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

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 next-generation 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 with MSI-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.

Expert panel consensus recommendations on the use of circulating tumor DNA assays for patients with advanced solid tumors

“…One expert proposed R because tissue‐based MSI testing remains the gold standard. However, a case report has suggested the usefulness of ctDNA MSI testing 33 . The patient had cancer of unknown primary origin and urgently needed effective treatment because the tumor was highly aggressive.…”

“…Plasma ctDNA may also more accurately assess the current genomic profile of an advanced solid tumor compared with the use of archival tissue specimens, such as when recurrence occurs many years after the resection of an early‐stage tumor. Previous studies have reported patients who showed a tumor response to targeted therapy based on an alteration detected by ctDNA CGP that could not be identified by tissue tests 33,58 . One expert proposed ECO because of little evidence for the efficacy of targeted therapy based on an actionable alteration detected only in ctDNA.…”

“… 32 One study compared the performance of a plasma‐based MSI assessment (Guardant360, a next‐generation sequencing‐based ctDNA assay) to that of a tissue‐based MSI assessment (a validated polymerase chain reaction‐based method) in patients with advanced GI cancer. 33 In 658 patients with advanced GI cancer who underwent MSI testing with both plasma and tissue, the overall percentage agreement, positive percentage agreement (PPA), and negative percentage 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 tumor fraction ≥1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0).…”

Clinical applications of circulating tumor-derived DNA in the management of gastrointestinal cancers – current evidence and future directions

“…Several studies have investigated the feasibility of ctDNA in assessing MSI, TMB status in GI cancers. Nakamura et al compared ctDNA NGS (Guardant 360) and tissue based MSI assessments in a cohort of 658 patients with advanced GI cancer in the SCRUM-Japan GOZILA study - an observational ctDNA-based study which screens patients with GI cancers for enrollment into clinical trials within a nation-wide trial network ( 111 ). The concordance between tumor and ctDNA for detection of MSI is high with an overall percent agreement of 98.2% (95% CI = 96.8 - 99.1).…”

“…The concordance between tumor and ctDNA for detection of MSI is high with an overall percent agreement of 98.2% (95% CI = 96.8 - 99.1). In particular, ctDNA was able to identify patients with MSI-high tumors who might benefit from anti-PD1 therapy ( 111 ). Using the Guardant360 assay, Maron et al reported a 100% concordance between tumor-derived MMR status (IHC) and plasma-derived MSI-status using ctDNA-NGS in 6 patients ( 64 ).…”