Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer Academic Article uri icon

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abstract

  • BACKGROUND: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. METHODS: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. RESULTS: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. CONCLUSIONS: ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

authors

  • Sonpavde, Guru
  • Agarwal, Neeraj
  • Pond, Gregory
  • Nagy, Rebecca J
  • Nussenzveig, Roberto H
  • Hahn, Andrew W
  • Sartor, Oliver
  • Gourdin, Theodore Stewart
  • Nandagopal, Lakshminarayanan
  • Ledet, Elisa M
  • Naik, Gurudatta
  • Armstrong, Andrew J
  • Wang, Jue
  • Bilen, Mehmet Asim
  • Gupta, Shilpa
  • Grivas, Petros
  • Pal, Sumanta K
  • Lanman, Richard B
  • Talasaz, AmirAli
  • Lilly, Michael B

publication date

  • May 2019

published in