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.
Highlights
Because androgen receptor (AR) plays a critical role in the proliferation and migration of prostate cancer (PCa) cells, the vast majority of patients with hormone sensitive PCa (HSPC) respond to androgen-deprivation therapy (ADT)
Between October 2016 and March 2018, the AdnaPanel® assay was prospectively performed on 41 patients with metastatic castration-resistant prostate cancer (mCRPC) treated at IC-HCL (Lyon, France)
31 (75%) were treated with androgen receptor signaling inhibitors (ARSI) including 14 patients treated with abiraterone and 17 patients treated with enzalutamide, 9 (22%) patients were treated with chemotherapy and one patient progressed rapidly before treatment initiation and was treated with best supportive care alone
Summary
Because androgen receptor (AR) plays a critical role in the proliferation and migration of prostate cancer (PCa) cells, the vast majority of patients with hormone sensitive PCa (HSPC) respond to androgen-deprivation therapy (ADT). Patients inevitably relapse despite castrate androgen levels, defined as castration resistance. Androgen receptor activity in castration-resistant PCa (CRPC) is partially restored through several mechanisms. Several androgen receptor signaling inhibitors (ARSI) have been recently developed to either suppress intratumoral androgen synthesis (CYP17A1 inhibitors such abiraterone) or block androgen activity (AR potent antagonists: enzalutamide, apalutamide or darolutamide). ARSI have dramatically improved patients outcomes, including overall survival (OS) in CRPC and metastatic HSPC patients [1]. Most of these patients develop mechanisms of resistance to ARSI, including AR reactivation, or activation of alternative cancer signaling pathways. ARSI resistance can be due to mutations of the ligand binding domain of AR, AR gene amplification, and the emergence of AR splice variants such as AR-V7 [2]
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