruddy, P. Peethambaram, T. Hobday, M. Goetz, R. Rao, B. Ernst, F. Batalini, R. Leon-Ferre, A. Tevaarwerk, K. Giridhar. Implementing an Our Practice Advisory (OPA) to provide clinical decision support for adjuvant CDK4/6 inhibitors in early-stage hormone receptor positive breast cancer: The Mayo Clinic Experience [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 PS5-11-10.

Abstract Introduction: Metaplastic breast cancer (MpBC) represents a rare subtype, constituting <1% of all breast cancer cases. It is pathologically characterized by epithelial and mesenchymal cellular components exhibiting a basal molecular pattern, hormone receptor and HER2-negativity, and high grade. Clinically, MpBC exhibits an aggressive course with early disease progression and poor survival. Antibody-drug conjugates (ADCs) have been shown to penetrate the central nervous system (CNS); however, little is known about the response of ADCs in MpBC, particularly in patients with CNS disease. Here we aimed to describe features of CNS disease in a subset of patients (pts) who received an ADC for MpBC . Methods: We conducted a multi-institutional retrospective observational study of pts with advanced MpBC treated with ADCs at 4 NCI-designated cancer centers (abstract #A-345). This analysis includes a subset of this cohort with CNS metastases, with the aim of examining the incidence, characteristics, and treatment patterns. Clinical outcomes were evaluated for pts with information available, including CNS median progression-free survival (mPFS; defined from initiation of systemic therapy to time of further documented CNS progression or death) and median real world PFS (rwPFS; defined from time of treatment initiation to documented disease progression or death). Results: We identified 48 pts with MpBC who received an ADC. Among them, we identified 15 (31%) who developed CNS metastases. Of these, the majority (n=11, 73%) had triple-negative breast cancer, and 4 (27%) had HER2-positive breast cancer. The median age was 50 years (32-75 years). The median interval from the initial MpBC diagnosis to CNS metastasis was 13 months (0-54 months). Excluding those with de novo CNS disease, the median interval from time of metastatic diagnosis to development of CNS metastasis [mets] was 3 months (0-22 months). 4 (27%) pts had de-novo metastatic disease, of which 2 (50%) presented with CNS disease. 4 (27%) pts had screening CNS imaging prior to their diagnosis of CNS metastatic disease. At the time of CNS disease diagnosis, 9 (60%) pts had oligometastatic intraparenchymal CNS disease (defined as <5 CNS mets), 5 (33%) had diffuse (>5 CNS mets) CNS disease, and 1 (6%) had leptomeningeal and intraparenchymal disease. Most pts 14(93%) with CNS disease were symptomatic at time of diagnosis. One pt underwent resection, 9 (60%) underwent stereotactic radiosurgery (SRS), 6 (40%) underwent whole brain radiation therapy (WBRT), and 1 pt received intrathecal chemotherapy with methotrexate. The median number of lines in the metastatic setting prior to documented CNS disease was 1 (range 0-3). The majority 13 (87%) underwent a change in systemic therapy at time of CNS disease diagnosis, with 60% changing to an ADC at the time of CNS diagnosis or progression. Among pts with progression of CNS disease warranting change in systemic therapy, the median time from first CNS event to further CNS progression was 6.5 months. Median CNS PFS was 3.5 months (range 1 -74 months) and median rwPFS was 4.4 months. For those patients who used ADCs after diagnosis of metastatic CNS diagnosis (12/15), median rwPFS was 4 months. Conclusions: Within this CNS sub-cohort study, we found that 31% of pts with MpBC developed CNS metastasis. The majority of pts had neurological symptoms at diagnosis, but most pts did not undergo routing screening for CNS disease. Given the high rate of CNS mets within a short timeframe from diagnosis with poor outcomes, CNS screening should be considered. The extremely short median CNS PFS and low median rwPFS of this cohort highlight the guarded prognosis associated with MpBC. Given the small sample size of this cohort, larger studies are warranted to validate these findings. Citation Format: S. Premji, S. Jacob, A. LeVee, S. Marion, S. Fisch, L. Huppert, J. Mortimer, D. Schmolze, A. Nayak, A. DeMichele, P. Shah, R. Leon-Ferre, D. Idossa. Central nervous system disease in patients with metaplastic breast cancer receiving antibody drug conjugates: a multi-institutional study [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 PS1-09-07.