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

PLoS One. 2019 Jan 25;14(1):e0210415. doi: 10.1371/journal.pone.0210415. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / secondary
  • Female
  • Genes, p53
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / pathology
  • Male
  • Middle Aged
  • Models, Genetic
  • Molecular Targeted Therapy*
  • Mutation
  • Prognosis
  • Progression-Free Survival
  • Proportional Hazards Models
  • Retrospective Studies
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

  • Biomarkers, Tumor
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Von Hippel-Lindau Tumor Suppressor Protein
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1
  • VHL protein, human

Grants and funding

NA receives salary support from Pfizer, Exelixis, Merck, Argos, EMD Serono, and Eisai, and he receives research funding from Pfizer, EMD Serono, and Eisai. SKP receives salary support from Exelixis, BMS, GSK, Novartis, Pfizer, Astellas, and Genentech. BG, VT, and JH have received salary support from Cancer Genetics, Inc. The funders provided support in the form of salaries for authors NA, SKP, BG, VT, and JH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.