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Please cite this article as: Lin J-X et al., Association of the age-adjusted Charlson Comorbidity Index and systemic inflammation with survival in gastric cancer patients after radical gastrectomy, European Journal of Surgical Oncology, https://doi.org/10.1016/j.ejso.2019.07.010 Lung Cancer 132 (2019) 65–71
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Association of TP53 mutations with response and longer survival under T
immune checkpoint inhibitors in advanced non-small-cell lung cancer
Sandra Assouna,b, Nathalie Theou-Antonc, Marina Nguenanga, Aurélie Cazesd, Claire Daneld, Baptiste Abbara, Johan Pluvya, Valérie Gounanta, Antoine Khalile, Céline Namoura, Solenn Brosseaua,b,f, Gérard Zalcmana,b,f,
a Thoracic Oncology Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France
c Genetics Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France
d Pathology Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France
e Radiology Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France
f Medicine Faculty, University Paris-Diderot, 46 rue Henri Huchard, 75018 Paris, France
Non-small-cell lung cancer
Tumor mutational burden Immune checkpoint inhibitors
Introduction: Tumor mutational burden (TMB) correlates with response to immune checkpoint inhibitors (ICI) in advanced non-small-cell lung cancer (aNSCLC). We hypothesized that TP53 mutations could reflect TMB and be associated with ICI benefit.
Methods: TP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with pro-grammed death-1 (PD-1) blockers. Clinical data, tumor programmed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS). Results: In total, 72 patients (median [interquartile range] age: 61 [33–83] years) were included; 52 (72%) were male; 39 (54%) had performance status 0–1; 53 (74%) had adenocarcinoma; 20 (28%) received first-line ICI, 52 (72%) second line or more.
Conclusions: TP53-mutated status correlated with immunotherapy OS benefit in aNSCLC.
The emergence of immune checkpoint inhibitors (ICI) has sig-nificantly influenced clinical therapeutic strategies for most cancer subtypes, notably in advanced non-small-cell lung cancer (aNSCLC). Programmed cell death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, and programmed cell death ligand-1 (PD-L1) in-hibitors (e.g. atezolizumab) have significantly improved progression-free survival (PFS) and overall survival (OS) of patients with aNSCLC,
achieving outstanding duration of disease control compared to standard platinum-based frontline chemotherapy or second-line docetaxel che-motherapy [1–3]. However, only 20 to 25% of patients treated with immunotherapy derive bona fide benefit from this therapy, and de-terminants of response remain desperately elusive. To date, the only approved predictive biomarkers of ICI eﬃcacy are microsatellite in-stability status [4,5] and strong PD-L1 expression, assessed by im-munohistochemical analysis for pembrolizumab in aNSCLC in first line . Nonetheless, although PD-L1 tumor cell expression appears
Corresponding author at: Service d'oncologie thoracique, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877, Paris Cedex 18, France. E-mail address: [email protected] (G. Zalcman).
positively correlated to ICI eﬃcacy , a significant proportion of se-lected patients with positive PD-L1 expression do not respond to ICI, or even show disease hyper-progression under treatment . Conversely, patients with PD-L1- negative tumors can surprisingly also manifest significant response to ICI. Thus, identifying more robust predictive tools of response to ICI in NSCLC patients is an urgent need that still has yet to be met.
Recently, several studies provided compelling evidence that tumor mutational burden (TMB) could predict the potential activity of im-munotherapy in numerous tumor types, including NSCLC [8,9]. By generating impaired cellular proteins recognized as neo-antigens by immune cells, the resulting genetic instability can enhance tumor im-munogenicity, thereby optimizing the antitumor cytotoxicity of T lymphocytes, reinstated by ICI therapy. As such, it has been suggested that mutations in oncogenes such as K-RAS are associated with favor-able outcomes under ICI therapy in NSCLC patients [10,11], though this eﬀect is thought to be merely mediated through high TMB , while, conversely, EGFR mutations were associated with low mutational burden and lower rates of response to ICI . Hailed as a historic “guardian of genome integrity”, the TP53 gene may also constitute a relevant tool to indirectly quantify TMB . Moreover, several studies demonstrated that PD-L1 expression was boosted in TP53-mutated tu-mors, whether TP53 status was assessed indirectly by im-munohistochemistry analysis  or directly using whole-exome se-quencing (WES) . Thus, in a recent study, Dong et al. retrospectively showed in 30 aNSCLC patients treated with pem-brolizumab that median PFS was significantly longer in the TP53-mu-tated group than in the TP53- wild-type group (14.5 versus 3.5 months, p = 0.042) . However, these interesting results were not adjusted for the clinical and pathological features likely to influence response to ICI. Finally, using WES, the influence of individual genes within the TMB variable was analyzed to identify whether a limited number of mutational events could drive the predictive eﬀect of TMB on PFS in patients treated with combined PD-1 and cytotoxic T-lymphocyte-as-sociated protein 4 (CTLA-4) blockade . TP53 mutations were identified as key events driving this predictive eﬀect, while STK11 and PTEN mutations were associated with worse response to this combined ICI treatment, suggesting that a mutational signature incorporating these alterations with positive and negative values should be assessed, since it is easier by far to obtain tumor specimens from patients, to perform targeted NGS assessing such genes, than generating the ex-pensive and complicated TMB in routine practice.