Citations

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.

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 <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 <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+ (>10% nuclear staining) and negative for HER2 amplification/overexpression were eligible. Prior adjuvant Tam was allowed if relapse was > 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 > 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.

Abstract The addition of two years (yrs) of adjuvant abemaciclib to ET resulted in statistically significant and clinically meaningful improvement in overall survival (OS) over ET in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. At 7 yrs, abemaciclib+ET demonstrated sustained IDFS and DRFS benefits ([HR=0.73, 95% CI: 0.66, 0.82), and (HR=0.75, 95% CI: 0.66, 0.84)]). Higher nodal involvement (N2 or N3) is an independent prognostic factor for worse outcomes in EBC. However, previous monarchE data highlight that pts with limited nodal disease (1-3 axillary lymph nodes (ALN)) are at high recurrence risk when additional clinical risk factors are present, such as high-grade (G) tumor and/or large tumor size. Here, we show subgroup analyses by ALN.monarchE is a phase 3, open-label, randomized trial in pts with HR+, HER2-, node-positive, high-risk EBC. Pts were randomized (1:1) to receive ET for at least 5 yrs +/- abemaciclib for 2 yrs (treatment (tx) period). High-risk EBC was defined as either 1-3 ALN (N1) with G3 disease and/or tumor ≥5 cm or, ≥4 ALN (N2: 4-9, N3: ≥10) (Cohort 1 (C1)). A smaller group of pts were enrolled with N1, G≤2, tumor size <5 cm, and central Ki-67 ≥20% (C2). IDFS, DRFS and OS were assessed in C1 by ALN (N1, N2, N3) using the Kaplan-Meier (KM) method, and unstratified Cox proportional hazard model including interaction effect between tx arm and ALN. Of 5120 randomized pts in C1, 1761 (34.4%) had N1, 2223 (43.4%) had N2, and 1123 (21.9%) had N3 disease. At this analysis (data cut off:15Jul2025), in the ET arm, a comparable number of patients with N1 and N2 disease had IDFS events at 6 yrs (21.6% and 25.4%), while event no. in the N3 subgroup was notably higher (38.1%). A similar trend was observed in DRFS and OS (Table). With a median follow-up time of 76.8 months in C1, the addition of abemaciclib to ET reduced the risk of developing an IDFS event by 24.8% (N1), 31.5% (N2) and 27.4% (N3) compared to ET. The absolute improvements in IDFS rates at 6 yrs were 4.6% (N1), 6.9% (N2), and 8.1% (N3). Reductions in the risk of developing DRFS events were 25.2% (N1), 31.2% (N2), and 25.7% (N3), with corresponding 6yr absolute benefit of 3.8% (N1), 6.4% (N2), and 6.8% (N3). Abemaciclib+ET consistently reduced the risk of death compared to ET across ALN subgroups by 12.3% (N1), 15.5% (N2), and 26.8% (N3), which resulted in absolute improvements in OS of 1.4% (N1), 1.6% (N2), and 2.7% (N3). Baseline disease characteristics, IDFS and DRFS KM curves by ALN will be presented. In the ET arm, pts with N1 + ≥1 additional risk factor had recurrence and death risks comparable to pts with N2, while pts with N3 had poorer prognosis. The addition of adjuvant abemaciclib to ET led to a clinically meaningful reduction in the risk of recurrence and death regardless of nodal burden, confirming the consistent and sustained benefit of 2 yrs of tx with abemaciclib and supporting its use in eligible pts with node-positive high-risk EBC. Citation Format: J. Cortes, S. R. D. Johnston, M. Martín, S. M. Tolaney, M. Goetz, H. Rugo, J. Sohn, O. Ozyilkan, M. Henriques Abreu, M. Zaiss, K. Maia Vianna, H. Melgaard Nielsen, A. Chan, H. Kalofonos, S. Morales, B. San Antonio, M. Munoz, B. R Grimes, S. Amdur, P. Neven. monarchE: subgroup analysis of adjuvant abemaciclib + endocrine therapy for HR+, HER2-, high-risk early breast cancer by nodal status [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 PS1-08-08.

Abstract Background: 18F-Fluoroestradiol (FES) positron emission tomography (PET) is approved for non-invasive detection of estrogen receptor (ER)-positive breast cancer (BC) and recent updates to the National Comprehensive Cancer Center Network clinical practice guidelines include FES-PET for staging recurrent/metastatic ILC. Given the wide range of FES-PET indications, we retrospectively reviewed the management of ER+ BC patients after FES-PET at Mayo Clinic. Methods: We identified ER+ BC patients who underwent FES-PET from April 2021 to June 2025 across the Mayo Clinic. BC context at the time of FES-PET requisition was categorized as early (EBC), locally recurrent (LRBC), or metastatic (MBC). Management changes were classified as either affecting BC or non-BC care (not mutually exclusive). For pts who underwent 18F-flurodeoxyglucose (FDG) PET-CT and had a discrepant result with FES-PET, we assessed the clinical impact of these discrepancies. Finally, we examined the change in clinical management when FES-PET was ordered to investigate rising tumor markers CA 15-3 or CA 27.29. Results: 166 pts underwent ≥1 FES-PET scan. At diagnosis, 57% had invasive lobular carcinoma (ILC), 33% invasive ductal carcinoma (IDC), and 5.4% mixed histology. ER expression ≥ 50% was observed in 81.4% and 1.2% were HER2+. Overall, FES-PET led to a change in management in 54.5% (n=90) of pts with 43.0% (n=71) experiencing a change in BC care and 16.4% (n=27) in non-BC care. Changes in BC care occurred in 36% of EBC, 68% of LRBC, and 43.7% of MBC. The most common BC management changes after FES-PET were change in treatment strategy in 23.6% (n=39), additional BC-related imaging including further FES-PET scans in 23.0% (n=38), upstaging in 10.3% (n=17), change in surgical planning in 10.3% (n=17), local therapy in 4.2% (n=7), and biopsy avoidance in 3% (n=5). Surgical planning changes were mostly deciding to proceed with curative intent surgery (n=11), though some surgeries were aborted upon FES-PET upstaging (n=6). Non-BC management changes included additional imaging to evaluate incidental findings in 11.5% (n=19) and procedures in 6.7% (n=11), including 5 biopsies, 2 bronchoscopies, 2 endoscopies, 1 hysterectomy, and 1 cholecystectomy. FDG/FES discordancy was observed in 22.3% of the overall population (n=37). The most common pattern was FDG-/FES+ (n=19), leading to upstaging of BC in 8 and the sole use of FES-PET for future restaging in 13 BC patients. The second most common pattern was FDG+/FES- (n=18), attributed to non-BC related FDG uptake in 11 (false-positive FDG) or post-treatment ER loss in 7. Three FDG+/FES- patients were found to have additional cancers: two non-small cell lung cancers and one lymphoma. Non-malignant causes of false positive FDG were inflammation (n=3), silicone implants (n=1), thymic hyperplasia (n=1), and unknown (n=5). Six patients initially upstaged with FDG-PET imaging proceeded to curative-intent surgery after negative FES-PET confirmatory scans (FDG+/FES-). When FES-PET was ordered to investigate rising CA 15-3 or CA 27.29 tumor markers, this led to upstaging/progression in 3 of 21 cases (1 EBC, 2 MBC). The mean tumor marker increase was 57.0% in patients with upstaging/progression versus 19.0% in those without (p=0.02, two-tailed Student’s t-test). Conclusions: FES-PET altered clinical management in approximately half of BC cases in this study. Changes in BC-specific management were most frequent in LRBC, followed by MBC and EBC. One in six patients had a non-BC clinical management change after FES-PET. FDG/FES discordance provided value in upstaging FDG non-avid cancers and downstaging FDG-avid lesions unrelated to BC, influencing curative treatment decisions. FES-PET ordered for rising tumor markers rarely changed management, though larger tumor marker increases were associated with upstaging or progression. Citation Format: N. Wiest, K. Bullock, T. Pai, M. Kornas, B. McKinley, E. Parent, P. Advani. FES-PET imaging in estrogen receptor-positive breast cancer: implications for clinical management [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 PS1-06-16.

Abstract Introduction: Endocrine therapy (ET) is central to treating hormone receptor-positive breast cancer (BC), but its side effects impact adherence and quality of life, especially in patients with metabolic dysfunction. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer cardiometabolic benefits, potentially improving inflammation, glycemic control, and physical well-being. However, data on SGLT-2 use in BC patients is scarce. This study is the first to evaluate the real-world effects of SGLT-2 inhibitors on all-cause mortality and ET tolerability in BC patients. Methodology: We conducted a real-world analysis using the TrinetX database, which includes data from 184 million patients in 156 healthcare organizations, to identify BC patients on ET (letrozole, anastrozole, exemestane, tamoxifen) who received SGLT-2 inhibitors vs. those who did not. Patients were grouped by age (≤50 and ≥51 years as a surrogate for menopausal status. Primary outcome: all-cause mortality from the start of the index event, defined as the first day meeting BC diagnosis and ET use, with or without SGLT-2. Secondary endpoint: ET tolerability. Propensity score matching completed by TriNetX adjusted for confounders. Multivariate analysis yielded odds ratios and risk differences with 95% CI. Results: Among 1,136 BC patients ≤50 years, 568 were assigned to each group (SGLT-2 vs non-SGLT-2). For patients ≥51 years (n=28,600), each group included 14,300. Demographics across cohorts were comparable. No mortality benefit was seen in premenopausal patients. In postmenopausal women, SGLT-2 use reduced all-cause mortality—647/13,676 events (SGLT-2) vs 953/13,517 (non-SGLT-2) [OR: 0.655 (0.591-0.726)]. In premenopausal patients, SGLT-2 reduced endometrial cancer risk [RD: -0.018 (-0.029, -0.007)] but increased diarrhea risk [OR: 2.305 (1.078, 4.930)]. No significant differences were found in hot flashes, PE, DVT, depression, osteoporosis, joint pain, fatigue, nausea/vomiting, abdominal pain, or dizziness. Among postmenopausal patients, SGLT-2 reduced PE [OR: 0.757 (0.605-0.948)] and osteoporosis [OR: 0.877 (0.784-0.981)], but increased risks of depression [OR: 1.153 (1.007-1.319)], nausea/vomiting [OR: 1.120 (1.001-1.253)], diarrhea [OR: 1.193 (1.058-1.345)], and dizziness [OR: 1.234 (1.103-1.380)]. No significant differences were found for hot flashes, DVT, EC, joint pain, fatigue, or abdominal pain. Conclusion: This analysis reveals novel evidence supporting the cardiometabolic potential of SGLT-2 inhibitors in hormone receptor-positive BC, particularly postmenopausal populations. These agents were linked to lower all-cause mortality and improved tolerance of specific ET-related effects. However, certain adverse risks require caution. Future prospective studies are essential to validate their role and safety in oncologic care. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Evaluating all-cause mortality and endocrine therapy tolerability with sodium glucose cotransporter-2 inhibitors in hormone receptor-positive breast cancer: A real-world analysis [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 PS1-05-28.

Abstract BACKGROUND: Anthracycline chemotherapy-related cardiomyopathy (CCM) is a serious adverse event that can occur several years after completion of breast cancer (BC) therapy. Demographic and clinical risk factors have failed to predict which patients will experience CCM. Genetic variants can account for a significant proportion of inter-individual variation. Knowledge of genetic risk variants prior to chemotherapy will be informative for risk stratification and early intervention. The goal of our study is to identify genetic variants that predispose patients to CCM. Methods: We developed a cardiotoxicity registry at Mayo Clinic, Florida that enrolls patients who are to undergo standard of care chemotherapy in the early BC setting. Patients were (and continue to be) enrolled and consented for chart review and DNA sequencing. We sequenced whole exomes of the first 136 patients (anthracycline N=55, anti-HER2 (no anthracycline) N=71, other chemotherapy, N=10), primarily focusing on Titin (TTN) truncating variants, known to be present in ∼25% of patients with primary dilated cardiomyopathy, and previously reported in 7.5% of patients with CCM, followed by exploration of increased burden of rare non-synonymous variants in 60 established genes for primary cardiomyopathy. Filtering of rare non-synonymous variants included minor allele frequency <0.5% (in GnomAD database European, African and Asian ancestries) and CADDv1.7 PHRED score ≥20. Results: 18/55 (33%) patients treated with anthracycline experienced CCM. TTN truncating variants in were identified in 2/18 (11%) CCM patients and absent in 37 patients who did not experience CCM. Both patients with TTN variants had severe HF and required cardiac transplant. We identified a pathogenic variant in LMNA (p.Arg190Gln) in 1/18 (5.5%) patients and the same rare (p.Glu1127Gly) variant in RYR2 occurred in 2/18 (11%) of patients (Table 1). We noted enrichment of rare missense variants in anthracycline CCM patients compared to HER2 treated without anthracycline, CCM, p=0.0001. Conclusions: Pathogenic variants in TTN, LMNA, are enriched in BC patients (17%) who develop anthracycline-related cardiomyopathy. Early genetic screening may improve risk stratification and guide personalized cardiac monitoring to prevent CCM. Further research is needed to clarify the role of additional rare variants like RYR2 and to develop a CCM risk score based in idiopathic CM genes. Incorporating genetic risk assessments into treatment planning has the potential to enhance oncologic outcomes as well as long-term survivorship by preserving cardiac health. Citation Format: P. P. Advani, A. McPherson, J. Reddy, J. Schneider, S. Baheti, T. Nguyen, J. C. Ray, N. Norton. Genomic Insights into Anthracycline Cardiotoxicity: Enhancing Survivorship Care through Early Risk Identification [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 PS1-01-22.

Abstract Background: Combinations of antibody-drug conjugates and immunotherapy, such as trastuzumab deruxtecan (T-DXd) and rilvegostomig (rilve), respectively, offer promising efficacy but are associated with a heightened risk of drug-induced interstitial lung disease (ILD)/pneumonitis. Early detection and management are critical for optimizing patient safety, yet there are no standard protocols for real-time evaluation. We hypothesized that vigilant monitoring would enable early detection, prevent symptoms, and minimize the chance of treatment delays while testing novel therapeutic combinations that have a potential risk of ILD. Methods: We tested the combination of T-DXd and rilve administered every 3 weeks in the I-SPY2.2 phase 2 platform trial (NCT01042379), which enrolls patients with clinical stage II/III breast cancer commencing neoadjuvant systemic therapy. Given the potential risk of overlapping pulmonary toxicity of these two agents, we added rigorous monitoring with pulmonary function tests (PFTs), six-minute walk test (6MWT), and high-resolution chest CT (HRCT) scanning pretreatment and every 6 weeks thereafter. A real-time safety workflow was implemented, with pre-specified criteria for halting treatment and escalation to the next block of treatment. All abnormal findings reported on chest CT by site radiologist were centrally reviewed in real time by the study pulmonologist (T.K.) and cases of suspected ILD were adjudicated promptly by a safety committee consisting of the pulmonologist and several medical oncologists, enabling early study drug interruption and therapeutic interventions. Toxicity data were evaluated in the first 51 patients treated with T-DXd plus rilve, and a preplanned hold was initiated until safety was ascertained by the data and safety monitoring board. Results: Safety data were evaluated in the first 51 patients receiving T-DXd plus rilve. Eight ILD events were confirmed (15.68% incidence): 5 grade 1, 2 grade 2, and 1 grade 3. One patient had an early chest CT scan because of dyspnea. All cases were identified by HRCT scans; PFTs and 6MWT did not enhance early detection and were subsequently dropped from the monitoring protocol. No patient was symptomatic for more than 24 hours. Radiographic findings resolved within 14-55 days. Patients with grade 2 & 3 ILD were treated with corticosteroids. No cases of ILD required intensive care or escalated therapy beyond steroids. Early treatment escalation to the subsequent block of therapy occurred in 3 patients; all 3 patients were subsequently able to receive appropriate therapy. At the meeting, safety data from all 100 patients treated with this combination will be reported. Conclusion: Real-time, centralized monitoring and adjudication allowed for early detection and prompt management of ILD, which both mitigated severity and supported timely therapeutic management. Among the monitoring tools studied, HRCT scanning performed every 6 weeks proved most effective for early ILD identification; PFT and 6MWT did not enhance early detection. This approach offers a potential framework for future studies assessing pulmonary safety in regimens combining agents that have a known risk for inducing ILD. Citation Format: T. Kulkarni, R. Nanda, H. S. Rugo, C. C. OSullivan, K. M. Kalinsky, J. C. Boughey, P. R. Pohlmann, J. Perlmutter, D. Yee, A. Borowsky, F. Symmans, N. Hylton, L. Van ‘t Veer, C. Yau, L. Esserman. Real-time monitoring for drug-induced interstitial lung disease with Trastuzumab Deruxtecan and Rilvegostomig combination therapy prevents persistent, symptomatic disease: Safety insights from the I-SPY2.2 platform 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 PS1-01-09.

Abstract Background: Assessing invasive lobular carcinoma (ILC) with standard-of-care (SOC) imaging, such as 18F-fluorodeoxyglucose (FDG) PET-computed tomography (CT), is challenging. In May 2025, National Comprehensive Cancer Center Network guidelines added FES PET for recurrent/metastatic ILC staging. However, perceptions of the value added by FES PET to SOC imaging may vary, as only small ILC cohorts have been published. We evaluated FES PET’s clinical utility in the largest-studied cohort, to our knowledge, of ILC pts who have undergone FES PET. Methods: We identified all ILC pts who had an FES PET [PET-magnetic resonance (MR) or PET-CT)] between April 1, 2021, and May 1, 2025, at Mayo Clinic. Clinical and radiological data, including indications and management (mgmt) changes related to pts’ first FES PET, were obtained from clinical records. FES and SOC FDG PET were compared. Data were summarized with descriptive statistics. Results: 102 female pts were included: 88% White and 4.9% Black. Median age at initial breast cancer (BC) diagnosis was 57 (range, 36-79). At initial ILC diagnosis, most tumors were strongly estrogen receptor (ER) positive. Highest tumor grade was 1 in 25% of pts and 2 in 57%, with grade not documented in 19%; none had documented grade 3 ILC. Initial clinical prognostic stage was as follows: 26% stage 1, 21% stage 2, 10% stage 3, and 16% stage 4. At the time of FES PET, 37% had biopsy-confirmed metastatic ILC at the time of FES PET. The most common indications for FES PET were (re)staging ILC (49%), detecting suspected metastatic/recurrent BC (30%), and evaluating rising tumor markers like CA 15-3 or CA 27.29 (15%). 16% of pts were upstaged due to the FES PET result: 14 pts to stage 4 and 2 pts to stage 3. FES PET led to a mgmt change in 38 pts (37%), for whom the most common FES PET indications were (re)staging ILC (21 pts), detecting suspected recurrent/metastatic BC (11 pts), and detecting ER expression when biopsy was not feasible/nondiagnostic (7 pts). 19 scans (50%) led to a systemic therapy (tx) decision, 10 (26%) to a biopsy, 4 (11%) to additional imaging like MRI, 3 (8%) to locoregional tx, and 2 (5%) to a non-oncologic specialty referral to evaluate a suspected new metastasis. 11 pts had stage 4 BC pre-FES PET; their FES PET was ordered primarily for restaging (5 pts) or detecting ER expression (5 pts). Notably, of the 19 pts with a systemic tx-related change, 4 began a triple-negative BC regimen due to low FES uptake on the scan. Of the 15 pts who had FES PET to evaluate a rising tumor marker, a direct change in systemic tx occurred in 2 pts. 63/102 pts (62%) had FDG PET-CT prior to FES PET. Of these, 57% had discordant FDG and FES PET results. 39% had a higher number of avid metastatic lesions on FES PET as compared to FDG PET, primarily in the bone (8 pts) and lymph nodes (4 pts). 25% had bone, nodal, or soft tissue metastatic lesions that were FDG but not FES avid. 13 pts had FES PET-MRI; 9 of these had a prior FDG PET-CT. 2 PET-MRI pts had FES-avid metastatic lesions in unusual sites (brain, peritoneum) that were not FDG avid. Among the 38 pts with a mgmt change due to their FES PET result, 63% had prior FDG PET; 32% of the 38 pts had FES-avid metastatic lesions that were not seen on FDG PET, and 8% had FDG-avid but not FES-avid lesions. Conclusions: FES PET was useful for evaluating not only stage 4, but also early-stage ILC, with 1/3 of pts with an FES PET-driven mgmt change having early-stage BC. FES PET was most helpful for ILC (re)staging, detection of suspected recurrent/metastatic BC, and detection of ER expression when biopsy was not feasible/nondiagnostic. FES PET added clinically meaningful information beyond SOC imaging, with detection of FES-avid but not FDG-avid metastatic lesions in 1/3 of pts with an FES PET-driven mgmt change. Notably, FES PET-MRI demonstrated potential superiority over FDG PET in identifying atypical ILC metastases. Citation Format: T. Pai, C. Bullock, N. Wiest, E. Parent, P. Advani. Clinical utility of 18F-fluoroestradiol positron emission tomography (FES PET) in patients (pts) with lobular breast cancer [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 PD9-09.

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common breast cancer (BC) subtype, accounting for up to 15% of cases. Although several biologic differences between ILC and invasive carcinoma of no special type (NST) have been described, most data are derived from primary tumors. In contrast, the biology of metastatic ILC remains poorly defined. This study aimed to investigate the unique genomic, transcriptomic, and immune landscapes of metastatic ILC using a multi-omic approach. Methods: This real-world study included patients with confirmed NST or pure ILC who had a biopsy of a metastatic lesion or a breast lesion in the setting of known metastatic disease. Tumors underwent whole exome sequencing (NGS 592, NextSeq; WES, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Demographic and baseline molecular features were compared across histologic subtypes. Tumor mutational burden (TMB; high ≥10 mut/MB) was assessed by NGS. Immune cell populations were estimated by RNAseq deconvolution (quanTIseq). Pathway enrichment analysis was determined by GSEA. Overall survival (OS) was defined from the date of biopsy to death from any cause using Kaplan-Meier estimates. Statistical tests included chi-square and Mann-Whitney U with multiple testing correction (q<0.05). Results: Among 2,651 metastatic BC samples (ILC n = 608; NST n = 2,043), patients with ILC were older (median 67 vs 63 yrs) and more likely white (81.5% ILC vs 73.1% NST), all p<0.05. By IHC, ILC were more frequently HR+/HER2- (83.6% vs 55.9%), less commonly triple-negative (11.9% vs 29.8%) or HER2+ (4.6% vs 14.3%), all p<0.05. PAM50 subtypes differed between ILC and NST: luminal A (Lum A) (31.1% vs 13.7%) and luminal B (Lum B) (44.9% vs 43.8%) intrinsic subtypes were enriched in ILC, while NST was more frequently basal (1.2% vs 22.4%) and HER2-enriched (19.8% vs 22.2%), all p<0.05. Within luminal BC, Lum B was more common than Lum A in both histologies, but Lum A was proportionally more frequent in ILC (ILC: 40.3% Lum A vs 59.7% Lum B; NST: 23.4% Lum A vs 76.6% Lum B), p<0.0001. Comparative multi-omic analysis focused on the 922 HR+/HER2- tumors (ILC n = 275; NST n = 647). Compared to NST, ILC had higher frequency of CDH1 (87.3% vs 6.1%), PIK3CA (52.7% vs 38.5%), FOXA1 (9.0% vs 3.4%), ERBB2 (7.1% vs 2.0%), ARID1A, and NF1 (both q < 0.05) mutations and TMB high (17.7% vs 9.9%), but lower frequency of TP53 (15.7% vs 33.3%), ESR1 (10.9% vs 18.1%) and GATA3 (2.3% vs 14.9%) mutations along with FGFR1 amplifications (15.3% vs 6.7%), all q<0.05. ILC had higher expression of androgen receptor (91.2% vs 83.5%, q<0.05) and higher MAPK activation score (-0.81 vs -1.19, q<0.05), consistent with a luminal, hormone-driven phenotype. NST tumors demonstrated enrichment of pathways involved in the cell cycle and metabolic activity, including E2F targets, G2M checkpoint, MYC targets, mTORC1 signaling, glycolysis, and unfolded protein response (NES: 1.5-2.7, FDR<0.25). ILC tumors had higher infiltration of B cells, dendritic cells, neutrophils, NK cells and M2 macrophages, but lower M1 macrophages, all q<0.05. ILC had differential expression of immune checkpoint genes (upregulation: CD274 (PD-L1), PDCD1 (PD-1), TNFSF14, CEACAM1, CD160, fold change (FC): 1.2-1.5; down: HAVCR2 (TIM-3): FC: 1.2), all q<0.05. Median OS (mOS) was similar between luminal ILC and NST (33.8 vs 35.4 months (mo); HR 1.0, 95% CI 0.91-1.3). No mOS difference was seen between Lum A ILC and NST (47.4 vs 50.5 mo; HR 1.0, 0.84-1.43), while Lum B ILC had worse mOS than NST (27.4 vs 35.3 mo; HR 1.3, 1.1-1.6). Conclusions: This study represents the largest cohort to date with multi-omic characterization of metastatic ILC, revealing distinct genomic, transcriptomic, and immune features compared to NST. These findings highlight the unique biology of ILC and may inform future subtype-specific therapeutic strategies. Citation Format: G. Nader-Marta, S. Kumar Deshmukh, K. Fanucci, P. Tarantino, S. Schnitt, A. Lee, S. Oesterreich, S. Wu, J. Xiu, P. Advani, M. Lustberg, N. Lin, S. Tolaney, E. Mayer, O. Metzger, G. Sledge Jr., R. Jeselsohn. The Genomic, Transcriptomic, and Immune Hallmarks of Metastatic Lobular Breast Cancer [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 PD9-07.