Clinical significance of estrogen receptor 1 gene mutations in hormonal resistant breast cancer patients

Background: About 70% of breast cancers are positive for estrogen receptor (ER) and consequently treated with endocrine therapy. Estrogen receptor gene (ESR1) was found to be mutated in recurrent and metastatic breast cancer under the intense selective pressure imposed by endocrine therapy (ET) on breast cancer cells. These mutations are a prominent cause of endocrine therapy resistance shortening the overall survival of breast cancer patient despite of recent improvement in the treatment. This study assessed the clinical significance of estrogen receptor mutations analysis in ER positive breast cancer patients who progressed on to ET resistance along with metastasis. Methods: Tumor DNA and circulating tumor DNA (ctDNA) were extracted from local recurrent and metastatic lesions of breast cancer patient and paired patient's plasma respectively. Detection of ESR1 mutations (D538G and Y5375) was carried out on tumor DNA and ctDNA using pyrosequencing. Primary tumor tissues of these patients were retrieved and tested also for the same ESR1 mutations to prove or to deny the hypothesis of they are acquired mutations. Results: ESR1 mutations (D538G and Y5375) were detected in 22% (11/50) of recurrent and metastatic tissue samples and 28% (14/50) of matched concomitant plasma samples of 50 ER positive breast cancer patients who progressed despite ET. All mutations were detected in patients previously treated with aromatase inhibitors (AI). A significant statistical correlation was found between ESR1 mutations and bone involvement (P value < 0.001*). Conclusion: ESR1 mutations (Y5375 and D538G) were detected in endocrine-treated breast cancer patients who showed progression despite ET. The concordance between results of ESR1 mutations in tissue biopsies and plasma (ctDNA) during relapse could make liquid biopsy analysis replace the tissue analysis in predicting endocrine resistance in breast cancer patients.