Association of Circulating Tumor Cells (CTCs) and Genomic Signatures in Prostate Cancer Patients

Abstract

Intermediate and high-risk prostate cancer patients who are candidates for radiotherapy (RT) are very heterogeneous. Genomic classifiers add to clinical-pathologic risk factors and have the potential to become integral to risk stratification. Since circulating tumor cells (CTCs) are determinate of metastasis and genomic predictors of CTCs are not yet understood in this population, we investigated the associations of CTC counts with several genomic classifiers in patients enrolled in a randomized Phase II radiotherapy clinical trial (BLaStM, NCT02307058). CTCs were enumerated in blood samples from 31 patients using a microfilter system. The number of single CTCs, CTC clusters and their sum were recorded. Several gene signatures were investigated. Decipher® (metastatic risk), PORTOS (predictor of RT response) and PAM50 (predictor hormone response, which includes gene expression-based "intrinsic" subtypes: luminal A, luminal B, HER2-enriched, and basal-like), were quantified in tissue obtained by MRI-Ultrasound fused biopsies. A high-density gene expression microarray processed at a biosciences laboratory was used. A Poisson regression model with demographic and disease characteristics variables (PSA, Gleason Score (GS), T stage, %tumor in biopsies, age, race/ethnicity) were used in the univariable analysis (UVA). Multivariable analysis (MVA) included the statistically significant variables, where each biomarker was examined, along with chosen covariates for association with CTC counts in a one-at-a-time manner. CTCs were evident in over 70% of patients tested. The single cell and cluster median values in 8 mL of blood were 33 (range 0-343) and 4 (range 0-26). In MVA, several of the signatures were associated with total CTC number (single cells and clusters). When the biopsy core containing the highest Gleason score (GS) and %tumor were analyzed, the significant relationships included PORTOS (RR 6.00; p<0.001), PAM50_basal (RR 2.21; p<0.001), and Decipher (RR 1.16; p=0.048). Since multiple biopsies were analyzed for gene expression, when the cores with the highest signature value were selected, PORTOS surged (RR=47.10; p<0.0001) in the MVA. Despite the relatively small sample size, the results indicate a strong signal related to radiation sensitivity. NCCN risk categories were not significantly related to CTC counts or gene signatures. Determinants of prostate cancer lethality in intermediate to high-risk prostate cancer are poorly understood. Our results show an association between tumor gene expression alterations and CTC number, indicating that genes linked to radiation sensitivity have a role in early metastatic risk.