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Background In breast cancer (BC), recurrent fusion genes of estrogen receptor alpha ( ESR1 ) and  AKAP12 ,  ARMT1  and  CCDC170  have been reported. In these gene fusions the ligand binding domain of ESR1 has been replaced by the transactivation domain of the fusion partner constitutively activating the receptor. As a result, these gene fusions can drive tumor growth hormone independently as been shown in preclinical models, but the clinical value of these fusions have not been reported. Here, we studied the prognostic and predictive value of different frequently reported  ESR1  fusion transcripts in primary BC. Methods We evaluated 732 patients with primary BC (131  ESR1- negative and 601  ESR1- positive cases), including two ER-positive BC patient cohorts: one cohort of 322 patients with advanced disease who received first-line endocrine therapy (ET) (predictive cohort), and a second cohort of 279 patients with lymph node negative disease (LNN) who received no adjuvant systemic treatment (prognostic cohort). Fusion gene transcript levels were measured by reverse transcriptase quantitative PCR. The presence of the different fusion transcripts was associated, in uni- and multivariable Cox regression analysis taking along current clinico-pathological characteristics, to progression free survival (PFS) during first-line endocrine therapy in the predictive cohort, and disease- free survival (DFS) and overall survival (OS) in the prognostic cohort. Results The  ESR1-CCDC170  fusion transcript was present in 27.6% of the  ESR1 -positive BC subjects and in 2.3% of the  ESR1 -negative cases. In the predictive cohort, none of the fusion transcripts were associated with response to first-line ET. In the prognostic cohort, the median DFS and OS were respectively 37 and 93 months for patients with an  ESR1-CCDC170  exon 8 gene fusion transcript and respectively 91 and 212 months for patients without this fusion transcript. In a multivariable analysis, this  ESR1 - CCDC170  fusion transcript was an independent prognostic factor for DFS (HR) (95% confidence interval (CI): 1.8 (1.2–2.8),  P  = 0.005) and OS (HR (95% CI: 1.7 (1.1–2.7),  P  = 0.023). Conclusions Our study shows that in primary BC only  ESR1-CCDC170  exon 8 gene fusion transcript carries prognostic value. None of the  ESR1  fusion transcripts, which are considered to have constitutive ER activity, was predictive for outcome in BC with advanced disease treated with endocrine treatment.

The prognostic and predictive value of ESR1 fusion gene transcripts in primary breast cancer