TP53/ATM co-mutation associated with NSCLC checkpoint blockade response
medwireNews: In immune checkpoint inhibitor (ICI)-treated patients with non-small-cell lung cancer (NSCLC), co-mutation in TP53 and ATM is associated with a higher tumor mutational burden (TMB) and better overall survival (OS) versus one or no mutations, according to a multi-cohort study.
“This study’s findings suggest that the TP53 and ATM comutation occurs in a subgroup of patients with NSCLC and is associated with an increased [TMB] and response to ICIs,” report Zeng-Qing Guo (Fujian Medical University Cancer Hospital, Fuzhou, China) and colleagues in JAMA Network Open.
“This suggests that TP53 and ATM comutation may have implications as a biomarker for guiding ICI treatment,” they write.
The researchers analyzed data on 2020 patients with NSCLC from the Geneplus Institute, 1031 from the Cancer Genome Atlas (TCGA), and 1527 from the Memorial Sloan Kettering Cancer Center (MSKCC) databases, and on 853 participants of the POPLAR and OAK randomized controlled trials of the PD-L1 inhibitor atezolizumab. The study also included data from 1662 patients who received ICI treatment for any cancer at MSKCC, 350 of whom had a diagnosis of NSCLC.
The TP53 and ATM co-mutation was found in 3.6% of patients with NSCLC in the TCGA database and 2.6% in the Geneplus database.
The co-mutation was associated with a significantly higher TMB compared with TP53 mutation alone, ATM mutation alone, or no mutation, with TMBs of 414.0, 251.5, 205.0, and 122.0, respectively, in the TCGA cohort, with similar results in the other cohorts. And although recent studies have shown that driver oncogenes, such as EGFR mutations, are associated with a low TMB, patients with EGFR mutations accompanied by the TP53 and ATM co-mutation still had a high TMB, say the researchers.
Analysis of the ICI-treated MSKCC cohort showed that presence of the co-mutation signaled improved survival response to ICI treatment. Specifically, in the 41 patients with any cancer, the co-mutation was associated with significantly better OS than either mutation alone or no mutation, with the median unreached for those with the co-mutation, and 14.0 months for those with TP53 mutation alone, 40.0 months for those with ATM mutation alone, and 22.0 months for those with no mutation.
And although the findings were similar for the eight NSCLC patients who received ICIs, with corresponding median OS values of not reached, 11.0, 16.0, and 14.0 months, the difference in this case was not statistically significant.
By contrast, in the POPLAR and OAK cohorts, where 429 patients received atezolizumab and 17 had the TP53 and ATM co-mutation, the disease control rate, progression-free survival, and OS were all significantly improved among patients harboring the co-mutation versus the other groups.
The researchers conclude: “This finding may have important implications for clinical practice, and we recommend TP53 and ATM screening for patients with NSCLC.
“Even in patients with EGFR and other driver genes mutations, TP53 and ATM comutation may be associated with an additional clinical benefit for ICI therapy.”
By Catherine Booth
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