Prognosis of immunotherapy for non-small cell lung cancer with CDKN2A loss of function
1Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Background:
Immunotherapy has been widely used to treat non-small cell lung cancer (NSCLC) but is only effective in 20% of patients. Cyclin-dependent kinase inhibitor 2A (CDKN2A) is an important tumor suppressor gene, and its loss of function (LOF) is quite common in NSCLC. Pre-clinical studies suggest CDKN2A LOF promotes immune evasion; however, the results in relation to NSCLC are controversial, and debate continues as to the effect of CDKN2A LOF on immunotherapy.
Methods:
In this study, we collected the data of 49 CDKN2A LOF and 173 CDKN2A wild-type NSCLC consecutive patients treated by any line of immunotherapy. Through immunohistochemical (IHC) and immunofluorescent (IF) staining, we analyzed the CDKN2A predominant transcription protein p16INK4A in the CDKN2A LOF and CDKN2A wild-type NSCLC patients. Using Kaplan-Meier curves, we also examined the relationship between CDKN2A LOF and immunotherapy.
Results:
The IHC and IF staining results showed that most CDKN2A LOF patients were p16INK4A negative, while most CDKN2A wild-type patients were p16INK4A positive. In the LOF group, five patients had partial responses, 35 had stable disease, and nine had progressive disease after the first evaluation of immunotherapy. The LOF group had a median progression-free survival (PFS) time of 4.67 months, while the wild-type group had a median PFS time of 8.63 months [hazard ratio (HR): 0.54; 95% confidence interval (CI): 0.38-0.77; P<0.001]. The LOF group had a median overall survival (OS) time of 9.07 months, while the wild-type group had a median OS time of 21.37 months (HR: 0.42; 95% CI: 0.29-0.61; P<0.001).
Conclusions:
Our study revealed that CDKN2A LOF NSCLC patients treated with immune checkpoint inhibitor (ICI) mono-therapy or combined therapy had a worse prognosis than those with CDKN2A wild-type NSCLC. However, our study also suggested that ICI could work quite effectively in selective CDKN2A LOF patients.
Insights
Loss of function in the Cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is common in non-small cell lung cancer (NSCLC) and is linked to poorer immunotherapy outcomes. However, some CDKN2A-deficient NSCLC patients may still benefit from immune checkpoint inhibitors.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Genomics
Background:
- Immunotherapy is a standard non-small cell lung cancer (NSCLC) treatment, yet efficacy is limited to 20% of patients.
- Cyclin-dependent kinase inhibitor 2A (CDKN2A) loss of function (LOF) is frequent in NSCLC and may influence immune evasion.
- The impact of CDKN2A LOF on NSCLC immunotherapy response remains controversial.
Purpose of the Study:
- To investigate the association between CDKN2A loss of function (LOF) and immunotherapy outcomes in non-small cell lung cancer (NSCLC).
- To analyze the expression of p16INK4A, the main transcription product of CDKN2A, in relation to CDKN2A status and immunotherapy response.
- To evaluate the prognostic value of CDKN2A LOF in NSCLC patients undergoing immunotherapy.
Main Methods:
- Retrospective analysis of 49 non-small cell lung cancer (NSCLC) patients with CDKN2A loss of function (LOF) and 173 with wild-type CDKN2A, all treated with immunotherapy.
- Immunohistochemical (IHC) and immunofluorescent (IF) staining to assess p16INK4A expression.
- Kaplan-Meier survival analysis to compare progression-free survival (PFS) and overall survival (OS) between CDKN2A LOF and wild-type groups.
Main Results:
- CDKN2A LOF NSCLC patients predominantly showed negative p16INK4A staining, while wild-type patients were mostly p16INK4A positive.
- The CDKN2A LOF group exhibited significantly shorter median progression-free survival (4.67 months) and overall survival (9.07 months) compared to the wild-type group (PFS: 8.63 months; OS: 21.37 months).
- A hazard ratio of 0.54 for PFS (95% CI: 0.38-0.77) and 0.42 for OS (95% CI: 0.29-0.61) indicated worse outcomes for the CDKN2A LOF group.
Conclusions:
- CDKN2A loss of function (LOF) in non-small cell lung cancer (NSCLC) is associated with a poorer prognosis in patients treated with immune checkpoint inhibitors (ICIs).
- Despite the overall trend, a subset of CDKN2A LOF NSCLC patients demonstrated positive responses to ICI therapy, suggesting potential for selective benefit.
- Further research is warranted to identify biomarkers predicting response to immunotherapy in CDKN2A-deficient NSCLC.
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