American Association for Cancer Research
10780432ccr191372-sup-221345_3_supp_5694436_pvt9ps.pptx (96.83 kB)

Supplementary Figure 2 from Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade

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posted on 2023-03-31, 21:01 authored by Andrew Georgiadis, Jennifer N. Durham, Laurel A. Keefer, Bjarne R. Bartlett, Magdalena Zielonka, Derek Murphy, James R. White, Steve Lu, Ellen L. Verner, Finey Ruan, David Riley, Robert A. Anders, Erika Gedvilaite, Sam Angiuoli, Siân Jones, Victor E. Velculescu, Dung T. Le, Luis A. Diaz, Mark Sausen

Plasma-Based Detection of Microsatellite Instability and High Tumor Mutation Burden in Patients with Sufficient Circulating Tumor DNA.






Microsatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers used to select patients for treatment with immune checkpoint blockade; however, real-time sequencing of unresectable or metastatic solid tumors is often challenging. We report a noninvasive approach for detection of MSI and TMB-High in the circulation of patients. We developed an approach that utilized a hybrid-capture–based 98-kb pan-cancer gene panel, including targeted microsatellite regions. A multifactorial error correction method and a novel peak-finding algorithm were established to identify rare MSI frameshift alleles in cell-free DNA (cfDNA). Through analysis of cfDNA derived from a combination of healthy donors and patients with metastatic cancer, the error correction and peak-finding approaches produced a specificity of >99% (n = 163) and sensitivities of 78% (n = 23) and 67% (n = 15), respectively, for MSI and TMB-High. For patients treated with PD-1 blockade, we demonstrated that MSI and TMB-High in pretreatment plasma predicted progression-free survival (hazard ratios: 0.21 and 0.23, P = 0.001 and 0.003, respectively). In addition, we analyzed cfDNA from longitudinally collected plasma samples obtained during therapy to identify patients who achieved durable response to PD-1 blockade. These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients who exhibit MSI or TMB-High and have a high likelihood of responding to immune checkpoint blockade.See related commentary by Wang and Ajani, p. 6887

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