Effect of prior therapy on tumor mutational burden in NSCLC

BACKGROUND: Higher tumor mutation burden (TMB) in advanced non-small cell lung cancer (NSCLC) is associated with superior outcomes with checkpoint inhibitor therapy. Tissue samples subject to TMB analysis may be acquired after DNA-damaging therapies such as chemotherapy or radiation. The impact of these therapies on TMB results is unclear. This retrospective analysis explored differences in TMB among treatment-naïve samples and treatment-experienced samples. METHODS: NSCLC samples that underwent molecular profiling at a CLIA-certified genomics laboratory (Caris Life Sciences, Phoenix, AZ) and had available treatment and clinical history were identified. TMB was estimated by counting all coding variants (missense, nonsense, frameshift, in-frame InDels) identified by next-generation sequencing. Exceptions were synonymous mutations and any single nucleotide polymorphisms described as germline. History was reviewed under an IRB approved protocol to determine whether patients had received cytotoxic chemotherapy or radiation therapy in the year prior to collection of the tissue subject to TMB analysis. TMB values were compared between cohorts using the Wilcoxon test. Smoking adjusted P values were calculated using the chi-squared test of deviance. RESULTS: TMB was calculated for 970 annotated tumor specimens. Of these, 155 patients received chemotherapy and/or radiation prior to tissue collection. The median TMB was 8 mut/Mb in both the treatment-naïve and treatment-experienced cohorts. After adjusting for smoking, there was no significant difference in TMB between these cohorts (P=0.22). When analyzed separately, neither prior chemotherapy nor prior radiation therapy influenced TMB. TMB was higher when the specimen source was collected from a metastatic site compared to the primary site. CONCLUSIONS: Prior exposure to chemotherapy or radiation therapy was not associated with a significant difference in TMB.