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Role of Genomic Instability in Immunotherapy with Checkpoint Inhibitors

George Yaghmour1, Manjari Pandey2, Catherine Ireland3

  • 1Department of Hematology/Oncology, The West Cancer Center, The University of Tennessee Health Science Center, Memphis, TN, U.S.A. gyaghmour@westclinic.com.

Anticancer Research
|July 29, 2016
PubMed
Abstract

Insights

Tumor genome sequencing can identify patients likely to benefit from immune checkpoint inhibitors. Higher tumor mutational load predicts improved overall survival in advanced cancer patients receiving immunotherapy.

Area of Science:

  • Oncology
  • Genomics
  • Immunotherapy

Background:

  • Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment.
  • Predictive biomarkers are crucial for optimizing ICI therapy efficacy.
  • Tumor mutational burden (TMB) is an emerging biomarker for ICI response.

Purpose of the Study:

  • To evaluate tumor genome sequencing for detecting alterations as a biomarker for ICI utility.
  • To assess the relationship between mutational load and clinical outcomes in advanced cancer patients treated with ICIs.

Main Methods:

  • Retrospective analysis of 50 advanced cancer patients treated with ICIs.
  • Next-generation sequencing (NGS) data from commercial platforms (Caris, Foundation Medicine, Guardant360).
  • Patients stratified into quintiles based on mutational load (pathogenic mutations + variants of undetermined significance).

Main Results:

  • Patients in the top quintile of mutational load had significantly more genomic alterations (median 16.5 vs 2).
  • Top quintile patients showed superior overall survival (OS) (722 vs 432 days).
  • No significant difference in progression-free survival (PFS); numerically higher objective response rate (50% vs 20%) in the top quintile.

Conclusions:

  • Higher tumor mutational load, identified via genome sequencing, is associated with improved OS in patients receiving ICIs.
  • Tumor genome evaluation may serve as a predictive biomarker for immunotherapy benefit.
  • Standard IHC markers for PD1/PDL1 were not associated with outcomes in this cohort.
Keywords:
ImmunotherapyPD1PDL1genomic instabilitynext generation sequencing

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