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

• Published in: Scientific reports Vol. 11; no. 1; p. 20059
• Main Authors: Gutiontov, Stanley I., Turchan, William Tyler, Spurr, Liam F., Rouhani, Sherin J., Chervin, Carolina Soto, Steinhardt, George, Lager, Angela M., Wanjari, Pankhuri, Malik, Renuka, Connell, Philip P., Chmura, Steven J., Juloori, Aditya, Hoffman, Philip C., Ferguson, Mark K., Donington, Jessica S., Patel, Jyoti D., Vokes, Everett E., Weichselbaum, Ralph R., Bestvina, Christine M., Segal, Jeremy P., Pitroda, Sean P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-10-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/251; 631/67/1612/1350; 631/67/69; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - genetics; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Clinical outcomes; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Drug Resistance, Neoplasm - genetics; Female; Follow-Up Studies; Humanities and Social Sciences; Humans; Immune checkpoint; Immunotherapy; Immunotherapy - methods; Loss of Function Mutation; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Middle Aged; multidisciplinary; Non-small cell lung carcinoma; Patients; PD-L1 protein; Prognosis; Retrospective Studies; Science; Science (multidisciplinary); Small cell lung carcinoma; Survival Rate; Therapeutic targets; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-99524-1

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.