Phosphorylation of the estrogen receptor α at serine 305 and prediction of tamoxifen resistance in breast cancer

Abstract

11058 Background: Phosphorylation of estrogen receptor α at serine 305 (ERαS305-P) induces tamoxifen resistance in experimental studies, but does not influence response to other anti-endocrine agents, such as fulvestrant. We evaluated ERαS305-P in 377 breast carcinomas from premenopausal participants of a randomized trial (n=248) and patients with advanced disease (n=129). Methods: Immunohistochemistry on formalin-fixed paraffin embedded tumor tissue was performed using a new monoclonal antibody. Results: Among the premenopausal patients, adjuvant tamoxifen improved recurrence-free survival (RFS) for ERαS305-P negative tumors (multivariate HR=0.53, 95%CI 0.32–0.86, p=0.010), but not for ERαS305-P positive tumors (multivariate HR=1.01, 95%CI 0.33–3.05, p=0.99) (interaction p=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 tumor progression. In advanced disease, the combined expression of phospho-protein kinase A and ERαS305-P, the former known to be involved in phosphorylation of ERαS305, was associated with poor outcome after tamoxifen. Conclusions: 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, alternative endocrine treatment should be considered for this subgroup. No significant financial relationships to disclose.