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

Abstract

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 In these gene fusions the ligand binding domain of ESR1 has been replaced by the transactivation domain of the fusion partner constitutively activating the receptor.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.

ESR1 fusions and therapeutic resistance in metastatic breast cancer

“…When first described, ESR1-e2>CCDC170 in ER+ breast cancer cells led to enhanced growth and reduced sensitivity to tamoxifen ( 75 ) suggesting a role for ESR1-e2>CCDC170 in ET resistance. Additional pre-clinical studies ( 74 , 75 , 79 ) showed that the expression of ESR1-e2>CCDC170 fusions in ER-positive breast cancer cells resulted in increased cell migration, increased colony formation, and increased cell proliferation as evidenced by the increase in the number of cells in S-G2/M phase. Li and colleagues ( 74 ) provided detailed evidence supporting the function of ESR1-e2>CCDC170 in promoting breast cancer cell survival and endocrine resistance both in vitro and in xenograft models.…”

“…These include fusion proteins associated with ER such as ESR1-CCDC170 ( 73 – 75 ), and ESR1-YAP1 ( 76 ) and non ER related fusions such as CTNNBL1-RAF1, ACTL6A-PIK3CA, S6KCI-AKT3 ( 71 ), SEC16A-NOTCH1 ( 77 ), SEC22B-NOTCH2 ( 72 ), and ETV6-NTRK3 ( 78 ). A number of these fusions promote tumor growth, and patients expressing these fusion proteins have more rapid disease progression and shorter survival than fusion-negative patients ( 70 , 71 , 75 , 79 ). Identifying the full spectrum of the ESR1 gene fusions and characterizing their role in intrinsic ET resistance is critical for developing novel and effective targeted therapies.…”

Clinical Implications and Treatment Strategies for ESR1 Fusions in Hormone Receptor-Positive Metastatic Breast Cancer: A Case Series

“… 6 , 7 The most prevalent fusions are between ESR1 and the adjacent gene CCDC170 , comprising over half of ESR1-FUS cases; the remaining fusions involve assorted gene partners. 6 , 8 , 10 , 12 , 13 Analysis of HR+ MBC samples has identified ESR1-FUS at 3-5% prevalence. 14 , 15 These sample sizes are small, and it is unknown how ESR1-FUS prevalence differs in treated versus treatment-naïve conditions.…”

“…Other studies suggest higher prevalence limits (up to 22-28%), although likely with higher false-positive rates. 12 , 13 Of note, some immortalized breast cancer lines also carry ESR1 :: CCDC170 fusions, including MCF7, HCC1428, and ZR75-1. 6 , 8 , 12 In summary, ESR1-FUS may be present in at least 1-10% of primary HR+ breast cancer, typically in luminal B tumors, and the most common are ESR1 :: CCDC170 fusions.…”

“…The most frequently detected ESR1-FUS in patients involves the ESR1 promoter and 5’ UTR exons (without any ESR1 coding sequence) truncating a fusion partner 6 , 8 , 12 , 13 ( Fig. 2C ).…”