Low-level Expression of ESR1 Tied to Tamoxifen Resistance

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Data from a retrospective analysis of two pivotal breast cancer studies suggest that the low-level expression of the estrogen receptor (ER) gene ESR1 “is a determinant of tamoxifen resistance in ER-positive breast cancer,” reported researchers in the Journal of Clinical Oncology.

“We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1),” the authors explained. Paraffin blocks with sufficient invasive breast cancer for RNA extraction were available from 645 of the 2,817 randomly assigned patients in the NSABP B-14 study and from 108 of the 13,338 patients in the P-1 study. In that study, “30% of ER-positive tumors were not prevented by tamoxifen,” the investigators noted.

“In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined,” the researchers found. “On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression,” the investigators wrote.

Study Implications

“The limitations of subset analysis have been detailed elsewhere and are always a concern in interpretation of data,” the authors acknowledged. “However, the confirmation of B-14 results by P-1 results supports the conclusion that low levels of ER are at least in part responsible for tamoxifen resistance in breast cancer.”

The finding that tamoxifen is less effective in preventing ER-positive tumors with low levels of ESR1 means that “strategies should be developed to identify, treat, and prevent such tumors,” the researchers concluded. ■

Kim C, et al: J Clin Oncol Sept. 26, 2011 (early release online).




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