Journal Article

Circulating tumor cell gene expression and plasma AR gene copy number as biomarkers for castration-resistant prostate cancer patients treated with cabazitaxel

Bondi, Isabella, Ulivi, Paola, Fornarini, Giuseppe, Nicodemo, Maurizio, Ravaglia, Giorgia, Basso, Umberto, Banna, Giuseppe Luigi, Mosca, Alessandra, Scarpi, Emanuela, Lolli, Cristian, Conteduca, Vincenza, Brighi, Nicole, Schepisi, Giuseppe, De Giorgi, Ugo, Gurioli, Giorgia

2022

Overview

Background Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor ( AR ) copy number (CN). Methods Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI. Results Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24–5.12, p =0.011), AKR1C3 (HR=2.01, 1.06–3.81, p =0.031), AR (HR=2.70, 1.46–5.01, p =0.002), EPCAM (HR=3.75, 2.10–6.71, p < 0.0001), PSMA (HR=2.09, 1.19–3.66, p =0.01), MDK (HR=3.35, 1.83–6.13, p < 0.0001), and HPRT1 (HR=2.46, 1.44–4.18, p =0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97–31.22, p =0.05), AR (OR=8.71, 2.32–32.25, p =0.001), EPCAM (OR=7.26, 1.47–35.73, p =0.015), PSMA (OR=3.86, 1.10–13.50, p =0.035), MDK (OR=6.84, 1.87–24.98, p =0.004), and HPRT1 (OR=7.41, 1.82–30.19, p =0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 ( p =0.05), EPCAM ( p =0.02), and MDK ( p =0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47–8.17], p =0.004). Conclusions Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis. Trial registration Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Androgen receptors / Androgen suppression therapy / Androgens / AR copy number / AR-V7 / Biomarkers / Biomarkers, Tumor - metabolism / Biomedicine / Biopsy / Cabazitaxel / Cancer therapies / Care and treatment / Castration / Chemotherapy / Clinical medicine / Copy number / CTC / Diagnosis / Gene Dosage / Gene Expression / Humans / Male / mCRPC / Medical prognosis / Medicine / Medicine & Public Health / Metastases / Metastasis / Neoplastic Cells, Circulating - pathology / Patient outcomes / Patients / Plasma / Prospective Studies / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - pathology / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Research Article / Risk factors / Steroids / Subgroups / Targeted Therapies / Taxoids / Treatment Outcome / Tumors