TP53, ATM comutation might help guide lung-cancer immunotherapy

By Reuters Staff

NEW YORK (Reuters Health) - 1/10/2019

In patients with non-small-cell lung cancer (NSCLC), the presence of tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) comutation might indicate better response to immune-checkpoint inhibitors (ICIs), according to Chinese researchers.

Only 20% to 25% of patients with NSCLC respond to treatment with checkpoint inhibitors, and biomarkers are needed to help identify those responders, Dr. Zeng-Qing Guo of Fujian Medical University and colleagues suggest in JAMA Network Open, online a September 20.

They note that as important genes in the DNA-damage-response pathway, comutation in TP53 and ATM genes may be associated with genomic instability and hypermutation.

The researchers analyzed data on more than 5,700 patients with NSCLC from five independent cohorts, including one from Memorial Sloan Kettering Cancer Center (MSKCC) in New York City.

Sites of TP53 and ATM comutation, the researchers say, were found scattered throughout the genes with no significant difference in their frequency within the histologic subtypes and driver genes. TP53 and ATM comutation was found in 3.6% of patients with NSCLC in one database and 2.6% in another.

TP53 and ATM comutation was associated with a significantly higher tumor mutation burden compared with the sole mutation and with no mutation.

Overall survival (OS) was defined from the date of first infusion of any ICI. Among patients treated with ICIs in the MSKCC cohort, TP53 and ATM comutation was associated with significantly better OS than a single mutation and no mutation among patients with any cancer.

For those in this cohort with NSCLC and TP53 and ATM comutation, median OS was not reached. With TP53 mutation alone the corresponding figure was 11.0 months. With ATM mutation alone it was 16.0 months and with no mutation it was 14.0 months (P=0.24).

There were similar findings in other cohorts, with disease-control benefit rate, progression-free survival, and OS all being significantly greater in patients with the TP53 and ATM comutation.

"This study's findings," the researchers conclude, "suggest that the TP53 and ATM comutation occurs in a subgroup of patients with NSCLC and is associated with an increased tumor mutation burden and response to ICIs. This suggests that TP53 and ATM comutation may have implications as a biomarker for guiding ICI treatment."

The study did not have commercial funding, and the researchers report no conflicts of interest.

Dr. Guo did not respond to requests for comments.


JAMA Netw Open 2019.

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