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Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors

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Abstract

As ErbB signaling is a determinant of prolactin synthesis, role of ErbB receptors was tested for prolactinoma outcomes and therapy. The objective of this study was to characterize ErbB receptor expression in prolactinomas and then perform a pilot study treating resistant prolactinomas with a targeted tyrosine kinase inhibitor (TKI). Retrospective analysis of prolactinomas and pilot study for dopamine agonist resistant prolactinomas in tertiary referral center. We performed immunofluorescent staining of a tissue array of 29 resected prolactinoma tissues for EGFR, ErbB2, ErbB3, and ErbB4 correlated with clinical features. Two patients with aggressive resistant prolactinomas enrolled and completed trial. They received lapatinib 1,250 mg daily for 6 months with tumor and hormone assessments. Main outcome measures were positive tumor staining of respective ErbB receptors, therapeutic reduction of prolactin levels and tumor shrinkage. Treated PRL levels and tumor volumes were suppressed in both subjects treated with TKI. EGFR expression was positive in 82 % of adenomas, ErbB2 in 92 %, ErbB3 in 25 %, and ErbB4 in 71 %, with ErbB2 score > EGFR > ErbB4 > ErbB3. Higher ErbB3 expression was associated with optic chiasm compression (p = 0.03), suprasellar extension (p = 0.04), and carotid artery encasement (p = 0.01). Higher DA response rates were observed in tumors with higher ErbB3 expression. Prolactinoma expression of specific ErbB receptors is associated with tumor invasion, symptoms, and response to dopamine agonists. Targeting ErbB receptors may be effective therapy in patients with resistant prolactinomas.

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Acknowledgments

This work was supported by NIH Grant K23DK085148 (O. Cooper). Dr. Shlomo Melmed for continuing mentorship, guidance, and patient consultations. GlaxoSmithKline for provision of lapatinib, Kolja Wawrowsky for confocal imaging of TMA and advise, Grace Labrado and Karen Geiser for assistance with preparation of the manuscript, Lori Korsakoff and Billy Gellepis for coordinating the research study.

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Authors and Affiliations

  1. Pituitary Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., B-131, Los Angeles, CA, 90048, USA

    Odelia Cooper, Adam Mamelak, John Carmichael, Vivien Bonert & Anat Ben-Shlomo

  2. Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Serguei Bannykh

  3. Division of Hematology and Oncology, Department of Medicine, CSMC, Los Angeles, CA, USA

    Stephen Lim

  4. Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, CSMC, Los Angeles, CA, USA

    Galen Cook-Wiens

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  1. Odelia Cooper
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Supplemental Fig. 1: Representative samples of intensity scores 0–3 in prolactinoma tissues (stained for ErbB2) ×20 magnification. a Intensity score 0; b intensity score 1; c intensity score 2 and d intensity score 3 (EPS 48058 kb)

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Cooper, O., Mamelak, A., Bannykh, S. et al. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine 46, 318–327 (2014). https://doi.org/10.1007/s12020-013-0093-x

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