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Association between the Estrogen Receptor A908G Mutation and Outcomes in Invasive Breast Cancer

Authors' Affiliations: ¹ Breast Center, Baylor College of Medicine, Houston, Texas and ² College of Life Science, Zhejiang University of Science and Technology, Hangzhou, China

Requests for reprints: Suzanne A.W. Fuqua, Breast Center, Baylor College of Medicine, One Baylor Plaza, 1220 Alkek, Houston, TX 77030. Phone: 713-798-1600; Fax: 713-798-1673; E-mail: sfuqua{at}bcm.edu.

Purpose: Estrogen receptor (ER) predicts the natural history of breast cancer without intervening therapy. Here, we have optimized the detection of a somatic mutation, an A908G transition of ER, and examined its association with clinical and biological features of invasive breast cancer.

Experimental Design: We compared two methods of sequencing to detect the A908G ER mutation. We then used primer extension sequencing with genomic DNA isolated from invasive breast tumors to determine whether the mutation was associated with clinical outcome in 267 axillary node–negative and axillary node–positive breast tumors. The presence of the mutation and clinical variables were analyzed for association with recurrence-free survival and overall survival by Cox proportional hazards regression models.

Results: We determined that dye-labeled terminator sequencing was not adequate for detection of the A908G ER mutation. The mutation was detected at a high frequency (50%) in invasive breast tumors using primer extension sequencing, and was found to be associated with clinical measures of poor outcome, including larger tumor size and axillary lymph node positivity. Although the mutation was associated with recurrence-free survival in univariate analysis, it was not an independent predictor of outcomes in multivariate analysis.

Conclusions: Consistent with our previous finding of this somatic ER mutation in breast ductal hyperplasias, we now present evidence that the A908G mutation is present in invasive breast tumors using an optimized sequencing method. We find that the mutation is significantly associated with aggressive biological tumor features, and with an unfavorable prognosis, but was not an independent prognostic marker in untreated patients.

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