Association of patient-reported stress and depression symptoms with ER-specific tumor transcriptional signatures in breast cancer (BC).

565 Background: Psychological distress is common among women with BC, yet tumor-level biological correlates remain poorly defined. We used tumor transcriptomics to identify pathways associated with patient-reported stress and depression symptoms. Methods: RNA sequencing was conducted on FFPE tumor samples in 195 women with stage I-III BC (152 ER+, 43 ER–) from the Women’s Health after Breast Cancer cohort. At diagnosis, participants completed Perceived Stress Scale (PSS-10) and Center for Epidemiologic Studies Depression (CES-D) Scale. High-low stress (PSS-10 >14 vs 0-14) and high-low somatic symptoms (CES-D somatic > 3 vs ≤ 3) were defined. Differential expression and gene-set enrichment analyses compared high-stress/low-somatic-symptom (HS/LSS) and low-stress/high-somatic-symptom (LS/HSS) groups with low-stress/low-somatic-symptom controls, stratified by estrogen receptor (ER) status, adjusted for age and education. Caris Life Sciences CODEai evaluated overall survival (OS) from tissue collection to last contact. Results: In ER+BC, HS/LSS showed increased humoral-immune activity and checkpoint signatures, with reduced neuroendocrine activation. LS/HSS enriched for a neuroendocrine state, ribosome biogenesis, immune and cell-cycle pathways, with loss of epithelial regulatory programs. In ER– BC, HS/LSS showed growth-factor-driven proliferation with reduced epithelial differentiation and greater immune-checkpoint engagement. LS/HSS exhibited metabolic-stress features with loss of epithelial/immune programs and increased keratinization, consistent with impaired antigen presentation and altered differentiation. Table outlines key up- and down-regulated signatures. Using CODEai, in ER+ (n=11309), higher PHOX2A (41 m vs 38.4 m) and TDGF1 ( 42 m vs 37.4 m), and in ER– (n=6402), higher SCL5A11 (24 m vs 20.7 m) and KRT40 (23.5 m vs 21.1 m) were associated with better OS, all p < 0.01. Conclusions: Patient-reported stress and depressive somatic symptoms map to distinct ER-specific tumor transcriptional signatures involving immune regulation, proliferation, metabolism and differentiation. Concordant survival associations support potential clinical relevance and warrant validation to identify actionable targets. ER+ ER– HS/LSS Genes (log 2 FC) Up IGLV3-16 (3.3) , IGHV3-30 (2.5) IGF2 (4.2) Down CHGA (–21.5) KRT40 (–18.4) , PADI3 (–24.1) Pathways (NES) Fcγ-receptor (2.7), B-cell receptor (BCR) (2.7), PD-1 co-inhibition (2.1) PD-1 co-inhibition (2.4), MHC-I (2.1), ribosome (–2.1) LS/HSS Genes (log 2 FC) Up PCSK1 (4.0) IGFBP1 (7.6), HSD11B1 (4.6), OSGIN2 (3.0) Down PHOX2A (–6.0) , TDGF1 (–5.4) IGHV7-4-1 (–18.9) , MUC2 (–21.5) , SLC5A11 (–21.1) , PADI3 (–22.3) Pathways (NES) Ribosome biogenesis (3.1), IFNα (2.7), G1/S (2.7), G2/M (2.6), BCR (2.6) Keratinization (2.7), cornified envelope (2.3), antigen presentation (–1.8), G1/S (–1.7)