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  • br As described in the materials and methods

    2020-08-18


    As described in the materials and methods section, based on their p-value in univariate analysis, variables analyzed in the PFS multivariate model were age, smoking status, PS, histological subtype, TP53 muta-tional status and PD-L1 expression level, while variables analyzed in the OS multivariate model were gender, age, smoking status, PS and TP53 mutational status. In multivariate analysis, performed in 65 patients with complete PD-L1 staining data, TP53 mutations were associated with a non-significant increase of PFS in patients receiving ICI, with a 29% decrease risk of progression or death (HR:0.71 [0.35–1.41], p = 0.32). Accordingly, TP53 mutations significantly correlated with longer OS in these patients, with a 65% decrease of death risk (HR: 0.35 [0.16-0.77], p = 0.009), suggesting that patients with TP53 mutations derive a larger benefit from ICI, possibly due to TP53′s role in genomic stability control (Table 2S). Multivariate analyses performed in the whole population including the seven patients without available PD-L1 data, showed the very same prognostic value of TP53 mutations (data not shown).
    4. Discussion
    In this study with mostly "real-life" patients, TP53 gene mutations in aNSCLC patients treated with ICI were found to correlate with better OS, PFS, and ORR, compared with TP53-wild-type patients, with the OS effect still present when adjusting for other important prognosis factors.
    These results are striking since TP53 mutations have repeatedly been associated with worse survival and resistance to classical che-motherapy 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 3-Methyladenine 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, re-spectively, consistent with prior studies assessing ICI in aNSCLC pa-tients in first or later lines [1–3]. 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 mu-tations are associated with favorable outcomes under ICI treatment.
    Our study therefore independently confirms the data recently pub-lished 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 as-sociated with increased mutation burden in patients treated by com-bination immunotherapy, along with the Cancer Genome Atlas, pub-licly-available NSCLC data.
    To the best of our knowledge, our study is the first to demonstrate
    Fig. 1. TP53 and KRAS genotype analysis and co-mutations. (A) TP53 point mutations and locations in dataset. (B) Type of TP53 mutations and exon distribution. (C) TP53 mutation effect on protein structure and transcriptional activity. (D) KRAS point mutations in dataset. (E) Distribution of TP53, KRAS, STK11, and EGFR co-occurring mutations, as depicted in a proportional Venn diagram.
    NA: non appropriate; SH3-like: src homology-3-like domain; NES: nuclear export signal.
    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 in-cidence 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 har-bored 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 [27–29]. 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 con-sequences. 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 muta-tions ultimately lead to a marked enhancement of tumor genomic