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Galletti et al. Using CTCs in prostate cancer

Taken together, these observations demonstrate that Detection of AR alternative splicing variants in
the interrogation of AR expression and subcellular CTCs
localization in CTCs is not only feasible but could also Alternative splicing of AR has emerged as one of the
be informative as predictive therapeutic biomarker main mechanisms of disease progression in PC. The
for AR-targeting treatments. More extensive clinically relevant ARv7 and ARv567 are truncated
prospective validation is required but initial findings versions of the receptor, which partially or entirely
are very encouraging. lack the C-terminal ligand-binding domain and are
constitutively active, independent of the ligand [64,65] .
Taxanes (docetaxel, cabazitaxel) are the only class of Recently, AR splice variants have been repeatedly
chemotherapy drugs that improve survival in CRPC associated with resistance to standard ADT and
patients. Even though traditionally considered as second-generation AR signaling inhibitors, abiraterone
anti-mitotic drugs, taxanes exert their PC-specific and enzalutamide .
[66]
mechanism of action by stabilizing microtubules and
consequently impairing the microtubule-dependent Several studies have been reported, in which CTCs
AR nuclear translocation and the consequent are used as liquid biopsy to detect AR variants in PC
signaling activation [62] . The combined inhibition of patients and monitor their expression longitudinally
the microtubule-AR axis mechanistically supports during treatment. In a single institution prospective
the unprecedented clinical benefit of survival study, Antonarakis et al. used a modified version
[42]
observed in the CHARTEED and the STAMPEDE of the EpCAM-based AdnaTest Prostate Cancer
trials, in which taxane treatment and ADT are Detect assay to evaluate ARv7 mRNA levels by RT-
combined to treat hormone-sensitive metastatic PCR in CTCs isolated from CRPC patients receiving
PC . Hence, AR cytoplasmic sequestration has enzalutamide (n = 31) or abiraterone (n = 31). They
[3]
been proposed as marker of response to taxane detected ARv7 transcript in 39% of the enzalutamide
activity. Darshan et al. [62] retrospectively correlated cohort and in 19% of the abiraterone cohort, and
AR subcellular localization in CTCs with clinical showed that ARv7-positive enzalutamide-treated
response in CRPC patients receiving taxanes patients had significantly lower biochemical response
and showed that 72% of subjects who progressed (0% vs. 53%) and shorter progression-free (PFS)
after treatment had AR nuclear localization and, and overall survivals (OS) than ARv7 negative
on the contrary, 70% of responding patients had subjects (2.1 months vs. 6 months and 5.5 months
cytoplasmic AR localization. These data have been vs. unreached, respectively). The authors observed
prospectively validated with the analysis of the similar results among the ARv7-positive subjects
TAXYNERGY trial, a phase II randomized trial in receiving abiraterone, who experienced lack of PSA
which AR subcellular localization was prospectively response (0% vs. 68%) and significantly shorted PFS
assessed in CTCs of taxane-treated CRPC and OS (2.3 months vs. not reached and 10.6 months
patients. In this trial, subjects were randomized vs. not reached, respectively) compared to ARv7-
2:1 to first line docetaxel or cabazitaxel and CTCs negative men.
were used as a source of tumor tissue to monitor
longitudinally potential predictive biomarkers Following previously reported in vitro data that
including AR nuclear localization, AR variants, associated ARv7 positivity with lack of response
presence of intra-tumoral drug-target engagement. to taxane treatment [67] , Antonarakis et al. [68] used
Of the 63 patients enrolled in the study, 26 had the above-mentioned CTC-based RT-PCR assay
CTC evaluable before the first cycle of treatment to investigate a clinical correlation between pre-
(C1D1) and after one week (C1D8); in these treatment ARv7 status and response to taxanes in
subjects, taxane-induced decrease in AR nuclear CRPC patients. Although no significant difference was
localization (C1D8 vs. C1D1) was associated with detected between ARv7-positive and ARv7-negative
a higher rate of biochemical response (≥ 50% PSA patients in terms of PSA response to treatment, PFS
decrease at cycle 4, P = 0.009), suggesting that AR and OS, a clear trend towards inferior response
nuclear localization assessment can serve as early rate to taxane was observed in ARv7-positive men.
biomarker of clinical benefit in patients treated with The sample size of this study was too small and the
taxanes [63] . median follow-up was relatively short to obtain any
meaningful clinical conclusion and validation in a
These results strongly support the use of CTCs larger cohort study is expected.
as source of tissue to interrogate AR subcellular
localization in tumor cells as marker to predict Sperger et al. also investigated the expression
[47]
response to taxane chemotherapy. of ARv7 in CTCs. Using the VERSA platform on 26
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ September 27, 2017 199