Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Abstract

Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.

Circulating Tumor Cells as a Marker of Disseminated Disease in Patients with Newly Diagnosed High-Risk Prostate Cancer

“…Gupta et al [48] presented results that are in line with the above statements. A paired comparison of genomic alterations between CTCs and cfDNA in metastatic castration-resistant prostate cancer, showed both concordance and disconcordance of certain alterations.…”

“…A paired comparison of genomic alterations between CTCs and cfDNA in metastatic castration-resistant prostate cancer, showed both concordance and disconcordance of certain alterations. The results enabled the prognosis of the clinical outcome for certain relations to be specified and proved that tumor heterogeneity is strictly linked to poor clinical outcomes [48].…”

Microfluidic Assaying of Circulating Tumor Cells and its Correlation with Muscle Invasiveness and Tumor Grade of Urothelial Bladder Cancer

“…Additionally, unraveling the phenotypic and molecular pro le of CTCs provides key information about tumor biology and contributing to individualized precision treatment [37]. Nevertheless, the applicability of CTCs as a clinical biomarker has been challenged by their rarity and heterogeneity [38,39]. Numerous approaches [37,40,41] for detecting CTCs were proposed but are still not commonly used.…”

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

“…However, the issue of tissue heterogeneity remains, as analysis of needle biopsies does not always represent the whole tumor. Interestingly, liquid biopsy analysis of PTEN genomic status within circulating tumor cells (CTCs) is also being investigated as a quick, non-invasive strategy to identify patients with PTEN-deficient prostate cancer, with a view to inform treatment decisions [ 74 , 75 ]. For instance, a blood-based CTC PTEN FISH assay is being employed in a clinical trial exploring abiraterone in combination with PI3K/AKT inhibitors in patients with CRPC (NCT01485861) [ 74 ].…”

“…For instance, a blood-based CTC PTEN FISH assay is being employed in a clinical trial exploring abiraterone in combination with PI3K/AKT inhibitors in patients with CRPC (NCT01485861) [ 74 ]. Importantly, PTEN loss in CTCs isolated from patients with mCRPC has been shown to significantly correlate with reduced survival in two independent studies [ 74 , 75 ], and several studies have revealed that PTEN loss can influence response to current therapies [ 34 , 35 , 76 , 77 , 78 , 79 ]. Indeed, a recent large phase II trial in breast cancer is already using CTC DNA analysis to match key driver mutations in CTCs, including PTEN inactivating mutations, to select personalized therapies for patients, such as AKT-targeted therapy for PTEN-deficient patients [ 80 ].…”