Work

Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer

Year: 2017

Type: article

Abstract: // Zhijie Wang 1, 6 , Sarina Piha-Paul 1 , Filip Janku 1 , Vivek Subbiah 1 , Naiyi Shi 1 , Jing Gong 1 , Chetna Wathoo 2 , Kenna Shaw 2 , Kenneth Hess 3 , Russell Broaddus 4 , Aung Naing 1 , David Hong 1 , Apostolia M. Tsimberidou 1 , Daniel Karp 1 , James Yao 5 , Funda Meric-Bernstam 1 and Siqing Fu 1 1 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 6 National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China Correspondence to: Siqing Fu, email: [email protected] Keywords: KRAS, TP53, chronic inflammation, phase I trial, gene aberration-related therapy Received: October 15, 2016 Accepted: March 16, 2017 Published: April 05, 2017 ABSTRACT Purpose: Genetic alterations such as activating KRAS and/or inactivating TP53 are thought to be the most common drivers to tumorigenesis. Therefore, we assessed phase I cancer patients with KRAS+ / TP53+ mutations. Results: Approximately 8% of patients referred to phase I clinical trials harbored concurrent KRAS and TP53 mutations. Patients who received a phase I trial therapy (n = 57) had a median OS of 12 months, compared with 4.6 months in those who were not treated (n = 106; p = 0.003). KRAS G13 and TP53 R273 mutations were associated with poor overall survival (OS), while antiangiogenesis and gene aberration-related therapies were associated with prolonged OS. A prognostic model using neutrophilia, thrombocytosis, hypoalbuminemia, body mass index <30 kg/m 2 , and the absence of lung metastasis was established and validated. Phase I cancer patients in the low-risk group had a median OS of 16.6 months compared with 5.4 months in the high-risk group ( p < 0.001). Untreated patients in the low-risk group had a median OS of 6.7 months compared with 3.6 months in the high-risk group ( p = 0.033). Experimental Design: We analyzed 163 consecutive patients with advanced KRAS+ / TP53+ mutant cancer who were referred to phase I clinical trials, to identify molecular aberrations, clinical characteristics, survivals, and potentially effective treatment regimens. Conclusions: This study provided preliminary evidence that besides modulation of the proinflammatory state, antiangiogensis and concomitant gene aberration-related therapies may improve the treatment of KRAS+ / TP53+ mutant cancer.

Source: Oncotarget

DOI: 10.18632/oncotarget.16840