Faculty Collaboration Database

TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics. Mol Cancer Ther 2016 Oct;15(10):2475-2485

Date

07/29/2016

Pubmed ID

27466356

DOI

10.1158/1535-7163.MCT-16-0196

Scopus ID

2-s2.0-84990927257 (requires institutional sign-in at Scopus site)   72 Citations

Abstract

TP53 tumor-suppressor gene mutations are among the most frequent abnormalities in cancer, affecting approximately 40% of patients. Yet, there is no accepted way to target these alterations in the clinic. At the same time, antagonists of VEGFR or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. Although only a subset of patients benefit from these antiangiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations upregulate VEGF-A and VEGFR2. We prospectively enrolled 500 patients, to be interrogated by comprehensive genomic profiling (CGP) (next-generation sequencing, 236 genes), and to be matched, whenever possible, with targeted agents. Herein, we analyze outcomes based on VEGF/VEGFR inhibitor treatment and presence of TP53 mutations. Of the 500 patients, 188 (37.6%; with ≥1 alteration) were treated; 106 (56% of 188) had tumors that harbored TP53 mutations. VEGF/VEGFR inhibitor therapy was independently associated with improvement in all outcome parameters [rate of stable disease (SD) ≥6 months/partial and complete remission (PR/CR); (31% versus 7%; TP53-mutant patients (who received no other molecular-matched agents) treated with versus without VEGF/VEGFR inhibitors), time-to-treatment failure, and overall survival (multivariate analysis: all P ≤ 0.01)] for the patients harboring TP53-mutant cancers, but improvement was not seen in any of these parameters for patients with TP53 wild-type neoplasms. We conclude that TP53 mutations predict sensitivity to VEGF/VEGFR inhibitors in the clinic. TP53 alterations may therefore be a ready biomarker for treatment with antiangiogenesis agents, a finding of seminal importance across the cancer field. Mol Cancer Ther; 15(10); 2475-85. ©2016 AACR.

Author List

Wheler JJ, Janku F, Naing A, Li Y, Stephen B, Zinner R, Subbiah V, Fu S, Karp D, Falchook GS, Tsimberidou AM, Piha-Paul S, Anderson R, Ke D, Miller V, Yelensky R, Lee JJ, Hong D, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Angiogenesis Inhibitors
Antineoplastic Agents
Biomarkers
Cell Line, Tumor
Combined Modality Therapy
Drug Resistance, Neoplasm
Female
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Molecular Targeted Therapy
Mutation
Neoplasms
Proportional Hazards Models
Protein Kinase Inhibitors
Receptors, Vascular Endothelial Growth Factor
Treatment Outcome
Tumor Suppressor Protein p53
Vascular Endothelial Growth Factor A