PLoS ONE (Jan 2019)

Predictive genomic markers of response to VEGF targeted therapy in metastatic renal cell carcinoma.

  • David D Stenehjem,
  • Andrew W Hahn,
  • David M Gill,
  • Daniel Albertson,
  • Banumathy Gowrishankar,
  • Joseph Merriman,
  • Archana M Agarwal,
  • Venkata Thodima,
  • Erik B Harrington,
  • Trang H Au,
  • Benjamin L Maughan,
  • Jane Houldsworth,
  • Sumanta K Pal,
  • Neeraj Agarwal

DOI
https://doi.org/10.1371/journal.pone.0210415
Journal volume & issue
Vol. 14, no. 1
p. e0210415

Abstract

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BACKGROUND:First-line treatment for metastatic renal cell carcinoma (mRCC) is rapidly changing. It currently includes VEGF targeted therapies (TT), multi-target tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and immunotherapy. To optimize outcomes for individual patients, genomic markers of response to therapy are needed. Here, we aim to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection. METHODS:From an institutional database, primary tumor tissue was obtained from 79 patients with clear cell mRCC, and targeted sequencing was performed. Clinical outcomes were obtained retrospectively. Progression-free survival (PFS) on first-line VEGF TT was correlated to genomic alterations (GAs) using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of significant GAs predicting PFS in the first-line setting was developed. RESULTS:Absence of VHL mutation was associated with inferior PFS on first-line VEGF TT. A trend for inferior PFS was observed with GAs in TP53 and FLT1 C/C variant. A composite model of these 3 GAs was associated with inferior PFS in a dose-dependent manner. CONCLUSION:In mRCC, a composite model of TP53 mutation, wild type VHL, and FLT1 C/C variant strongly predicted PFS on first-line VEGF TT in a dose-dependent manner. These findings require external validation.