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CDKN2A Alterations and Response to Immunotherapy in Solid Tumors

Elio Adib1,2, Amin H Nassar1,2, Elie W Akl2

  • 1Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|June 2, 2021
PubMed
Abstract

Insights

Loss-of-function CDKN2A alterations predict poor response to immune checkpoint inhibitors (ICI) in urothelial carcinoma. These genomic alterations also impact the tumor microenvironment, suggesting reduced benefit from ICI therapy.

Area of Science:

  • Oncology
  • Genomics
  • Immunotherapy

Background:

  • Immune checkpoint inhibitors (ICI) offer clinical benefits in metastatic cancers, but predictive biomarkers are limited.
  • Genomic alterations in CDKN2A are common in cancers, yet their association with ICI response remains unclear.
  • Prior studies show conflicting evidence regarding CDKN2A alterations and ICI treatment outcomes.

Purpose of the Study:

  • To investigate the impact of loss-of-function CDKN2A alterations on patient response and survival following ICI therapy.
  • To examine the association between CDKN2A genomic alterations and ICI treatment efficacy across various cancer types.

Main Methods:

  • Analysis of two independent patient cohorts (DFCI and MSKCC) totaling 2,039 patients treated with ICIs.
  • Tumor sequencing using Oncopanel or MSK-IMPACT for genomic alterations.
  • RNA sequencing data utilized to assess the tumor microenvironment and immuno-inflammatory pathways.

Main Results:

  • Loss-of-function CDKN2A alterations correlated with poor response and survival in urothelial carcinoma patients receiving ICIs.
  • No significant association was found between CDKN2A status and ICI outcomes in esophagogastric, head and neck, non-small cell lung, renal cell, or melanoma.
  • Tumors with CDKN2A alterations exhibited significantly reduced expression of immuno-inflammatory pathways.

Conclusions:

  • CDKN2A genomic alterations are associated with diminished benefit from ICI therapy specifically in urothelial carcinoma.
  • CDKN2A alterations influence the tumor-immune microenvironment, potentially explaining reduced ICI efficacy.
  • CDKN2A status may serve as a predictive biomarker for ICI response in specific cancer types.

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