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

Abstract

Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.

Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma

“…Our findings did not support a link with BAP1 loss and the immune ‘hot’ phenotype in MPM. Compared to peritoneal mesothelioma, MPM harbour more frequent loss of CDKN2A , and loss of CDKN2A has been linked to resistance to immunotherapy in non-small cell lung cancer [ 77 ]. Therefore, the CDKN2A loss may contribute to the lack of association with the immune ‘hot’ phenotype in MPM.…”

Morphological and Molecular Characterization of KRAS G12C-Mutated Lung Adenocarcinomas

“…For example, CDKN2A mutations which were identified in 6.9% of samples were recently associated with increased resistance to immune checkpoint inhibitors. A study by Gutiontov et al showed that NSCLC harboring a CDKN2A loss-of-function mutation had a twofold increase in immunotherapy resistance, irrespective of PD-L1 expression, and a poorer clinical outcome [ 23 ]. In addition, DDR2 gene mutations were associated with 4.5% of our cases; DDR2-mutated LUADs showed sensitivity to dasatinib, supporting a possible role for combined chemotherapy in these patients [ 24 ].…”

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

“…Among challenges faced by the future of cancer immunotherapy, is understanding cancer-intrinsic factors regulating TME leading to immune evasion (Wellenstein and de Visser, 2018;Hegde and Chen, 2020). Recent studies found that genomic CDKN2A loss-of-function is associated with worse clinical outcome in patients treated with cancer immunotherapy in multiple cancer types (Adib et al, 2021;Gutiontov et al, 2021;Zhu et al, 2021). The reduced benefit of cancer immunotherapy can be attributed to altered tumorimmune microenvironment and compromised immune cell functions.…”