title: Phosphorylation of the oestrogen receptor alpha at serine 305 and prediction of tamoxifen resistance in breast cancer.
abstract: Phosphorylation of oestrogen receptor alpha at serine 305 (ERalphaS305-P) induces tamoxifen resistance in experimental studies, but does not influence response to other endocrine agents, such as fulvestrant. We evaluated ERalphaS305-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 ERalphaS305-P-negative tumours (multivariate HR=0.53, 95% CI 0.32-0.86, p=0.010), but not for ERalphaS305-P-positive tumours (multivariate HR=1.01, 95% CI 0.33-3.05, p=0.99) (interaction p=0.131). Notably, ERalphaS305-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 ERalphaS305-P is a marker for treatment outcome rather than tumour progression. Given the direct experimental link between ERalphaS305-P and tamoxifen resistance and these first clinical data suggesting that premenopausal patients with ERalphaS305-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.
authors.affiliation: Centre for Molecular Pathology, Lund University, Malmö University Hospital, Malmö, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Holm
authors.forename: M
authors.initials: M
authors.lastname: Kok
authors.forename: R
authors.initials: R
authors.lastname: Michalides
authors.forename: R
authors.initials: R
authors.lastname: Fles
authors.forename: R H T
authors.initials: RH
authors.lastname: Koornstra
authors.forename: J
authors.initials: J
authors.lastname: Wesseling
authors.forename: M
authors.initials: M
authors.lastname: Hauptmann
authors.forename: J
authors.initials: J
authors.lastname: Neefjes
authors.forename: J L
authors.initials: JL
authors.lastname: Peterse
authors.forename: O
authors.initials: O
authors.lastname: Stål
authors.forename: G
authors.initials: G
authors.lastname: Landberg
authors.forename: S C
authors.initials: SC
authors.lastname: Linn
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D010766:Phosphorylation; D012189:Retrospective Studies; D012694:Serine / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D012694:Serine