Abstract A40: ESR1 gene alterations in the metastatic breast cancer with resistance to aromatase inhibitor

• Published in: Molecular cancer research 2016-02, Vol.14 (2_Supplement), p.A40-A40
• Main Authors: Iwase, Hirotaka, Takeshita, Takashi, Yamamoto-Ibusuki, Mutsuko, Inao, Touko, sueta, Aiko, Fujiwara, Saori
• Format: Article
• Language: English
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1557-3125.ADVBC15-A40

Background: Estrogen receptor (ER) positive breast cancer can be treated by endocrine therapy; however a certain population of ER-positive patients becomes resistant to endocrine therapy after long-term estrogen deprivation treatment. ESR1 gene alterations, mutations, translocation and amplification, have been reported as one of the reasons. Patients and Methods: We successfully obtained metastatic tissue samples from 30 patients with resistance to aromatase inhibitor (AI), and 7 patients with resistance to ethinylestradiol (EE2). ER and PgR expression by immunohistochemistry, and ESR1 gene amplification using FISH and copy number variation (CNV) by PCR, and ESR1 gene mutation including Y537N, Y537C, Y 537S and D538G by droplet digital PCR, were examined, in order to evaluate the endocrine responsiveness. Results: High expression of ER (median; 90%) and low expression of PgR (median 5%) were seen in majority of the patients treated by AI. Signal enhancement of DNA-FISH (> 2.0 fold) was seen in 2 (8%) of 25 patients, and signal gain (1.0< ≤2.0 fold) was seen in 11 (44%) of 25 patients. The increasing of DNA-CNV of ESR1 gene was seen in 3 cases of the 25 examined cases. There was no relationship between DNA-FISH and CNV of ESR1. High frequent ESR1 mutations were seen in 7 (28%) at Y537N, 4 (16%) at Y537C, 11 (44%) at Y 537S, and 2 (8%) at D538G. Double mutation, Y537N/S, was seen in 6 (24%) patients, who tended to unresponsive to subsequent endocrine therapy. After EE2 treatment, ER expression was decreased and PgR expression was increased, but there was no relationship between EE2 treatment and ESR1 gene alteration. Conclusion: In the patients with resistance to AI, high ER / low PgR expression was frequently seen, which was no correlation to ESR1 DNA-amplification. The long non-coding RNA in ESR1 gene locus might be related to this discrepancy (Tomita et al; Nat Commun. 2015). Furthermore, accumulation of ESR1 gene mutations tended to be related to endocrine unresponsiveness. Citation Format: Hirotaka Iwase, Takashi Takeshita, Mutsuko Yamamoto-Ibusuki, Touko Inao, Aiko sueta, Saori Fujiwara. ESR1 gene alterations in the metastatic breast cancer with resistance to aromatase inhibitor. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A40.