Boughey, JC

Importance Many patients are diagnosed with atypical lesions or lobular carcinoma in situ (LCIS); however, evidence- and consensus-based guidelines for the management of many of these lesions are limited. Observations The American Society of Breast Surgeons, in collaboration with the Society of Breast Imaging and College of American Pathology, assembled a steering group to create guidelines for the management of atypical lesions and LCIS, inclusive of flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), classic LCIS (C-LCIS), and the variant LCIS forms pleomorphic LCIS (P-LCIS) and florid LCIS (F-LCIS). The natural history of ADH, ALH, and C-LCIS suggests that these lesions are associated with an elevated future breast cancer risk; therefore, patients diagnosed with these lesions should be recommended to undergo comprehensive risk assessment and counseling about breast cancer risk-reducing strategies. The magnitude of future breast cancer risk associated with P-LCIS and F-LCIS remains uncertain, yet if these lesions are determined to be hormone receptor positive, risk-reducing medications should be considered. There is no evidence that FEA is associated with an elevated future breast cancer risk. A second pathology review confirmation is recommended for ADH, should be considered for FEA, and is not necessary for ALH or LCIS. Currently available evidence supports the need to diagnostically excise most ADH, P-LCIS, and F-LCIS cases identified on core biopsy, although some ADH cases fulfilling strict criteria and multidisciplinary consensus can be observed. P-LCIS and F-LCIS require a negative margin, but ADH does not. ALH and C-LCIS can be safely observed if the core biopsy diagnosis is concordant with imaging features (ie, radiographic-pathologic concordance is established). Provided radiologic-pathologic concordance is confirmed, diagnostic excision is generally not indicated after a diagnosis of FEA alone. Conclusions and Relevance These guidelines provide evidence-informed, consensus-based recommendations for the management of atypical lesions of the breast, including ADH, ALH, FEA, C-LCIS, P-LCIS, and F-LCIS. Practicing clinicians who treat patients with atypical breast lesions or LCIS should consider integrating these guidelines into clinical management.

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

Abstract Background: MHC class II molecules are normally restricted to professional antigen-presenting cells. Prior TNBC studies have focused on immune-compartment MHC-II. Using spatial transcriptomics, we recently identified aberrant tumor-cell MHC-II expression. Here, we characterized the immune architecture surrounding HLA-DRA-expressing tumor cells. Methods: High-plex single-cell spatial transcriptomics (CosMxTM SMI) was performed on treatment-naïve TNBC (Mayo TMA, n=65) and two neoadjuvant pembrolizumab cohorts (Mayo n=8; Emory n=4). Spatial neighborhoods were mapped relative to HLA-DRA-high tumor cells. Differential expression and adaptive immune gene-set scores were evaluated. Clinical relevance was assessed using FinXX (n=114), I-SPY2 (n=364), and Caris CODEai (n=3,662). Results: HLA-DRA-high tumor regions showed significant enrichment of adaptive immune subsets within ≤50 μm, including B cells, CD8+ T cells, NK cells, macrophages, and plasmacytoid dendritic cells. In pembrolizumab-treated cohorts, responders exhibited higher proportions of HLA-DRA-high tumor cells and greater numbers of B cells, plasmablasts, CD4+ and CD8+ T cells, and macrophages near tumor cells. Responders’ tumors showed upregulation of antigen-presentation machinery, B-cell/plasma-cell programs, CXCL13, and NOTCH3/DLL1. Across I-SPY2 and FinXX, higher HLA-DRA correlated with pathologic complete response and improved survival. In CODEai TNBC, high HLA-DRA expression correlated with higher CXCL13 (median TPM 7.5 vs. 1.1, q<0.05) and longer overall survival (24.2 vs. 18.5 months, HR 0.77, 95% CI 0.71-0.83, p<0.0001). This association was TNBC-specific. High CXCL13 also predicted improved survival (26.6 vs. 16.5 months, HR 0.64, 95% CI 0.59-0.69, p<0.0001). Conclusions: Tumor-cell HLA-DRA expression defines a highly organized adaptive immune niche enriched with B cells and activated T-cell populations in close proximity. Adaptive immune programs—including enhanced antigen presentation and CXCL13-mediated B-cell/plasma-cell pathways—consistently associate with improved outcomes across TNBC cohorts treated with chemotherapy and immune checkpoint blockade. Aberrant tumor-cell MHC-II expression may contribute to antitumor immunity and warrants further investigation as a potential therapeutic target. Citation Format: Yi Liu, Sachin Kumar Deshmukh, Thiti Susiriwatananont, Panuch Eiamprapaporn, Bogang Wu, Heikki Joensuu, Roberto A. Leon-Ferre, David Zahrieh, Judy C. Boughey, James Newell Ingle, Fergus J. Couch, Sharon Wu, Shipra Gandhi, Maryam Lustberg, George W. Sledge, Matthew P. Goetz, Keith L. Knutson, E Aubrey Thompson, Jodi Carter, Saranya Chumsri. Spatially resolved tumor-cell MHC class II shapes adaptive immunity and therapeutic response in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1200.

ABSTRACT The normal adult male breast has not been characterized at single-cell resolution, leaving the cellular basis of male breast cancer (MBC) biology undefined. Here we present an integrated single-cell RNA sequencing atlas of the adult human breast comprising 174,471 cells from 17 donors (3 male, 14 female), including 18,117 male-derived cells. This revealed that the male breast retains all three epithelial populations, basal (BC), luminal progenitor (LP), and luminal committed cells (LC), but with an increase in LC at the expense of BC and LP across all three male donors. Male LC were distinguished from female by elevated ESR1 and PGR mRNA, enrichment of RNA processing and ribosome biogenesis programs, reduced inflammatory cytokine and growth factor signaling, elevated estradiol gene set enrichment scores, and higher inferred activity of developmental patterning transcription factors. This pattern was observed across differential expression, gene ontology, ligand profiling, and regulon-based analyses, and was not restricted to sex chromosome-linked gene expression. This is consistent with the near-universal estrogen receptor (ER) positivity that characterizes MBC clinically. This atlas provides the first cellular and transcriptional reference for the normal male breast and a resource for investigating sex differences in mammary biology, germline susceptibility variant interpretation, and modeling breast malignancies.

Abstract Introduction Cancer clinical trials have historically faced challenges in achieving fully representative trial population, particularly in terms of including patients from diverse ethnic and racial groups, those with low socioeconomic status, and those living in rural regions. This has contributed to inequities in access to novel therapeutic options. Background The I-SPY adaptive platform trials have prioritized diversity since inception, consistently enrolling in >10% of trial patients being Black and/or Hispanic individuals. The majority of participating institutions in the I-SPY 2.2 study are academic or large well-resourced health systems. In 2023, the I-SPY ACCESS (Achieving Cancer Clinical Trial Equity in Socioeconomically Diverse Sites) Initiative was launched to enhance representation by engaging and involving nontraditional trial sites- such as safety-net hospitals, community cancer centers, and rural cancer centers- that serve historically excluded patient populations. Methods The I-SPY ACCESS Initiative offers customized and personalized tailored support to under-resourced sites. This includes comprehensive feasibility and readiness assessments, onboarding guidance, enhanced site-specific training, centralized institutional review board (IRB) navigation, site peer mentorship, and educational materials for both patient and provider. Additionally, patients gain access to I-SPY advocate peer trial navigators. Sites are provided culturally responsive patient education tools- including multilingual brochures, a dedicated patient website, and content co-developed with community partners. A Clinical Trial Navigator supports both patients and sites, helping to locate logistical, social, and trial specific resources.Tools such as virtual Clinical Research Coordinators (vCRC's) and OneSource technology are deployed strategically based on assessed site need and resource availability. OneSource is an innovative platform that enables direct extraction of clinical data from electronic health records into trial databases, reducing site workload and improving data quality. Funding models are currently being explored to extend OneSource and vCRC services across more ACCESS sites. In the future, there are plans to pilot financial navigation services and integrative care resources for all patients enrolled in I-SPY with particular focus on those enrolled at ACCESS sites. Results and Progress As of June 2025, seven sites have been assessed as ACCESS sites for I-SPY 2.2, with two sites having successfully completed activation and currently enrolling participants. Beginning in mid-2024, one DCIS RECAST ACCESS site has been activated and 11 additional sites are in the onboarding process. The modest pace of I-SPY 2.2 activation reflects the complexity and operational demands associated with resource-intensive platform trial. In contrast, the DCIS RECAST protocol was designed with a lower burden, facilitating easier implementation by under-resourced sites, reflected by increased interest in the study among ACCESS sites. The ACCESS framework is being explored for potential future application in the Pre I-SPY Phase 1 platform trial, particularly considering the historical underrepresentation of such sites in the early-phase clinical research. Conclusion and Future Goals The I-SPY ACCESS initiative demonstrates that investing in thoughtful, innovative, and effective means for trial delivery, as well as incorporating community-based support, can strengthen representation in complex, adaptive breast cancer trials. The initiative offers a flexible, equity-driven framework that is impactful now and scalable for future innovation in oncology research. Citation Format: S. L. Horton, D. A. Idossa, K. C. Hewitt, J. Perlmutter, L. Van't Veer, N. Hylton, A. Borowsky, F. Symmans, D. Yee, C. Yau, P. Pohlmann, J. Boughey, L. Esserman. Expanding Diversity through Innovation: Development of the I-SPY ACCESS Initiative for the I-SPY2.2 and DCIS RECAST Clinical Trials [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 PS4-09-08.

PURPOSE Adjuvant endocrine therapy (ET) improves overall survival (OS) in estrogen receptor (ER)–positive early-stage breast cancer (BC). However, the benefit of ET for those with ER-low BC (ER 1%-10%) is unclear. METHODS Using the National Cancer Database, we studied patients with high-risk stage I to III, ER-low BC (defined as immunohistochemistry 1%-10%) who received (neo)adjuvant chemotherapy and did or did not initiate ET. OS was analyzed with ET initiation as a time-dependent covariate using Cox proportional hazards regression. RESULTS Of 10,362 patients with stage I to III ER-low BC, 7,018 received chemotherapy and met inclusion criteria. ET omission was 42% at 12 months and more common in patients with tumors that were progesterone receptor–negative, human epidermal growth factor receptor 2–negative, higher-grade (grade 2/3) and higher Ki-67 (≥20%; all P < .001) and those who received neoadjuvant chemotherapy (NAC; P < .001). With a median follow-up of 3 years, 586 deaths were observed. In a multivariable analysis, ET omission was associated with a higher risk of death (hazard ratio [HR], 1.23 [95% CI, 1.04 to 1.46]; P = .02), with a greater impact in those with higher ER levels: ER 1%-5% (HR, 1.15 [95% CI, 0.91 to 1.45]; P = .24) versus ER 6%-10% (HR, 1.42 [95% CI, 1.00 to 2.02]; P = .048). Among patients treated with NAC (n = 4,377, 62%), ET omission was associated with worse OS in those with residual disease (RD; HR, 1.26 [95% CI, 1.00 to 1.57]; P = .046) but not in those who achieved a pathologic complete response (HR, 1.06 [95% CI, 0.62 to 1.80]; P = .84). CONCLUSION In ER-low, early-stage BC, ET omission is associated with significantly worse OS, especially in patients with RD after NAC and those with higher (6%-10%) ER levels. Until prospective data are available, patients with ER-low BC should be counseled regarding the potential benefit of ET.

PURPOSE Over 50% of households in the United States have at least one musician—many musicians are also breast cancer survivors. This group has not been well studied, and given the level of fine sensory-motor skill required for musicianship, we hypothesized that musicians experience unique manifestations of breast cancer treatment toxicities. METHODS A nine-item Musical Toxicity Questionnaire (MTQ) was distributed to patients who had consented to participate in the Mayo Clinic Breast Cancer Registry. The MTQ screened participants by asking if they played a musical instrument or sang in the last 10 years: questions populated for those who answered yes. Respondents were asked if they noticed difficulty with their musical endeavor during or after breast cancer treatment, defined as acute musical toxicity (AMT). The questionnaire asked which side effect and cancer-directed therapy most influenced musical ability, what musical attributes were affected, and the timeline of resolution. Multivariable and classification tree analyses assessed relationships between AMT and treatment characteristics. RESULTS Of 1,871 survey respondents, 29% (535/1,871) self-identified as musicians. Over a quarter (27%, 144/535) reported AMT, and for 57% (82/144), AMT had not resolved at the time of survey. Of the treatments each participant received, chemotherapy was most often reported as most negatively impactful (63/89 who received chemotherapy, 71%). Decreased endurance was the most common musical difficulty (64% of those with AMT, 92/144), followed by decreased accuracy, trouble playing/singing quickly, and difficulty using proper technique. Multivariable and classification tree analyses revealed that receipt of chemotherapy was most strongly correlated with AMT. CONCLUSION These results will help oncology care teams counsel musicians, answer questions about impacts on musicality, and provide a timeline for resolution of musical symptoms.

Abstract Chemotherapy regimens for triple-negative breast cancer (TNBC) combine agents without knowing which agents drive response. Consequently, predictors derived from multi-agent regimens cannot be assumed to generalize to individual drugs or other regimens, motivating development of treatment-matched predictors. Here, we used TNBC patient-derived xenografts (PDXs) treated with carboplatin, docetaxel, or the combination to deconvolute drug-specific responses and identify associated molecular features. Combination treatment rarely improved upon the best single agent, with enhanced responses in only 13% of PDXs and antagonism in a comparable fraction. Proteogenomic analyses identified high cytokeratin-5 (KRT5) as a general marker of chemotherapy responsiveness and KRT5 immunohistochemistry discriminated responsive PDXs (AUROC, 0.83). To train treatment-specific predictors, we integrated these data with independent PDX and clinical cohorts with responses assessed after anthracycline-free platinum, taxane, or platinum-taxane therapy, ensuring response corresponded to the modeled treatment. Four feature selection strategies yielded largely nonoverlapping biomarker panels converging on treatment-relevant pathways. On independent test data, RNA-based predictors of complete response (CR) to platinum-based (carboplatin or cisplatin) and taxane-based (docetaxel or paclitaxel) chemotherapy achieved AUROCs of 0.80 and 0.86, respectively. For platinum-taxane regimens (carboplatin plus docetaxel or paclitaxel), proteomic-guided feature selection generated a 10-biomarker, protein- informed RNA predictor of pathologic complete response (pCR) that outperformed RNA-only feature selection and achieved an AUROC of 0.85 in an independent clinical cohort, while retaining practicality as an RNA-based assay. Treatment-matched integration of multi-omic PDX and clinical datasets provides a framework for chemotherapy-specific predictors with clinically relevant performance, supporting biomarker-guided precision selection and treatment optimization for patients with TNBC. Statement of significance Integration of multi-omic data from patient-derived xenografts with treatment-matched clinical cohorts yielded three retrospectively validated predictors of platinum, taxane, and platinum+taxane response, enabling biomarker-guided chemotherapy selection for patients with triple-negative breast cancer.

PURPOSE The nodal burden of patients with residual isolated tumor cells (ITCs) in the sentinel lymph nodes (SLNs) after neoadjuvant chemotherapy (NAC) (ypN0i+) is unknown, and axillary management is not standardized. We investigated rates of additional positive lymph nodes (LNs) at axillary lymph node dissection (ALND) and oncologic outcomes in patients with ypN0i+ treated with and without ALND. METHODS The Oncoplastic Breast Consortium-05/ICARO cohort study (ClinicalTrials.gov identifier: NCT06464341 ) retrospectively analyzed data from patients with stage I to III breast cancer with ITCs in SLNs after NAC from 62 centers in 18 countries. The primary end point was the 3-year rate of any axillary recurrence. The rate of any invasive recurrence was the secondary end point. RESULTS In total, 583 patients were included, of whom 182 (31%) had completion ALND and 401 (69%) did not. The median age was 48 years. Most patients (74%) were clinically node-positive at diagnosis and 41% had hormone receptor–positive/human epidermal growth factor receptor 2–negative tumors. The mean number of SLNs with ITCs was 1.2. Patients treated with ALND were more likely to present with cN2/3 disease (17% v 7%, P < .001), have ITCs detected on frozen section (62% v 8%, P < .001), have lymphovascular invasion (38% v 24%, P < .001), and receive adjuvant chest wall (89% v 78%, P = .024) and nodal radiation (82% v 75%, P = .038). Additional positive nodes were found at ALND in 30% of patients, but only 5% had macrometastases. The 3-year rates of any axillary and any invasive recurrence were 2% (95% CI, 0.95 to 3.6) and 11% (95% CI, 8 to 14), respectively, with no statistical difference by type of axillary surgery. CONCLUSION The nodal burden in patients with ypN0(i+) was low, and axillary recurrence after ALND omission was rare in patients selected for this approach. These results do not support routine ALND in all patients with ypN0(i+).