Influence of EMT on CTCs and Disease Progression in Prostate Cancer

The presence of circulating tumor cells (CTCs) in the blood of prostate cancer patients has been shown to be an important indicator of metastatic disease and poor prognosis. Additionally, changes in CTC number throughout treatment have been demonstrated to reflect therapy response. However, the CellSearch® (Menarini-Silicon Biosystems) is the only FDA- and Health Canada-cleared CTC platform available at the present time, and is thus considered the current "gold standard" for clinical CTC analysis. Notably, CTCs are undetectable in \~35% of metastatic CRPC patients. This suggests that either CTCs are truly not present in \>1/3 of patients with advanced metastatic disease; and/or that CTCs are present but not detectable as they do not meet the standard CellSearch® definition of CTCs. Given the accumulating evidence that prostate cancer cells can lose epithelial characteristics as they evolve towards a more metastatic phenotype, the investigators believe the latter scenario is most likely. The epithelial-to-mesenchymal transition (EMT) is a critical process during embryonic development and cancer metastasis. Although the role of androgen receptor (AR) signaling in EMT is poorly understood, studies have also demonstrated that EMT may be facilitated by androgen deprivation, castration-resistance, and/or disruption of androgen signaling. Importantly, several clinical studies have demonstrated that CTCs with a purely mesenchymal phenotype are undetectable by CellSearch®, but that the presence of mesenchymal marker expression on CTCs with a hybrid epithelial-mesenchymal phenotype is indicative of poor prognosis. In addition, previous pre-clinical data from the Allan laboratory has demonstrated that in animal models, prostate cancers with a mesenchymal phenotype shed greater numbers of CTCs more quickly and with greater metastatic capacity than those with an epithelial phenotype. Notably, the clinically-used CellSearch®-based assay captured the majority of CTCs shed during early-stage disease in vivo, and only after the establishment of metastases were a significant number of undetectable CTCs present. This suggests that current clinical assays may be limiting ability to capitalize on the full potential of CTCs, and that a greater understanding of CTC biology is necessary in order to guide future technology development and translation to the clinic.

Sex

Male

Minimum age

18 Years

Inclusion Criteria (all patients):

* histologically diagnosed prostate cancer
* signed informed consent

HR-HSPC cohort

* previous prostatectomy
* previous treatment with androgen deprivation therapy for \<90 days and/or recommended but not yet started new line of androgen deprivation therapy
* adverse pathological findings (\>=1 of extracapsular extension, positive margins, and/or seminal vesicle invasion)
* documented evidence of biochemical failure following adjuvant/salvage radiation therapy
* PSA of \>1 ng/ml

LV-mHSPC cohort

* previous treatment with androgen deprivation therapy for \<90 days and/or recommended but not yet started new line of androgen deprivation therapy
* documented evidence of metastatic disease (bone only; less than 4 lesions contained within the vertebral column or pelvis)

HV-mHSPC cohort

* previous treatment with androgen deprivation therapy for \<90 days and/or recommended but not yet started new line of androgen deprivation therapy
* documented evidence of "high volume" metastatic disease (visceral metastases \[extranodal\] and/or bone metastases \[\>=4 bone lesions with \>=1 lesion outside the vertebral column or pelvis\])

mCRPC cohort

* documented evidence of progression while receiving androgen ablation therapy (medical or surgical castration) according to PCWG2 criteria
* documented evidence of metastatic disease (bone or visceral)

Exclusion Criteria:

* patients with a history of other malignancies, except for adequately treated non-melanoma skin cancer (all cohorts)
* documented evidence of metastatic disease (HR-HSPC cohort)
* documented evidence of castrate-resistance (all HSPC cohorts)
* currently on active androgen deprivation therapy (all HSPC cohorts)