SUO 2017: Circulating Tumor DNA and Clinical Outcomes in Metastatic Prostate Cancer

Washington, DC (UroToday.com) Dr. Wyatt discussed circulating tumor DNA (ctDNA) and clinical outcomes in patients with metastatic prostate cancer during the management of metastatic castrate sensitive prostate cancer session at the 2017 SUO winter meeting. ctDNA is DNA released into the blood by malignant and non-malignant cells, and in cancer patients a proportion of ctDNA is tumor-derived. Early studies in metastatic castration-resistant prostate cancer (mCRPC) noted that heavily treated patients had a ctDNA fraction frequently >1%. One of the limitations and an unmet need prior to 2017 was that no studies have been conducted in the castrate-sensitive metastatic disease setting. 

Dr. Wyatt notes that the Vancouver Prostate Centre methodology is to target sequencing across a custom 73-gene panel, allowing an accurate prediction of ctDNA fraction. Ultimately, this represents a tradeoff between cost, sensitivity to low ctDNA fractions and the fraction of the genome covered. Work from Dr. Wyatt’s group has demonstrated high concordance between ctDNA and matched metastatic tissue biopsy. Using their 73-gene panel tested on 45 mCRPC patients (78% previously treated with abiraterone or enzalutamide), they found that 94% of mutations detected in whole exome sequencing from matched metastatic tissue biopsy were detected in ctDNA. Furthermore, there was 88.9% concordance for individual gene copy number cells across AR, BRCA2, ATM, PTEN, PIK3CA, PIK3R1, TP53 and RB1. Recent work (in press) from Dr. Wyatt’s group has noted that ctDNA may be more accurate than metastatic lesion biopsy, specifically noting that some driver alterations detected in plasma ctDNA may be missed by tissue biopsy of a single metastatic lesion. 

The main challenge in the de novo M1 castrate sensitive setting is that any prior ADT (without disease progression) will significantly reduce ctDNA. At the Vancouver Prostate Centre, they have made a concerted effort to collect true baseline samples in patients (40 patients in the past year) with de novo M1 disease.  In the first 24 patients examined to date, 12 patients had ctDNA >2% (50% of patients), which is lower than 1st line CRPC (60%) and 2nd/3rd line CRPC (80%). 

Dr. Wyatt concluded with several important take-home messages:

  • • ctDNA is an effective tool to identify somatic mutations and copy number alterations in the majority of men with mCRPC
  • • ctDNA is highly representative of matched metastatic tissue biopsy
  • • ctDNA shows promise in the castrate-sensitive setting for capturing somatic information, but prior ADT is a strong confounder
  • • Preliminary results suggest opportunities for guiding therapy intensification/combination therapy

Presented by: Dr. Alexander Wyatt, B.Sc.D.Phil Vancouver Prostate Centre, Vancouver, BC, Canada

Written by: Zachary Klaassen, MD, Society of Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre @zklaassen_md at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC
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