Applications of Circulating Tumor DNA in a Cohort of Phase I Solid Tumor Patients Treated with Immunotherapy
Menée à l'aide d'échantillons sanguins et d'échantillons tumoraux prélevés sur 38 patients inclus dans des essais cliniques évaluant une immunothérapie, cette étude analyse la corrélation entre la charge mutationnelle déterminée à partir de l'ADN tumoral circulant et celle déterminée à partir des tissus tumoraux, puis évalue l'association entre l'évolution des mutations au niveau de l'ADN tumoral circulant et la réponse thérapeutique
Background : The correlation between blood-based tumor mutation burden (bTMB) and tissue-based TMB (tTMB) has not been broadly tested in a multi-cancer 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. Pre-treatment 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 a PD-1/PD-L1 inhibitor. Thirty patients (78.9%) had detectable mutations in ctDNA, of which the median (range) bTMB was 5 (1–53) 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 (VAF) of mutations detected in ctDNA at a second time-point 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.
JNCI Cancer Spectrum , article en libre accès, 2020