Maruzzo, Marco (2018) Prognostic and predictive role of miRNAs, CTCs AND AR-V7+ CTCs expression in advanced prostate cancer treated with new hormonal agents: a feasibility study. [Tesi di dottorato]
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Background. Circulating tumor cells (CTC) counts of 5 or more/7.5 mL predict shorter survival in men with mCRPC. Moreover, the presence of androgen receptor splice variant-7 mRNA (AR-V7) in CTCs is thought to play a relevant role in the development of primary or acquired resistance to enzalutamide or abiraterone.
MiRNAs, small endogenous mRNA, have been identified as associated to the presence and aggressiveness of prostate cancer and for instance, overexpression of some miRNAs contributes to resistance to docetaxel and cabazitaxel.
We developed a new immunofluorescence-based assay for AR-V7 expression in CTCs and tested its prognostic association with PFS and OS.
Co-primary aims are to investigate AR-V7 with a new integrated assay and to study role of miRNAs in mCRPC patients treated with abiraterone or enzalutamide, and to study the relationship between AR-V7 expression, CTCs, and miRNAs with PFS or OS.
Methods. We performed a single-centre, observational, prospective trial enrolling patients with mCRPC candidate to receive enzalutamide or abiraterone. CTC samples have been collected at baseline, after 1 month and every three months thereafter until progression or at 12 months without progression. CTCs have been enumerated with CellSearch System. We integrated the standard assay with a monoclonal antibody able to recognize the AR-V7 protein. Slides created from pts’ samples underwent automated immunofluorescent staining and AR-V7+ CTCs were enumerated. MiRNAs have been evaluated at the same time point.
Results. Since Sep 2016, 31 patients have been enrolled. We compared CTC counts between standard assay and the integrated assay and found no statistical differences in the mean total CTC number ± SD (Wilcoxon Signed Rank test, p= 0.313).
Sixteen out of 28 evaluable patients (57%) had 1 or more CTCs at baseline, 9 pts (32%) had more than 5 CTCs/7.5 ml, and 4 pts (14.3%) were AR-V7+ before any exposure to abiraterone or enzalutamide.
After a median follow-up time of 8.1 months, 6 patients have progressed and 4 have died. No association has been found between CTCs ≥ 5/7.5 mL and survival. The presence of at least one AR-V7+ CTC at baseline did not correlate with PSA response, but had a weak association with shorter PFS (log-rank test, p = 0.055) and a statistically significant impact (p = 0.02) on OS.
MiRNA failed in this analysis to correlate with survival outcome.
Conclusion. We developed a new integrated assay for detecting AR-V7+ CTCs, based on an automated platform that permits serial sampling with low inter- and intra-test variability. The clinical utility of this test in anticipating the resistance to abiraterone or enzalutamide is under study.
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