TY - JOUR
T1 - Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer
AU - Wang, Zhijie
AU - Piha-Paul, Sarina
AU - Janku, Filip
AU - Subbiah, Vivek
AU - Shi, Naiyi
AU - Gong, Jing
AU - Wathoo, Chetna
AU - Shaw, Kenna
AU - Hess, Kenneth
AU - Broaddus, Russell
AU - Naing, Aung
AU - Hong, David
AU - Tsimberidou, Apostolia M.
AU - Karp, Daniel
AU - Yao, James
AU - Meric-Bernstam, Funda
AU - Fu, Siqing
N1 - Publisher Copyright:
© Wang et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Chronic inflammation
KW - Gene aberration-related therapy
KW - KRAS
KW - Phase I trial
KW - TP53
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U2 - 10.18632/oncotarget.16840
DO - 10.18632/oncotarget.16840
M3 - Article
C2 - 28430579
AN - SCOPUS:85019205784
SN - 1949-2553
VL - 8
SP - 33796
EP - 33806
JO - Oncotarget
JF - Oncotarget
IS - 20
ER -