Novel ESR1 gene fusion detected through the CGP as a probable mechanism of resistance to endocrine therapy

Prof. Dr. MD. Mofazzel Hossain

Cancer Specialist & Medical Oncologist, BRB Hospital, Dhaka

This is a case where Genetic testing was chosen by the consulting physician to determine potential therapeutic alternatives and the underlying cause of endocrine therapy resistance.

Clinical Presentation and Diagnosis

The proband is a 59-year-old woman who diagnosed with HR +ve/HER2 -ve breast cancer in 2016, for which she was treated with a first line of endocrine therapy (combination of Paclitaxel and Letrozole). Following metastasis, the patient was treated with combination of Gemcitabine, Bevacizumab and Carboplatin in 2020 and Exemestane + Fulvestrant in 2021. Genetic testing was chosen by the consulting physician to determine potential therapeutic alternatives and the underlying cause of endocrine therapy resistance.

SUMMARY OF FINDINGS IN THE PATIENT’S TUMOR SAMPLE

ER+ breast cancer patients primarily respond to treatment with endocrine and aromatase inhibitors, whereas few develop resistance due to ESR1 loss, secondary mutations, amplification or by forming fusions. Some of the well-established fusion partners for ESR1 include CCDC170, YAP1, GYG1, DAB2 and SOX9, and it accounts to 2% of ER +ve breast cancers. We identified a novel ESR1-IMPG1 fusion in this patient’s tumor sample.

Fig 1: Image depicting the breakpoints and the retained domains in the ESR1-IMPG1 fusion detected in the patient’s tumor

The AF1 domain, DBD, and H domain of the ESR1 protein are conserved in the identified fusion, but the AF2 domain containing LBD is lost. The most reported active ESR1 fusions retained AF1, DBD, H domains and were deficient of the AF2/LBD domain. Here, the breakpoints were around the Exon 6-Intron 6 boundary, fusing with the C-terminal gene partners. Although there is no evidence of the detected fusion in the literature, ESR1 fusions without LBD have been found to be resistant to endocrine therapy and sensitive to CDK4/6 inhibitors, according to well established clinical studies.

The take home lesson here is that identification of variants through CGP, may aid in the identification of biomarkers associated with therapeutic sensitivity and resistance to certain drugs in certain cancers during disease progression.

ABBREVIATIONS: AF1- Activating function 1, DBD-DNA-binding domain, H domain- Hinge domain, AF2- Activating function 2, LBD-Ligand binding domain
Authors: Ashwini P, Kritika Verma, Saranya Rangan, Sharanya J