• 2019-06
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  • br Materials and methods br


    Materials and methods
    Discussion These results are striking since TP53 mutations have repeatedly been associated with worse survival and resistance to classical chemotherapy in lung and breast cancers, especially when TP53 mutations lead to a change in conformation of the central domain of mutant p53, which is the essential component in this interaction with p73, or when they associate with arginine Ruxolitinib (INCB018424) 72 polymorphism, which also drives the interaction with p73 [21,22]. In our population of 72 patients treated with ICI, median OS and PFS were 15.4 and 3.7 months, respectively, consistent with prior studies assessing ICI in aNSCLC patients in first or later lines [[1], [2], [3]]. Median OS in the TP53-mutated group and TP53-wild-type group were 18.1 and 8.1 months, respectively (HR: 0.48; p = 0.04). These findings support the hypothesis that TP53 mutations are associated with favorable outcomes under ICI treatment. Our study therefore independently confirms the data recently published of the CA-209-227 trial on the predictive value of TMB for PFS in patients receiving PD-1 and CTLA-4 blockers [15,23]. In this analysis of individual genes’ contribution to predicting response or resistance to combination immunotherapy, some gene mutations such as STK11 or PTEN were confirmed to be exclusively associated with resistance. Conversely, only TP53 mutations are enriched in responders and associated with increased mutation burden in patients treated by combination immunotherapy, along with the Cancer Genome Atlas, publicly-available NSCLC data. To the best of our knowledge, our study is the first to demonstrate the association of TP53 mutational status assessed by NGS not only with response or PFS but also with OS, in an ICI therapy context. In the Dong et al. study involving 30 NSCLC patients treated with pembrolizumab, PFS was the only endpoint found to be significantly lengthened in TP53-mutated patients as compared to TP53-wild-type patients (p = 0.042) [11]. Recent studies have suggested that PFS and ORR are not appropriate surrogates for OS for ICI treatment owing to the incidence of pseudoprogression with delayed clinical benefit and the uncertainty that surrounds RECIST or immune RECIST criteria use to evaluate tumor response in such ICI-treated patients. Actually a recent study has suggested that only 6-month PFS could be a surrogate for OS [24]. Therefore, OS remains the most reliable and meaningful measure of clinical benefit under ICI [25,26]. Consistent with how the TP53 mutational landscape in lung cancer is described in the literature, 56.9% of the patients in our cohort harbored TP53 mutations, 73.2% of which were missense mutations [16]. As previously reported, 34.1% of reported mutations in our cohort were G-to-T transversions, considered a tobacco exposure signature in lung cancer, and resulting from DNA adduct formation from carcinogens in tobacco smoke, prominently polycyclic aromatic hydrocarbons and nicotine-derived nitrosamine ketone [[27], [28], [29]]. Interestingly, most of the recorded TP53 mutations resulted in disabled TP53 genes (65.9%), a molecular event that causes a wide array of downstream cellular consequences. First, inactivating TP53 mutations hamper TP53 canonical functions of tumor suppressor by impeding its transcriptional activity involved in promoting cell cycle arrest, damaged DNA repair, cellular senescence, and apoptosis [13]. As such, loss-of-function TP53 mutations ultimately lead to a marked enhancement of tumor genomic instability [30], thereby spurring tumor immunogenicity by generating tumor neo-antigens or resulting in mutations in dominant oncogenes, such as KRAS [31]. That gain in tumor immunogenicity fueled by the loss of TP53 may also cause increased recruitment of cytotoxic T lymphocytes into the tumor stroma, consequently potentiating the efficacy of ICI [32]. Additionally, it has been proven that destabilizing TP53 mutations could lead to altered unfolded TP53 proteins, which may also independently constitute tumor-specific antigens enhancing T cell reactivity, when involving major histocompatibility (MHC) Class I molecules [33].