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. 2017 May 16;8(20):33796-33806.
doi: 10.18632/oncotarget.16840.

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

Zhijie Wang  1   2 , Sarina Piha-Paul  1 , Filip Janku  1 , Vivek Subbiah  1 , Naiyi Shi  1 , Jing Gong  1 , Chetna Wathoo  3 , Kenna Shaw  3 , Kenneth Hess  4 , Russell Broaddus  5 , Aung Naing  1 , David Hong  1 , Apostolia M Tsimberidou  1 , Daniel Karp  1 , James Yao  6 , Funda Meric-Bernstam  1 , Siqing Fu  1
Affiliations

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

Zhijie Wang et al. Oncotarget. .

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.

Keywords: KRAS; TP53; chronic inflammation; gene aberration-related therapy; phase I trial.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1. Kaplan-Meier overall survival (OS) curves in patients with KRAS+/TP53+ mutant colorectal cancer who received therapy in a phase I clinical trial, stratified by KRAS G13 mutation status (due to sample size, all p values are unadjusted)
.
Figure 2
Figure 2. Kaplan-Meier overall survival (OS) curves in patients with KRAS+/TP53+ mutant colorectal cancer who received therapy in a phase I clinical trial, stratified by TP53 R273 mutation status (due to sample size, all p values are unadjusted)
.
Figure 3
Figure 3. A prognostic model was established from 57 patients with advanced KRAS+/TP53+ mutant cancer who received therapy in a phase I clinical trial
Kaplan-Meier overall survival (OS) curves are shown, stratified by risk score (low-risk group: score ≤1, high-risk group: score >1) (due to sample size, all p values are unadjusted).
Figure 4
Figure 4. The established prognostic model was validated in 104 patients with advanced KRAS+/TP53+ mutant cancer who did not receive therapy in a phase I clinical trial
Kaplan-Meier overall survival (OS) curves are shown, stratified by risk score (low-risk group: score ≤1, high-risk group: score >1) (due to sample size, all p values are unadjusted).
See this image and copyright information in PMC

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