Association of circulating tumor DNA (ctDNA) tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC).

Abstract

11537 Background: Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies in NSCLC is critical. TMB is a potential biomarker of genomic instability and neoantigen binding sites to activated effector T cells. The goal of this study was to derive a measure of ctDNA TMB and to examine the association between TMB and clinical variables, DNA repair mutations, and response to checkpoint blockade. Methods: We retrospectively examined 136 patients with NSCLC who had undergone ctDNA next-generation sequencing (NGS) in our institution. The ctDNA testing, performed by Guardant360, is not currently clinically indicated for TMB. We derived ctDNA TMB using coding base substitutions and indel alterations both including and excluding potentially functional variants, but excluded rearrangements, fusions, and copy number variants. In addition, survival data were obtained for 17 patients who were treated with anti-PD-1/PD-L1 therapy and had ctDNA before first line therapy or within 90 days of therapy initiation. Results: ctDNA TMB was associated with the number of direct and indirect DNA repair gene mutations (t-test, p < 0.05). Smoking was also associated with higher TMB when including functional variants (chi-square test, p = 0.034). Driver mutations (EGFR, KRAS) and prior radiation therapy were not correlated with TMB. Lower ctDNA TMB (below the median, 15 mutations/MBp) was associated with longer PFS and OS (Kaplan-Meier log-rank test, p < 0.05). Conclusions: ctDNA TMB was derived and was significantly associated with greater number of DNA repair mutations. Smoking predicted higher TMB score. However, in a small subset of patients, lower ctDNA TMB predicted response to checkpoint blockade. Potential reasons include the small sample size, the possibility of ctDNA reflecting tumor burden, and the limited length of DNA sequenced (~78,000-138,000 bp). Larger, prospective studies are necessary to validate these findings.