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CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer

Stanley I Gutiontov1, William Tyler Turchan1, Liam F Spurr2

  • 1Department of Radiation and Cellular Oncology, The University of Chicago, 5758 S Maryland Ave, MC 9006, Chicago, IL, 60637, USA.

Scientific Reports
|October 9, 2021
PubMed

Insights

Loss of CDKN2A function predicts poor outcomes in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint blockade (ICB). This finding holds even in tumors with high PD-L1 and high tumor mutational burden (TMB), suggesting CDKN2A as a therapeutic target.

Area of Science:

  • Oncology
  • Immunotherapy
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) offers improved outcomes for non-small cell lung cancer (NSCLC) patients, but resistance remains a challenge.
  • Identifying molecular predictors of ICB resistance is crucial for optimizing treatment strategies.
  • The role of CDKN2A loss-of-function (LOF) in ICB resistance is controversial and requires further investigation.

Purpose of the Study:

  • To investigate the association between CDKN2A loss-of-function (LOF) and clinical outcomes in advanced NSCLC patients treated with ICB.
  • To explore CDKN2A LOF as a potential molecular predictor of response and progression in NSCLC patients undergoing ICB therapy.

Main Methods:

  • Analysis of 139 advanced NSCLC patients who underwent next-generation sequencing (NGS) before ICB initiation.
  • Assessment of CDKN2A loss-of-function (LOF) status and its correlation with progression-free survival (PFS) and overall survival (OS).
  • Stratification analysis in subgroups with high tumor mutational burden (TMB) and high PD-L1 expression.

Main Results:

  • CDKN2A LOF was identified in 26% of patients and was significantly associated with inferior PFS (MVA-HR 1.66) and OS (MVA-HR 2.08) compared to wild-type (WT) tumors.
  • These negative impacts on survival were observed even in patients with high TMB and high PD-L1 expression (≥50%).
  • Tumors with CDKN2A LOF were twice as likely to experience disease progression after ICB (46% vs. 21%).

Conclusions:

  • CDKN2A loss-of-function is a significant negative predictor of clinical outcomes in advanced NSCLC patients treated with ICB.
  • This association persists across different molecular subgroups, including those with high PD-L1 and high TMB.
  • CDKN2A LOF represents a potential therapeutic target and warrants prospective validation in larger cohorts.

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