Applications of Circulating Tumor DNA in a Cohort of Phase I Solid Tumor Patients Treated With Immunotherapy.

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.

• Authors: Daniel V Araujo, Ao Wang, Dax Torti, Alberto Leon, Kayla Marsh, Aoife McCarthy, Hal Berman, Anna Spreafico, Aaron R Hansen, Albiruni-Abdul Razak, Philippe L Bedard, Lisa Wang, Eric Plackmann, Helen Chow, Hua Bao, Xue Wu, Trevor J Pugh, Lillian L Siu
• Journal: JNCI cancer spectrum (JNCI Cancer Spectr) Vol. 5 Issue 3 (06 2021) ISSN: 2515-5091 [Electronic] England
• PMID: 34056539 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press.

Chemical References

• Circulating Tumor DNA
• Immune Checkpoint Inhibitors

Topics

• Adult
• Aged
• Circulating Tumor DNA (blood, genetics)
• Clinical Trials, Phase I as Topic
• Cohort Studies
• DNA Mutational Analysis (methods)
• Female
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Immunotherapy
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mutation Accumulation
• Neoplasms (blood, genetics, pathology, therapy)
• Paraffin Embedding
• Pilot Projects
• Prognosis
• Proportional Hazards Models
• Treatment Outcome
• Young Adult