Visceral adiposity and breast cancer outcomes: transcriptomic analysis of the tumor microenvironment by intrinsic subtype.

BACKGROUND

Obesity is linked to poor breast cancer outcomes, but evidence within molecular intrinsic subtypes is limited. We measured visceral and subcutaneous adipose tissue (VAT and SAT) on routine clinical imaging and examined survival and tumor microenvironment (TME) differences across PAM50 subtypes.

METHODS

We sampled 1,377 individuals diagnosed with stage II-III breast cancer at Kaiser Permanente Northern California between 2005 and 2015, enriched for HER2 + and ER- tumors. VAT and SAT areas (cm2) were quantified at L3-level from clinically acquired CT scans. Tumor RNA profiling (NanoString BC360™) provided PAM50 and TME-related signatures. Cox models estimated associations of VAT and SAT with overall and disease-specific outcomes. Differential expression and signature analyses were stratified by PAM50 subtype.

RESULTS

Participants had a mean (± SD) age of 56 ± 13 years. Intrinsic subtype distribution was: Basal-like (31%), HER2-E (25%), Luminal B (22%), and Luminal A (22%). Over a median follow-up of 11 years, patients with HER2-E tumors and high-VAT had higher breast cancer-specific mortality (HR = 2.14, 95%CI 1.25-3.65) and distant relapse (HR = 2.05, 95%CI 1.23-3.42). No VAT associations were observed in other subtypes. Transcriptomic analyses revealed enhanced abundance of cancer-associated fibroblasts (CAF) with corresponding stromal signatures exclusively in high-VAT HER2-E tumors. Higher CAF and stromal activation signatures were associated with worse outcomes in the full cohort. SAT showed no associations in any subtype.

CONCLUSIONS

Visceral adiposity identified a high-risk subset of HER2-E breast cancer characterized by high CAF and stromal activation signatures and inferior survival, highlighting an opportunity for VAT-targeted interventions and mechanistic studies to clarify adiposity-TME interactions.