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J Clin Oncol. 2018 Aug 14:JCO2018781963. doi: 10.1200/JCO.2018.78.1963. [Epub ahead of print]

Tumor Mutation Burden as a Biomarker in Resected Non-Small-Cell Lung Cancer.

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Siddhartha Devarakonda, Irena Lanc, and Ramaswamy Govindan, Washington University School of Medicine; Siddhartha Devarakonda and Ramaswamy Govindan, Siteman Cancer Center; Robert Fulton, Washington University School of Medicine, St. Louis; Ashiq Masood, University of Missouri Kansas City, Kansas City, MO; Federico Rotolo, Ken A. Olaussen, Gwénaël Le Teuff, Jean-Pierre Pignon, and Stefan Michiels, Université Paris-Saclay; Federico Rotolo, Ken A. Olaussen, Gwénaël Le Teuff, Jean-Pierre Pignon, Jean-Charles Soria, and Stefan Michiels, Gustave Roussy Cancer Campus, Villejuif; Elisabeth Brambilla and Anne McLeer-Florin, Centre Hospitalier Universitaire de Grenoble, La Tronche, France; Ming-Sound Tsao, Shingo Sakashita, and Frances A. Shepherd, Princess Margaret Cancer Centre and University of Toronto, Toronto; Keyue Ding and Lesley Seymour, Queen's University Kingston, Ontario, Canada; Stephen L. Graziano, State University of New York Upstate Medical University, Syracuse, NY; Robert Kratzke, University of Minnesota Medical School, Minneapolis, MN.


Purpose The survival benefit with adjuvant chemotherapy for patients with resected stage II-III non-small-cell 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 criteria were 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 (> 8 mutations/Mb) was prognostic for favorable outcomes (ie, overall survival, disease-free survival, and LCSS) in patients with resected NSCLC. LCSS benefit with adjuvant chemotherapy was more pronounced in patients with low nonsynonymous TMBs (≤ 4 mutations/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 false-discovery 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.


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