ASCO 2017: Whole exome sequencing of circulating tumor DNA (ctDNA) in patients with neuroendocrine prostate cancer informs tumor heterogeneity

Chicago, IL ( The authors of this study previously published a manuscript identifying the divergent clonal evolution of castration-resistant prostate cancer (CRPC) to a neuroendocrine prostate cancer histology (NEPC).1 NEPC represent a histologic subtype of prostate cancer that demonstrate low to absent AR expression and often have neuroendocrine features, and thus have low PSA production. Progression to NEPC histology may represent a mechanism of resistance.

In their original paper, the authors analyzed whole-exome sequencing (WES) data of metastatic biopsies, and observed significant genomic overlap between CRPC tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE). Subsequent analysis of biopsy samples from the same individuals over time led to identification of divergent clonal evolution.

Based on this original study, the authors aimed to develop a non-invasive tool to assess progression to a NEPC phenotype, as it may be an indicator of potential progression. In this study, they did whole-exome sequencing of matched ctDNA, germline DNA, and metastatic biopsies from patients with CRPC-Adeno histology and NEPC histology. They then calculated the fraction of tumor DNA and clonality of genomic lesions. They enrolled 64 patients with CRPC prospectively and followed them over time.

The concordance of overall fraction of mutations shared between plasma and metastases tumor DNA was approximately 80%. On initial assessment comparing the three samples from patients, the similarity of copy number alterations between tumor tissue and ctDNA was higher in NEPC cohort compared to patients CRPC-Adeno (p = 0.0001) suggesting less heterogeneity in NEPC. There was enrichment of RB1 and TP53 loss in NEPC ctDNA and AR gains in CRPC-Adeno.

They then looked at a single patient over time - CRPC-Adeno in a lymph node, CRPC-Adeno in a bone metastasis, and NEPC in a liver metastasis. The baseline ctDNA profile (at time of CRPC-Adeno) displayed genomic features most similar to the NEPC liver biopsy, suggesting that the genomic predisposition for NEPC existed well before phenotypic expression.

In another patient, they compared the ctDNA with 6 sites of NEPC metastases; the relative contribution of tumor alterations in ctDNA was highest for the liver metastasis (similarity 0.59) versus other sites. This suggests differential contribution of metastatic sites in the circulation. Hence the site of tumor biopsy can affect the results obtained.

Importantly, this is the first study to show that whole exome sequencing of ctDNA is feasible in CRPC. It can be used to better understand intratumoral heterogeneity, particularly in patients with multiple sites of disease. ctDNA may also help potential identify patients with predisposition towards NEPC transformation before clinical progression.

These results are quite promising and we look forward to more of their work.

Presented By: Himisha Beltran, MD, Weill Cornell Medical College, New York, NY

Co-Author(s): Alessandro Romanel, Nicola Casiraghi, Michael Sigouros, Matteo Benelli, Jenny Xiang, Francesca Demichelis

Institution(s): University of Trento, Trento, Italy; Centre for Integrative Biology, University of Trento, Trento, Italy

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA

1. Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, Marotz C, Giannopoulou E, Chakravarthi BV, Varambally S, Tomlins SA, Nanus DM, Tagawa ST, Van Allen EM, Elemento O, Sboner A, Garraway LA, Rubin MA, Demichelis F. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016 Mar;22(3):298-305. doi: 10.1038/nm.4045. Epub 2016 Feb 8.
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