Mina, Lida A.

A 64-year-old Asian woman diagnosed with synchronous breast ductal carcinoma in situ (DCIS) and stage IV EGFR-mutated non-small cell carcinoma of the lung (NSCLC). A decision was made to defer management of the DCIS and initiate Osimertinib for lung cancer treatment, since this was a life-limiting diagnosis. At 9 months, restaging FDG-PET CT showed an interval response in the NSCLC and complete loss of FDG avidity at the biopsy-proven DCIS site. Breast MRI confirmed complete imaging resolution of the DCIS. The clinical resolution of breast DCIS during third-generation EGFR inhibitor therapy has not been previously reported in humans and highlights a potential role for the EGFR/HER2 (ERBB) pathway in pre-invasive 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 .

639 Background: Large cohort studies have shown a survival benefit with the use of GLP1 receptor agonists (GLP1 RA) in cancer patients. The impact of GLP1 RA usage in breast cancer (BC) and the different subtypes is unknown. To investigate the potential influence of GLP1 RA usage on BC survival, a study was conducted on a large institutional database. Methods: A de-identified institutional database identified newly diagnosed Stage I, II, and III BC patients from 2005 to present and use of GLP1 RA. The study compared survival rates for BC patients with and without GLP1 RA and further stratified by BC subtype [ER+HER2-, HER2+, ER-PR-HER2-(triple negative BC (TNBC))], BMI, and age. Kaplan-Meier survival curves were used to estimate overall survival. This study analyzed de-identified data accessed through Mayo Clinic Platform Discover. Per 45 CFR 46.102, this activity did not require IRB review. Data was extracted using an established privacy-preserving protocol and de-identified via expert determination under the HIPAA Privacy Rule. Raw EHR data and other unreported data cannot be shared due to de-identification parameters. Results: 88015 BC patients were identified, of which 3919 (4.5%) received GLP1 RA. The 5-year survival rate was 98.5% with vs 85.5% without GLP1 RA (p-value <0.0001). The survival benefit persisted for different BMI’s and ages: BMI >30 (98.4% vs 85.1%), >25 (98.4% vs 85.4%), and age <50 (99.5% vs 89.3%) and >50 (98.1% vs 84.8%) [all p<0.0001]. 21770 patients with ER+ disease were identified, of which 1412 (6.5%) received GLP1 RA. The 5-year survival rate was 99.0% vs 87.7% (p-value <0.0001). The survival benefit persisted by BMI and age: BMI >30 (99.0% vs 86.2%), >25 (98.9% vs 87.1%) and age <50 (99.6% vs 90.5%) and >50 (98.7% vs 87.2%) [all p<0.0001]. 3599 patients with HER2+ disease were identified, of which 202 (5.6%) received GLP1 RA. The 5-year survival rate was 99.3% vs 80.1% (p-value <0.0001). The survival benefit persisted by stratification: BMI >30 (100.0% vs 80.0%, p-value <0.0004), and <25 (97.7% vs 76.2%, p-value <0.019), and age <50 (100% vs 87.0%, p-value <0.043) and > 50 (99.0% vs 77.2%, p-value <0.0002). 8389 patients with TNBC disease were identified, of which 360 (4.3%) received GLP1 RA. The 5-year survival rate was 91.0% vs 71.9% (p-value <0.0001). The survival benefit persisted by stratification: BMI >30 (96.4% vs 72.9%, p-value <0.0001), >25 (93.2% vs 71.8%, p-value <0.0001), and age <50 (96.0% vs 73.0%, p-value <0.0028) and >50 (88.9% vs 71.8%, p-value <0.0001). For those TNBC patients who received GLP1 RA, having a BMI >30 conferred a protective effect with a 5-year survival rate was 97.9 vs 89.8% (p-value <0.0014). Conclusions: The study suggests that GLP1-RA improves 5-year survival rates of patients with BC and this applies to all subtypes of BC. These results suggest that further study of the impact of GLP1-RA on BC patients is warranted.

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 &gt; 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 &gt; 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 &gt;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&gt; 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&gt;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.

Pleomorphic adenoma of the breast is a rare tumor, with fewer than 100 patients described in the English literature, mainly as case reports and small case series. Histologically, breast pleomorphic adenoma resembles its more common salivary gland counterpart; however, it can present diagnostic challenges, particularly on core needle biopsy and fine-needle aspiration. The differential diagnosis includes benign and malignant tumors, which carry major treatment implications, from the extent of surgical intervention to the potential use of chemotherapy. Herein we describe a tumor that was initially diagnosed as a triple-negative matrix-producing metaplastic carcinoma, but a secondary review led to the diagnosis of pleomorphic adenoma of the breast. Prior to the secondary review, the patient underwent an excisional biopsy, sentinel lymph node biopsy, and one round of chemotherapy. This report adds to the limited literature surrounding this entity and discusses the differential diagnosis along with histopathologic and immunohistochemical findings that aid in the diagnosis and reviews the radiologic findings observed throughout the patient's clinical course. This patient underscores the difficulty of diagnosis and highlights the need for multidisciplinary consideration and communication to avoid overtreatment.

1089 Background: T-DXd has become an important treatment option in mBC and other malignancies. Interstitial lung disease/pneumonitis (ILD) occurred in 10-14% of pts in the DESTINY-Breast trials (0-2% G5 ILD), and with potential lower incidence/severity in earlier line settings (Krop et al, ASCO 2023). We previously reported the Mayo Clinic Rochester, MN experience with T-DXd related ILD in mBC (Hoppenworth et al, ASCO 2024). Here, we expand the data to include patients treated at all locations of the Mayo Clinic Enterprise. Methods: We retrospectively identified pts with mBC who received ≥1 dose of T-DXd across the Mayo Clinic enterprise (Rochester, MN; Mayo Clinic Health System locations in MN/WI; Scottsdale, AZ; and Jacksonville, FL) between July 2022-December 2023. Demographic, mBC characteristics, and pulmonary clinical variables were abstracted from the clinical records. Data were summarized using descriptive statistics. Diagnosis of ILD was determined by treating clinicians, and severity was approximated to CTCAE V5 based on clinical documentation. Results: 252 pts with mBC received T-DXd during the study period. The majority were Caucasian (86%) and female (99%) with a median age of 63. 91 pts (36%) were current/formers smokers and 97 (39%) had prior pulmonary comorbidities. The majority had HER2 low (155, 62%) and HR positive (164, 65%) mBC. 35 (14%) developed any grade ILD [G1: 6 (17%), G2: 13 (37%), G3: 3 (8.6%), G4: 3 (8.6%), G5: 10 (29%)], with 15 (43%) presenting with ≥G3. 29 (83%) presented with at least 1 symptom (cough or SOB). Among those with previous pulmonary toxicity, 4 (33%) had previous pneumonitis in the ILD cohort. The median prior lines of all therapies (including endocrine therapy) were 5, with a median of 3 prior lines of chemotherapy in both the ILD (range 1-13) and non-ILD cohorts (range 1-13). Median onset to any grade ILD was 7 cycles. 20 pts (57%) received steroids for ILD. 14 (40%) had a bronchoscopy, all had a CT chest, 16 (46%) were hospitalized, 7 (20%) were intubated and 1 (3%) had a lung biopsy. Pts with G5 ILD had a median of 3 lines of chemo and a median of 8 cycles prior to onset of ILD, compared to 3 lines of chemo and a median of 7 cycles for those with G1-4 ILD. G5 pts were all Caucasian females, 5 were former smokers, 5 were non-smokers, 1 had a history of pneumonitis. T-DXd was rechallenged in 4 pts (G1-2 ILD) without ILD recurrence. Conclusions: In this retrospective case series,14% of pts treated with T-DXd experienced any grade ILD (4% G5) which is in alignment with the rate observed in the pivotal DESTINY-Breast trials, though with higher rates of G5 toxicity. Among those with ILD, increased lines of therapy were not associated with increased risk. Further research is needed to correlate risk.

Abstract The Phase 2 IMPRIME 1 study evaluated the combination of the pathogen-associated molecular pattern (PAMP) Imprime with the immune checkpoint inhibitor (ICI) pembrolizumab as second or later line of treatment (2 L+) for patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients with mTNBC received weekly Imprime (4 mg/kg) intravenously in combination with pembrolizumab (200 mg every 3 weeks). Primary endpoints were overall response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression free survival (PFS), and overall survival (OS). Exploratory endpoints included correlations between immune cell activation markers in tumor tissues and blood and response to therapy. Of the 42 evaluable patients, six had a response (one complete, five partial), with an ORR of 14.3% by RECIST v1.1. Median PFS was 2.7 months, median OS was 16.4 months, and DCR was 54.8%, with responders achieving a median DoR of 15.2 months. Therapy was generally well tolerated and resulted in an increase of immune activation markers, with higher levels of activation in peripheral blood associated with response and improved survival. The combination of Imprime and pembrolizumab was safe and demonstrated immune activation in tumor tissues and peripheral blood in patients with TNBC. Improved response rates were observed compared to historical studies of ICI monotherapy in similar patient populations. Study number (ClinicalTrials.gov trial registration): NCT02981303.

Abstract Background: Endocrine therapy (ET) with aromatase inhibitors (AI) plus ovarian function suppression (OFS) is standard for premenopausal women with ER+/HER2- breast cancer. However, many premenopausal women are intolerant of AI + OFS, leaving tamoxifen (with or without OFS) as their only option. Extensive studies have demonstrated that premenopausal women treated with neoadjuvant ET whose tumors exhibit Ki-67 ≤ 10% following 4 weeks of therapy (defined as endocrine sensitive disease (ESD)) achieve 5-year distant disease-free survival &gt; 96%. Problematically, only 41% of patients reach this ESD threshold with tamoxifen compared to 78% with AI+OFS (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent selective estrogen receptor modulator (SERM) that inhibits ERα at plasma concentrations of 3-5 ng/ml and dually targets PKCβ1, a suspected oncogene in breast tumors, at concentrations ≥ 500 ng/ml. We therefore developed the EVANGELINE study (NCT05607004) is an open label, randomized neoadjuvant phase II study that includes a pharmacokinetic (PK) Run-in, aiming to evaluate whether ENDX +/- goserelin is non-inferior to exemestane plus goserelin with respect to ESD rate. Following the completed PK run-in portion of the study, where 40mg/day or 80mg/day ENDX were assessed, the 40 mg/day dose was selected for further evaluation in the second part of the trial. The second part is comprised of a randomized treatment cohort, for patients with a Ki-67% &gt;10% at preregistration randomized to either 40mg (Z)-endoxifen + goserelin or exemestane + goserelin neoadjuvant treatment and a Single Arm Treatment Cohort for patients who have a Ki-67 ≤ 10% at pre-registration assigned to 40mg/day (Z)-endoxifen monotherapy neoadjuvant treatment. Methods: To investigate ENDX further in premenopausal women, a multicenter study in the United States, was designed(EVANGELINE; NCT05607004). This phase 2, open-label, randomized, neoadjuvant trial includes a PK run-in phase designed to assess whether the 4-week ESD rate with (Z)-endoxifen + goserelin is non-inferior to that of exemestane + goserelin in premenopausal women with Stage IIA or IIB ER+/HER2- breast cancer with diagnostic Ki67 &gt; 10%. Additionally, a single arm Phase 2, open-label neoadjuvant Cohort was designed to assess the 4-week ESD rate with ENDX monotherapy in premenopausal women with Stage IIA or IIB ER+/HER2- BC with diagnostic Ki67 ≤10%. Subjects will undergo neoadjuvant treatment for six months before receiving surgical treatment in the involved breast. This study will additionally assess safety, tolerability, response rates, surgical outcomes, and monitor disease progression. Comprehensive biomarker evaluations will be conducted using paired tumor biopsies and blood samples collected at baseline and week four, as well as 6 month surgical specimens. Enrollment in the PK run-in phase (n-22) was completed in Fall 2024 with the second portion of the trial slated to begin early in 2025. Citation Format: Matthew P. Goetz, Vera J. Suman, Claudia Lopez, Hayley Erickson, Lonnissa Nguyen, Sandra S. Hammer, Lida Mina, Pooja Advani, Roberto Leon-Ferre, Karthik Giridhar, Felipe Batalini, Daniel Flora, Jason M. Jones, Nusayba A. Bagegni, Katie N. Hunt, Mara Piltin, Amy Degnim, James N. Ingle, Judy C. Boughey, Sarah A. Buhrow, Joel M. Reid, Matthew Schellenberg, John R. Hawse, Steven C. Quay. A randomized phase 2 non-inferiority trial of (Z)-endoxifen + goserelin and exemestane + goserelin as neoadjuvant treatment for premenopausal women with ER+/HER2- breast cancer (EVANGELINE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT237.

Abstract One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.