Her2 Expression in Circulating Tumor Cells Is Associated with Poor Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer

SIMPLE SUMMARY: Although the role of HER2 in prostate cancer remains controversial, HER2 can be overexpressed during prostate cancer progression. In this study, we prospectively isolated circulating tumor cells (CTCs) from 41 men with metastatic castration-resistant prostate cancer (mCRPC). Then, we analyzed HER2 expression in CTCs with a highly sensitive assay. HER2 was frequently detected in CTCs of patients (n = 26, 63%) and we showed, for the first time, to our knowledge, that HER2 expression in CTCs was associated with poor long-term clinical outcomes in mCRPC. Moreover, the impact of HER2 expression in CTCs was an independent prognostic factor of progression-free survival. ABSTRACT: HER2-dependent signaling may support the development of metastatic castration-resistant prostate cancer (mCRPC) by activating androgen receptor signaling through ligand-independent mechanisms. From 41 mCRPC patients (including 31 treated with Androgen Receptor Signaling Inhibitors [ARSI]), Circulating Tumor Cells (CTCs) were prospectively enriched with AdnaTest platform and analyzed with a multiplexed assay for HER2 and AR-V7 mRNA expression. Then, we evaluated the impact of HER2 expression on PSA-response, Progression Free Survival (PFS) and Overall Survival (OS). HER2 expression was detected in CTCs of 26 patients (63%). Although PSA response was similar regardless of HER2 status, patients with HER2 positive CTCs had shorter PSA-PFS (median: 6.2 months versus 13.0 months, p = 0.034) and radiological-PFS (6.8 months versus 25.6 months, p = 0.022) than patients without HER2 expression. HER2 expression was also associated with a shorter OS (22.7 months versus not reached, p = 0.05). In patients treated with ARSI, multivariate analyses revealed that the prognostic impact of HER2 status on PSA-PFS was independent of AR-V7 expression and of the detection of CTCs by an AdnaTest. We showed for the first time the poor prognostic value of HER2 expression in CTCs from patients with mCRPC. The therapeutic interest of targeting this actionable pathway remains to be explored.