Cargando…

Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer

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 cons...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Yudong, Wang, Zhijie, Piha-Paul, Sarina, Janku, Filip, Subbiah, Vivek, Shi, Naiyi, Hess, Kenneth, Broaddus, Russell, Shan, Baoen, Naing, Aung, Hong, David, Tsimberidou, Apostolia M., Karp, Daniel, Lu, Charles, Papadimitrakopoulou, Vali, Heymach, John, Meric-Bernstam, Funda, Fu, Siqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161801/
https://www.ncbi.nlm.nih.gov/pubmed/30279957
http://dx.doi.org/10.18632/oncotarget.25947
_version_ 1783359054258634752
author Wang, Yudong
Wang, Zhijie
Piha-Paul, Sarina
Janku, Filip
Subbiah, Vivek
Shi, Naiyi
Hess, Kenneth
Broaddus, Russell
Shan, Baoen
Naing, Aung
Hong, David
Tsimberidou, Apostolia M.
Karp, Daniel
Lu, Charles
Papadimitrakopoulou, Vali
Heymach, John
Meric-Bernstam, Funda
Fu, Siqing
author_facet Wang, Yudong
Wang, Zhijie
Piha-Paul, Sarina
Janku, Filip
Subbiah, Vivek
Shi, Naiyi
Hess, Kenneth
Broaddus, Russell
Shan, Baoen
Naing, Aung
Hong, David
Tsimberidou, Apostolia M.
Karp, Daniel
Lu, Charles
Papadimitrakopoulou, Vali
Heymach, John
Meric-Bernstam, Funda
Fu, Siqing
author_sort Wang, Yudong
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6161801
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-61618012018-10-02 Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer Wang, Yudong Wang, Zhijie Piha-Paul, Sarina Janku, Filip Subbiah, Vivek Shi, Naiyi Hess, Kenneth Broaddus, Russell Shan, Baoen Naing, Aung Hong, David Tsimberidou, Apostolia M. Karp, Daniel Lu, Charles Papadimitrakopoulou, Vali Heymach, John Meric-Bernstam, Funda Fu, Siqing Oncotarget Research Paper 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. Impact Journals LLC 2018-09-07 /pmc/articles/PMC6161801/ /pubmed/30279957 http://dx.doi.org/10.18632/oncotarget.25947 Text en Copyright: © 2018 Wang et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Wang, Yudong
Wang, Zhijie
Piha-Paul, Sarina
Janku, Filip
Subbiah, Vivek
Shi, Naiyi
Hess, Kenneth
Broaddus, Russell
Shan, Baoen
Naing, Aung
Hong, David
Tsimberidou, Apostolia M.
Karp, Daniel
Lu, Charles
Papadimitrakopoulou, Vali
Heymach, John
Meric-Bernstam, Funda
Fu, Siqing
Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer
title Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer
title_full Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer
title_fullStr Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer
title_full_unstemmed Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer
title_short Outcome analysis of Phase I trial patients with metastatic KRAS and/or TP53 mutant non-small cell lung cancer
title_sort outcome analysis of phase i trial patients with metastatic kras and/or tp53 mutant non-small cell lung cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161801/
https://www.ncbi.nlm.nih.gov/pubmed/30279957
http://dx.doi.org/10.18632/oncotarget.25947
work_keys_str_mv AT wangyudong outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT wangzhijie outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT pihapaulsarina outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT jankufilip outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT subbiahvivek outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT shinaiyi outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT hesskenneth outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT broaddusrussell outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT shanbaoen outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT naingaung outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT hongdavid outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT tsimberidouapostoliam outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT karpdaniel outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT lucharles outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT papadimitrakopoulouvali outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT heymachjohn outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT mericbernstamfunda outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer
AT fusiqing outcomeanalysisofphaseitrialpatientswithmetastatickrasandortp53mutantnonsmallcelllungcancer