PMON169 D2R Expression in Dopamine-Agonist Resistant Prolactinomas
Authors: Levine Alice , Bass Ilana , Alba Eva , Umphlett Melissa , Shuman William , Milgrim Emily , Milgrim Lucas , Bederson Joshua , Post Kalmon , Shrivastava Raj 
Published: November 2022

Abstract

Introduction
Dopamine-agonist (DA) resistant prolactinomas are characterized by failure to achieve normal prolactin levels or reduce tumor size by at least 50% on maximal conventional DA dosages. This occurs in about 10% of patients on cabergoline and is more common in larger macroadenomas, and in men compared with women. The underlying cause of resistance may be a lack of D2 receptor (D2R) tumor expression. As high dose DA therapy may have serious cardiac side effects, it is important to determine the D2R expression. Further, the sexual dimorphism observed in resistant prolactinomas may be due to estrogen receptor alpha (ERα) expression in female tumors, as ERα signaling has been shown to enhance sensitivity to DAs. We investigated the possibility that androgen receptor (AR) signaling in males promotes resistance via induction of transmembrane serine protease 2 (TMPRSS2), a cell surface serine protease, a known promoter of tumor progression in prostate and lung cancer.

Methods
This is a retrospective, single-center study conducted at an academic quaternary-care center. Immunohistochemical (IHC) analysis was performed on 16 specimens from surgically removed lactotroph cell type tumors, including D2R, growth hormone (GH), prolactin (PRL), TMPRSS2, ERα, AR, and the stem cell marker, CD133. We simultaneously conducted a chart review of the Electronic Medical Record to determine age at diagnosis, tumor size, initial PRL level, medical treatment, and reason for surgical resection.

Results
A total of 14 patients were included in our study. Two patients had multiple surgeries for resistant prolactinomas such that the sample size included 16 specimens- 7 resistant prolactinomas and 9 controls (resected for another reason other than treatment resistance). There were 2 men and 3 women in the resistant group, and 5 women and 4 men in the control group. Baseline prolactin level was higher in the resistant group (2413ng/mL) than the control group (676.4ng/mL) and tumor size was larger—2.05cm vs. 1.57cm in the largest diameter in the resistant vs. control groups, respectively. D2R expression was positive in 8 out of 9 controls vs. 1 out of 7 in resistant tumors. ERα positivity did not correlate with DA resistance. AR expression was negative in all specimens although the majority of tumors in both groups did express TMPRSS2. CD133 was negative in all but one of the resistant tumors.

Conclusion
We found that 80% of specimens from patients with DA-resistant prolactinomas had negative D2R expression. The one resistant tumor that had positive D2R and negative TMPRSS2 expression was from an 11 year old girl who also had negative ERα expression that may explain the lack of response to dopamine agonist therapy. D2R IHC can identify lack of D2R expression in DA-resistant tumors and provide a rationale for discontinuation of high dose DA therapy to avoid toxicity.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.