Estrogen receptor-alpha phosphorylation at serine-118 and tamoxifen response in breast cancer.
Although estrogen receptor-alpha (ER) [corrected] is a marker used to identify breast cancer patients most likely to benefit from endocrine therapy, approximately 50% of ER-positive [corrected] breast carcinomas are resistant to tamoxifen. Preclinical studies have shown that phosphorylation of ER [corrected] at serine-118 (ER alpha S118-P) is required for tamoxifen-mediated inhibition of ER-induced [corrected] gene expression. We evaluated the association between recurrence-free survival after tamoxifen treatment and ER alpha S118-P expression by use of Cox proportional hazards regression. Data were from 239 premenopausal patients with breast cancer who participated in a randomized trial of 2 years of adjuvant tamoxifen treatment vs no systemic treatment. ER alpha S118-P expression was assessed by immunohistochemistry and categorized by use of the Allred score (low expression = score of 0-6; high expression = score of 7-8). All statistical tests were two-sided. Compared with systemically untreated patients, we found evidence of a benefit from adjuvant tamoxifen among patients whose tumors had high ER alpha S118-P expression (23.7 recurrences per 1000 person-years versus 72.2 recurrences per 1000 person-years, hazard ratio [HR] of recurrence = 0.36, 95% confidence interval [CI] = 0.20 to 0.65) but not among patients whose tumors had low expression (51.0 recurrences per 1000 person-years versus 57.0 recurrences per 1000 person-years, HR of recurrence = 0.87, 95% CI = 0.51 to 1.48), a statistically significant difference (P for interaction = .037). ER alpha 118-P was not associated with recurrence-free survival among untreated patients. Thus, ER alpha S118-P expression appears to be associated with response to tamoxifen. [corrected]
Kok
Marleen
M
Department of Experimental Therapy, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Holm-Wigerup
Caroline
C
Hauptmann
Michael
M
Michalides
Rob
R
Stål
Olle
O
Linn
Sabine
S
Landberg
Göran
G
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D015999:Multivariate Analysis; D016017:Odds Ratio; D010766:Phosphorylation / Q000187:drug effects; D017697:Premenopause; D016016:Proportional Hazards Models; D012694:Serine / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D012694:Serine