Activating somatic ESR1 mutation in an aggressive prolactinoma

Ticiana Silva; Mebarak Jacobo Buelvas; Magnotto John C.; Stamatiades George A.; Yanan Kuang; Cloud Paweletz; Laws Edward R.; Carroll Rona Stephanie; Rinath Jeselsohn; Dipika Mohan; Lerario Antonio Marcondes; Minh-Tam Truong; Bi Wenya Linda; Reardon David A.; Meredith David M.; Ursula Kaiser; Abreu Ana Paula

doi:10.1530/endoabs.99.P191

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Endocrine Abstracts (2024) 99 P191 | DOI: 10.1530/endoabs.99.P191

ECE2024 Poster Presentations Late-Breaking (77 abstracts)

Activating somatic ESR1 mutation in an aggressive prolactinoma

Ticiana Silva ¹ , Jacobo Buelvas Mebarak ² , John C. Magnotto ² , George A. Stamatiades ² , Yanan Kuang ³ , Cloud Paweletz ³ , Edward R. Laws ⁴ , Rona Stephanie Carroll ² , Rinath Jeselsohn ³ , Dipika Mohan ⁵ , Antonio Marcondes Lerario ⁶ , Minh-Tam Truong ⁷ , Wenya Linda Bi ⁴ , David A. Reardon ³ , David M. Meredith ⁸ , Ursula Kaiser ² & Ana Paula Abreu ¹

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Author affiliations

¹Brigham and Women’s Hospital and Harvard Medical School, Department of Internal Medicine, Division of Endocrinology, Diabetes and Hypertension, Boston, United States; ²Brigham and Women’s Hospital and Harvard Medical School, Department of Internal Medicine, Division of Endocrinology, Diabetes and Hypertension, Boston, United States; ³Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, United States; ⁴Brigham and Women’s Hospital and Harvard Medical School, Department of Neurosurgery, Boston, United States; ⁵Washington University School of Medicine, Department of Medicine, St. Louis, United States; ⁶University of Michigan, Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Ann Arbor, United States; ⁷Boston University Chobanian & Avedisian School of Medicine, Department of Radiation Oncology, Boston, United States; ⁸Brigham and Women’s Hospital and Harvard Medical School, Department of Pathology, Boston, United States

Introduction: Prolactinomas are benign tumors usually well controlled with dopamine agonists; few progress on medical therapy through unclear molecular mechanisms. Although the SF3B1 mutation has been recently associated with aggressive prolactinomas, in most cases, no genetic mutations have been reported. We aimed to identify somatic genetic alterations associated with prolactinomas using a gene panel.

Method and Results: Oncopanel, a massively parallel sequencing panel, was performed to identify somatic genomic variants and copy number variation (CNV) in a cohort of 20 patients with prolactinomas (age, mean &mplus; SD 38.6 &mplus; 14.49 years; 12 women). 40% of our patients who underwent surgery were resistant to dopamine agonists. None of our patients had metastatic disease. We identified a somatic ESR1 (encoding estrogen receptor alpha) mutation (p.y537S) in a post-menopausal woman with a recurrent prolactinoma in DNA obtained from her fourth surgery. No SF3B1 variants or other pathogenic variants were identified in this cohort. The median CNV events was 46 events (IQR: 1-80) with 64% gene amplification and 36% gene losses. The prolactinoma harboring the ESR1_Y537S had 233 CNV events consistent with a highly disrupted genome and much higher than the remaining of our cohort samples. We then sought to investigate if there was circulating cell-free DNA. We were able to identify ESR1_Y537S in peripheral blood using droplet digital PCR, indicating high tumor shredding, which is not commonly seen in pituitary adenomas and raises the question of the benign nature of this tumor. ESR1_Y537S is a hotspot mutation in metastatic breast cancer. ESR1_Y537S confers resistance to classic hormonal treatment in breast cancer by activating the receptor independent of ligand binding. This results in high cell proliferation and confers an advantage over cells expressing wild-type estrogen receptors. Elacestrant, a second-line ER degrader, increases overall progression-free survival in patients with resistant breast cancer and ESR1_Y537S. Given the lack of response to multimodality therapies, elacestrant was initiated after completition of the third cycle of radiotherapy in this patient with aggressive prolactinoma harboring ESR1_Y537S. The combination of radiotherapy with this personalized treatment was able to control tumor growth and significantly reduce prolactin levels after years without adequate control.

Conclusion: ESR1 regulates lactotroph differentiation and proliferation. Our data supported a role for ESR1_Y537S in the unusually aggressive behavior of this patient’s prolactinoma in the postmenopausal setting. Molecular profiling revealing the ESR1_Y537S mutation allowed us to use targeted therapy to promote control of a previously resistant prolactinoma.