Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer - PubMed (original) (raw)

. 2011 Nov 1;29(31):4160-7.

doi: 10.1200/JCO.2010.32.9615. Epub 2011 Sep 26.

Gong Tang, Katherine L Pogue-Geile, Joseph P Costantino, Frederick L Baehner, Joffre Baker, Maureen T Cronin, Drew Watson, Steven Shak, Olga L Bohn, Debora Fumagalli, Yusuke Taniyama, Ahwon Lee, Megan L Reilly, Victor G Vogel, Worta McCaskill-Stevens, Leslie G Ford, Charles E Geyer Jr, D Lawrence Wickerham, Norman Wolmark, Soonmyung Paik

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Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer

Chungyeul Kim et al. J Clin Oncol. 2011.

Abstract

Purpose: Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors.

Patients and methods: 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). This was a retrospective subset analysis based on available materials.

Results: In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. 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.

Conclusion: These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Fig 1.

CONSORT diagram. NSABP, National Surgical Adjuvant Breast and Bowel Project; RT-PCR, reverse transcriptase polymerase chain reaction. (*) Included in analysis.

Fig 2.

Fig 2.

Quantitative estrogen receptor expression by reverse transcriptase polymerase chain reaction and distant recurrence at 10 years. Each Kaplan-Meier plot represents tamoxifen and placebo arms of patients diagnosed with tumors that express (A) low, (B) middle, and (C) high tertile levels of ESR1 mRNA. HR, hazard ratio.

Fig 3.

Fig 3.

RNA and protein measurement of estrogen receptor (ER) and clinical outcome. (A) Rate of distant recurrence at 10 years as a function of quantitative ER by reverse transcriptase polymerase chain reaction (RT-PCR) in the placebo (blue line) and tamoxifen (gold line) groups. Solid lines are estimates, and dashed lines are 95% confidence bands. (B) Log-hazard ratio against the mean versus ESR1 mRNA on the basis of 290 patients randomly assigned to tamoxifen. Dashed lines are 95% confidence bands. (C) Log-hazard ratio against the mean versus ER by ligand binding assay (LBA) on the basis of 1,345 patients randomly assigned to tamoxifen, with ER by LBA less than 450 fmol/mg. (D) Log-hazard ratio against the mean versus ER by immunohistochemistry (IHC) on the basis of 177 patients randomly assigned to tamoxifen. DRFI, distant recurrence–free interval.

Fig 4.

Fig 4.

Results of microarray gene expression analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1) estrogen receptor (ER) –positive cancer events. (A) Volcano plot of the results of t test for differences of expression levels of all filtered genes (N = 7,743) from Agilent array (Agilent Technologies, Santa Clara, CA) between ER-positive invasive cancer events that occurred initially in the tamoxifen versus the placebo arm from NSABP P-1 (N = 84). The x axis represents log (fold difference between two phenotypes); the y axis represents log (P value). Each spot represents a gene. Locations of the ER gene probe (ie, ESR1) and of GRFA1 are noted. (B) Scattergram of normalized ESR1 mRNA levels of ER-positive invasive breast cancer events from the NSABP P-1 according to treatment assignment (N = 84). Note the absence of tumors with high levels of ESR1 mRNA in the tamoxifen arm. Horizontal bars represent mean with standard errors. P value for the difference was less than .001. Data are plotted in a natural scale to better demonstrate the differences in higher expression level data range.

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