Validity and utility of blood tumor mutational burden (bTMB) is dependent on circulating tumor DNA (ctDNA) shed: SCRUM-Japan MONSTAR-SCREEN

Saori Mishima ¹, Yoshiaki Nakamura ^1,2, Hanna Tukachinsky ³

¹Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
²Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan.
³Foundation Medicine, Massachusetts, USA.
⁴Department of Clinical Oncology, Aichi Cancer Center, Aichi, Japan.
⁵Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁶Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁷Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁸Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
⁹Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
¹⁰Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
¹¹Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Kanagawa, Japan.
¹²Department of Gastrointestinal Medical Oncology, Shikoku Cancer Center, Ehime, Japan.
¹³Department of Clinical Oncology, St. Marianna University School of Medicine, Kanagawa, Japan.
¹⁴Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
¹⁵Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.

⁰Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

The Journal of Liquid Biopsy +

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March 3, 2025

View abstract on PubMed

Summary

Elevated blood tumor mutational burden (bTMB) in circulating tumor DNA correlates with tissue tumor mutational burden (TMB), showing potential as a non-invasive biomarker for immune checkpoint inhibitor (ICI) therapy benefits. High plasma tumor fraction is key for bTMB utility.

Area Of Science

Genomics
Oncology
Biomarker Discovery

Background

Tumor mutational burden (TMB) is a key genomic biomarker for predicting response to immune checkpoint inhibitors (ICIs).
Elevated blood TMB (bTMB) detected in circulating tumor DNA (ctDNA) offers a promising non-invasive approach.
The clinical validity and utility of bTMB across diverse cancer types require thorough examination.

Purpose Of The Study

To evaluate the concordance between blood TMB (bTMB) and tissue TMB (tTMB) across multiple cancer types.
To assess the association between bTMB and the efficacy of immune checkpoint inhibitor (ICI) therapy.
To determine the impact of plasma tumor fraction (TF) on the reliability of bTMB detection.

Main Methods

A large pan-tumor clinical cohort and the MONSTAR-SCREEN study were utilized.
FoundationOne Liquid CDx and FoundationOne CDx assays were employed for TMB and bTMB measurements.
A subset of patients received ICIs to evaluate the correlation between bTMB and treatment outcomes.

Main Results

Prevalence of TMB ≥10 mutations/megabase and bTMB ≥10 was similar across most cancer types.
High concordance (Spearman's coefficient 0.74) between bTMB and tTMB was observed when plasma tumor fraction (TF) was ≥1%.
Sensitivity for detecting high microsatellite instability (MSI-H) via ctDNA was 79% at TF ≥1% but only 6% at TF <1%.
Patients with bTMB ≥14 and TF ≥10% showed a trend towards improved progression-free and overall survival with ICI therapy.

Conclusions

Elevated bTMB is a pragmatic biomarker correlated with tTMB, indicating potential benefits from ICIs.
The clinical utility of bTMB as a predictive biomarker is significantly influenced by plasma tumor fraction (TF) levels.
Future prospective studies should focus on high TF levels to optimize the application of bTMB in cancer therapy.

Keywords:

Blood tumor mutational burden Circulating tumor DNA Immunotherapy Liquid biopsy Precision oncology Tumor mutational burden