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

Silvia R. Vitale, Kirsten Ruigrok-Ritstier, A. Mieke Timmermans, Renée Foekens, Anita M.A.C. Trapman-Jansen, Corine M. Beaufort, Paolo Vigneri, Stefan Sleijfer, John W.M. Martens, Anieta M. Sieuwerts, Maurice P.H.M. Jansen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 In these gene fusions the ligand binding domain of ESR1 has been replaced by the transactivation domain of the fusion partner constitutively activating the receptor.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

Original languageEnglish
Article number165
JournalBMC Cancer
Issue number1
Publication statusPublished - 12 Feb 2022

Bibliographical note

Funding Information:
AMS and JWM were supported by the Cancer Genomics Netherlands ( Organization for Scientific Research (NWO). SRV was supported by an ERC Advanced grant (No 322737).

Funding Information:
The authors are especially grateful to all patients, to Steven van Laere and Luc Dirix?Department Oncology, Antwerp University, Belgium and to Sabine C. Linn ? Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands for their contribution of tissues from patients treated with 1st line aromatase inhibitor.

Publisher Copyright:
© 2022, The Author(s).


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