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 in situ hybridization on a minimum of thirty isolated CTCs. The patients were divided into five groups based on the changes of number of telomeres vs. 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.
Highlights
Androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (PCa) [1]
Contrary to circulating tumor cell (CTC) enumeration and prostate-specific antigen (PSA) serum levels, we showed that nuclear 3D telomere architectural analysis is highly sensitive in detecting cellular events that affect the genome stability in CTCs, and we described three distinct telomere signatures in CTCs
CTCs were collected and analyzed at 0 m, 2 m, 6 m, 12 m, 18 m and 24 months and PSA end levels at 6 months ADT, 6 months after finished RT and 36 months after initial treatment were used as early surrogates of treatment response
Summary
Androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (PCa) [1]. There is an urgent need for a biomarker, which can reliably identify patients at high risk for recurrence and metastases [2] For those patients, intensification of treatment beyond standard combination of ADT with radiation may be required [2]. It is critically important to ascertain the subgroup of patients in need of that step While clinical factors such as prostate-specific antigen (PSA) values, T-category, and Gleason scores have traditionally been used to risk-stratify prostate cancer patients, their accuracy is low (25%–40%) to predict important end points such as progression or metastases after radiation and ADT [4,5]. Due to the lack of a better surrogate, PSA measurement continues to be the main method to monitor treatment response and recurrence after treatment for prostate cancer [6] This is fraught with difficulty as there is no reliable method to differentiate
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