Prognostic and predictive role of ESR1 status for postmenopausal patients with endocrine-responsive early breast cancer in the Danish cohort of the BIG 1-98 trial

Abstract

Background: Estrogen Receptor 1 (ESR1) aberrations may be associated with expression of estrogen receptor (ER) or progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2) or Ki-67 labeling index and prognosis.

Patients and methods: ESR1 was assessed in 1129 (81%) of 1396 postmenopausal Danish women with early breast cancer randomly assigned to receive 5 years of letrozole, tamoxifen or a sequence of these agents in the Breast International Group 1-98 trial and who had ER ≥ 1% after central review.

Results: By FISH, 13.6% of patients had an ESR1-to-Centromere-6 (CEN-6) ratio ≥ 2 (amplified), and 4.2% had ESR1-to-CEN-6 ratio <0.8 (deleted). Deletion of ESR1 was associated with significantly lower levels of ER (P < 0.0001) and PgR (P = 0.02) and more frequent HER2 amplification. ESR1 deletion or amplification was associated with higher-Ki-67 than ESR1-normal tumors. Overall, there was no evidence of heterogeneity of disease-free survival (DFS) or in treatment effect according to ESR1 status. However, significant differences in DFS were observed for subsets based on a combination of ESR1 and HER2 status (P = 0.02).

Conclusions: ESR1 aberrations were associated with HER2 status, Ki-67 labeling index and ER and PgR levels. When combined with HER2, ESR1 may be prognostic but should not be used for endocrine treatment selection in postmenopausal women with endocrine-responsive early breast cancer.

Figures

Figure 1.

Box plots illustrating the distribution of ER, PgR and Ki-67 labeling index expression levels according to ESR1 status. Boxes indicate 25th, 50th (median) and 75th percentiles. P values were derived from Wilcoxon rank-sum test for ER percent (P < 0.0001), PgR percent (P = 0.02) and Ki-67 labeling index percent (P < 0.0001) and from Fisher’s exact tests for HER2 (P = 0.04). Missing values were omitted. ER, estrogen receptor; PgR, progesterone receptor; HER2, human epidermal growth factor receptor-2.

Figure 2.

Kaplan–Meier estimates of disease-free survival according to ESR1 status (A) and according to ESR1 status and HER2 status categories (B). HER2, human epidermal growth factor receptor-2.

Figure 3.

Cox proportional hazards model for disease-free survival comparing ESR1-deleted and ESR1-amplified cohorts (aberrant cohorts) versus the ESR1-normal cohort overall and for subgroups defined by HER2 status and Ki-67 labeling index category. Hazard ratio values <1.0 indicate a better outcome for the aberrant (either deleted or amplified) compared with ESR1 normal. HER2, human epidermal growth factor receptor-2.