Citations

Abstract Background: Invasive lobular carcinoma (ILC) accounts for up to 15% of breast cancer (BC) cases and has distinct clinical and biological features compared to invasive carcinoma of no special type (IBC-NST). Prior studies, including PENELOPE-B, suggested greater benefit from adjuvant palbociclib (palbo) in ILC. We assessed the prognostic and predictive value of histology in patients (pts) treated with endocrine therapy (ET) ± palbo. Methods: PALLAS is a global, phase III trial in which pts with stage II-III, HR+/HER2− BC were randomized to 2 years (y) of adjuvant palbo + ET or ET alone. Pts with IBC-NST or pure ILC per local pathology assessment were included. Endpoints included invasive disease-free (IDFS; primary), distant recurrence-free (DRFS), locoregional recurrence-free (LRRFS), and overall survival (OS). Prognostic value was assessed using univariable and multivariate Cox models adjusted for age, T and N stage, grade, and progesterone receptor. Predictive value was assessed using histology-by-treatment interactions. Results: Among 5,748 pts in the ITT population, 4,982 (87%) were included (3,838 IBC-NST [67%], 1,144 ILC [20%]); median follow-up 6.9y. Compared with IBC-NST, ILC was associated with older age (median 54 vs 51 y), higher T stage (T3/T4: 41.7% vs 20.4%), fewer grade 3 tumors (12.7% vs 33.5%), higher mastectomy rates (74.5% vs 58.4%), less (neo)adjuvant chemotherapy (72.2% vs 86.2%), and less tamoxifen as initial ET (28.8% vs 34.5%) (all p<0.001). ILC prevalence varied by country: lower in Asia (Japan 10.5%, Korea 0%, Taiwan 2.8%) and higher in Europe (23.1%) and North America (24.0%). When evaluating the predictive value, palbo appeared to confer greater benefit in ILC for all endpoints (HRs ranging from 0.41 to 0.86) and not in IBC-NST (HRs ranging from 0.97 to 1.01), although the histology-by-treatment interaction was significant only for LRRFS (Table). In the overall population, 7-year IDFS was 79.3% for IBC-NST and 75.8% for ILC. While the difference was significant in univariable analysis (HR 1.17, 95% CI 1.01-1.35), it was not in multivariable analysis (HR 1.06, 0.91-1.24). Notably, the proportional hazards assumption was violated, and time-dependent modeling demonstrated that worse outcomes for ILC on IDFS, DRFS, and other endpoints emerged predominantly beyond 3 years. Conclusions: In this large, randomized dataset of pts with early HR+/HER2− breast cancer with long-term follow-up, ILC demonstrated distinct clinicopathologic features and geographic distribution. While ILC was not an independent prognostic factor over the entire follow-up, time-dependent modeling revealed worse long-term outcomes which only emerged after 3 years. Palbo appeared to be associated with more favorable outcomes in ILC than in IBC-NST across endpoints. These findings suggest a potential benefit of palbo in ILC that warrants further investigation in other adjuvant trials evaluating CDK4/6 inhibitors. Citation Format: G. Nader-Marta, C. Desmedt, D. Hlauschek, A. DeMichele, G. Zoppoli, E. Blondeaux, E. de Azambuja, M. Bellet-Ezquerra, O. Metzger-Filho, J. M. Suga, G. Pfeiler, M. P. Goetz, M. Ruiz-Borrego, S. Loibl, J. Meisel, A. Ring, K. Van Baelen, E. P. Mamounas, N. Zdenkowski, E. Agostinetto, M. Lambertini, E. Gauthier, L. Soelkner, A. C. Dueck, M. Gnant, E. L. Mayer. Long-term prognostic and predictive value of lobular histology in the PALLAS trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-06.

ABSTRACT Cardiovascular diseases, particularly heart failure (HF), are leading causes of morbidity and mortality worldwide. Limited patient knowledge about HF is associated with poor treatment adherence and worse health outcomes, emphasizing the importance of educational interventions. This randomized clinical trial evaluated the effectiveness of a nurse‐led educational intervention combining home visits and telephone follow‐up on patients' knowledge and quality of life (QoL). Conducted in six Brazilian hospitals, the study included 120 patients hospitalized with decompensated HF and randomly assigned to a control group (CG) or an intervention group (IG). The IG received structured education at discharge, followed by home visits on days 7, 30, and 60 and telephone follow‐up on days 15 and 45, while the CG received usual care. Outcomes were assessed at 60 days. At this time point, adequate HF knowledge was observed in 82% of patients in the IG compared with 38% in the CG, and good QoL in 73% versus 33%, respectively ( p < 0.001). The intervention was effective in improving knowledge and QoL in patients with HF.

Abstract Background: Hispanic/Latinx (HL) and African American (AA) breast cancer (BC) patients (pts) have increased prevalence of high-risk features such as incidence of BC at age &lt;50 and estrogen receptor negativity. We previously showed that AA and HL had a lower fraction of neutrophils and M2 macrophages (Mɸ) despite higher percentage of PD-L1 positive cases. This study aims to further characterize differences in the tumor immune microenvironment between racial and ethnic groups, with a focus on how these differences vary by site of biopsy. Methods: We analyzed 19,459 BC samples tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences). Race/ethnicity data were self-reported by pts. Immune cell proportions were estimated using WTS deconvolution (Quantiseq). Gene expression was analyzed for T-cell inflammed score (TIS), MAPK Activation Score (MPAS) and interferon-gamma (IFNy) score. Real-world overall survival (OS) data were derived from insurance claims, calculated from tissue collection or treatment initiation to last contact, and analyzed using Kaplan-Meier. Statistical significance was assessed by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q&lt;0.05). Results: There were 9674 Non-Hispanic Whites (NHW) (primary BC, defined as biopsy (bx) from breast) pBC: n=3,537, 36.6%; (metastatic BC, defined as biopsy outside of the breast) mBC: n=6,137 63.4%, 1800 AA (pBC: n=750, 42%, mBC: n=1,050, 58%), and 1795 HL (pBC: n=842, 47%; mBC n=953, 53%) samples. There were 2364 TNBC (66% NHW, 19% NHB, 15% HL), 4318 HR+/HER2- (76% NHW, 11.6% NHB, 12.4% HL), and 893 HER2+ (68% NHW, 15% NHB, 17% HL). In pBC overall, AA had lower median cell fraction (%) of B cells (4.8% vs 5.3%), M2 Mɸ (3.4% vs 4.4%), but higher median cell fraction of dendritic cells (DC) (2.8% vs 2.6%) compared to NHW while HL had lower median cell fraction of M2 Mɸ (3.9% vs 4.4%) and higher median cell fraction of CD8+ T cell (0.4% vs 0.2%), all q&lt;0.05. In pBC, HL had higher IFNy score (-0.3 vs -0.34), while AA had lower MPAS (-1.2 vs -0.96), all q&lt;0.05. In lymph node bx, AA had lower median % of M2 Mɸ (3.4% vs 4.4%, q&lt;0.05). No significant differences were seen in the liver bx by race but notably there were lower median cell fractions of CD4+, CD8+, and regulatory T cells (0.0 across NHW, AA, HL) across all race/ethnicities vs. other biopsy sites. By subtype, TNBC primary bx yielded much of the significant changes with AA having lower median cell fraction of M2 Mɸ (2.49% vs 3.04%, q= 0.01) compared to NHW. In primary bx, AA (35.6 m vs 48.5 m, HR 1.4, 95% CI 1.2-1.5, p&lt;0.001) and HL (42.4 m vs 48.5 m, HR 1.2, 95% CI 1.1-1.4, p&lt;0.001) had worse median OS versus NHW. In lymph node bx, AA also had worse OS (29.2 m vs 37.2 m, HR 1.2, 95% CI 1-1.5, p=0.03) compared to NHW. In liver bx, there was worse mOS overall but no difference by race (NHW 18.65m, AA 18.79m, HL 20.6m, p =0.73). In HR+/HER2- liver bx AA had worse OS (14.2 m vs 20.9 m, HR 1.3, 95% CI 1-1.7, p=0.03) versus NHW. In HER2+ primary bx, HL had worse OS (43.2m vs 66.9m, HR 1.7, 95% CI 1.1-2.6, p=0.009). There was a trend towards worse mOS in TNBC AA patients receiving pembrolizumab (18.42m vs HL 23.69m vs NHW 35.30m; p=0.16) and HER2+ AA patients receiving trastuzumab deruxtecan (AA: 16.06m vs HL: 26.81m vs NHW: not reached; p = 0.05). Conclusions: We found race and biopsy site specific differences in the breast cancer immune microenvironment. AA pts had lower M2 Mɸ in primary and lymph node bx while NHW pts showed higher CD8+ T cell in primary tumors. Liver biopsies exhibited low T cell infiltration across all groups. AA pts had worse mOS in primary and lymph node bx compared to NHW but not in liver bx of which we saw worse mOS in all races. These results highlight the need to consider both race and bx site in treatment decisions. Citation Format: R. Hsu, S. Deshmukh, N. Gyabaah-Kessie, E. Rallos, B. Al-Zubeidy, E. Gonzalez, A. G. Baugh, S. Carrel, M. Li, D. Zavala, A. Martynova, P. Jayachandran, D. Stewart, D. Spicer, S. Wu, J. Xiu, G. W. Sledge Jr., R. L. Mahtani, A. C. Sandoval Leon, S. Gandhi, S. Chumsri, M. Lustberg, M. C. Stern, E. T. Roussos Torres. Immune microenvironment and survival differences among Hispanic and African American breast cancer cases by biopsy site [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 PS3-12-06.

Abstract Background Management of metastatic breast cancer (MBC) continues to present obstacles, as many pts develop resistance to or cannot tolerate standard of care treatments. Bria-IMT combines two modalities to both overcome immune exhaustion and minimize the toxic safety profiles commonly observed in contemporary late stage therapies: an allogeneic whole-cell vaccine (SV-BR-1-GM) and checkpoint inhibition (CPI). The SV-BR-1-GM cell line originates from breast cancer cells and are engineered to secrete GM-CSF and irradiated before administration. These cells upregulate surface presentation of tumor associated antigens on both HLA class I and II, enhancing tumor recognition by T cells. Coadministration w/ an anti-PD-1 CPI, the vaccine response is reinforced, counteracting the immuno-suppressive tumor microenvironment. Methods This phase I/II study evaluated the Bria-IMT regimen: low-dose cyclophosphamide (Day –2) followed by SV-BR-1-GM and CPI (pembrolizumab or retifanlimab), then low-dose local peg- interferon α. Cycles q3w. In the phase II study, pts were randomized 1:1 to start CPI immediately at cycle 1 (C1) or delayed start at cycle 2 (C2). There were 2 formulations of SV-BR-1-GM w/ IFNγ stimulation (IFNγ) or unstimulated (PH3). Cancer-associated macrophage-like cells (CAMLs), circulating tumor cells (CTCs), and PD-L1 expression scores on these cells were monitored as biomarkers. Candida skin test assessed anergy status before cycle 1, and a delayed type hypersensitivity (DTH) skin test to SV-BR-1-GM was assessed at each cycle w/ a small SV-BR-1-GM dose before the full dose. Results Results of the randomized phase II study cohort are reported (n = 32). Retifanlimab was co-administered w/ SV-BR-1-GM at C1 or C2. Median age 61 (41-80) years; median number of prior regimens was 6 (2-13). 20(63%) pts were ER+/PR+/HER2-; 3(9%) HER2+, and 9 (28%) triple-negative (TNBC). The Bria-IMT regimen was well tolerated, w/ no drop-outs attributable to Bria-IMT. The majority of adverse events (93.8%) grade 1-2, w/ (40.6%) grades 3 and 4. Common AEs included injection site reactions (53%), nausea (43.8%), and fatigue (34%). The median progression free survival (PFS) was 3.5 (range: 1.8-24.5) and overall survival (OS) 9.5 (2.4-31.6) months. One patient remains on therapy, approaching 25 months of PFS. PFS and OS among pts who received immediate vs. delayed start of CPI (PFS 3.7 vs. 3.3 mo, HR: 0.59; 95% CI 0.3-1.2, p=0.16 | OS 13.3 vs. 7.4 months, HR: 0.78; 95% CI 0.34-1.8, p = 0.56). Pts who received the SV-BR-1-GM Ph3 formulation (n=21) had an increase in both PFS (4.1 vs 2.6 months, p = 0.005) and OS (16.6 vs. 9.1 months, HR: 0.6; 95% CI 0.2 - 1.4, p = 0.24); best objective response rate was 12% and the clinical benefit rate was 53%. In ER+/PR+/HER2-, overall OS was 11.7 (3.5-31.6) mo, 17.3 mo (3.5-27.9) in Ph3; HER2+ 7.2 (4.7-24.5) mo, all received Ph3; TNBC 9.9 (2.4-23.0) mo, 16.6 mo (2.4-23.0) in Ph3. In pts w/ available data, pts w/ post-dose CTC count &lt; 5 significantly improved OS compared w/ a CTC count &gt; 5 (16.6 vs. 5.5 months, p = 0.0003). Pts w/ positive DTH response had significantly improved PFS (3.6 vs. 2.4 months, p = 0.01) and OS (11.9 vs. 4.7 months, p &lt; 0.0001). Conclusions In heavily pretreated MBC pts, the Bria-IMT regimen demonstrated promising results and a favorable safety profile across all subtypes of breast cancer. A clinically meaningful, though not statistically significant, difference in OS was observed between pts receiving CPI at C1 versus C2. Superior outcomes were observed in pts receiving SV-BR-1-GM w/o IFNγ incubation, guiding selection of Ph3 formulation for ongoing and subsequent clinical trials. Pts w/ post-dose CTC count &lt; 5, and positive DTH response had significantly improved outcomes. On basis of these results, a randomized phase III trial comparing the Bria-IMT regimen to physician's choice is ongoing (NCT06072612). Trial information: NCT03328026. Citation Format: C. Nangia, S. Chumsri, K. Rowland, L. Negret, J. Knecth, B. Bayer, T. Aghajanian, W. Williams, G. Del Priore, C. Calfa. Survival Results of Phase II Bria-IMT Allogenic Whole Cell-Based Cancer Vaccine [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 PS1-13-23.

Abstract Background: Tumor-infiltrating lymphocytes (TILs) in HER2+ and triple-negative breast cancer (BC) are prognostic and associated with therapy response; however, there are few data regarding distribution and significance of TIL values in ER+ HER2-negative (HER2-) MBC patients (pts) treated with CDK4/6 inhibitors (CDK4/6i). CDK4/6 inhibition may promote antitumor immunity by production of type III interferons and tumor antigen presentation, and by inhibition of regulatory T cells (Goel, Nature 2017). Further, the addition of immune checkpoint therapy to palbociclib numerically prolonged PFS in the 2nd line (2L) setting (Mayer, JCO 2024). We aimed to investigate the prognostic role of TILs derived from fresh metastatic tumor biopsies in pts with ER+HER2- MBC prior to starting CDK4/6i and endocrine therapy (ET) in the first line (1L) and 2L setting. Methods: PROMISE (NCT0281902) is a multicenter, prospective study that enrolled women commencing the CDK4/6i palbociclib (Pb) with letrozole (1L) or fulvestrant (2L) for HR+HER2- MBC. The primary goal was to identify novel genomic variants and pathways associated with PFS. Here, we performed a secondary analysis to quantitate stromal TILs using protocol mandated pretreatment tumor biopsies and determine their association with PFS. Using the Kaplan-Meier method, we reported median PFS (mPFS) and 3-year PFS percentage (%) (95% confidence intervals [CIs]) by TILs [≥20% vs &lt;20%] separately within 1L and 2L. As sample TIL values were generally concentrated at zero (27/58 = 46.6%), coupled with wide spread of sample TIL values ≥20% [range: 20%- 80%], we applied a ≥20% threshold for PFS analysis (high vs low TIL group) as described by Luen, Salgado et al. Lancet Oncol 2017. Statistical significance was based on the Wilcoxon test of the null hypothesis that there was no difference in the PFS curves by TILs. PFS is reported at median follow-up of 21 months. Results: Pretreatment tumor biopsies from 58/68 (85.3 %) pts were evaluable (42 in 1L and 16 in 2L). Median [Q1, Q2] TIL values were higher in 1L (5% [0, 10]) vs 2L (0% [0, 15]). The most common biopsy sites were bone (44.8%), lymph node (17.2%), liver (17.2%) and breast (12%). Overall, TILs frequency (&gt;20%) by the 4 most common biopsy sites were bone (2/20, 10%), lymph node (4/7, 57%), liver (2/6, 33%), and breast (1/7, 14%). In 1L, although PFS was not significantly different (P = 0.237), mPFS (44 vs 34 months) and 3-year PFS 75.0%, [95% CI: 50.3%, 100%] vs 46.4% [95% CI: 31.0%, 69.5%]) were longer in pts with high versus low TILS, respectively. In 2L, the 3-year PFS was numerically similar comparing high and low TILs groups, (25.0%, [95% CI: 4.6%, 100%] vs 22.5% [95% CI: 6.7%, 76.1%]) with no significant difference in PFS (P = 0.761). Conclusions: In pts with ER+HER2- MBC treated with Pb and ET, PFS was numerically longer comparing high vs low TIL values in 1L but not 2L settings. Future studies evaluating TILs in larger datasets are needed to validate these findings. Genomic analysis (DNA/RNA) and its association with TIL levels is underway and will be presented at the meeting. Funding: The Center for Individualized Medicine, Mayo Clinic; Mayo Clinic Breast Specialized Program of Research Excellence (SPORE P50CA116201); Mayo Clinic Cancer Center (CA15083-40A2); TEMPUS (https://www.tempus.com/) and Conquer Cancer Foundation of ASCO (Career Development Award 2018, Dr. O’Sullivan) Citation Format: C. C. O'Sullivan, A. M. Moyer, A. Nassar, D. M. Zahrieh, V. Suman, X. Tang, K. J. Thompson, R. C. Hentz, J. J. Harrington, A. Moreno-Aspitia, D. W. Northfelt, T. C. Haddad, S. Chumsri, P. P. Peethambaram, K. J. Ruddy, K. V. Giridhar, R. A. Leon-Ferre, R. Weinshilboum, L. Wang, K. R. Kalari, M. P. Goetz. Tumor-infiltrating lymphocytes in advanced ER-positive, HER2-negative breast cancer prior to treatment with palbociclib and endocrine therapy: a retrospective analysis of the PROMISE 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 PS1-10-22.

Abstract Background: Aurora kinase A (AURKA) plays an integral role in the mitotic cell cycle, regulating spindle assembly, centrosome function, chromosome alignment, and mitotic entry. In addition to its mitotic role, activated AURKA has been shown to induce epithelial-mesenchymal transition reprogramming and contribute to endocrine resistance in ER+ breast cancer (BC) models. Amplification/overexpression of AURKA is linked to poor prognosis across multiple tumor types, including ER+/HER2- BC. Alisertib is a selective, reversible, ATP-competitive AURKA inhibitor that has been shown to disrupt spindle formation, leading to mitotic defects and cell death. In xenografts, the potent inhibition of AURKA by alisertib led to antitumor activity across a variety of tumor types. Preliminary clinical data with alisertib have shown significant antitumor activity and a manageable safety profile in patients with various cancers, including ER+/HER2- BC. This study aims to better characterize the role of alisertib in patients with BC to provide a rationale for future clinical studies. Methods: Three studies evaluating alisertib in patients with ER+/HER2- MBC have been completed, including a phase I study of alisertib + fulvestrant (Haddad 2018), a phase II alisertib monotherapy study (Melichar 2015), and a phase II study of alisertib ± fulvestrant (TBCRC 041; Haddad 2023). Descriptive summary statistics were utilized for patient characteristics, as well as clinical safety and efficacy data. Results: A total of 126 patients were enrolled and evaluable in the 3 clinical studies, as per Table 1. All patients had MBC and received prior endocrine therapy and chemotherapy. All patients in TBCRC 041 also received a prior CDK4/6 inhibitor (CDK 4/6i). In these heavily pretreated patients, tumor objective response rates (ORR) were ∼20%, and 6-month clinical benefit rates (CBRs) were 29-78%. The most common grade 3/4 adverse events (AEs) across studies were hematologic AEs (neutropenia, leukopenia, and anemia), and fatigue. In TBCRC 041, ctDNA- and tumor-derived RNA-Seq-based biomarker assessments are ongoing to investigate associations with clinical benefit from alisertib alone or combined with fulvestrant. Conclusions: Alisertib has shown efficacy and safety across multiple clinical studies in patients with ER+/HER2- MBC and could provide a novel option for treating those who have progressed on endocrine therapy and a CDK 4/6i. These findings provide a strong rationale for further development of alisertib in this patient population. The ongoing phase II ALISCA-Breast1 study (NCT06369285) is investigating the optimal dose of alisertib in combination with standard endocrine therapies in this setting. Citation Format: T. C. Haddad, K. McCann, P. Advani. The Aurora Kinase A Inhibitor Alisertib Alone or in Combination with Endocrine Therapy for Patients with Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Metastatic Breast Cancer (MBC) [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 PS1-10-03.

Abstract Introduction: Metaplastic breast cancer (MpBC) is a rare, aggressive subtype of breast cancer that has limited evidence-based data to guide treatment. Historically, MpBC has had limited response to chemotherapy; however, the response of MpBC to antibody-drug conjugates (ADCs) remains poorly characterized. Methods: We performed a retrospective cohort study of patients (pts) with pathologic diagnosis of MpBC who received ADC therapy as part of standard of care in the metastatic setting across 4 NCI-designated cancer centers. The primary endpoints were objective response rate (ORR) at time of best response to ADC & real world PFS (rwPFS) of ADC compared to non-ADC therapy, defined as time from treatment start to time of progression or death. Results: We identified 48 pts with MpBC who received at least one ADC between 3/2016 and 10/2025. Median age was 54 years (range 31-77); all pts were biological females. Most pts had triple negative disease (n=39, 81%), 5 (10%) had HER2+ disease, 3 (6%) had hormone receptor positive disease & 17 (35%) were confirmed HER2-low (IHC 1+ or 2+, ISH nonamplified). The most common MpBC subtypes were with squamous differentiation (n=17, 35%), chondroid (n=11, 23%), matrix-producing (n=11, 23%) & spindle cell differentiation (n=10, 21%). Ten pts (21%) had de novo metastatic disease & 38 (79%) had recurrent disease. Most common metastatic sites were lung (n=33, 69%) & liver (21, 44%). 37/38 (97%) patients had curative intent anthracycline & taxane, with median disease-free interval of 16 months (range 2-241). 18 pts (38%) received curative intent immune checkpoint inhibitor. Most pts received ADC in the first (n=19, 40%) or second line (n=18, 38%) with Sacituzumab govitecan being the most common (n=38, 79%) ADC, followed by Trastuzumab deruxtecan (n=9, 19%). 7 pts (15%) received a second ADC. ORR at time of best response was 38% (n=18), with 4 pts experiencing complete response (1 patient who received ADC in 1L, 3 in the 2L) & 14 experiencing partial response. 3 pts (6%) experienced stable disease, & 27 pts (56%) experienced progressive disease as best response. Median rwPFS of pts receiving ADC in the first line was 2.3 months, compared to 4.3 months in those receiving non-ADC/chemotherapy (HR 1.34; 95% CI 0.72-2.49, p=0.89). Median rwPFS of pts receiving ADC in the second line was 2.6 months, compared to 2.3 months in those receiving non-ADC/chemotherapy (HR 0.56; 0.28-1.11; p=0.10). Toxicity resulted in dose reductions in 17 pts (35%), dose delays in 14 (29%), & ADC discontinuation in 2 (4%). Conclusion: In this multi-institutional cohort of pts with metastatic MpBC, ADC treatment yielded a 38% ORR, including four complete responses. However, rwPFS was poor overall & similar between ADC & non-ADC therapy. These findings highlight the need to develop new treatment strategies for MpBC, though a subset of pts may experience meaningful response to ADC. Citation Format: S. Jacob, S. Premji, S. Fisch, A. LeVee, S. Marion, D. Schmolze, J. Mortimer, L. Huppert, D. Idossa, A. Nayak, P. Wileyto, A. DeMichele, P. D. Shah. Efficacy of antibody drug conjugates in patients with advanced metaplastic breast cancer: a multi-institutional retrospective cohort 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 PS1-09-18.

Abstract Introduction: Metaplastic breast cancer (MpBC) represents a rare subtype, constituting &lt;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 &lt;5 CNS mets), 5 (33%) had diffuse (&gt;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.

Abstract Introduction: Patients with metastatic breast cancer frequently develop bone metastases and experience other skeletal-related events (SREs). These complications substantially impair quality of life and may negatively influence clinical outcomes. In this context, bisphosphonates and denosumab are the most commonly utilized therapeutic agents. We aim to study the real-world comparative data between bisphosphonates and denosumab in breast cancer patients with bony metastases along with evaluation of their toxicity profiles. Methods: A retrospective cohort study was conducted using the US Collaborative Network, TriNetX, covering January 2000 to December 2023, encompassing data from 105 global healthcare organizations. Female patients aged 18 and above with breast cancer metastatic to the bone were identified and then stratified into two groups based on treatment with zoledronic acid or pamidronate. The two groups were then propensity-matched based on age, sex, race, and comorbidities. We followed these patients for 5 years to assess outcomes, including mortality, osteoporotic fracture, hypercalcemia, pathological fracture, fall, and osteonecrosis. Results: We identified 7887 patients in the zoledronic acid cohort and 635 patients in the pamidronate cohort. After propensity matching, each cohort consisted of 625 patients with similar baseline characteristics. The average age was 66.4 years in the zoledronic acid cohort and 68.5 in the denosumab cohort. In the zoledronic acid cohort, the ethnicity distribution was 74.68 % White, 6.36% Hispanic, and 11.55% African American. In comparison, the denosumab group had an ethnicity distribution of 74.49% White, 10.31% African American, and 5.68% Hispanic. Our analysis found that within 5 years, patients with breast cancer metastatic to the bone who received zoledronic acid had a significantly lower risk of mortality (Risk difference: -3.49%, 95% Confidence Interval [CI]: -5.063 to -1.916), p-value &lt;0.001) compared to denosumab. However, patients in the zoledronic acid arm were noted to have a higher risk of osteoporotic fracture (Risk difference: 0.817%, 95% CI: 0.232 to 1.402), p-value = 0.006), hypercalcemia [Hazard Ratio [HR]: 1.524, 95% CI: 1.407 to 1.65, p-value &lt;0.001), and pathological fracture (HR: 1.501, 95% CI: 1.349 to 1.671), p-value =0.03). There was no significant difference in the occurrence of falls and osteonecrosis between the two subgroups. Conclusion: Our study revealed that patients with breast cancer with metastatic disease to the bone who received zoledronic acid had significantly lower rates of mortality but higher occurrence of osteoporotic fracture, hypercalcemia, and pathological fracture compared to those receiving denosumab. Additional longitudinal cohort studies are imperative to explore the outcomes between these agents and inform clinical practice guidelines in these patients. Citation Format: A. Syal, Y. Arya, C. Jones, H. Mahadevia, N. Batra, A. Uriepero Palma. Real-world outcomes comparing zoledronic acid and denosumab in patients with metastatic breast cancer and bone metastases: A propensity score matched analysis from a global federated health research network [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 PS1-08-17.

Abstract Background: In the treatment of ER+/HER2- metastatic breast cancer (MBC), randomized phase II/III trials testing selective estrogen receptor degraders (SERDs), proteolysis-targeting chimeras (PROTACs), complete estrogen receptor antagonists (CERANs) and selective ER modulators (SERMs) (mostly compared to fulvestrant) have demonstrated modest (1-2 months) improvements in progression-free survival (PFS), mainly limited to patients with ESR1-mutated MBC. In these studies, the median PFS (mPFS) ranges from 3 to 6 months, with shorter mPFS in patients with prior progression on CDK 4/6 inhibitor (CDK 4/6i). Here we report the final results of a randomized phase II study that compared Z-endoxifen (Endx) 80 mg/day with tamoxifen (Tam) 20 mg/day in postmenopausal women with estrogen receptor (ER)- positive/ HER2-negative MBC, and report outcomes according to ESR1, PIK3CA, PTEN and AKT alterations (Alliance A011203; NCT02311933). Methods: Postmenopausal women with unlimited prior endocrine regimens (including CDK 4/6i) and up to two chemotherapy regimens for MBC, with tumor biopsy confirmation of ER+ (&gt;10% nuclear staining) and negative for HER2 amplification/overexpression were eligible. Prior adjuvant Tam was allowed if relapse was &gt; 1 year following Tam completion. Patients randomized to Tam could cross over to Endx at progression. The primary end point was PFS analyzed by the interval censored data analytic approach. ctDNA was analyzed for ESR1 and PIK3CA/PTEN/AKT alterations using Guardant360 CDx 74-gene next-generation sequencing-based assay (Guardant Health). Results: Among 108 women who preregistered, 76 (Endx: 40; Tam: 36) were randomized and eligible. Patients were heavily pretreated; all patients had prior exposure to an aromatase inhibitor (AI), 50% had ≥ 2 AI based regimens in the metastatic setting and 50% in each arm had received fulvestrant. Approximately half on each arm received at least one chemotherapy regimen in the metastatic setting. Prior CDK 4/6i therapy was imbalanced (48% on Endx and 28% on Tam). Endx did not significantly prolong PFS compared to Tam (median PFS [mPFS] 4.3 vs 1.7 months; HR 0.72, p=0.168). Because arms were imbalanced according to prior CDK 4/6i exposure, we performed an unplanned analysis demonstrating that Endx improved PFS relative to Tam in CDK 4/6i-naïve patients (mPFS 8.3 vs 2.1 months; HR 0.39, p=0.0097) but not in patients treated with prior CDK 4/6i (mPFS 3.0 vs 1.5 months). In the subset of patients who consented for ctDNA testing (n=28), the mPFS for those with either an activating alteration in the PIK3CA/PTEN/AKT pathway or with an ESR1 mutation was similar as the overall trial. For the 24 patients who progressed on Tam and crossed-over to Endx, the median PFS was 3.5 months (range 1.5-15.0 months) with a 6-month clinical benefit rate of 33.3% (8/24; 90% CI: 17.8-52.1%). Conclusions: Endx did not meet the prespecified threshold for concluding that it significantly improved PFS relative to Tam in a cohort of heavily pretreated MBC. However, the observations of a &gt; 6-month improvement in mPFS in CDK 4/6i-naïve patients, anti-tumor activity following crossover to Tam, and mPFS estimates similar to other novel endocrine agents in development all support the ongoing development of Endx. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180820 (ECOG-ACRIN) and 5P50CA116201. Clinicaltrials.gov Id: NCT02311933. https://acknowledgments.alliancefound.org. Citation Format: M. P. Goetz, V. Suman, J. Reid, T. Dockter, C. Strand, W. F. Symmans, J. Hawse, A. Storniolo, J. Doroshow, J. M. Collins, H. Streicher, M. M. Ames, A. Tarnower, O. M. Hahn, J. N. Ingle, L. Carey, A. Partridge. Final results from the Randomized Phase II study of Z-Endoxifen and Tamoxifen in Endocrine Refractory, Estrogen Receptor Positive, HER2 negative Metastatic Breast Cancer (Alliance A011203) [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 PS1-08-07.