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

Abstract

<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>

Microtube Array Membrane Hollow Fiber Assay (MTAM-HFA)—An Accurate and Rapid Potential Companion Diagnostic and Pharmacological Interrogation Solution for Cancer Immunotherapy (PD-1/PD-L1)

“…Additionally, other methods such as the tumor mutation burden (TMB)-which works on the basis of the potential for mutations in tumors to generate immune triggering neoantigens-have also been utilized to predict the response of cancer patients towards ICBs [18,19]. In these studies, it was demonstrated that the TMB method accurately predicted the response rate of cancer patients in cancer types with high tumor mutation burden (TMB-H), such as lung cancer, bladder cancer and melanoma with an objective response rate (ORR) of 39.8% (95% confidence interval; CI: 34.9-44.8) [18].…”