Abubakar Mustapha, Duggan Máire A, Fan Shaoqi, Pfeiffer Ruth M, Lawrence Scott, Mutreja Karun, Klein Alyssa, Koka Hela, Ahearn Thomas U, Henry Jill E, Sprague Brian L, Vacek Pamela M, Weaver Donald L, Richert-Boe Kathryn, Kimes Teresa M, Titiloye Nicolas, Edusei Lawrence, Figueroa Jonine D, Yang Xiaohong R, Garcia-Closas Montserrat, Rohan Thomas E, Gierach Gretchen L
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health (NIH), Bethesda, MD, United States.
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
J Natl Cancer Inst. 2025 May 14. doi: 10.1093/jnci/djaf070.
Aggressive (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.
Spatially 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).
Epidemiologic 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.
Our 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.
侵袭性（通常为高级别）乳腺癌（BC）仍是全球BC相关死亡率的主要原因。然而，其病因和预后的组织变化仍未得到充分表征。
使用空间分辨机器学习算法将“基质破坏”表征为正常、良性乳腺疾病（BBD）和侵袭性苏木精和伊红（H&E）染色乳腺组织中细胞外基质减少/改变以及免疫、炎症和/或伤口反应相关过程增加的形态学指标。在4023名健康乳腺组织供体中评估基质破坏与BC病因因素的关联，在一项巢式病例对照研究中评估其对974名BBD患者BC发病率的影响，同时在4个BC患者队列（n = 4223）中评估其预后关联。
侵袭性BC的流行病学危险因素，包括年轻、多产、黑人种族、肥胖和家族史，在肿瘤发生前的H&E切片中显示出与基质破坏增加的强烈关联。BBD的H&E中大量基质破坏与侵袭性（高级别）BC风险增加约4倍以及从BBD到BC诊断的潜伏期缩短约3年相关，与BBD组织学无关。在BC队列中，H&E中的基质破坏与侵袭性（大多为高级别）肿瘤表型以及ER阳性患者中明显较差的预后相关，与组织学无关。基质破坏的免疫生物学反映了先天（CD68+）、适应性（CD3+CD4+、CD3+CD8+）、免疫调节（CD3+CD4+FOXP3+）、免疫逃逸（PD1+PDL1+）、内皮（CD31+）和成肌纤维细胞（α-SMA+）标志物表达的增加。
我们的研究结果突出了活跃的基质在侵袭性BC病因和预后中的作用，为在BC连续体中轻松识别可能从以基质为中心的预防或治疗策略中受益的高危女性开辟了可能性。
