Oncotarget

Research Papers:

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

Zhijie Wang, Sarina Piha-Paul, Filip Janku, Vivek Subbiah, Naiyi Shi, Jing Gong, Chetna Wathoo, Kenna Shaw, Kenneth Hess, Russell Broaddus, Aung Naing, David Hong, Apostolia M. Tsimberidou, Daniel Karp, James Yao, Funda Meric-Bernstam and Siqing Fu _

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Oncotarget. 2017; 8:33796-33806. https://doi.org/10.18632/oncotarget.16840

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Abstract

Zhijie Wang1,6, Sarina Piha-Paul1, Filip Janku1, Vivek Subbiah1, Naiyi Shi1, Jing Gong1, Chetna Wathoo2, Kenna Shaw2, Kenneth Hess3, Russell Broaddus4, Aung Naing1, David Hong1, Apostolia M. Tsimberidou1, Daniel Karp1, James Yao5, Funda Meric-Bernstam1 and Siqing Fu1

1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

6National 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/m2, 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.


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