Validity and utility of blood tumor mutational burden (bTMB) is dependent on circulating tumor DNA (ctDNA) shed: SCRUM-Japan MONSTAR-SCREEN
Saori Mishima, Yoshiaki Nakamura, Hanna Tukachinsky, Hiroya Taniguchi, Shigenori Kadowaki, Ken Kato, Eiji Oki, Taroh Satoh, Daisuke Aoki, Kentaro Yamazaki, Taito Esaki, Makoto Ueno, Tomohiro Nishina, Yu Sunakawa, Tadamichi Denda, Hideaki Bando, Naomi Kuramoto, Satoshi Horasawa, Hikaru Abutani, Jessica Lee, Russell W. Madison, Geoffrey R. Oxnard, Takayuki Yoshino
Abstract
Background: The tumor mutational burden (TMB) is a genomic biomarker associated with the benefits from immune checkpoint inhibitors (ICIs) cancer therapy. An elevated blood TMB (bTMB) in circulating tumor DNA (ctDNA) represents a compelling non-invasive diagnostic approach; however, the validity and utility of this emerging biomarker across cancer types have not been examined. Patient and methods: The blood and tissue TMB was measured in a large pan-tumor clinical cohort and the MONSTAR-SCREEN observational study (UMIN000036749) using the FoundationOne Liquid CDx and FoundationOne CDx assays. A subset of the MONSTAR-SCREEN cohort was used to evaluate the association between the bTMB and the efficacy of ICIs therapy. Results: The majority of cancer types showed similar prevalence of TMB≥10 mutations/megabase and bTMB≥10. There was high concordance between bTMB and TMB in blood and tissue biopsy from the same patient when the plasma tumor fraction (TF) was at least 1% (Spearman's coefficient 0.74 and > 80% sensitivity to detect TMB-high). High microsatellite instability (MSI-H) was detected by ctDNA with 79% sensitivity when TF was at least 1%, but only 6% sensitivity when TF was <1%. Among patients with bTMB≥14 and elevated TF≥10% treated with ICIs, there was a trend toward a longer progression-free survival and overall survival compared with patients with bTMB<14 and elevated TF≥10% (HR, 0.62 [95%CI, 0.39-0.98]; p = 0.04 and HR, 0.60 [95%CI, 0.34-1.1]; p = 0.05). Conclusions: Our findings suggest that an elevated bTMB is correlated with elevated TMB and represents a pragmatic biomarker for assessing ICIs benefits. The utility of this biomarker is likely to be associated with high TF levels, informing future prospective investigations.