Novel biomarker predicts how non-small cell lung cancer will progress after immunotherapy

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers and is the leading cause of cancer-related mortality in the U.S.

A form of treatment known as immune checkpoint blockade (ICB) improves clinical outcomes in patients diagnosed with NSCLC; however, there is limited data about what genes can predict the progression of the disease after treatment with ICB. Recently, researchers at the University of Chicago Medicine Comprehensive Cancer Center identified a novel biomarker for predicting the progression of NSCLC after ICB therapy.

“A large fraction of patients don’t benefit from immunotherapy and, therefore, it’s very important as doctors we give the right therapy to the right patient at the right time,” said Sean Pitroda, MD, Assistant Professor of Radiation and Cellular Oncology at UChicago Medicine. “Part of that is using biomarkers to identify which patients are most likely to respond to therapy.”

To this end, researchers led by Pitroda identified a tumor suppressor gene, CDKN2A, that’s loss of function was associated with inferior outcomes of ICB treatment in patients with NSCLC. These results present a novel biomarker and potential target for therapy in a large subset of patients with this disease.

A large fraction of patients don’t benefit from immunotherapy and, therefore, it’s very important as doctors we give the right therapy to the right patient at the right time.
In the study, researchers examined a cohort of 139 patients who had ICB therapy for metastatic or advanced NSCLC and whose genes were sequenced before receiving immunotherapy. Researchers found that CDKN2A, a gene known to be recurrently mutated or deleted in NSCLC, was associated with treatment response. Patients with silenced CDKN2A were only half as likely to respond to immunotherapy and were twice as likely to progress with NSCLC.

In fact, patients with silenced CDKN2A had decreased overall survival and progression-free survival even with high PD-L1 expression and tumor mutational burden, features that are known to correlate with improved outcomes with ICB. “In those patients who were predicted to respond to treatment, the CDKN2A loss-of-function biomarker identified a subset of patients that were unlikely to respond,” said Pitroda. In the clinic, this biomarker has the potential to provide stronger predictions for ICB therapy than previously validated biomarkers.

The researchers also found that predictions of clinical outcome based on the loss of function of CDKN2A were specifically associated with ICB. The researchers examined three independent cohorts of patients who were diagnosed with NSCLC but instead treated with surgery and chemotherapy. Statistical analyses revealed that there was only a correlation between the outcome of NSCLC and ICB treatment specifically rather than the overall prognosis of NSCLC.

In addition, a large proportion of lung cancer patients have CDKN2A mutations, increasing the use of this biomarker for predicting lung cancer. In fact, CDKN2A is silenced in 40% of lung adenocarcinomas. “This is a gene commonly altered in lung cancer. It was nice to see that a gene whose alteration is seen in a large fraction of patients could help guide therapy for patients,” said Pitroda.

His team is also taking steps to keep driving this research area forward. In addition to validating their findings with other datasets, they are considering whether or not tumors are more sensitive to other therapies. “We are also exploring whether there are other drugs in clinical trials that can be used in patients to improve outcomes of those who have CDKN2A loss-of-function,” he said. “We hope that these findings will help clinicians personalize treatment for patients who have lung cancer who need immunotherapy.”