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Journal of the National Cancer Institute Advance Access published online on November 25, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp412
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© The Author 2009. Published by Oxford University Press.

BRIEF COMMUNICATION

Estrogen Receptor-{alpha} Phosphorylation at Serine-118 and Tamoxifen Response in Breast Cancer

Marleen Kok, Caroline Holm-Wigerup, Michael Hauptmann, Rob Michalides, Olle Stål, Sabine Linn, Göran Landberg

Affiliations of authors: Department of Experimental Therapy (MK), Department of Bioinformatics and Statistics (MH), Department of Tumor Biology (RM), Department of Molecular Biology (SL), and Department of Medical Oncology (SL), Netherlands Cancer Institute, Amsterdam, the Netherlands; Center for Molecular Pathology, Lund University, Malmö University Hospital, Malmö, Sweden (CH-W, GL); Breakthrough Breast Cancer Research Unit, School of Cancer, Enabling Sciences and Technology, University of Manchester, Paterson Institute for Cancer Research, Manchester, UK (CH-W, GL); Department of Clinical and Experimental Medicine, Division of Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden (OS)

Correspondence to: Göran Landberg, Breakthrough Breast Cancer Research Unit, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester Academic Health Science Centre, Paterson Institute for Cancer Research, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK (e-mail: glandberg{at}picr.man.ac.uk); Center for Molecular Pathology, Lund University, Malmö University Hospital, Entrance 78, 2nd Floor, UMAS, Malmö SE-205 02, Sweden (e-mail: goran.landberg{at}med.lu.se).

Although estrogen receptor-{alpha} (ER{alpha}) is a marker used to identify breast cancer patients most likely to benefit from endocrine therapy, approximately 50% of ER{alpha}-positive breast carcinomas are resistant to tamoxifen. Preclinical studies have shown that phosphorylation of ER{alpha} at serine-118 (ER{alpha}S118-P) is required for tamoxifen-mediated inhibition of ER{alpha}-induced 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.


CONTEXT AND CAVEATS

Prior knowledge

Approximately 50% of estrogen receptor-{alpha} (ER{alpha})–positive breast carcinomas are resistant to tamoxifen. Preclinical studies have shown that phosphorylation of ER{alpha} at serine-118 (ER{alpha}S118-P) is required for response to tamoxifen.

Study design

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. The association between recurrence-free survival and ER{alpha}S118-P expression in tumor tissue was investigated.

Contribution

Among patients treated with adjuvant tamoxifen, improved recurrence-free survival was associated with high ER{alpha}S118-P expression and not with low ER{alpha}S118-P expression. Among patients who received no systemic treatment, ER{alpha}S118-P expression was not associated with recurrence-free survival.

Implications

Future studies should determine whether these results can be extended to postmenopausal patients. Response of patients with high ER{alpha}S118-P status to tamoxifen vs an aromatase inhibitor should be investigated.

Limitations

Tumor tissue was not available for approximately 25% of patients with an ER{alpha}-positive tumor, particularly those with lobular breast cancers.

From the Editors

 
Manuscript received January 16, 2009; revised October 9, 2009; accepted October 13, 2009.


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