Prognostic impact of ATM mutations in patients with metastatic colorectal cancer

Tumors bearing homologous recombination defciency are extremely sensitive to DNA double strand
breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA
damage response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive
and prognostic biomarker has not been fully investigated. We carried out a multicenter efort aimed
at defning the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients.
Mutational profles were obtained by means of next-generation sequencing. Overall, 35 out of 227
samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM
mutated tumors showed a signifcantly longer median overall survival (OS) versus ATM wild-type ones
(64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29–0.85; P=0.01). In the multivariable model, ATM mutations
confrmed the association with longer OS (HR, 0.57; 95% CI, 0.33–0.98; P=0.04). The prognostic impact
of ATM mutations was independent from TP53 mutational status and primary tumor location. High
heterogeneity score for ATM mutations, possibly refecting the loss of wild-type allele, was associated
with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated
with longer OS in patients with mCRC.