Abstract
BackgroundCabazitaxel 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).MethodsPatients 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.ResultsSeventy-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).ConclusionsBaseline 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 registrationClinicaltrials.govNCT03381326. Retrospectively registered on 18 December 2017.
Highlights
Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer patients progressing after docetaxel
EPCAM and HPRT1 Circulating tumor cells (CTC) expression, plasma androgen receptor (AR) copy number (CN) gain, ECOG Eastern Cooperative Oncology Group performance status (PS)=2, and liver metastases and prostate-specific antigen (PSA) were independently associated with poorer OS
In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR splice variant 7 (AR-V7) positive than negative patients (6.6 versus 14 months, hazard ratio (HR)=3.46, 1.47–8.17], p=0.004)
Summary
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). Androgen-deprivation therapy (ADT) is the cornerstone of treatment for advanced PCa until progression of disease (PD) to castration-resistant prostate cancer (CRPC). Taxanes seem to be able to overcome different mechanisms of resistance to androgen-signaling-targeted inhibitors, such as increased AR signaling [7,8,9]. This suggests that other mechanisms of resistance occur in taxanes-treated patients. There is a need for biomarkers to predict outcomes to cabazitaxel-treated mCRPC, in order to achieve a better selection of potentially responsive patients, maximize benefits, and avoid unnecessary treatedrelated adverse events
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