Boughey, Judy C.

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.

BACKGROUND: Social determinants of health (SDOH) are associated with adverse cancer outcomes, yet the prevalence and impact of SDOH screening across Commission on Cancer (CoC)-accredited programs are unknown. We evaluated national SDOH screening practices and their association with adherence to CoC quality measures. STUDY DESIGN: A cross-sectional survey of 1,445 CoC-accredited programs (October to December 2024) was linked to National Cancer Database data (2020 to 2022). Adult patients treated at 435 responding hospitals (30.1%) were included. Programs were categorized by routine outpatient SDOH screening status. Multivariable logistic regression assessed associations between screening and receipt of quality measure–concordant care, adjusting for screening duration, age, race, ethnicity, Charlson Comorbidity Index, insurance status, rurality, and program type or case count. RESULTS: Of 435 programs, 165 (37.9%) reported routine SDOH screening. Screening programs more frequently treated ≥10% Medicaid or uninsured patients (29.1% vs 19.6%, p = 0.023). Mean performance was higher at screening hospitals for breast radiation within 60 days (66.6% vs 64.6%, p = 0.046), colon adjuvant chemotherapy within 120 days (84.6% vs 81.9%, p = 0.018), and lung systemic therapy within 90 days (77.2% vs 75.4%, p = 0.043). On adjusted analysis, screening for more than 3 years was independently associated with timely colon adjuvant chemotherapy (odds ratio 1.05; 95% CI 1.01 to 1.07; p = 0.033). Findings persisted after excluding safety net hospitals. CONCLUSIONS: Only one-third of responding CoC programs routinely screen for SDOH. Sustained screening was independently associated with improved adherence to time-sensitive colon cancer chemotherapy, supporting integration of patient-level SDOH assessment into oncology care delivery.

BACKGROUND: The National Cancer Database (NCDB) captures 73.7% of newly diagnosed cancers in the USs and underpins thousands of outcomes studies informing oncologic practice. To remain relevant amid rapid therapeutic and policy changes, the NCDB has undergone substantial structural and variable-level revisions. We characterized major updates during the past decade and their implications for research. STUDY DESIGN: We performed a narrative review of annual NCDB data dictionary revisions, American College of Surgeons bulletins, and internal program updates in collaboration with NCDB leadership. Structural modifications, variable additions, and policy changes affecting data capture, follow-up, staging, and accessibility were systematically summarized. RESULTS: The NCDB now includes data from 1,413 Commission on Cancer–accredited hospitals and more than 55 million records. Since 2020, the Rapid Cancer Reporting System enables near–real-time monthly submissions. Embargo periods were reduced from 5 to 3 years for survival data and 2 years for other variables, increasing analytic timeliness. Follow-up was limited to 15 years beginning January 1, 2022. Variable refinements include continuous tumor size in millimeters (since 2016), separation of tumor grade into clinical, pathologic, and posttherapy fields (since 2018), phased radiation treatment reporting (since 2018), and American Joint Committee on Cancer eighth edition staging implementation in January 2018 with nineth edition rollout ongoing. New data elements include Medicaid expansion status (2020), COVID-19 variables (2020 to 2021; 12.4% reduction in cases in 2020), smoking status (2023), and planned programmed death-ligand 1 reporting for non–small cell lung cancer beginning in 2025. CONCLUSIONS: The NCDB has evolved toward more granular, contemporary, and policy-relevant data capture while maintaining broad national coverage. Investigators must account for staging transitions, variable maturation, follow-up limits, and registry-specific biases to ensure valid interpretation of NCDB-based research.

Importance Many patients are diagnosed with benign breast lesions; however, evidence- and consensus-based guidelines for the management of benign breast disease (BBD) are limited. Observations The American Society of Breast Surgeons (ASBrS) and the Society of Breast Imaging (SBI) developed guidelines for the management of benign fibroepithelial lesions (FELs) using a modified Delphi consensus methodology and public comment. There was strong consensus that core biopsy–proven concordant fibroadenomas without atypia only require excision if they were symptomatic, patient preferred, attained a certain size, or demonstrated substantive growth over time on clinical examination. There was strong consensus that when removing a fibroadenoma, complete excision without transection of the mass is recommended and surgeons should consider aesthetics, sensation, and other factors when selecting incision placement. Patients with core biopsy–proven concordant fibroadenomas do not require imaging follow-up and may return to age-appropriate screening. Many benign phyllodes tumors (BPTs) present as an FEL on core biopsy, and these lesions along with any lesions with suspicion of or concern for phyllodes tumors (PTs) require surgical excisional biopsy with complete excision of the mass. Re-excision of a BPT is not required for patients with a positive margin for BPT, but a margin re-excision may be considered if the mass was transected or there is concern of residual disease after excisional biopsy. Patients with BPT who have undergone excision do not require follow-up imaging and may return to age-appropriate screening. Conclusions and Relevance Evidence-informed, consensus and expert opinion-based guidelines for the management of benign FELs of the breast were developed. These guidelines provide clarification on the controversial management of benign FELs of the breast. Any practicing clinicians who treat patients with benign FELs should integrate these guidelines into treatment of their patients.

BACKGROUND: Significant disparities persist in timely, guideline-concordant breast cancer treatment across the US, impacting cancer outcomes. The influence of both patient-level and facility-level socioeconomic status (SES) on adherence to Commission on Cancer quality measures remains incompletely understood. STUDY DESIGN: We conducted a retrospective cohort study using the National Cancer Database to assess associations between patient and facility SES and concordance with timeliness of 3 Commission on Cancer breast cancer quality measures: surgery, multiagent chemotherapy, and radiotherapy, among patients diagnosed from 2018 to 2022. Multivariable logistic regression models were used to evaluate predictors of concordant care, including a composite measure of facility-level social risk. RESULTS: The analytic cohorts included 471,425 patients for surgery, 82,734 for chemotherapy, and 311,523 for radiotherapy. Black race, uninsured status, and lower educational attainment were each independently associated with lower odds of receiving guideline-concordant care across all measures. Patients treated at low-SES facilities had higher odds of receiving timely surgery (adjusted odds ratio [OR] 1.27, 95% CI 1.24 to 1.31) but lower odds of receiving timely chemotherapy (OR 0.85, 95% CI 0.79 to 0.91) and radiotherapy (OR 0.95, 95% CI 0.92 to 0.97) compared with those at other institutions. Facility type, fragmented care, and comorbidities also contributed to variation in concordance. CONCLUSIONS: Significant disparities in guideline-concordant breast cancer care persist by race, insurance, education, and facility-level social risk, highlighting intervention opportunities to improve outcomes for these already vulnerable populations. These findings highlight the importance of policy and institutional strategies that address both patient- and facility-level barriers to ensure equitable access to high-quality multidisciplinary treatment.

BACKGROUND: To reduce technical variation in cancer surgery, the Commission on Cancer (CoC) recently implemented 6 operative standards as part of its national cancer center accreditation process. CoC sites are evaluated for compliance with these standards through scheduled visits conducted by trained site reviewers. We characterized site reviewers’ perspectives on the implementation of the operative standards. STUDY DESIGN: Twenty interviews were conducted with CoC site reviewers using a semistructured interview guide based on the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. Themes were identified using thematic analysis mapped to the updated Consolidated Framework for Implementation Research. RESULTS: Site reviewers viewed the operative standards as an effective starting point for improving technical quality and were optimistic the standards would lead to positive change. Compliance was associated with supportive site leadership, effective interdisciplinary communication, and the availability of adequate personnel and institutional resources. In contrast, resistance from surgeons was identified as a key barrier. CoC site reviewers interpret their role as extending beyond assessing compliance, viewing themselves as advocates, educators, and partners to the sites. CONCLUSIONS: Overall, CoC site reviewers perceive the operative standards favorably. To enhance implementation of the operative standards, efforts should focus on modifiable institutional and individual-level factors, such as leadership support and surgeon engagement. Additionally, the multifaceted role of the site reviewers presents a valuable opportunity to improve compliance by formalizing the supportive relationship between reviewers and sites.

Abstract: Lymphedema is a prevalent, incurable, and morbid condition with the potential to degrade the health and quality of life of patients living with cancer and beyond cancer. Effective long term control requires coordination by an interdisciplinary team to ensure that lymphedema progression, complications, and related disablement are detected and appropriately addressed. This review provides an overview of lymphatic function and lymphedema pathogenesis with focused discussion of the unique characteristics of cancer related lymphedema (CRL) including natural history, clinical presentation, and risk factors for onset and progression. Surgical practice changes and supportive evidence for lymph node sparing and lymphatic reconstruction for CRL prevention are described. The review outlines evaluations to diagnose, stage, and monitor CRL, and characterizes evidence for current CRL prevention and management practices, including surgeries to restore lymphatic function. Multimodal management with complete decongestive therapy remains first line treatment for CRL, though patient-specific customization might be required to optimize patients’ clinical response and quality of life as outlined in the review.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.