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Phosphorylation of oestrogen receptor α at serine 305 (ERαS305-P) induces tamoxifen resistance in experimental studies, but does not influence response to other endocrine agents, such as fulvestrant. We evaluated ERαS305-P using immunohistochemistry in 377 breast carcinomas from premenopausal participants of a randomized trial (n= 248) and patients with advanced disease (n= 129). Among the premenopausal patients, adjuvant tamoxifen improved recurrence-free survival (RFS) for ERαS305-P-negative tumours (multivariate HR = 0.53, 95% CI 0.32–0.86,p= 0.010), but not for ERαS305-P-positive tumours (multivariate HR = 1.01, 95% CI 0.33–3.05,p= 0.99) (interactionp= 0.131). Notably, ERαS305-P was not significantly associated with RFS in patients not treated with tamoxifen (multivariate HR = 0.64, 95% CI 0.30–1.37,p= 0.248), indicating that ERαS305-P is a marker for treatment outcome rather than tumour progression. Given the direct experimental link between ERαS305-P and tamoxifen resistance and these first clinical data suggesting that premenopausal patients with ERαS305-P-positive breast cancer are resistant to adjuvant tamoxifen, further research is encouraged to study whether alternative endocrine treatment should be considered for this subgroup. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.