Wheler Jennifer J, Janku Filip, Naing Aung, Li Yali, Stephen Bettzy, Zinner Ralph, Subbiah Vivek, Fu Siqing, Karp Daniel, Falchook Gerald S, Tsimberidou Apostolia M, Piha-Paul Sarina, Anderson Roosevelt, Ke Danxia, Miller Vincent, Yelensky Roman, Lee J Jack, Hong David, Kurzrock Razelle
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Foundation Medicine, Cambridge, Massachusetts.
Mol Cancer Ther. 2016 Oct;15(10):2475-2485. doi: 10.1158/1535-7163.MCT-16-0196. Epub 2016 Jul 27.
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.
TP53肿瘤抑制基因突变是癌症中最常见的异常之一，约40%的患者受其影响。然而，临床上尚无公认的针对这些改变的方法。与此同时，VEGFR或其配体的拮抗剂是畅销的肿瘤药物，有多种昂贵的化合物已获批准。尽管只有一部分患者从这些抗血管生成药物中获益，但尚未鉴定出相关的生物标志物。有趣的是，TP53突变会上调VEGF-A和VEGFR2。我们前瞻性地招募了500名患者，通过综合基因组分析（CGP）（二代测序，236个基因）进行检测，并尽可能与靶向药物进行匹配。在此，我们根据VEGF/VEGFR抑制剂治疗情况和TP53突变的存在情况分析结果。500名患者中，188名（37.6%；有≥1种改变）接受了治疗；106名（188名中的56%）肿瘤携带TP53突变。对于携带TP53突变癌症的患者，VEGF/VEGFR抑制剂治疗与所有预后参数的改善独立相关[疾病稳定（SD）≥6个月/部分缓解和完全缓解（PR/CR）率；（31%对7%；接受与未接受VEGF/VEGFR抑制剂治疗的TP53突变患者（未接受其他分子匹配药物））、治疗失败时间和总生存期（多变量分析：所有P≤0.01）]，但对于TP53野生型肿瘤患者，这些参数均未出现改善。我们得出结论，TP53突变在临床上可预测对VEGF/VEGFR抑制剂的敏感性。因此，TP53改变可能是抗血管生成药物治疗的现成生物标志物，这一发现对整个癌症领域具有至关重要的意义。《分子癌症治疗》；15(10)；2475 - 2485。©2016美国癌症研究协会。
