Advertisement

Liquid Biopsy to Determine Patient Response to Immune Checkpoint Blockade


Advertisement
Get Permission

Although studies have demonstrated that microsatellite instability (MSI) and high tumor mutational burden (TMB) are promising pan-tumor biomarkers for identifying patients for treatment with immune checkpoint blockade, obtaining tissue from unresectable or metastatic solid tumors for genetic sequencing is often challenging. A study investigating the viability of using a liquid biopsy method to identify tumors in patients with MSI and high TMB found that the test was effective in determining those likely to respond to treatment with immune checkpoint inhibitors. The study by Georgiadis et al is published in Clinical Cancer Research.

“Our data also demonstrates that liquid biopsy analysis of MSI and TMB may be more predictive of immunotherapy response than archival tissue, given that it is both a real-time and global measurement and resolves the inherent sampling bias of tissue biopsy."
— Andrew Georgiadis, MS

Tweet this quote

Study Methodology

The researchers developed a liquid biopsy approach that utilized a hybrid capture–based 98-kb pan-cancer 58-gene panel, including targeted microsatellite regions. A multifactorial error correction method and a novel peak-finding algorithm were established to identify rare microsatellite instability frameshift alleles in cell-free DNA (cfDNA).

The study was based on formalin-fixed, paraffin-embedded tumor and matched normal buffy coat specimens from 61 patients with advanced cancer and plasma samples from 163 individuals without cancer.

In this study, the researchers flagged certain sequence data for error correction, then subjected the data to a peak-finding algorithm that identified instability in the loci. If 20% or more of the loci were determined to have MSI, the samples were classified as MSI-high. For TMB-high, next-generation sequencing data were processed and variants were identified using VariantDX software. The researchers set five mutations in the targeted plasma panel as the threshold for identifying tumors as having exceptionally high mutational burden.

Results

Through their 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 programmed cell death protein 1 (PD-1) blockade, researchers 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, they analyzed cfDNA from longitudinally collected plasma samples obtained during therapy to identify patients who had achieved durable response to PD-1 blockade.

KEY POINTS

  • Liquid biopsy test accurately identified MSI and TMB in patients with metastatic cancer and was effective in determining patients likely to respond to immune checkpoint inhibitors.
  • Detection of circulating tumor DNA derived from plasma provides a viable alternative to tissue biopsy due to its ability to capture tumor heterogeneity, and may be more predictive of immunotherapy response than archival tissue.

“These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients with exhibit MSI or TMB-high and have a high likelihood of responding to immune checkpoint blockade,” concluded the researchers.

Clinical Relevance

According to the lead author of this study, Andrew Georgiadis, MS, liquid biopsies may prove more predictive of response to checkpoint inhibitors than tumor tissue biopsies in patients with MSI and high TMB.

“Our data also demonstrates that liquid biopsy analysis of MSI and TMB may be more predictive of immunotherapy response than archival tissue, given that it is both a real-time and global measurement and resolves the inherent sampling bias of tissue biopsy,” said Mr. Georgiadis in a statement.

Mark Sausen, PhD, of Personal Genome Diagnostics, is corresponding author of this study.

Disclosure: For full disclosures of the study authors, visit clinccancerres.aacrjournals.org.


Advertisement

Advertisement



Advertisement