Purpose: 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.Experimental Design: 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 cellfree DNA (cfDNA).Results: 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 ¼ 163) and sensitivities of 78% (n ¼ 23) and 67% (n ¼ 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 ¼ 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.Conclusions: 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
Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. While labs have standardized validation procedures to develop single locus tests, the efficacy of on-site plasma-based next-generation sequencing (NGS) assays still need to be proven. In this retrospective study, we profiled DNA from matched tissue and plasma samples from 75 cancer patients. We applied the NGS test PGDx elio™ plasma resolve-RUO (EPR), which detects clinically relevant alterations in 33 genes and microsatellite instability (MSI), to analyze plasma cell-free DNA (cfDNA). The concordance between alterations detected in both tissue and plasma samples was higher in patients with metastatic disease. EPR detected 77% of sequence alterations, amplifications, and fusions that were found in metastatic samples compared to 45% of those alterations found in the primary tumor samples (P = 0.00005). There was
<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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).</p>Results:<p>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% (<i>n</i> = 163) and sensitivities of 78% (<i>n</i> = 23) and 67% (<i>n</i> = 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, <i>P</i> = 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.</p>Conclusions:<p>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.</p><p><i>See related commentary by Wang and Ajani, p. 6887</i></p></div>
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