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Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor-Based Immunotherapy

Yulian Khagi1, Aaron M Goodman2,3, Gregory A Daniels4

  • 1Department of Medicine, Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, La Jolla, California. ykhagi@ucsd.edu.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 4, 2017
PubMed

Insights

Hypermutated circulating tumor DNA (ctDNA) in blood shows promise as a biomarker for predicting response to checkpoint inhibitor immunotherapy, correlating with improved progression-free and overall survival outcomes.

Area of Science:

  • Oncology
  • Genomics
  • Immunotherapy

Background:

  • Tissue-based tumor mutational burden (TMB) predicts response to checkpoint inhibitors.
  • Tissue biopsies for TMB are costly and invasive.
  • Liquid biopsies offer a less invasive alternative for biomarker assessment.

Purpose of the Study:

  • To investigate the association between hypermutated blood-derived circulating tumor DNA (ctDNA) and response to checkpoint inhibitor immunotherapy.
  • To explore ctDNA as a predictive biomarker for immunotherapy outcomes.

Main Methods:

  • Assessed 69 patients with diverse malignancies receiving checkpoint inhibitor immunotherapy.
  • Performed blood-derived ctDNA next-generation sequencing (NGS) (54-70 genes).
  • Evaluated outcomes including stable disease (SD), partial/complete response (PR/CR), progression-free survival (PFS), and overall survival (OS) based on alteration numbers (total and VUS).

Main Results:

  • High number of variants of unknown significance (VUS) (>3 alterations) in ctDNA significantly correlated with improved PFS (45% vs. 15% SD≥6m/PR/CR, P=0.014).
  • High total alteration number (≥6 vs. <6) also showed similar associations with improved outcomes.
  • Statistically significant improvement in OS was associated with high VUS alteration status.
  • Responders with VUS >3 had a median PFS of 23 months versus 2.3 months for non-responders (P=0.0004).

Conclusions:

  • The number of alterations detected in ctDNA via liquid biopsy is associated with immunotherapy outcomes.
  • Hypermutated ctDNA shows potential as a predictive biomarker for checkpoint inhibitor response.
  • Further investigation into hypermutated ctDNA is warranted for clinical application.

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