ArticleJournal of the National Cancer Institute2025
Unraveling the role of stromal disruption in aggressive breast cancer etiology and outcomes.
Article in Journal of the National Cancer Institute, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Methylation profiling of normal tissue adjacent to breast tumors reveals two distinct groups with divergent tumor microenvironment features.NPJ breast cancer · 2026Article
- The contribution of rare germline variants to the immune landscape of breast cancer.Genome medicine · 2026Article
- Can DNA Methylation in Peritumoral and Contralateral Breast Tissue Predict Recurrence or Second Breast Cancers?Current issues in molecular biology · 2026Article
- Breast Cancer Incidence Rates in Ghanaian and US Black Women From 2013 Through 2015.JAMA network open · 2025Article
- Deep learning analysis of hematoxylin and eosin-stained benign breast biopsies to predict future invasive breast cancer.JNCI cancer spectrum · 2025Article
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Authors and funding
22 authors.
Funding
Abstract
backgroundAggressive (typically high-grade) breast cancers (BCs) remain major contributors to BC-related mortality globally. The tissue changes underpinning their etiology and outcomes, however, remain poorly characterized.
methodsSpatially resolved machine-learning algorithms were used to characterize "stromal disruption" as a morphological metric of reduced/altered extracellular matrix and increased immune, inflammatory, and/or wound response-related processes in normal, benign breast disease (BBD), and invasive hematoxylin and eosin (H&E)-stained breast tissues. Associations of stromal disruption with BC etiologic factors were assessed among 4023 healthy breast tissue donors, its impact on BC incidence was assessed among 974 BBD patients in a nested case-control study, while its prognostic associations were assessed in 4 BC patient cohorts (n = 4223).
resultsEpidemiologic risk factors for aggressive BC, including younger age, multiparity, Black race, obesity, and family history, demonstrated strong associations with increasing stromal disruption in H&E sections prior to tumor development. Substantial stromal disruption in BBD H&E was associated with ∼4-fold increased risk of aggressive (high-grade) BC and ∼3 years shorter latency from BBD to BC diagnosis, independently of BBD histology. Across BC cohorts, stromal disruption in H&E was associated with aggressive (mostly high-grade) tumor phenotypes and with markedly poor prognosis among ER-positive patients, irrespective of histology. The immunobiology of stromal disruption reflected heightened innate (CD68+), adaptive (CD3+CD4+, CD3+CD8+), immunoregulatory (CD3+CD4+FOXP3+), immune escape (PD1+PDL1+), endothelial (CD31+), and myofibroblast (α-SMA+) marker expression.
conclusionOur findings highlight the active stromal role in aggressive BC etiology and outcomes, opening possibilities for readily identifying high-risk women across the BC continuum that may benefit from stroma-centric preventative or therapeutic strategies.
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