The tumour microenvironment influences long-term tamoxifen benefit in postmenopausal ER+/HER2- breast cancer patients: a secondary analysis of the randomised Stockholm Tamoxifen (STO-3) trial.

Abstract

Background: The tumour microenvironment (TME) influences breast cancer progression and treatment response. We investigated whether TME composition predicts tamoxifen benefit in postmenopausal women with oestrogen receptor-positive, HER2-negative (ER+HER2-) breast cancer.

Methods: This study included 513 patients from the Stockholm Tamoxifen (STO-3) trial, which randomised postmenopausal, lymph node-negative women to tamoxifen or no endocrine therapy. Bulk tumour transcriptomes were deconvoluted with the ConsensusTME algorithm to estimate the relative abundance of 18 immune and stromal cell types. A summary score of combined immune cells was created on a per patient basis and evaluated alongside fibroblast and endothelial stromal compartments. Patients were categorised into immune and stromal tertiles on the basis of these scores. Associations between TME composition and tumour characteristics were evaluated using Spearman correlations and Fisher's exact test. Tamoxifen benefit was analysed by univariable Kaplan-Meier (log-rank) and multivariable Cox proportional hazards adjusting for age, tumour size, grade, progesterone receptor, Ki-67, and radiotherapy. Differential expression was assessed with limma and pathway enrichment with fgsea using Hallmark gene sets from MSigDB.

Results: Low immune abundance was significantly associated with higher ER expression (Kruskal-Wallis test p < 0.001). Among tamoxifen-treated patients, those with low immune scores showed improved distant recurrence-free interval (DRFI) relative to untreated patients (log-rank p < 0.001). Similarly, intermediate endothelial (p < 0.001) and low/intermediate fibroblast abundances (p = 0.042, p = 0.009) were associated with favourable DRFI. In multivariable models, low immune (adjusted HR = 0.17, 95% CI 0.08-0.40), intermediate endothelial (aHR = 0.21, 95% CI 0.09-0.51), and low/intermediate fibroblast tertiles (aHR = 0.50, 95% CI 0.27-0.93; aHR = 0.36, 95% CI 0.17-0.77) retained significance. Transcriptomic analysis revealed enrichment of oestrogen-response, MYC-target, and oxidative-phosphorylation pathways in low-immune and low-fibroblast tumours, while interferon-γ response and allograft rejection pathways were downregulated.

Conclusions: TME composition modulates tamoxifen benefit in postmenopausal ER+HER2- breast cancer. Low immune, intermediate endothelial, and low/intermediate fibroblast abundances are associated with improved benefit from tamoxifen, suggesting that both immune and stromal compartments influence endocrine treatment efficacy.