Currently Viewing:
Newsroom

New Liquid Biopsy Test Found to Identify Patients Who May Respond to Immune Checkpoint Blockade

Matthew Gavidia
A new liquid biopsy test could detect microsatellite instability and tumor mutational burden, which can distinguish which patients are likely to respond to immune checkpoint inhibitors.
A liquid biopsy test, developed by Personal Genome Diagnostics, was shown to possibly detect microsatellite instability (MSI) and tumor mutational burden (TMB), which may assist in determining which patients are likely to respond to immune checkpoint inhibitors, according to a study published today in the journal Clinical Cancer Research.

Back in May 2017, the FDA approved immune checkpoint inhibitor pembrolizumab, sold as Keytruda, for patients with unresectable or metastatic tumors that tested high for MSI (MSI-H) or mismatch repair deficiency (dMMR). While this approval addressed the treatment of MSI-H or dMMR in these patients, detecting these conditions can be troublesome.

Current MSI detection processes include tissue biopsies and technologies such as polymerase chain reaction-based amplification or next-generation sequencing. These approaches have been found to be complicated and contain sensitivity limitations, which can exclude patients whose tumor samples may lack enough tissue for accurate testing.

Co-study authors Andrew Georgiadis, MS, scientist at Personal Genome Diagnostics, and Dung Le, MD, associate professor of oncology at the Sidney Kimmel Cancer Center at Johns Hopkins, sought to evaluate the sensitivity and specificity of a liquid biopsy test that would assist in creating an alternative for MSI detection and cater to patients affected by these complications. “A liquid biopsy test assessing MSI could reach a larger subset of patients, such as those where tissue is limited or where there are safety concerns around additional surgical intervention,” said Georgiadis.

The study analyzed 61 patients with metastatic cancer and 163 plasma samples from healthy subjects. Researchers developed a 98 kb pan-cancer 58-gene panel, then employed a multifactorial error-correction method and a novel peak-finding algorithm to identify MSI frameshift alleles in the study group’s cell-free DNA. As the authors explained, MSI can be detected by measuring the length of altered microsatellite sequences in tumor DNA as compared with normal DNA:
  • Researchers flagged certain sequence data for error correction, then subjected data to the peak-finding algorithm that identified instability in the loci
  • If 20% or more of loci contained MSI, samples were classified as MSI-H
The liquid biopsy test produced a specificity of greater than 99% and a sensitivity of 78%, which speaks to its prowess for identifying MSI levels in patients.

Researchers then tested for TMB, in which next-generation sequencing data were processed, and variants were identified using the VariantDx software. The threshold for identifying a high mutational burden in the analyzed tumors was set at 5 mutations in the targeted plasma panel. The liquid biopsy test produced similar results toward TMB to that of MSI as a specificity of greater than 99% was achieved, while its sensitivity was lower at 67%. The VariantDx test identified MSI-H in 18 of the 23 MSI-H patients (78.3%), and correctly detected the 6 microsatellite stable cases.

Researchers also found that for patients treated with PD-1 blockade, a type of immune checkpoint blockade, MSI and high levels of TMB in pretreatment plasma predicted progression-free survival (hazard ratios: 0.21 and 0.23, P = .001 and .003).

Co-author Le stressed the potential of the liquid biopsy test to enhance MSI-H detection in more at-risk patients who can benefit from the immune checkpoint blockade treatment. “If tests become more accessible, less expensive, and require fewer resources such as tissue acquisition and pathology resources, more patients could be tested,” said Le.

Limitations to the study involved the small population of cancer patients analyzed. Researchers noted that further research on a broader range of tumor types is warranted to confirm the results of the study.

Reference

Georgiadis A, Durham JN, Keefer LA, et al. Noninvasive Detection of Microsatellite Instability and High Tumor Mutation Burden in Cancer Patients Treated with PD-1 Blockade. [published online September 10, 2019]. Clinical Cancer Research. doi: 10.1158/1078-0432.CCR-19-1372.

 
Copyright AJMC 2006-2019 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up