Long-Term Dynamics of Three Dimensional Telomere Profiles in Circulating Tumor Cells in High-Risk Prostate Cancer Patients Undergoing Androgen-Deprivation and Radiation Therapy

Abstract

Patient-specific assessment, disease monitoring, and the development of an accurate early surrogate of the therapeutic efficacy of locally advanced prostate cancer still remain a clinical challenge. Contrary to prostate biopsies, circulating tumor cell (CTC) collection from blood is a less-invasive method and has potential as a real-time liquid biopsy and as a surrogate marker for treatment efficacy. In this study, we used size-based filtration to isolate CTCs from the blood of 100 prostate cancer patients with high-risk localized disease. CTCs from five time points: +0, +2, +6, +12 and +24 months were analyzed. Consenting treatment-naïve patients with cT3, Gleason 8-10, or prostate-specific antigen > 20 ng/mL and non-metastatic prostate cancer were included. For all time points, we performed 3D telomere-specific quantitative fluorescence <i>in situ</i> hybridization on a minimum of thirty isolated CTCs. The patients were divided into five groups based on the changes of number of telomeres <i>vs</i> telomere lengths over time and into three clusters based on all telomere parameters found on diagnosis. Group 2 was classified as non-respondent to treatment and the Cluster 3 presented more aggressive phenotype. Additionally, we compared our telomere results with the PSA levels for each patient at 6 months of ADT, at 6 months of completed RT, and at 36 months post-initial therapy. CTCs of patients with PSA levels above or equal to 0.1 ng/mL presented significant increases of nuclear volume, number of telomeres, and telomere aggregates. The 3D telomere analysis of CTCs identified disease heterogeneity among a clinically homogeneous group of patients, which suggests differences in therapeutic responses. Our finding suggests a new opportunity for better treatment monitoring of patients with localized high-risk prostate cancer.