Applications of Circulating Tumor DNA in a Cohort of Phase I Solid Tumor Patients Treated With Immunotherapy. Issue 3 (23rd January 2021)

• Record Type: Journal Article
• Authors: Araujo, Daniel V; Wang, Ao; Torti, Dax; Leon, Alberto; Marsh, Kayla; McCarthy, Aoife; Berman, Hal; Spreafico, Anna; Hansen, Aaron R; Razak, Albiruni-Abdul; Bedard, Philippe L; Wang, Lisa; Plackmann, Eric; Chow, Helen; Bao, Hua; Wu, Xue; Pugh, Trevor J; Siu, Lillian L
• Is Part Of: JNCI cancer spectrum. Volume 5:Issue 3(2021)
• Publication Date: 2021-01-23
• DOI: 10.1093/jncics/pkaa122
• Languages: English
• ISSNs: 2515-5091

Abstract

Abstract: Background: The correlation between blood-based tumor mutation burden (bTMB) and tissue-based tumor mutation burden(tTMB) has not been broadly tested in a multicancer cohort. Here, we assess the correlation between bTMB with tTMB in phase I trial patients treated with immunotherapy. As an exploratory analysis, we evaluated circulating tumor DNA (ctDNA) dynamics in responders. Methods: Patients treated with immunotherapy at the Princess Margaret phase I trials unit were enrolled. Pretreatment plasma ctDNA and matched normal blood controls were collected. Available archival tissue formalin-fixed paraffin-embedded (FFPE) samples were analyzed. A 425-gene panel was used to sequence both ctDNA and FFPE samples. Samples with TMB within the highest tertile were considered as high TMB. Results: Thirty-eight patients were accrued from 25 different trials, 86.8% of which involved an anti-PD-1/PD-L1 agent. Thirty patients (78.9%) had detectable mutations in ctDNA, of which the median (range) bTMB was 5 (1-53) mutations per megabase (mut/Mb). Of the 22 patients with available FFPE samples, mutations were detected in 21 (95.4%); the median (range) tTMB was 6 (2-124) mut/Mb. Among the 16 patients with detectable mutations in both FFPE and ctDNA, a statistically significant correlation between bTMB and tTMB was observed ( ρ = 0.71; P = .002). High TMB was not associated with better survival. All 3 responders had a decrease in the variant allele frequency of mutations detected in ctDNA at a second timepoint relative to baseline, indicating a potential early marker of response. Conclusions: In this small series, bTMB correlated with tTMB. An on-treatment decrease in VAF of mutations detected in ctDNA at baseline was observed in responders. Larger studies to verify our findings are warranted.