12136 Background: Taxane-induced peripheral neuropathy (TIPN) affects up to 70% of patients receiving taxanes and can lead to severe, irreversible symptoms that impair daily functioning and quality of life. Approximately 25% of patients require taxane dose modification or discontinuation to prevent TIPN, compromising treatment effectiveness and survival. Self-reported Black patients experience nearly two times greater incidence of TIPN compared to White patients, contributing to treatment alterations and worse cancer outcomes. Vitamin D insufficiency, which is more common among Black patients, has been implicated as a modifiable risk factor for TIPN. This study assessed the extent to which vitamin D insufficiency mediates the racial disparity in TIPN. Methods: This secondary analysis included self-reported Black or White female patients with early-stage breast cancer treated with paclitaxel-based chemotherapy on the SWOG S0221 phase III trial. The primary endpoint was clinician-assessed grade ≥3 sensory neuropathy per NCI CTCAE attributed to paclitaxel. The mediator was pretreatment vitamin D insufficiency, defined as total 25-hydroxyvitamin D ≤20 ng/mL. Causal mediation analysis decomposed the total effect of race on TIPN into its direct effect and an indirect effect mediated through vitamin D insufficiency, adjusted for age and paclitaxel regimen (weekly or every other week). Log-linear model with modified Poisson regression and weighted logistic regression were used for the outcome model and the mediator model, respectively. Confidence intervals were computed via bootstrapping, and significance was set at α=0.05. Results: A total of 1,106 participants (mean age 51.2 [SD 10] years) were included, of whom 109 were Black and 997 were White. Black patients had a higher prevalence of vitamin D insufficiency (77% vs. 28%, p <0.001) and a higher incidence of grade ≥3 sensory TIPN (29% vs. 14%, p <0.001). The adjusted risk ratio (RR) for TIPN comparing Black to White patients was 2.24 (95% CI, 1.54-3.19; p <0.001). Vitamin D insufficiency statistically mediated this association, with an indirect effect RR of 1.18 (95% CI, 1.01-1.38; p = 0.048), accounting for 27% of the racial disparity in TIPN. The direct effect of race on TIPN, independent of vitamin D status, remained significant (RR 1.90; 95% CI, 1.30-2.85; p <0.001). Conclusions: Vitamin D insufficiency contributes to, but does not entirely explain, the racial disparity in TIPN. While other unaccounted factors may interact with or modify this association, vitamin D supplementation in insufficient patients could partially reduce racial disparities in TIPN and improve pharmacoequity.

107 Background: Despite effective endocrine therapy, the absolute benefit of adjuvant chemotherapy varies widely in node-positive HR+ disease, particularly among patients with 1-3 positive nodes. Prognostic tools for these patients often rely on genomic assays, which are costly, timely, or inaccessible in many clinical settings. We present a multimodal artificial intelligence (MMAI) model that integrates clinical and histopathological data to quickly stratify risk of distant metastasis and inform therapeutic decisions. Developed in six phase III randomized clinical and validated for chemotherapy benefit in N0 patients, MMAI offers an accessible alternative to genomic tools. Here, we validated MMAI for prognosis and prediction of chemotherapy benefit in SWOG S8814 – a randomized phase III trial of tamoxifen ± chemotherapy (CT) in postmenopausal women with node-positive (N+) HR+ breast cancer. Methods: Patients with digitized baseline H&E- stained diagnostic slides and clinical data (age, tumor size, nodal status) were analyzed (N = 413). The locked MMAI generated a continuous risk score and categorical risk groups (low, high). Associations with disease-free survival (DFS; 168 events) and overall survival (OS; 125 events) were assessed using univariable and multivariable Cox Proportional Hazard models. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated. Differential CT benefit was evaluated by estimating relative risk reduction by MMAI risk groups. Results: MMAI was prognostic for DFS (HR per SD 1.73, 95% CI 1.48–2.03; p < 0.001) and OS (HR per SD 1.93, 95% CI 1.60–2.32; p < 0.001), remaining significant after adjustment for age, tumor size, and nodal burden. In the subset of patients with 1–3 positive nodes (n = 253), MMAI identified differential CT benefit: high-risk patients (56% of the patients) demonstrated a 26.3% relative reduction in 10-year DFS risk with CAF-T+TAM versus TAM alone, while low-risk patients (44% of the patients) derived minimal benefit (1.8% relative reduction in 10-year DFS risk). Additionally, the addition of CT resulted in DFS HRs of 1.21 (95% CI: 0.51-2.83) and 0.85 (95% CI: 0.55-1.23) in low- and high-risk patients, respectively. Conclusions: In SWOG S8814, a locked MMAI model using routinely available pathology and clinical data independently stratified prognosis and identified node-positive HR+ patients most likely to benefit from adjuvant CT, with minimal benefit among MMAI low-risk patients with 1–3 nodes. These findings support the use of MMAI as a fast (hours instead of weeks), scalable, cost-effective, and non-tissue consumptive alternative to genomic testing to inform adjuvant decisions in HR+ N+ EBC patients.

Importance The NRG Oncology research organization and NSABP B-35 randomized clinical trial prospectively collected margin width data on postmenopausal women with hormone receptor (HR)–positive ductal carcinoma in situ (DCIS) who underwent lumpectomy, whole-breast irradiation (WBI), and randomly assigned adjuvant anastrozole or tamoxifen therapy. This permitted analysis of outcomes per margin width. Objective To analyze the effect of margin width on ipsilateral breast tumor recurrence (IBTR). Design, Setting, and Participants NSABP B-35 was a phase 3, double-blind, randomized clinical trial in which patients were randomized to either 5 years of tamoxifen or anastrozole. Postmenopausal women with HR-positive DCIS and tumor-free margins were eligible. Enrollment was from January 6, 2003, to June 15, 2006, in academic and community hospital members of the NSABP. Study data were analyzed from July 2024 to April 2025. Interventions There were no specific interventions based on lumpectomy margin width. Main Outcomes and Measures Lumpectomy margin width data were prospectively collected within 3 months of randomization. A pathology form classified margins as positive (ink on tumor), close (<1 mm), or negative (≥1 mm). For the negative margin subgroup, closest margin width was stated separately. Thus, an ancillary analysis using 1-mm and 2-mm margin width partitions was performed. Results A total of 3104 postmenopausal women (mean [SD] age, 61 [7.8] years) were enrolled in NSABP B-35. In an ancillary analysis, 2707 patients were included in the 1-mm margin width partition group, and 2546 patients were included in the 2-mm margin width partition group. IBTR was the most common first event, occurring in 90 of 2707 patients (3.3%): 24 of 502 patients (4.8%) with a margin width less than 1 mm and 66 of 2205 patients (3.0%) with a margin width greater than or equal to 1 mm. Ten-year unadjusted cumulative incidence of IBTR events was 5.6% vs 4.0% for margins less than 1 mm vs margins greater than or equal to 1 mm ( P = .04). Using 2 mm as the discriminant threshold for margin width, 39 of 879 patients (4.4%) with margins less than 2 mm and 49 of 1667 patients (2.9%) with margins greater than or equal to 2 mm experienced an IBTR first. Ten-year unadjusted cumulative incidence of IBTR events with margins less than or equal to 2 mm was 5.3% vs 3.8% for those with margins greater than 2 mm ( P = .05). In models adjusting for other patient and tumor factors, margin width was not a significant predictor of IBTR risk (2-mm threshold hazard ratio, 1.33; 95% CI, 0.86-2.06). Conclusions and Relevance Results of this ancillary analysis of the NSABP B-35 trial show that absolute differences in IBTR rates using margin width groupings of less than 1 mm or greater than or equal to 1 mm and margin width groupings of less than 2 mm or greater than or equal to 2 mm in postmenopausal women with HR-positive DCIS receiving lumpectomy, WBI, and adjuvant endocrine therapy were small. Omission of reexcision lumpectomies based on margin widths of less than 1 mm or less than 2 mm can be reconsidered in appropriate patients. Trial Registration ClinicalTrials.gov Identifier: NCT00053898

Importance:Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood. Objective:To compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated. Design, Settings, and Participants:This was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor-positive ERBB2-negative (formerly HER2-negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025. Intervention:Random assignment to CET or ET. Main Outcomes and Measures:Mean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes. Results:Of the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was -3.02 (95% CI, -5.33 to -0.72; P = .01) for premenopausal and -2.37 (95% CI, -3.92 to -0.82; P = .003) for postmenopausal participants. Conclusions and Relevance:This secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy. Trial Registration:ClinicalTrials.gov Identifier: NCT01272037.

We developed and validated IICM+, a multimodal model integrating clinicopathologic variables, transcriptomic features, and multiscale histopathology-derived image representations to predict distant recurrence in hormone receptor-positive, HER2-negative, node-negative early breast cancer. Image features included tile-level embeddings and slide-level representations generated by a custom multimodal foundation model pretrained on paired histopathology images, RNA sequencing, and pathology reports. Using TAILORx specimens with long-term follow-up, models were trained in a development cohort with five-fold cross-validation (n = 2808) and evaluated in an independent institutional holdout validation set (n = 1621). In holdout validation, IICM+ showed strong prognostic discrimination for overall distant recurrence (C-index 0.735, 95% CI 0.681–0.782), early distant recurrence (0.791, 95% CI 0.715–0.858), and late distant recurrence (0.710, 95% CI 0.645–0.773). IICM+ separated high- versus low-risk groups for overall distant recurrence (HR 5.25, 95% CI 3.50–7.86; P < 0.001) and remained prognostic (HR 3.56, 95% CI 2.22–5.70, P < 0.001) after adjustment for clinicopathologic covariates and RS category. IICM+ also identified RS/IICM+ discordant groups with different observed recurrence risks, supporting additional prognostic stratification beyond RS.

BACKGROUND:S0221 investigated weekly vs every 2 weeks dosing of doxorubicin (A) and cyclophosphamide (C) followed by paclitaxel in patients with high-risk early breast cancer. After an interim analysis, random assignment to the 2 AC arms was stopped for futility, and the trial was modified to study only the paclitaxel schedules. METHODS:Between December 2003 and November 2010, a total of 2716 patients were randomly assigned in a 2 × 2 factorial design to 15 weeks of weekly A and daily C vs 6 cycles of every 2 weeks AC; and weekly paclitaxel for 12 weeks vs 6 cycles of every 2 weeks paclitaxel. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of every 2 weeks AC and randomly assigned to weekly vs every 2 weeks paclitaxel. Updated survival was assessed using log-rank tests and Cox regression models. We compared outcomes by breast cancer subtype as well. RESULTS:At a median follow-up of 12.1 years, there were no statistically significant differences among the 4 treatment arms in disease-free survival (DFS) (P = .91) or overall survival (P = .34) in the original protocol. Among the 578 patients assigned AC for 4 cycles and randomly assigned to paclitaxel weekly vs every 2 weeks paclitaxel, there were no overall differences in DFS (P = .32) or overall survival (P = .42). CONCLUSION:As there were no statistically significant outcome differences in DFS or overall survival between the studied schedules of AC and paclitaxel with extended follow-up in the original or revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference.

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Importance:The NRG Oncology research organization and NSABP B-35 randomized clinical trial prospectively collected margin width data on postmenopausal women with hormone receptor (HR)-positive ductal carcinoma in situ (DCIS) who underwent lumpectomy, whole-breast irradiation (WBI), and randomly assigned adjuvant anastrozole or tamoxifen therapy. This permitted analysis of outcomes per margin width. Objective:To analyze the effect of margin width on ipsilateral breast tumor recurrence (IBTR). Design, Setting, and Participants:NSABP B-35 was a phase 3, double-blind, randomized clinical trial in which patients were randomized to either 5 years of tamoxifen or anastrozole. Postmenopausal women with HR-positive DCIS and tumor-free margins were eligible. Enrollment was from January 6, 2003, to June 15, 2006, in academic and community hospital members of the NSABP. Study data were analyzed from July 2024 to April 2025. Interventions:There were no specific interventions based on lumpectomy margin width. Main Outcomes and Measures:Lumpectomy margin width data were prospectively collected within 3 months of randomization. A pathology form classified margins as positive (ink on tumor), close (<1 mm), or negative (≥1 mm). For the negative margin subgroup, closest margin width was stated separately. Thus, an ancillary analysis using 1-mm and 2-mm margin width partitions was performed. Results:A total of 3104 postmenopausal women (mean [SD] age, 61 [7.8] years) were enrolled in NSABP B-35. In an ancillary analysis, 2707 patients were included in the 1-mm margin width partition group, and 2546 patients were included in the 2-mm margin width partition group. IBTR was the most common first event, occurring in 90 of 2707 patients (3.3%): 24 of 502 patients (4.8%) with a margin width less than 1 mm and 66 of 2205 patients (3.0%) with a margin width greater than or equal to 1 mm. Ten-year unadjusted cumulative incidence of IBTR events was 5.6% vs 4.0% for margins less than 1 mm vs margins greater than or equal to 1 mm (P = .04). Using 2 mm as the discriminant threshold for margin width, 39 of 879 patients (4.4%) with margins less than 2 mm and 49 of 1667 patients (2.9%) with margins greater than or equal to 2 mm experienced an IBTR first. Ten-year unadjusted cumulative incidence of IBTR events with margins less than or equal to 2 mm was 5.3% vs 3.8% for those with margins greater than 2 mm (P = .05). In models adjusting for other patient and tumor factors, margin width was not a significant predictor of IBTR risk (2-mm threshold hazard ratio, 1.33; 95% CI, 0.86-2.06). Conclusions and Relevance:Results of this ancillary analysis of the NSABP B-35 trial show that absolute differences in IBTR rates using margin width groupings of less than 1 mm or greater than or equal to 1 mm and margin width groupings of less than 2 mm or greater than or equal to 2 mm in postmenopausal women with HR-positive DCIS receiving lumpectomy, WBI, and adjuvant endocrine therapy were small. Omission of reexcision lumpectomies based on margin widths of less than 1 mm or less than 2 mm can be reconsidered in appropriate patients. Trial Registration:ClinicalTrials.gov Identifier: NCT00053898.

BACKGROUND:The RxPONDER trial has guided adjuvant chemotherapy use in node-positive HR+/HER2- breast cancer; however, prior analyses showed poorer outcomes among non-Hispanic Black (NHB) women compared with non-Hispanic White (NHW) women despite similar 21-gene Recurrence Score® (RS) results. This suggests contributors to disparities may not be captured by the composite RS. We evaluated RS gene group components-proliferation, estrogen receptor (ER), HER2 (GRB7), and invasion-by ethnicity, body mass index, and menopausal status, and assessed associations with outcomes. METHODS:RxPONDER enrolled 5,083 women with HR+/HER2- breast cancer, 1-3 positive nodes, and RS ≤ 25, randomized to endocrine therapy ± chemotherapy. 3,102 participants with ethnicity and gene expression data were included. RS components were compared across subgroups, and associations with invasive disease-free survival (IDFS) and distant recurrence-free interval were evaluated using multivariable Cox models adjusted for clinicopathologic factors and treatment. RESULTS:Among 3,102 women (70.2% NHW, 15.5% Hispanic, 9.5% Asian, 4.7% NHB), RS distributions were similar across groups and prognostic overall. Tumors from NHB (p = 0.003) and Hispanic (p = 0.02) had higher proliferation scores versus NHW women, while Asian women had higher HER2 (p = 0.006) and ER scores (p = 0.028). IDFS differences were not statistically significant for NHB vs. NHW women (HR 1.41; 95% CI 0.98-2.03), whereas Asian women had improved IDFS (HR 0.63; 95% CI 0.43-0.91). CONCLUSIONS:Despite similar overall RS distributions, component pathways vary by ethnicity and may contribute to outcome differences. These findings support evaluating gene-specific biology beyond composite scores to better understand disparities and refine risk stratification. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01272037.

Importance:Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective:To evaluate the combination of anti-programmed cell death 1 protein (PD-1) cemiplimab and anti-lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2-negative early-stage, high-risk breast cancer. Design, Setting, and Participants:The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2-negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions:Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures:Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results:A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2, 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2-negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance:In this randomized clinical trial, the combination of PD-1 and anti-LAG-3 inhibition with standard NAC was effective in early-stage ERBB2-negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration:ClinicalTrials.gov Identifier: NCT01042379.

QuestionHow does chemoendocrine therapy (CET) compared to endocrine therapy (ET) alone affect cancer-related cognitive impairment (CRCI) in pre- and postmenopausal patients?FindingsThis secondary analysis of the RxPONDER randomized clinical trial included 568 participants assessed at 6, 12, and 36 months and found that CET had a greater negative association with patient-reported cognitive function compared to ET alone in both the pre- and postmenopausal groups.MeaningThese findings indicate that cognitive impairment occurs and persists more frequently with CET than with ET alone among both pre- and postmenopausal patients; therefore, interventions to prevent and treat CRCI are needed. ImportanceBreast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood.ObjectiveTo compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated.Design, Settings, and ParticipantsThis was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor-positive ERBB2-negative (formerly HER2-negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025.InterventionRandom assignment to CET or ET.Main Outcomes and MeasuresMean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes.ResultsOf the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was -3.02 (95% CI, -5.33 to -0.72; P = .01) for premenopausal and -2.37 (95% CI, -3.92 to -0.82; P = .003) for postmenopausal participants.Conclusions and RelevanceThis secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy.Trial RegistrationClinicalTrials.gov Identifier: NCT01272037 This secondary analysis of the RxPONDER randomized clinical trial assesses patient-reported cognitive impairment by menopausal status among women with breast cancer treated with chemoendocrine therapy vs endocrine therapy alone.

BACKGROUND:The phase III RxPONDER trial has affected treatment for node-positive (1-3), hormone receptor-positive, HER2-negative breast cancer with a 21-gene recurrence score (RS) less than 26. We investigated how these findings apply to different racial and ethnic groups within the trial. METHODS:The trial randomly assigned women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS), with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathological characteristics, RS, and treatment. RESULTS:A total of 4048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB) (6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW) (70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHB participants (5-year IDFS 91.6% vs 87.1%, HR = 1.37; 95% CI = 1.03 to 1.81) and better for Asians (91.6% vs 93.9%, HR = 0.64; 95% CI = 0.46 to 0.91). Relative to NHW, DRFS was worse for NHB participants (5-year DRFS 95.8% vs 91.0%, HR = 1.65; 95% CI = 1.17 to 2.32) and better for Asians (95.8% vs 96.7%, HR = 0.59; 95% CI = 0.37 to 0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity. CONCLUSIONS:NHB women had worse clinical outcomes compared with NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01272037.

Background: While the landscape of metastatic breast cancer treatment has evolved over the years with incorporation of targeted agents and antibody drug conjugates, chemotherapy continues to be the mainstay of adjuvant treatment for high-risk early breast cancer. S0221 was a previously reported phase III randomized trial performed by the North American Breast Cancer Intergroup (now known as the National Clinical Trials Network [NCTN]) investigating alternative dosing schedules of chemotherapy for early breast cancer. Methods: S0221 investigated weekly (arms 2 and 4) doxorubicin (A)/cyclophosphamide (C) + granulocyte colony stimulating factor (GCSF; filgrastim or pegfilgrastim) versus (vs.) every 2 weeks (Q2W) (arms 1 and 3) schedule AC, followed by paclitaxel (P) given Q2W or weekly for 12 weeks as post-operative adjuvant therapy in node-positive or high-risk node-negative breast cancer. Weekly AC was given as doxorubicin 24mg/m2 IV once per week and cyclophosphamide 60mg/m2 orally once per day with GCSF. Between December 2003 and November 2010, 2716 patients were randomized in a 2x2 factorial design to: 1) 15 weeks of weekly AC vs. 6 cycles of Q2W AC and 2) P weekly vs. P Q2W with GCSF support and this accounted for arms 1-4. After enrollment of 2716 patients, randomization to the two AC arms was stopped for futility and the trial was modified to study only the P schedules. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of Q2W AC and randomized to P weekly vs. Q2W accounting for arms 5-6. Here, we present updated survival outcomes of four arms on the original protocol and report, for the first time, analysis of 578 patients from two additional arms on the revised protocol. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 12.1 years, among the patients treated in the original protocol, there were no significant differences among the four treatment arms for disease free survival [DFS] (p=0.91) or overall survival [OS] (p=0.34). When stratified by disease subtype, the human epidermal receptor-2 (HER2) positive cohort had the highest 10-year DFS rate (77.7%) compared to HR-positive/HER2-negative (70.6%) or HR-negative/HER2-negative (70.3%) cohorts (p value = 0.0005). The HER2-positive cohort also had a superior 10-year OS rate of 82.3% compared to HR-positive/HER2-negative (78.1%) or HR-negative/HER2-negative (74.9%) cohorts (p=0.0044). Among the 578 patients assigned AC for 4 cycles and randomized to P weekly vs. Q2W P, there were no overall differences in DFS (p=0.32) or OS (p=0.42). There was no difference in 10-year DFS rate between original (71.3%) or revised (74.4%) protocol (HR 0.80; 95% CI 0.75-1.05). Patients were also stratified in terms of sex (23 men enrolled) and race (379 Blacks enrolled). While women have superior DFS and OS compared to men, due to small number of men and wide CI, these data should be interpreted with caution. Black patients had worse DFS and OS (10-year DFS rate of 64.2% vs. 72.8%; 10-year OS rate of 70.4% vs. 79.0%) compared to non-Blacks. In terms of toxicity, cardiac toxicity profile was more favorable in arms 2 and 4 (0.5-0.7%) that used weekly AC compared to the other four arms that incorporated AC Q2W (1.1-3.3%). There was more skin toxicity with weekly AC schedule with 15.7-16.1% events compared to 2.4-4.0% events in the other four arms. There was no difference in infectious risk or changes in metabolic profile but there were more neurological AEs, and more pain with arms that used Q2W paclitaxel compared to weekly paclitaxel. Conclusion: As there were no significant outcome differences in DFS or OS between the studied schedules with extended follow-up in the original cohort or in the additional 578 patients treated on the revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Citation Format: Azka Ali, William E Barlow, Halle CF Moore, Timothy J Hobday, Claudine Isaacs, Muhammad Salim, Jonathan K Cho, Kristine J Rinn, Kathy S Albain, Helen K Chew, Gary V Burton, Timothy D Moore, Gordan Srkalovic, Bradley A McGregor, Lawrence E Flaherty, Danika. Long-Term Follow-up and updated analysis from S0221, Comparing Alternative Dose-Schedules of Adjuvant Anthracycline/Taxane Therapy in High-Risk Early Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF1-04.

Background: Mechanisms of response and/or resistance to chemotherapy, immunotherapy, or PARP inhibitors in triple negative breast cancer (TNBC) are not well understood. Death Domain-Associated Protein 6 (DAXX) is a multifunctional protein that promotes cell death, represses gene transcription, and maintains a heterochromatin state. We showed previously that DAXX is a potent inhibitor of breast cancer stem cells and resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer (Peiffer et al., Cancer Res. 2018). In this study, we explored the role of DAXX in TNBC and sensitivity to chemotherapy and olaparib in vitro and in vivo. We also investigated mechanisms by which DAXX modulated growth and response to chemotherapy in TNBC cell lines using RNA sequencing. Methods: Proliferation and cell cycle analysis were performed for three TNBC cell lines (MDA-MB-231, BT549, and MDA-MB-468) that expressed DAXX or were depleted for DAXX using siRNA. Sensitivity to carboplatin, paclitaxel, and doxorubicin was determined by measuring proliferation. PARP-1 activity was assessed by detecting global protein PARylation levels using Western blotting. Olaparib was used to assess the role of PARP-1 activation in DAXX-depleted TNBC cell lines. Xenografts studies in vivo measured tumor growth of MDA-MB-231 DAXX-expressing or DAXX-depleted tumord treated with vehicle, paclitaxel, olaparib, or the combination. Overall survival of mice was assessed using Kaplan-Meier and a Mantel-Cox Log Rank test. RNA-sequencing was performed on RNA from two TNBC cell lines (MDA-MB-231 and MDa-MB-468) expressing DAXX or depleted for DAXX. The KMplotter tool interrogated recurrence free survival of patients with high DAXX versus low DAXX RNA expressing TNBC. Results: Depletion of DAXX increased cell proliferation of three TNBC cell lines by promoting cell cycle progression through the S-phase compared to DAXX-expressing cell lines. DAXX-depleted TNBC cell lines were 2-5 fold more sensitive to carboplatin and paclitaxel, but not to doxorubicin as measured by IC50 calculations. Depletion of DAXX increased PARP-1 activity and modestly increased sensitivity to olaparib. In vivo, DAXX-depleted TNBC tumors grew at a faster rate than DAXX-expressing tumors. Although DAXX expression did not change the anti-tumor efficacy of paclitaxel or olaparib in vivo, overall survival of mice was 100% up to 40 days when TNBC tumors had low DAXX compared to only 25% of mice surviving with TNBC expressing high DAXX and treated with paclitaxel. Mechanistically, RNA-sequencing followed by Gene Ontology pathway analysis showed that DAXX-depleted TNBC cells have higher expression of genes that regulate cell cycle progression and lower expression of genes that regulate the unfolded protein response. The KMPlotter tool revealed that patients (N=370) with TNBC have better recurrence free survival (hazard ratio = 1.79, P=0.0032) if their tumors have lower DAXX RNA levels. Conclusions: These results suggest that DAXX is a critical growth regulator and potential predictor of response to carboplatin or paclitaxel in TNBC. The mechanism by which DAXX modulates sensitivity to chemotherapy and drug resistance could be through regulation of cell cycle genes. Future studies will focus on elucidating the mechanism by which DAXX regulates these enriched genes and pathways and if DAXX is a potential predictive biomarker for recurrence free survival. Citation Format: Debra Wyatt, Michelle Fernandez, Ava Gureghian, Kathy S. Albain, Clodia Osipo. Mechanistic Insight into DAXX-Modulated Sensitivity to Chemotherapy in Triple Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-09-22.

Breast cancer subtyping is essential for precision oncology, influencing prognosis, treatment selection, and clinical trial design. The Integrative Subtype Classification (IC) categorizes breast tumors into groups with distinct long-term outcomes based on genomic and correlated transcriptomic features. This method relies on sequencing data, which, despite decreasing costs, is not always available in research or clinical settings. Here we introduce PATH-IC, a computational pathology model that predicts ER+ breast cancer IC subtype risk of relapse categories from routine histology data. We enhance the current state-of-the-art computational pathology approach with BERGERON, which leverages generative AI to correct class imbalance and reduce overfitting, showing that synthetic data improves PATH-IC's performance by the equivalent of 41% more real training samples. PATH-IC achieves a testing AUROC of 0.814, with predictions correlating to Oncotype DX scores and long-term relapse risk. Using attention-based model interpretation and CRAWFORD, a novel embedding-to-image foundation model, we demonstrate that PATH-IC identifies expected tumor microenvironment patterns for IC subtypes and highlights heterochromatin condensation as a key feature of high-risk tumors. Matched single-cell spatial transcriptomics confirm IC subtype-specific gene expression patterns identified by PATH-IC, including active metabolic, proliferative, and proteostasis pathways in the high-risk group. PATH-IC advances computational pathology through generative AI, enabling subtype inference from histopathology data. ### Competing Interest Statement Unrelated to this work, the following interests are declared: C.C. has advised Bristol Myers Squibb, DeepCell, Genentech, NanoString, Pfizer and 3T Biosciences and has equity in 3T Biosciences, DeepCell and Illumina. All other authors declare no competing interests.

LBA509 Background: I-SPY2.2 is a multicenter phase 2 platform sequential multiple assignment randomized trial (SMART) evaluating novel experimental regimens in the neoadjuvant breast cancer setting. The novel therapy is given as first in a sequence (Block A), followed by standard chemo/targeted therapies (Block B/C) if indicated. The goal is to identify agents that lead to pCR after novel targeted agents alone, or in sequence with optimal therapy assigned based on the tumor response predictive subtype (RPS). RPS incorporates expression-based immune, DNA repair deficiency (DRD), and luminal signatures with hormone receptor (HR) and HER2 status to classify patients by subtype: S1: HR+HER2-Immune-DRD-; S2: HR-HER2-Immune-DRD-; S3: HER2-Immune+; S4: HER2-Immune-DRD+; S5: HER2+/non-Luminal; S6: HER2+/Luminal. Methods: RPS S1, S2, S3 and S4 were eligible for assignment to Dato in Block A. Patients (pts) were followed by MRI during treatment (at 3, 6 and 12 weeks after start of Blocks A and B). Predicted responders by MRI and biopsy at the end of Block A or B have the option of going to surgery early, otherwise they proceed to next treatment Block (B +/- C). Randomization to Block B includes a taxane-based regimen specific to the RPS, and options include S1: paclitaxel; S2 and S3: paclitaxel + carboplatin + pembrolizumab; S4: paclitaxel + carboplatin vs. paclitaxel + carboplatin + pembrolizumab. Patients who did not go to surgery after Block B proceeded to Block C (AC or AC + Pembrolizumab if HR-HER2-). The primary endpoint is pCR. Efficacy is evaluated within each RPS and HR+HER2- and HR-HER2- signatures. To estimate the arm's efficacy as a stand-alone therapy, we use a Bayesian covariate-adjusted model to estimate the pCR rate and compare the posterior distribution to a subtype-specific fixed threshold. This model uses pCR data when available and MRI data when pCR is not. To estimate pCR rate in the context of a multi-decision treatment regimen, we use a Bayesian model based on if and when a pCR occurred in the trial. The posterior is compared to a subtype-specific dynamic control generated from historical I-SPY data. Results: 103 pts were randomly assigned to the Dato arm between August 2022 and August 2023. All patients have proceeded beyond Block A; 33 went to surgery after Dato alone. The efficacy results for Dato as a stand-alone therapy are summarized in Table. Conclusions: Dato monotherapy was active, particularly in the HR-HER2- signature, but did not meet the pre-specified threshold for graduation in I-SPY 2.2. Clinical trial information: NCT01042379 . [Table: see text]

PURPOSELong-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need.METHODSIn the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia.RESULTSAfter a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively.CONCLUSIONAdjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

AbstractPurpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy “graduates” if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%–99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.