TP53 and VEGF/VEGFR Inhibitor Response

TP53 tumor suppressor gene mutations are amongst 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 vascular endothelial growth factor (VEGF) receptor (VEGFR) or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. While only a subset of patients benefit from these anti-angiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations up-regulate 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 {greater than or equal to}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) {greater than or equal to}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{less than or equal to} 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 anti-angiogenesis agents, a finding of seminal importance across the cancer field.

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