Positive HER-2 protein expression in circulating prostate cells and micro-metastasis, resistant to androgen blockage but not diethylstilbestrol

Abstract

Introduction:HER-2 expression in prostate cancer is associated with a worse prognosis and is suggested to play a role in androgen resistance. We present a study of HER-2 expression in circulating tumor cells and micrometastasis in bone marrow and the effect of androgen blockage or DES in the presence of HER-2 expressing cells.Patients and Methods:A multicenter study of men with prostate cancer, treated with surgery, radiotherapy, or observation, and with or without hormone therapy. Mononuclear cells were separated from blood and bone marrow aspirate by differential centrifugation, touch preps were made from bone marrow biopsy samples. Prostate cells were detected using anti-PSA monoclonal antibody and standard immunocytochemistry. Positive samples were processed using Herceptest® to determine HER-2 expression. After 1 year, patients were re-evaluated and the findings of HER-2 expression and PSA change compared with treatment.Results:Total 199 men participated, and 97 had a second evaluation 1 year later, frequency of HER-2 expression in circulating tumor cells and micrometastasis was 18% and 21%, respectively. There was no significant difference in HER-2 expression in the pretreatment group, after radical surgery or radiotherapy or with biochemical failure. Men with androgen blockade had a significantly higher expression of HER-2 (58%) (P =0.001). Of the 97 men with a second evaluation, 56 were in the observation arm, 27 androgen blockade, and 14 DES. Use of androgen blockade or DES significantly reduced serum PSA levels in comparison with observation (P =0.001). However, there was a significant increase in HER-2 expression in patients with androgen blockade (P =0.05) en comparison with observation or DES treatment. No patient with observation or DES became HER-2 positive, en comparison 4/22 patients initially HER-2 negative became HER-2 positive with androgen blockade.Conclusions:The results suggest that HER-2 positive cells are resistant to androgen blockade. In an environment lacking androgens, HER-2 positive cells are selected and survive, while HER-2 negative cells are eliminated thus decreasing the serum PSA. The population of HER-2 positive cells proliferate producing androgen-independent disease. DES does not increase HER-2 expression possibly by stimulating beta-estrogen receptors and blocking HER-2 androgen receptor activation.

Redefining micrometastasis in prostate cancer - a comparison of circulating prostate cells, bone marrow disseminated tumor cells and micrometastasis: Implications in determining local or systemic treatment for biochemical failure after radical prostatectomy

“…HER-2 expression increased significantly with an increasing Gleason score, without significant differences between CPCs, DTCs and micrometastasis. This is explained by the fact that men with androgen blockade had higher Gleason scores as was previously reported (19). The differential expression of MMP-2 may explain in part the differences in the concordance among CPCs, DTCs and micrometastasis.…”

Biomarkers in Prostate Cancer Epidemiology

“…Research is also needed in the area of prostate cancer therapy. In one study where patients were treated with surgery, radiation and hormone therapy, it was observed that HER-2 expression played a significant role in androgen resistance and helps prostate cancer prognosis [111]. In this study prostate cancer cells were detected using anti-PSA monoclonal antibodies.…”

How localized is pathologically localized prostate cancer? The use of secondary circulating prostate cells as a marker of minimal residual disease and their association with patient outcome

“…Thus although they identify patients at high risk of treatment failure their presence does not specify which treatment option, local or systemic could be beneficial to the patient. With regards to the election of systemic therapy, CPCs can be classified by their phenotypic characteristics, expression of the androgen receptor splice variant -7 (Arv7) [25] or HER-2 expression [26] in predicting the efficacy of hormonal therapy. This may aid in the decisions of treatment selection, and as such personalized medicine.…”