Estrogen Receptor Alpha Gene Amplification Is an Independent Predictor of Long-Term Outcome in Postmenopausal Patients with Endocrine-Responsive Early Breast Cancer

Abstract

Purpose: Estrogen receptor (ER) expression is a prognostic parameter in breast cancer, and a prerequisite for the use of endocrine therapy. In ER+ early breast cancer, however, no receptor-associated biomarker exists that identifies patients with a particularly favorable outcome. We have investigated the value of ESR1 amplification in predicting the long-term clinical outcome in tamoxifen-treated postmenopausal women with endocrine-responsive breast cancer.

Experimental design: 394 patients who had been randomized into the tamoxifen-only arm of the prospective randomized ABCSG-06 trial of adjuvant endocrine therapy with available formalin-fixed, paraffin-embedded tumor tissue were included in this analysis. IHC ERα expression was evaluated both locally and in a central lab using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis using the ESR1/CEP6 ratio indicating focal copy number alterations.

Results: Focal ESR1 copy-number elevations (amplifications) were detected in 187 of 394 (47%) tumor specimens, and were associated with a favorable outcome: After a median follow-up of 10 years, women with intratumoral focal ESR1 amplification had a significantly longer distant recurrence-free survival [adjusted HR, 0.48; 95% confidence interval (CI), 0.26-0.91; P = 0.02] and breast cancer-specific survival (adjusted HR 0.47; 95% CI, 0.27-0.80; P = 0.01) as compared with women without ESR1 amplification. IHC ERα protein expression, evaluated by Allred score, correlated significantly with focal ESR1 amplification (P < 0.0001; χ2 test), but was not prognostic by itself.

Conclusions: Focal ESR1 amplification is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received tamoxifen for 5 years.

Figure 1.

Representative examples of ESR1 status in breast carcinomas as determined by FISH. A, High-level ESR1 amplification (4–10 copies per nucleus). B, Low-level ESR1 amplification (1–4 gene copies per nucleus. 28–30 ESR1 signals to 22 CEP6 signals shown altogether). C, Normal, copy number not increased. The red signals correspond to centromere.

Figure 2.

Description of the process of tumor block and patient selection.

Figure 3.

Histogram detailing the levels of ESR1 amplification in the study population in whole-digit steps.

Figure 4.

DRFS in patients treated with tamoxifen according to ERα expression by Allred score (A), and ESR1 amplification status (B), and BCSS in patients treated with tamoxifen according to ERα expression by Allred score (C), and ESR1 amplification status (D).

Figure 5.

DRFS in patients treated with tamoxifen in nodal-negative (A) and in nodal-positive (B) patients. BCSS in patients treated with tamoxifen in nodal-negative (C) and in nodal-positive (D) patients.