Oestrogen receptor β in colorectal cancer: exploring sex-related differences of prognostic impact and association with tumour T-cell infiltration
Isac Norrgård, Jussi Kasurinen, Harri Mustonen, Jaana Hagström, Ines Beilmann-Lehtonen, Caj Haglund, Tuomas Kaprio, Camilla Böckelman, Malin SundAbstract
Introduction
There are sex-related differences in colorectal cancer (CRC), with higher incidence and mortality in males. Oestrogen could contribute to this. Tumour expression of oestrogen receptor β (ERβ) seems to be prognostic in CRC, but its role in sex-related differences remains unclear. In this retrospective cohort study, it was assessed if the prognostic impact of ERβ in CRC differs by sex and whether ERβ expression is associated with tumour T-cell infiltration.
Methods
The study cohort included 511 CRC patients. Tumour ERβ expression and CD3+CD8+ T-cell infiltration were determined by immunohistochemistry in tissue microarrays. Associations were evaluated with Pearson's Chi-square; disease-specific survival was analysed with Kaplan-Meier curves and multivariable Cox regression. A sensitivity analysis using multiple imputation for missing covariate data was performed.
Results
Tumour ERβ expression was positive in 412 (80.6%) patients and negative in 99 (19.4%). Negative ERβ expression was associated with higher stage (P < 0.001) and distant metastasis (P < 0.001), but not with sex (P = 0.169) or T-cell infiltration (P = 0.325). Females with ERβ-negative tumours exhibited poor survival. The multivariable model revealed a significant interaction between ERβ and sex (P = 0.031); positive ERβ expression was an independent marker of favourable prognosis in females (HR 0.54, P = 0.015), but not in males (HR 1.27, P = 0.431). The sensitivity analysis showed similar results, but the interaction did not reach statistical significance (P = 0.083).
Discussion
The prognostic impact of ERβ expression in CRC may differ by sex, which could contribute to sex-related differences in outcomes. Negative ERβ expression could help identify high-risk female patients. Therapy activating ERβ signalling could improve CRC outcomes.