The prevalence and clinical significance of HER2 overexpression in prostate adenocarcinoma.
Authors: Estephan Fayez , Lap Coen , Jain Maneesh Rajiv , Nava Victor , Zara Rozalen Alexandra , Byrne Morgan , Diao Guoqing , Subrahmanyam Ramesh , Rajendran Rithika , Martha Antonio , Banagan Jeff 
Published: March 2023

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Background: The HER2 oncogene serves as a prognostic marker in breast cancer and is a therapeutic target in breast, lung, and GI malignancies, including cancers with low Her2 overexpression. A prior study by Minner et al ( Clin Cancer Res, 2010) evaluating Her2 overexpression in prostate cancer (PCa) showed a prevalence ~20%. The goal of this study is to evaluate the prevalence and clinical significance of Her2 overexpression in PCa in a predominantly African American (AA) cohort. Methods: 124 PCa patients managed at the Washington DC VA Medical Center between 2000-2021 were randomly selected: 35 indolent (AJCC stage I), 46 locally advanced (AJCC stages II&III), 19 locally advanced at diagnosis but progressed to metastatic (AJCC stage IV), and 24 de novo metastatic (AJCC stage IV). Immunohistochemistry (IHC) for Her2 was performed on one representative tissue section from core biopsies or a radical prostatectomy for each case. IHC intensity was scored independently by two experienced pathologists as negative (0, no staining), low positive (1+, faint membranous staining), moderate positive (2+, weak to moderate complete, basolateral or lateral membranous staining) or strong positive (3+, strong complete, basolateral or lateral membranous staining). Fisher’s exact test was used to test the association between Her2 expression and categorical variables. Results: 108 patients (87%) self-identified as AA. The mean age at diagnosis was 62.9 years. The prevalence of positive Her2 expression (1+, 2+,3+) was 48% (59/124) in the entire cohort, 29% (10/35) in the indolent group, 48% (22/46) in the locally advanced group, 68% (13/19) in the locally advanced group that progressed to metastatic disease, and 58% (14/24) in the de novo metastatic group ( p=0.0014). Prevalence of Her2 positive expression was 28% (10/36) in patients with a Gleason Score (GS) of 6, whereas in patients with a GS of 9 it was 78% (9/11) ( p<0.0001). Mean (non-zero) Her2 expression was highest in the de novo metastatic group (Her2 2.0, SD 0.78), followed by the locally advanced group that progressed to metastatic disease (Her2 1.54, SD 0.66), the locally advanced group without metastatic disease (Her2 1.36, SD 0.58), and lowest in the indolent group (Her2 1.0, SD 0.0) ( p=0.0016). Next generation sequencing data was available for 20 metastatic patients (12 positive for Her2 expression) and did not show the presence of HER2 mutations or amplifications. Conclusions: In this predominantly AA cohort, expression of Her2 was identified in almost 50% of patients with PCa. Her2 scores ≥2 were associated with higher GS and advanced disease. Moreover, a Her2 score of 3 was seen in 6 patients in our cohort. Historic studies on targeting Her2 in advanced PCa have failed to demonstrate clinical benefit. However, in the era of targeted therapy, Her2 inhibition addressing low-levels of Her2 overexpression should be considered in future trials.