Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors

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.

Figure 1

Representative IHC of EGFR and ErbB2 receptors in prolactinomas on tissue array (20× magnification). Top corner box shows magnification of selected area. EGFR staining was nuclear and ErbB2 staining membranous/cytoplasmic. Positive control tissue is breast cancer A. EGFR staining of prolactinoma B. EGFR staining of breast cancer (63× magnification). C. ErbB2 staining of prolactinoma D. ErbB2 staining of breast cancer (63× magnification).

Figure 2

Representative IHC of ErbB3 and ErbB4 receptors in prolactinomas on tissue array (20× magnification). Top corner box shows magnification of selected area. Positive control tissue is breast cancer for ErbB3 and kidney tubules for ErbB4. A. ErbB3 staining of prolactinoma B. ErbB3 staining of breast cancer (20× magnification) C. ErbB4 staining of prolactinoma D. ErbB4 staining of kidney tubules (63× magnification).

Figure 3

Prolactin levels and tumor volumes in first lapatinib treated subject. The MRI of subject 1 is depicted. A. Baseline MRI demonstrates homogeneously enhancing mass in right aspect of sella extending into cavernous sinus and encasing the carotid vessel, and abutting inferior aspect of right prechiasmatic optic nerve. Lesion measures 23 × 27 × 34 mm. B. MRI after 6 months on lapatinib shows regression of central portion of the tumor mass. C. Graph shows PRL levels (ng/mL) and tumor volumes (mm ³) at baseline (study visit 1) and at monthly intervals.

Figure 4

Prolactin levels and tumor volumes in second lapatinib treated subject. The MRI of subject 2 is depicted. A. Baseline MRI demonstrates a hypoenhancing intrasellar mass inferolateral on the left side growing into the left cavernous sinus. The mass measures 9.9 mm transversely, 6.8 mm cephalocaudad, and 13.1 mm anteroposteriorly. B. MRI after 6 months on lapatinib shows no change. C. Graph shows PRL levels (ng/mL) and tumor volumes (mm³) at baseline (study visit 1) and at monthly intervals.