Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer
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Yudong Wang1,5, Zhijie Wang1,6, Sarina Piha-Paul1, Filip Janku1, Vivek Subbiah1, Naiyi Shi1, Kenneth Hess2, Russell Broaddus3, Baoen Shan7, Aung Naing1, David Hong1, Apostolia M. Tsimberidou1, Daniel Karp1, Charles Lu4, Vali Papadimitrakopoulou4, John Heymach4, Funda Meric-Bernstam1 and Siqing Fu1
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People’s Republic of China
6Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China
7Department of Cancer Research, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People’s Republic of China
Siqing Fu, email: [email protected]
Keywords: KRAS; TP53; Phase I trial; overall survival; non-small cell lung cancer
Received: May 22, 2018 Accepted: July 18, 2018 Published: September 07, 2018
KRAS and TP53 mutations, which are the most common genetic drivers of tumorigenesis, are still considered undruggable targets. Therefore, we analyzed these genetic aberrations in metastatic non-small cell lung cancer (NSCLC) for the development of potential therapeutics. One hundred eighty-five consecutive patients with metastatic NSCLC in a phase 1 trial center were included. Their genomic aberrations, clinical characteristics, survivals, and phase 1 trial therapies were analyzed. About 10%, 18%, 36%, and 36% of the patients had metastatic KRAS+/TP53+, KRAS+/TP53-,KRAS-/TP53+, and KRAS-/TP53- NSCLC, respectively. The most common concurrent genetic aberrations beside KRAS and/or TP53 (>5%) were KIT, epidermal growth factor receptor, PIK3CA, c-MET, BRAF, STK11, ATM, CDKN2A, and APC. KRAS+/TP53+ NSCLC did not respond well to the phase 1 trial therapy and was associated with markedly worse progression-free (PFS) and overall (OS) survivals than the other three groups together. KRAS hotspot mutations at locations other than codon G12 were associated with considerably worse OS than those at this codon. Gene aberration-matched therapy produced prolonged PFS and so was anti-angiogenesis in patients with TP53 mutations. Introduction of the evolutionary action score system of TP53 missense mutations enabled us to identify a subgroup of NSCLC patients with low-risk mutant p53 proteins having a median OS duration of 64.5 months after initial diagnosis of metastasis. These data suggested that patients with metastatic dual KRAS+/TP53+ hotspot-mutant NSCLC had poor clinical outcomes. Further analysis identified remarkably prolonged survival in patients with low-risk mutant p53 proteins, which warrants confirmatory studies.
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