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Early Changes in Tumor-Naive Cell-Free Methylomes and Fragmentomes Predict Outcomes in Pembrolizumab-Treated Solid Tumors

  • 0Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Cancer Discovery +

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February 23, 2024

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February 23, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Early changes in cell-free methylated DNA (cfMeDIP-seq) can predict patient outcomes with pembrolizumab treatment. This tumor-naive approach analyzes methylation and fragment length, offering a new way to monitor cancer patients.

Area Of Science

  • Oncology
  • Genomics
  • Biomarkers

Background

  • Circulating tumor DNA (ctDNA) kinetics predict response to pembrolizumab but often require tumor tissue sequencing.
  • Existing ctDNA methods typically rely on tumor-informed or fixed gene panels.

Purpose Of The Study

  • To develop and validate a tumor-naive, mutation-agnostic ctDNA assay using methylomics and fragmentomics.
  • To assess the predictive value of this novel ctDNA approach for pembrolizumab treatment outcomes.

Main Methods

  • Genome-wide methylation and fragment-length profiling using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) on plasma samples from 87 patients with advanced solid tumors.
  • Training a pan-cancer methylation signature to quantify cancer-specific methylation (CSM) and fragment-length score (FLS).
  • Analyzing early kinetics of CSM and FLS in relation to treatment response, overall survival (OS), and progression-free survival (PFS).

Main Results

  • CSM and FLS strongly correlated with tumor-informed ctDNA levels.
  • Early kinetics of CSM independently predicted OS and PFS across tumor types, irrespective of PD-L1 status or tumor mutation burden.
  • Early kinetics of FLS were associated with OS independently of CSM.

Conclusions

  • A tumor-naive ctDNA approach integrating methylomics and fragmentomics can predict outcomes in patients treated with pembrolizumab.
  • Early changes in CSM and FLS are robust biomarkers for treatment response and survival.
  • This method offers a promising alternative for ctDNA analysis without the need for matched tumor tissue.