Reference Detail

Ref Type

Journal Article

PMID

(29764856)

Authors

Biton J, Mansuet-Lupo A, Pécuchet N, Alifano M, Ouakrim H, Arrondeau J, Boudou-Rouquette P, Goldwasser F, Leroy K, Goc J, Wislez M, Germain C, Laurent-Puig P, Dieu-Nosjean MC, Cremer I, Herbst R, Blons H, Damotte D

Title

TP53, STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	24	22	2018 Nov 15	5710-5723	Clin Cancer Res

URL

Abstract Text

Purpose: By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed.Experimental Design: We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained.Results: We showed that distinct combinations of STK11, EGFR, and TP53 mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations (TP53-mut/STK11-EGFR-WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16-0.63, P < 0.001) was observed in anti-PD-1-treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression.Conclusions: Our study reveals that different combinations of TP53, EGFR, and STK11 mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Clin Cancer Res; 24(22); 5710-23. ©2018 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References