Circulating Tumor Cells as a Predictor of Treatment Response in Clinically Localized Prostate Cancer

Abstract

PURPOSE Using nonenrichment-based, potentially more sensitive Epic Sciences circulating tumor cell (CTC) platform, we sought to detect and characterize CTCs in untreated, high-risk localized prostate cancer and to evaluate their clinical implication. METHODS Between 2012 and 2015, blood samples were prospectively collected from patients with National Comprehensive Cancer Network high-risk localized prostate cancer undergoing either radiotherapy (XRT) plus androgen deprivation therapy or radical prostatectomy (RP) with curative intent. Samples were analyzed with the Epic Sciences platform with 4′,6-diamidino-2-phenylindole, CD45, cytokeratin (CK), and androgen receptor (AR) N-terminal staining. CTC counts were correlated with biochemical recurrence (BCR). RESULTS A diversity of CTC subtypes, including CK-positive, CK-negative, AR-positive, and CTC clusters, were observed in 73.3% (33 of 45) of patients with evaluable data. The median follow-up was 14.2 months (range, 0.5 to 43.7 months). BCR occurred more frequently in the RP group than XRT (15 of 26 v one of 19), with most patients in the XRT group continuing to receive androgen deprivation therapy. A higher proportion of metastatic events were observed in the RP group (five of 26 v one of 19). In the RP group, BCR and development of metastases were associated with a higher total number of CTCs, AR-positive CTCs, and CTC phenotypic heterogeneity. One patient who developed BCR and metastases quickly after RP had diverse phenotypical CTC subtypes, and single-cell genomic analyses of all detectable CTCs confirmed common prostate cancer copy number alterations and PTEN loss. CONCLUSION CTCs can be identified in most patients with high-risk localized prostate cancer before definitive therapy using the Epic Sciences platform. If confirmed in a larger cohort with longer follow-up, phenotypic and genomic characterization of CTCs pretherapy may provide an additional means of risk stratifying patients with newly diagnosed high-risk disease and potentially help identify patients who could require multimodal therapy.

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

“…In a cohort of 68 patients with muscle invasive bladder cancer, a personalized assay to sequence somatic variants as markers of ctDNA in preoperative plasma was highly prognostic for recurrence after cystectomy. 37 Among patients with recurrent disease, ctDNA detected before chemotherapy also tracked with worse overall survival. 37 Similar successes were achieved in a cohort of 130 patients with colorectal cancer: A personalized ctDNA detection assay detected ctDNA in 88.5% of preoperative plasma samples, and 70% of patients with detectable ctDNA at the start of adjuvant chemotherapy subsequently experienced disease recurrence.…”

“…37 Among patients with recurrent disease, ctDNA detected before chemotherapy also tracked with worse overall survival. 37 Similar successes were achieved in a cohort of 130 patients with colorectal cancer: A personalized ctDNA detection assay detected ctDNA in 88.5% of preoperative plasma samples, and 70% of patients with detectable ctDNA at the start of adjuvant chemotherapy subsequently experienced disease recurrence. 21 The striking difference between our findings and these reports from bladder and colorectal cancer cohorts may reflect some of the same differences between primary and metastatic prostate cancer with respect to ctDNA shedding, including cell proliferation rate and proximity to vasculature.…”

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

“…Bespoke approaches to detect ctDNA from urothelial and colorectal cancers have demonstrated success in risk stratification and therapy monitoring. In a cohort of 68 patients with muscle invasive bladder cancer, a personalized assay to sequence somatic variants as markers of ctDNA in preoperative plasma was highly prognostic for recurrence following cystectomy [36]. Amongst recurrent patients, ctDNA detected prior to chemotherapy also tracked with worse overall survival [36].…”

“…In a cohort of 68 patients with muscle invasive bladder cancer, a personalized assay to sequence somatic variants as markers of ctDNA in preoperative plasma was highly prognostic for recurrence following cystectomy [36]. Amongst recurrent patients, ctDNA detected prior to chemotherapy also tracked with worse overall survival [36]. Similar successes were achieved in a cohort of 130 colorectal cancer patients, in which a personalized ctDNA detection assay detected ctDNA in 88.5% of preoperative plasma, and 70% of patients with detectable ctDNA at the start of adjuvant chemotherapy subsequently recurred [21].…”

“…Because these locus-level analyses of individual genomes are below the limits of detection, other circulating nucleic acid analytes may be more representative of phenotype and thus offer better detection characteristics. Circulating tumor cells, circulating cell-free miRNA, circular RNA, posttranscriptionally modified RNA species, and genome-wide tissue-of-origin patterns of DNA methylation do not correlate 1:1 with tumor cell number, and thus may give a much greater signal than allele-dependent assays for the early noninvasive detection of aggressive and potentially recurrent prostate cancer [36,37]. MATERIALS AND METHODS…”