Tumor mutation burden and immunological, genomic, and clinicopathological factors as biomarkers for checkpoint inhibitor treatment of patients with non-small-cell lung cancer

• Published in: Cancer Immunology, Immunotherapy Vol. 69; no. 1; pp. 127 - 134
• Main Authors: Ozaki, Yuki, Muto, Satoshi, Takagi, Hironori, Watanabe, Masayuki, Inoue, Takuya, Fukuhara, Mitsuro, Yamaura, Takumi, Okabe, Naoyuki, Matsumura, Yuki, Hasegawa, Takeo, Ohsugi, Jun, Hoshino, Mika, Shio, Yutaka, Tanaka, Daisuke, Nanamiya, Hideaki, Imai, Jun-ichi, Isogai, Takao, Watanabe, Shinya, Suzuki, Hiroyuki
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-01-2020; Springer Nature B.V
• Subjects: Aged; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Biomarkers, Tumor - metabolism; Cancer Research; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - therapy; Cell death; Cell size; Chemotherapy, Adjuvant; Cyclin-dependent kinase; Cyclin-dependent kinases; Enzyme inhibitors; Epidermal growth factor receptors; ErbB Receptors - genetics; Exome Sequencing; Female; Genomics; Humans; Immune checkpoint inhibitors; Immunohistochemistry; Immunology; Lung - pathology; Lung - surgery; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - therapy; Lymphocytes; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Medicine; Medicine & Public Health; Multivariate analysis; Mutation; Non-small cell lung carcinoma; Oncology; Original; Original Article; p53 Protein; Patients; PD-L1 protein; Pneumonectomy; Point mutation; Sequence analysis; Squamous cell carcinoma; Surgery; Treatment Outcome; Tumor Suppressor Protein p53 - genetics; Tumor-infiltrating lymphocytes; Non-small-cell lung cancer; Biomarker; Immune checkpoint inhibitor; Immunological; Tumor mutation burden
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-019-02446-1

Cancer treatment using immune checkpoint inhibitors is widely used, although biomarkers predictive of response are not well established. However, both the expressions of programmed cell death ligand 1 (PD-L1) and the tumor mutation burden (TMB) hold promise as such biomarkers for immune checkpoint inhibitors; however, its characteristics and clinical and immunological impacts have not been fully analyzed. We, therefore, evaluated the clinical and immunological parameters related to TMB to identify potential new biomarkers. We enrolled 92 patients with non-small-cell lung cancer who underwent surgery at Fukushima Medical University Hospital from 2013 to 2016. TMB of individual tumors was calculated by whole-exome sequencing analysis. Major cancer-related gene mutations were evaluated using panel sequencing. Expression of PD-L1 and abundance of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry using surgical samples. The median TMB value was 60. TMB was significantly higher in men, current or former smokers, and in patients with squamous cell carcinoma, tumor size ≥ 2.8 cm, wild-type EGFR, TP53 gene mutation-positive status, and cyclin-dependent kinase-inhibitor gene 2A mutation-positive status. According to multivariate analysis, TMB was significantly associated with EGFR gene mutation-negative status (
p
 = 0.0111) and TP53 gene mutation-positive status (
p
 = 0.0425). If TMB is identified as a robust biomarker for immune checkpoint inhibitor administration, analysis of TP53 and EGFR mutations may provide a relatively rapid and easy proxy for predicting TMB.