Chumsri, Saranya

564 Background: HER2+ ILC is rare (~5% of ILC), with limited data on long-term adjuvant trastuzumab outcomes. We investigated late recurrence and immune landscapes of HER2+ ILC vs invasive ductal carcinoma (IDC) in the phase III NCCTG N9831 trial (NCT00005970) and a real-world cohort. Methods: We evaluated 3304 early-stage HER2+ breast cancer patients (pts) enrolled in N9831 (122 ILC, 3182 IDC). Recurrence-free survival (RFS) and overall survival (OS) were estimated (Kaplan-Meier) and compared using multivariable Cox regression adjusting for age, tumor size, grade, hormone receptor (HR), and nodal status. Findings were validated in a real-world cohort of HER2+ pts (Caris Life Sciences CODEai platform). Immune microenvironments were profiled by WTS deconvolution (Quantiseq). Real-world overall survival was calculated from trastuzumab start to last contact. Results: In N9831, ILC pts were older (median 54 vs 49 y), more ER+ (74.6% vs 51.4%), and had more N3 disease (25.4% vs 12.7%) compared to IDC. ILC pts derived a comparable magnitude of benefit from adjuvant trastuzumab compared to the overall population (HR 0.58 vs 0.67). However, long-term outcomes diverged: while the 5-year RFS was similar (77.1% vs 82.7%), ILC pts experienced a steep decline between years 5-15 (77.1% to 57.7%; ~20% decline) vs IDC (82.7% to 72.7%; ~10% decline) after multivariable Cox analysis (Table). In the real-world early/advanced cohort (n=1328; 26 ILC vs 1302 non-ILC [subset IDC n=595]) treated with trastuzumab-based therapy, ILC pts had worse mOS (33.7 vs 68.6 m, HR 2.01, 95%CI 1.00-4.07, p=0.04) compared to non-ILC. However, there was no statistically significant difference when compared specifically to IDC (HR 1.77, 95% CI 0.87-3.61, p=0.11). ILC had: i) numerically lower tumor mutation burden (TMB)-high (4.2% vs 9.5%, p=0.38); ii) higher infiltration of B cells, Tregs, and M2 macrophages (p<0.05); iii) upregulated MHC class II expression (HLA-DOA, p<0.05); and iv) downregulated proliferative and DNA repair pathways (E2F, G2M, MYC; FDR <0.25) compared to non-ILC. Conclusions: HER2+ ILC carries late recurrence risk despite initial trastuzumab benefit. The unique immune landscape (Treg/M2 macrophage enrichment and lower proliferative signatures) distinguishes HER2+ ILC from IDC, highlighting the need for tailored strategies. Long-term RFS and OS in HER2-positive ILC vs IDC (N9831 trial). Population N 5-year% (95% CI) 10-year% (95% CI) 15-year% (95% CI) ILC 122 RFS 77.13% (69.9, 85.1) OS 84.04% (77.7, 90.9) RFS 70.57% (62.7, 79.4) OS 76.0% (68.7, 84.2) RFS 57.67% (44.2, 75.1) OS 65.22% (56.6, 75.2) IDC 3182 RFS 82.71% (81.4, 84.1) OS 90.18% (89.1, 91.2) RFS 77.45% (75.9, 78.9) OS 81.81% (80.4, 83.2) RFS 72.68% (70.77, 74.6) OS 76.68% (75, 78.4)

536 Background: Folate receptor alpha (FRα) is overexpressed in ~80% of triple-negative breast cancers (TNBC). We previously demonstrated that patients (pts) with breast cancer naturally mount immune responses to FRα. In prior Phase I and II studies, a GM-CSF-adjuvanted FRα peptide vaccine (FRPV) was safe and induced durable FRα-specific T-cell immunity in 83–90% of pts with breast and ovarian cancer. Methods: Eligible pts were women ≥18 years with TNBC (ER/PR ≤10%) with 1+ of the following: stage ≥T1c disease, node-positivity, or residual disease after neoadjuvant chemotherapy. Pts were randomized 2:1 to receive FRPV or placebo (GM-CSF alone) every 28 days for cycles 2-7 and then every six months for 7 booster doses, with cycle 1 consisting of cyclophosphamide 50mg orally twice daily for days 1-7 and 15-21 (in both arms). Randomization was stratified by chemotherapy setting (adjuvant only vs neoadjuvant) and stage (I/II vs III). FRα expression was evaluated by immunohistochemistry. The study was designed to detect (at 30 months after the last pt enrolled) a disease-free survival (DFS) difference of 14% assuming a 3.5-year DFS rate of 70% in the control group and with 78% power. Results: 280 pts were enrolled (median age 52). The majority had stage I or II tumors (n = 219, 78%). There were numerically more node-positive tumors in the vaccine arm, 78 (41%) vs 27 (32%), p = 0.15. Median follow-up was 3.5 years, and 33 (FRPV: 25, placebo: 8) DFS events were observed; 3.5-year DFS rate was 88% with FRPV and 90% with placebo (HR 1.42, 95% CI 0.64–3.15; p = 0.39). Overall survival (OS) also did not differ by arm (HR 2.48, 95% CI 0.55–11.20; p = 0.22). Among node-positive pts (n = 105), DFS did not differ between arms (HR 0.95, 95% CI 0.34–2.66; p = 0.92). However, a numerical DFS event rate improvement (14% for vaccine vs. 26% for placebo) was observed in 61 patients with stage III disease (HR 0.51, 95% CI 0.16–1.68; p = 0.26). DFS did not differ by chemotherapy setting or by receipt of anthracycline, capecitabine, and/or an immune checkpoint inhibitor. FRPV was well tolerated, with predominantly grade 1–2 adverse events (AEs) and no vaccine-related grade ≥4 AEs. FRα expression was available from tumor in 230 pts, with 72% expressing > 0. Overall, DFS was not significantly associated with FRα expression (0 vs > 0; HR 0.55, 95% CI 0.21–1.44; p = 0.21), and no significant differences in DFS by FRα expression were observed between treatment arms. Conclusions: FRPV following oral cyclophosphamide was safe, with no vaccine-related high-grade AEs. While no significant improvement in DFS or OS was observed overall, a numeric trend toward improved DFS was observed in pts with stage III TNBC. This finding is hypothesis-generating and supports further evaluation of FRα-targeted vaccination in higher-risk TNBC. Immune correlative analyses are ongoing to better define vaccine immunogenicity and its relationship to clinical outcomes. Clinical trial information: W81XWH-15-1-0293.

1591 Background: The 21-gene OncotypeDX (ODX) recurrence score (RS) is the standard for chemotherapy decision-making in HR+/HER2- early breast cancer (EBC), but cost limits accessibility in resource-constrained settings. The Magee equations (MEs) use routine pathology features (Nottingham grade and IHC; ER/PR/HER2/Ki-67) to estimate RS. We performed a meta-analysis to validate MEs performance as a triage tool for ODX testing and a qualitative synthesis to identify sources of discordance, highlighting the transition toward objective digital pathology AI models. Methods: A systematic review identified validation studies comparing MEs with RS in HR+ EBC. Studies with sufficient data to construct a 2X2 contingency table were included; neoadjuvant trials were excluded. Primary outcomes were Negative Predictive Value (NPV) for identifying low-risk cases (RS <26 for the current TAILORx cutoff and RS<31 for the historical cutoff) and ODX test sparing rate (TSR). Data were pooled using random-effects models. Qualitative themes regarding interpretation variability were extracted from study results and discussion sections. Results: Thirteen studies met the inclusion criteria, representing 5396 patients in global cohorts from the USA, Mexico, Colombia, Jordan, France, Belgium, and Canada. For RS >26, Magee <18 achieved pooled NPV of 0.96 (95% CI: 0.94-0.97) and TSR 61% (95% CI:51%-69%). For RS >31, NPV increased to 0.99 (95% CI: 0.97-1.00) and TSR 52% (95% CI: 44%-59%). Pooled diagnostic performance for Magee <18 predicting RS <26 demonstrated 83% sensitivity and 71% specificity (AUC 0.81, LR+:2.53, LR-:0.28). Qualitative analysis of discordance identified: (1) Inter-observer variability: Nottingham mitotic counts and Ki-67 scoring were the primary drivers of score fluctuations. (2) IHC quantification: Variations in H-score calculation and Allred-to-H-score conversion introduced heterogeneity (3) Pre-analytical and biological factors: Inflammation and stromal proliferation occasionally inflated genomic RS; selection of non-representative blocks and intratumor heterogeneity further contributed to discordance (4) Technological solutions: Digital pathology and AI models emerge as solutions to standardize these variables. Conclusions: Magee-based triage provides a safe and cost-effective strategy for HR+ EBC risk stratification, with NPV up to 99% for excluding high-risk disease and sparing up to 61% of ODX testing. These results confirm a robust histopathological signal. Transitioning to objective digital pathomics provides a pathway to reduce manual subjectivity and democratize precision oncology globally. Pooled diagnostic accuracy of Magee equations by cutoff. Magee score and RS cutoff Number of studies Total patients Pooled NPV (95% CI) ODX test sparing rate (95% CI) Magee <18/ RS>26 8 4153 0.96 (0.94-0.97) 61% (51%-69%) Magee <18/ RS>31 5 1243 0.99 (0.97-1.00) 52% (44%-59%)

12122 Background: Aromatase Inhibitors (AI) have become the standard of care to reduce breast cancer recurrence in hormone receptor-positive (HR+) breast cancer patients. AIs have been shown to be effective in reducing the risk of breast cancer recurrence by 47%. However, up to 52% of patients prematurely discontinue their use due to AI-associated musculoskeletal pain symptoms called Aromatase Inhibitor-associated musculoskeletal pain syndrome (AIMSS). No effective treatment exists to treat AIMSS. The present study examined the effectiveness of a multicomponent pain treatment program in reducing symptoms of AIMSS with the goal of improving adherence to AI medication. Methods: This trial enrolled breast cancer survivors with AIMSS in an intensive multicomponent pain treatment program. Pain, impact on functioning, fatigue, and mood were assessed with the Brief Pain Inventory, Center for Epidemiologic Studies of Depression- Revised Questionnaire, Pain Catastrophizing Scale, Symptom Impact Questionnaire Revised, and Fatigue Questionnaire at baseline, 3-month, 6-month, 9-month, and 12-month intervals. Adherence to AI medication was obtained from patients’ self-reports. The treatment program consisted of a two-day structured intervention focused on Cognitive-Behavioral skills to address strategies to improve pain control, fatigue, sleep disturbance, and stress while educating patients on the efficacy of Aromatase Inhibitors in prolonging cancer-free survival. Results: A total of 73 patients were enrolled, with a median age of 63 years (range 31-79). Participants were primarily white, married, and highly educated. The measures showed elevated levels of pain, fatigue, and psychological distress at baseline with decrements in self-reported levels of functioning. Significant improvements across all measures were observed at the 3-month follow-up after participation in the multicomponent pain treatment program. Significant improvements in painrelated outcomes were observed at 3 months (WPI Δ −1.6; SS Δ −4.0; both p < 0.001), with sustained reductions in symptom severity through 6-month, 9-month, and 12-month follow-up. Self-report of AI medication adherence at one year showed that 77.9% of patients were still taking their prescribed medication. Conclusions: Patients with AIMSS experienced substantial emotional distress, pain, fatigue, and functional impairment at baseline. Following the intervention, significant improvements were observed across pain, physical functioning, fatigue, and psychological distress, with benefits sustained at one year. Importantly, the intervention was associated with high long-term adherence at one-year follow-up, highlighting its potential to improve both quality of life and treatment persistence.

1107 Background: Bria-IMT is an allogeneic whole cell immunotherapy expressing tumor associated antigens and GM-CSF to stimulate adaptive and innate immunity. The phase 3 Bria-ABC trial (NCT06072612) evaluates Bria-IMT + retifanlimab vs physician’s choice in MBC w/ no meaningful therapeutic options. Characterization of on-trial pt experience, including quality of life (QOL) and tolerability, remains clinically relevant yet underreported. We evaluated QoL and toxicity to assess feasibility of home self administration. Methods: EORTC QLQ-C30 at baseline (BL) and subsequent visits. Raw item responses were aggregated into domain scores. Changes quantified as absolute point differences; domain scores defined as medians of constituent items. Lower functional/symptom and higher global scores indicate better outcomes. Wilcoxon matched pairs test assessed change from BL. Missing QoL data handled by observed cases approach. QoL evaluated at BL, V3, V6, and V9. TWiST and TOX summarized descriptively. TOX defined as cumulative time w/ grade ≥3 TEAEs w/o progression; TWiST as time w/o grade ≥3 toxicity or progression. TOX and TWiST constitute component health states for planned QTWiST analysis pending mature OS. Results: At submission, 251 pts screened, 173 randomized, 147 treated. 75% Caucasian, 20% other, 5% not reported; median 6 prior lines (2-15); ECOG 2 -6%; intracranial mets 9%; 42% HR+, 37% TNBC, 12% HER2+. Median 5 QoL assessments/pt completed. 127 pts completed ≥2 assessments. Paired data available at V3 52%, V6 17%, V9 6%. Global health medians BL 5.0, V3 5.0, V6 5.0, V9 4.5. Score maintenance/improvement: @V3 63% (p=0.7), V6 62%, V9 71%. Functional domains: role (BL 1.5, V3 2.0, V6 2.0, V9 2.0; maintenance 62.7% [p=0.02], 52.4%, 71.4%). Physical (BL 1.0, V3 2.0, V6 2.0, V9 2.0; maintenance 68.7% (p=0.002), 47.6% (p=0.03), 71.4%), cognitive (BL 1.5, V3 1.5, V6 1.5, V9 1.5; maintenance 63.6%, 61.9%, 85.7%). Emotional (BL 1.5, V3 1.5, V6 1.5, V9 1.5; maintenance 75.8% (p=0.9), 81.0%, 85.7%). Social (BL 1.5, V3 1.5, V6 2.0, V9 2.5; maintenance 58.5%, 75.0%, 57.1%). Symptoms: nausea/vomiting (1.0 throughout; maintenance V3 73%, V6 86%, V9 86%), fatigue median 2.0 all timepoints; maintenance 61%, 67%, 71%), pain (BL/V3 1.5, V6/V9 2.0; maintenance V3 57% [p=0.03], V6 62% [p=0.9], V9 86%). TWiST and TOX restricted mean 3.12 mo and 0.63 mo, respectively; 83.2% and 16.8% of observed follow-up. Pts w global health maintenance demonstrated longer median TWiST v deterioration (4.3 v 2.7 mo). ECOG stable in 78% (n=99). Conclusions: Heavily pretreated MBC pts in Bria-ABC demonstrated stable global health and key functional domains. Findings support sustained QoL in advanced disease. TWiST demonstrates meaningful benefit w/o significant toxicity. Ongoing follow up will further characterize durability of pt-reported outcomes and clinical correlation. Results support decentralized care and potential home self administration. Clinical trial information: NCT06072612 .

1108 Background: Metastatic breast cancer (MBC) remains limited by resistance and cumulative toxicity in heavily pretreated patients. Bria-IMT combines a whole-cell vaccine (SV-BR-1-GM) with anti-PD-1 (CPI) to enhance tumor antigen presentation and overcome immune exhaustion. SV-BR-1-GM is an irradiated breast cancer cell line engineered to secrete GM-CSF, promoting HLA class I and II antigen presentation and T-cell activation. We identified a subset with durable clinical benefit and biologic correlates. Methods: Phase I/II evaluating the Bria-IMT regimen (SV-BR-1-GM with CPI (pembrolizumab or retifanlimab). In the phase II portion, pts were randomized 1:1 to CPI initiation at cycle 1 (C1) or delayed start at cycle 2 (C2). Two SV-BR-1-GM formulations were administered: IFNγ-stimulated (IFγ) or unstimulated (≠IFγ). Baseline circulating tumor cells (CTCs) and delayed-type hypersensitivity (DTH) responses to SV-BR-1-GM were assessed as biomarkers. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan Meier (KM). Subgroup comparisons (CPI sequencing, IP formulation, DTH status, and baseline CTC status) are exploratory. Results: 32 phase 2 pts were randomized: median age 61 (range 41-80); median prior lines 6 (range 2-13); PFS 3.5 mo (95% CI 3.0 - 4.2); OS 9.5 mo (95% CI 7.0 - 17.4). Among CPI C1 vs C2 starts: median OS 13.3 v 7.4mo (HR 0.8; 95% CI 0.4-1.9, p = 0.6); OS KM probability at 12 mo 47% v 58%. Median OS w ≠IFγ v IFNγ IP =16.6 v 9.1 mo (HR 0.58; 95% CI 0.2-1.4, p = 0.23); OS KM at 12 mo 52.4% v 27.3%. DTH+ v DTH- median OS 11.9 v 4.7 mo (HR 0.0009; p = <0.001), OS KM @12 mo 48% v 0%. CTCs <5 v > 5 at baseline had median OS 16.6 v 5.5 mo (HR 0.005; 95% CI 0.0003-0.09, p < 0.001), OS at 12 mo 49% vs 33%. Among long term survivors @12mo, OS probability 44.0% (95% CI 26.2-59.7%) and @24 mo 26% (95% CI 12.1-42.4%). Median follow up 25.8 with PFS 5.4 mo. 5 received ≠IFγ formulation v 1 w IFNγ. All 6 (3 with CPI @C1, 3@C2) experienced delayed type hypersensitivity reaction to inoculation. 67% of long responders matched HLA at >1 allele, 33% no match. Grade ≥3 AEs in 47% of pts, most common injection site rxn, nausea, fatigue; no tx related D/C; no unexpected safety signals. Conclusions: In heavily pretreated MBC, Bria-IMT demonstrated a tolerable safety profile and the emergence of a long-term survivor cohort. Durable survival was observed beyond 12 and 24 months. Differential survival favoring Ph3 formulation, DTH positivity, lower baseline CTC burden, and early CPI sequencing was observed. These findings support prospective validation of DTH and CTC as predictive biomarkers and the continued use of the Ph3 IP formulation in the ongoing phase 3 study Bria-ABC (NCT06072612). Clinical trial information: NCT06072612 .