Clinical Validity of Plasma-Based Genotyping for Microsatellite Instability Assessment in Advanced GI Cancers: SCRUM-Japan GOZILA Substudy

Yoshiaki Nakamura, Wataru Okamoto, Tadamichi Denda, Tomohiro Nishina, Yoshito Komatsu, Satoshi Yuki, Hisateru Yasui, Taito Esaki, Yu Sunakawa, Makoto Ueno, Eiji Shinozaki, Nobuhisa Matsuhashi, Takashi Ohta, Ken Kato, Koushiro Ohtsubo, Hideaki Bando, Hiroki Hara, Taroh Satoh, Kentaro Yamazaki, Yoshiyuki YamamotoNaohiro Okano, Tetsuji Terazawa, Takeshi Kato, Eiji Oki, Akihito Tsuji, Yosuke Horita, Yasuo Hamamoto, Akihito Kawazoe, Hiromichi Nakajima, Shogo Nomura, Ryuta Mitani, Mihoko Yuasa, Kiwamu Akagi, Takayuki Yoshino

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. Patients and Methods: The performance of plasma-based MSI assessment using Guardant360, a nextgeneration sequencing.based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction.based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. Results: In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2%(95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0%(15/15; 95%CI, 78.2 to 100.0). Three patients withMSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti.programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. Conclusion: ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment.

Original languageEnglish
Article numbere2100383
JournalJCO Precision Oncology
Issue number6
DOIs
Publication statusPublished - 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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