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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

570 Background: Major histocompatibility complex class I (MHC I) plays a critical role in immune surveillance by binding peptides derived from intracellular proteins and presenting them on the cell surface for recognition by CD8+ T cells. Loss or downregulation of MHC I expression has been identified as a key mechanism of immune evasion in cancers. Here, we evaluated MHC I expression and outcomes in all subtypes of breast cancer (BC). Methods: 9,038 BC samples were analyzed via NGS (592-gene panel, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences, Phoenix, AZ), including triple-negative BC (TNBC) 3,038, HER2-positive (HER2+) 1,082, and hormone receptor-positive (HR+HER2-) 4,918. Immune cell fractions were estimated using WTS deconvolution (Quantiseq). MHC I ( HLA-A / HLA-B / HLA-C )-high (H) and -low (L) were classified by RNA expression above or below the 25th percentile. Real-world overall survival (OS) was derived from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier. NanoString IO360 was performed in 114 samples from the FinXX trial (NCT00114816). Statistical significance was assessed using chi-square, Mann-Whitney U, ANOVA, and Cox regression with multiple comparison adjustments (q<.05). Results: TNBC had higher expression of HLA-A and HLA-B (median TPM: 169 and 191) compared to HER2+ (146.6 and 170, q<0.05) and HR+HER2- (141.7 and 157.5, q<0.05). However, there was no significant difference in HLA-C expression across 3 BC subtypes. In TNBC, MHC I-H tumors had higher frequencies of PD-L1 positivity (66.2% vs. 13.1%) as well as higher infiltration of B cells (4.5% vs. 3.2%), M1 macrophages (5% vs. 1.5%), M2 macrophages (4% vs. 2.1%), Tregs (2.8% vs. 0.8%), CD8 + T cells (1.8% vs. 0%), dendritic cells (3.2% vs. 2.8%), higher T-cell inflamed score (137 vs. -144), and IFN g score (0.02 vs. -0.49) compared to MHC I-L TNBC (all q<.05). MHC I-H TNBC was associated with significant improvement in median OS (30.1 vs. 15.2 months, HR 0.55, 95% CI 0.46-0.65, p<0.0001). However, this survival difference was not observed in patients with MHC I-H vs. MHC I-L in HER2+ (HR 1.04, 95% CI 0.74-1.47, p = 0.81) and HR+HER2- (HR 0.87, 95% CI 0.75-1.02, p= 0.09) BC subtypes. We further validated the MHC I expression in the FinXX trial. Similarly, patients with MHC I-H had significant improvement in recurrence-free survival (HR 0.27, 95%CI 0.11-0.66, p = 0.002) and OS (HR 0.23, 95% CI 0.09-0.57, p = 0.0005) compared to MHC I-L. Conclusions: Our findings demonstrate that higher MHC I expression is associated with higher immune infiltration and improved outcomes in TNBC but not in HER2+ or HR+HER2- BC subtypes. These results suggest that MHC I expression plays a critical role in the tumor microenvironment of TNBC. Future studies are needed to evaluate the prognostic value and potential therapeutic target of MHC I in TNBC. Support: Breast Cancer Research Foundation, Bankhead Coley, W81XWH-18-1-0564. Clinical trial information: NCT00114816 .

Abstract Purpose: While an addition of immune checkpoint inhibitor (ICI), pembrolizumab, has improved outcomes of patients with TNBC, early-stage TNBC patients with residual cancer burden (RCB) II/III after neoadjuvant chemotherapy in combination with pembrolizumab (NAP) still have poor outcomes. Previously, we demonstrated that intratumoral HLA-DRA expression and interferon-alpha (IFNα) responses were associated with immune-inflamed phenotype and better outcomes in TNBC patients receiving chemotherapy. This study utilized the CosMx™ SMI to investigate in early-stage TNBC treated with NAP. Methods: Of 151 samples from TNBC patients treated with NAP at Mayo Clinic, 8 pre-treatment biopsy samples (5 pCR and 3 RCB II/III were analyzed using the CosMx™ SMI platform. Linear mixed models to assess differential expression (DE), adjusting for hierarchical data structures. DE analyses were expressed as log2-fold changes (logFC), with the Benjamini-Yekutieli method. GSEA and IPA for signaling pathway exploration. Results: 1.7 million cells were identified across 8 samples after stringent quality control. Immune cell profiling revealed higher B cells, plasma cells, plasmablasts, and T cells (CD4 and CD8) in responders, whereas fibroblasts and myeloid cells were enriched in non-responders. DE analysis showed significantly elevated expression of HLA-DRA (logFC 1.955, p&lt;0.001), other MHC class I and II components, and IFNα in responders. Tumor cells in responders exhibited the highest IFNα expression across cell types. GSEA and IPA analysis revealed enrichment in interferon signaling, antigen presentation, and the cGAS-STING pathway, which drives IFNα production. Spatial analysis categorized cells by their proximity to tumor cells: within 50 µm, 50-100 µm, and over 100 µm. T cells, particularly CD8 T cells, showed a distance-dependent distribution, with a higher abundance near tumor cells in responders. CD8 T cell activation scores declined with increasing distance from IFNα-positive tumor cells but remained consistently low near IFNα-negative tumor cells. IFNγ-positive CD8 T cells exhibited higher activation compared to IFNγ-negative cells, with activation levels influenced by proximity to tumor cells. Lastly, MHC expression in tumor cells was examined relative to CD8 T cell proximity. HLA-DRA and CIITA expression decreased as tumor cells were farther from CD8 T cells. Conclusions: This spatially resolved single-cell analysis highlights the pivotal role of tumor-immune interactions in response to pembrolizumab in TNBC. Our data suggest that tumor cells secrete IFNα through the activation of the cGAS-STING pathway, which activates T cells within close proximity, highlighting the potential role of cGAS-STING agonist as well as IFNα signaling and antigen presentation in augmenting TNBC responses to ICIs. Citation Format: Yi Liu, Saranya Chumsri, Yaohua Ma, Jodi M. Carter, Aziza Nassar, Edith Perez, Roberto A. Leon-Ferre, David Zahrieh, David W. Hillman, Judy C. Boughey, James Ingle, Krishna R. Kalari, Fergus J. Couch, Matthew P. Goetz, Keith L. Knutson, E. Aubrey Thompson. Spatially resolved single-cell analysis reveals cGAS-STING-mediated tumor-immune interactions via IFNα as determinants of pembrolizumab sensitivity in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7130.

PURPOSE Predictive biomarkers to better tailor therapy for patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer are a priority. We hypothesized that HER2 and immune-based biomarkers would be predictive of pathologic complete response (pCR) to preoperative trastuzumab/pertuzumab (HP). MATERIALS AND METHODS Patients with stage II/III, estrogen receptor (ER)-negative, HER2-positive breast cancer received neoadjuvant HP in the TBCRC026 clinical trial. The pCR after receiving HP alone was 22% (18/83). Tumor biopsies were performed at baseline. Secondary correlative objectives were to determine the relationship between HER2-based biomarkers and immune processes with pCR. NanoString code sets BC360 and IO360 were used to compare differential gene expression in baseline tumors that underwent pCR versus no pCR. NanoString GeoMx digital spatial profiling was used to assess immune protein abundance in intraepithelial and stromal segments. Stromal tumor-infiltrating lymphocytes and Ki67 were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. RESULTS Intraepithelial HER2 protein abundance was significantly associated with pCR ( P = .001). Low HER2 abundance tumors were primarily basal-like, and essentially all (19/20) failed to achieve pCR. High HER2 abundance tumors that achieved pCR (14/51) exhibited a high degree of immune cell activity, whereas high HER2 abundance tumors that failed to achieve pCR tumors (37/51) were enriched for M-phase processes and epidermal growth factor receptor signaling. Baseline Ki67 was significantly higher in nonresponders ( P = .04). CONCLUSION ER-negative, HER2-positive breast cancer has unique molecular and immunologic features that may predict pCR after neoadjuvant HP. Validation of these potential biomarkers and composite biomarker analyses may guide design of future clinical trials.

Abstract Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer. Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Patients and Methods: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic triple-negative breast cancer with ≤3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL −1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response &gt;12 months and ongoing even after stopping treatment (5.4–69.0 months). Patients with PD-L1–positive tumors (modified proportion score ≥10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1–negative tumors. Consistent with preclinical studies, four of six patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

Abstract 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: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor–positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC. Patients and Methods: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials. Results: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12–1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98–1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09–3.17; P=.02) compared with N0–N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50–1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category. Conclusions: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab. ClinicalTrials.gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).

AbstractBackgroundThe management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus.MethodsDuring the 14th Breast‐Gynecological and Immuno‐Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer.Results and ConclusionsThe consensus recommendations addressed different escalation and de‐escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified.

PURPOSE ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS MA.27 (ClinicalTrials.gov identifier: NCT00066573 ) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤–1; (–1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS ( P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated ( P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS ( P = .001) in models with ER. CONCLUSION Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤–1.

567 Background: We proposed adjunctive statistical standardization of quantitated ER and PgR to improve inter-laboratory comparability of biomarker results and therapeutic management of breast cancer. Methods: We utilized CCTG MA.27 (NCT00066573), an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumours. IHC ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation, and each statistically standardized to mean of 0, standard deviation of 1 following Box-Cox variance stabilization transformations of square for ER; for PgR, 1.) natural logarithm (0.1 added to 0 HSCOREs and 0 %+), 2.) square root. The primary endpoint was STEEP distant disease-free survival (DDFS) at the longest trial follow-up of median 4.1 years; a secondary endpoint was event-free survival (EFS). Survival was described with Kaplan-Meier plots and tested with the univariate Wilcoxon (Peto-Prentice) test statistic. We examined cut-points at standard deviations about mean of 0 (<-1; (-1,0]; (0,1]; >1) and explored single cut-points. Cox multivariate regressions were adjusted for age, T and N stage, grade, lymphovascular invasion, treatment, and baseline patient demographics; 2-sided Wald tests had nominal significance if p<0.05. Results: Of the 7576 women accrued, 3048 women had machine-quantitated image analysis results: 2900 (95%) for ER; 2726 (89%) for PgR. Statistically standardized HSCORE and %+ units differentiated both univariate DDFS and EFS; DDFS was significantly different by ER levels (p<0.001) and PgR levels (p<0.001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (p=0.52-0.88) with the DDFS primary endpoint in models with PgR, while higher PgR HSCORE and %+ had significantly better DDFS (p=.001, in all instances) in models with ER. Conclusions: DDFS was superior for patients with higher ER and PgR standardized units compared with those with HSCOREs and %+ <-1. The adjunctive statistical standardization of ER and PgR performed here is similar to that mandated for clinical practice by the World Health Organization for BMD. [Table: see text]