Evaluation of Commercial Circulating Tumor DNA Test in Metastatic Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•This study compared a commercially available sequencing test (Guardant360) with an academic research prostate-specific sequencing assay (Vancouver) using circulating tumor DNA from 24 patients with metastatic prostate cancer. In most cases (94%), somatic mutations with allele fraction >1% were detected by both assays. Similarly, amplifications and mutations of the AR gene were detected with high concordance in 14 patients. In contrast, several clinically relevant DNA repair gene alterations (eg, germline BRCA2, ATM mutations, BRCA2 stop gain reversal mutation) not detected by Guardant360 were identified by the research assay.

•In this study, concordance for somatic mutations with allele fraction >1% was very high, but low allele frequency mutations were often missed, suggesting that NGS assays may be further optimized for clinical utility in prostate cancer.

– Pedro C. Barata, MD

PURPOSE

Circulating tumor DNA (ctDNA) sequencing provides a minimally invasive method for tumor molecular stratification. Commercial ctDNA sequencing is increasingly used in the clinic, but its accuracy in metastatic prostate cancer is untested. We compared the commercial Guardant360 ctDNA test against an academic sequencing approach for profiling metastatic prostate cancer.

PATIENTS AND METHODS

Plasma cell-free DNA was collected between September 2016 and April 2018 from 24 patients with clinically progressive metastatic prostate cancer representing a range of clinical scenarios. Each sample was analyzed using Guardant360 and a research panel encompassing 73 prostate cancer genes. Concordance of somatic mutation and copy number calls was evaluated between the two approaches.

RESULTS

Targeted sequencing independently confirmed 94% of somatic mutations identified by Guardant360 at an allele fraction greater than 1%. AR amplifications and mutations were detected with high concordance in 14 patients, with only three discordant subclonal mutations at an allele fraction lower than 0.5%. Many somatic mutations identified by Guardant360 at an allele fraction lower than 1% seemed to represent subclonal passenger events or non–prostate-derived clones. Most of the non-AR gene amplifications reported by Guardant360 represented single copy gains. The research approach detected several clinically relevant DNA repair gene alterations not reported by Guardant360, including four germline truncating BRCA2/ATM mutations, two somatic ATM stop gain mutations, one BRCA2 biallelic deletion, 11 BRCA2 stop gain reversal mutations in a patient treated with olaparib, and a hypermutator phenotype in a patient sample with 42 mutations per megabase.

CONCLUSION

Guardant360 accurately identifies somatic ctDNA mutations in patients with metastatic prostate cancer, but low allele frequency mutations should be interpreted with caution. Test utility in metastatic prostate cancer is currently limited by the lack of reporting on actionable deletions, rearrangements, and germline mutations.

Evaluation of Commercial Circulating Tumor DNA Test in Metastatic Prostate Cancer

JCO Clin Cancer Inform 2019 Jun 12;[EPub Ahead of Print], S Taavitsainen, M Annala, E Ledet, et al