AUTHOR=Xiang Luochengling , Fu Xiao , Wang Xiao , Li Wenyuan , Zheng Xiaoqiang , Nan Kejun , Tian Tao 

TITLE=A Potential Biomarker of Combination of Tumor Mutation Burden and Copy Number Alteration for Efficacy of Immunotherapy in KRAS-Mutant Advanced Lung Adenocarcinoma

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.559896

DOI=10.3389/fonc.2020.559896

ISSN=2234-943X

ABSTRACT=<sec><title>Objectives</title><p>The <italic>Kirsten Rat Sarcoma</italic> (<italic>KRAS</italic>) mutation is the commonest oncogenic drive mutation in lung adenocarcinoma (LUAD) and immunotherapy may be quite promising for <italic>KRAS</italic>-mutant LUAD. While the effects of tumor mutation burden (TMB) and copy number alteration (CNA) are poorly understood in this illness, our study aimed to explore the roles TMB and CNA play in the prediction of response to immune checkpoint inhibitor (ICI) therapy in advanced <italic>KRAS</italic>-mutant LUAD.</p></sec><sec><title>Methods</title><p>Mutation and clinical data were downloaded from cBioPortal. We evaluated <italic>KRAS</italic> mutation status and divided patients into different subgroups based on TMB and CNA cutoffs to investigate the predictive value of these biomarkers on ICI response.</p></sec><sec><title>Results</title><p><italic>KRAS</italic> mutation with concurrent <italic>TP53</italic> or <italic>STK11</italic> mutations had higher TMB and CNA compared to <italic>KRAS</italic> mutation alone. The <italic>KRAS</italic> G12C and G &gt; T mutation subgroups, with <italic>TP53</italic> or <italic>STK11</italic> co-mutation, also had higher TMB and CNA. We found that TMB and CNA were independently associated with progression-free survival (PFS) and durable clinical benefits (DCB); TMB was positively correlated with PFS (<italic>P</italic> = 0.0074) and DCB (<italic>P</italic> = 0.0008) while low CNA was associated with prolonged PFS (<italic>P</italic> = 0.0060) and DCB (<italic>P</italic> = 0.0018). However, TMB alone did not distinguish benefits among <italic>KRAS</italic>-mutant patients. Notably, when combining TMB and CNA, low TMB and high CNA revealed worse outcomes of ICI therapy (mPFS: 2.20m, <italic>P</italic> = 0.0023; proportion of DCB: 24%, <italic>P</italic> = 0.0001).</p></sec><sec><title>Conclusion</title><p>The combination of TMB and CNA provides more sensible and accurate prediction of ICI response than individual factors in <italic>KRAS</italic>-mutant LUAD. Moreover, low TMB and high CNA can be utilized as a potential biomarker to predict adverse outcome in <italic>KRAS</italic>-mutant LUAD.</p></sec>