Tumor mutation burden as a biomarker in resected non-small-cell lung cancer

Siddhartha Devarakonda, Federico Rotolo, Ming Sound Tsao, Irena Lanc, Elisabeth Brambilla, Ashiq Masood, Ken A. Olaussen, Robert Fulton, Shingo Sakashita, Anne McLeer-Florin, Keyue Ding, Gwenäel Le Teuff, Frances A. Shepherd, Jean Pierre Pignon, Stephen L. Graziano, Robert Kratzke, Jean Charles Soria, Lesley Seymour, Ramaswamy Govindan, Stefan Michiels

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48 Scopus citations

Abstract

Purpose The survival benefit with adjuvant chemotherapy for patients with resected stage II-III non-smallcell lung cancer (NSCLC) is modest. Efforts to develop prognostic or predictive biomarkers in these patients have not yielded clinically useful tests. We report findings from the Lung Adjuvant Cisplatin Evaluation (LACE)-Bio-II study, in which we analyzed next-generation sequencing and long-term outcomes data from . 900 patients with early-stage NSCLC treated prospectively in adjuvant landmark clinical trials. We used a targeted gene panel to assess the prognostic and predictive effect of mutations in individual genes, DNA repair pathways, and tumor mutation burden (TMB). Methods A total of 908 unmatched, formalin-fixed, paraffin-embedded, resected lung cancer tumor specimens were sequenced using a targeted panel of 1,538 genes. Stringent filtering criteriawere applied to exclude germline variants and artifacts related to formalin fixation. Disease-free survival, overall survival, and lung cancer-specific survival (LCSS) were assessed in Cox models stratified by trial and adjusted for treatment, age, sex, performance score, histology, type of surgery, and stage. Results Nonsynonymous mutations were identified in 1,515 genes in 908 tumor samples. High nonsynonymous TMB (. 8mutations/Mb) was prognostic for favorable outcomes (ie, overall survival, disease-free survival, and LCSS) in patients with resected NSCLC. LCSS benefit with adjuvant chemotherapy wasmore pronounced in patients with low nonsynonymous TMBs (#4mutations/ Mb). Presence of mutations in DNA repair pathways, tumor-infiltrating lymphocytes, TP53 alteration subtype, and intratumor heterogeneity was neither prognostic nor predictive. Statistically significant effect of mutations in individual genes was difficult to determine due to high falsediscovery rates. Conclusion High nonsynonymous TMB was associated with a better prognosis in patients with resected NSCLC. In addition, the benefit of adjuvant chemotherapy on LCSS was more pronounced in patients with low nonsynonymous TMBs. Studies are warranted to confirm these findings.

Original languageEnglish
Pages (from-to)2995-3006
Number of pages12
JournalJournal of Clinical Oncology
Volume36
Issue number30
DOIs
StatePublished - Oct 20 2018

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    Devarakonda, S., Rotolo, F., Tsao, M. S., Lanc, I., Brambilla, E., Masood, A., Olaussen, K. A., Fulton, R., Sakashita, S., McLeer-Florin, A., Ding, K., Le Teuff, G., Shepherd, F. A., Pignon, J. P., Graziano, S. L., Kratzke, R., Soria, J. C., Seymour, L., Govindan, R., & Michiels, S. (2018). Tumor mutation burden as a biomarker in resected non-small-cell lung cancer. Journal of Clinical Oncology, 36(30), 2995-3006. https://doi.org/10.1200/JCO.2018.78.1963