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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.

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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.