Abstract
Tumors bearing homologous recombination deficiency 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 effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles 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 significantly 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 confirmed 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 reflecting 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.
Highlights
IntroductionSignificant advances in the implementation of biomarkers in the clinical practice have been achieved in metastatic colorectal cancer (mCRC), even if only few of them (such as RAS and BRAF mutational status or microsatellite instability [MSI]) are endowed with clinical relevance
Significant advances in the implementation of biomarkers in the clinical practice have been achieved in metastatic colorectal cancer, even if only few of them are endowed with clinical relevance
The exposure to specific agents approved for metastatic colorectal cancer (mCRC) and the number of treatment lines received are summarized in Supplementary Table S1
Summary
Significant advances in the implementation of biomarkers in the clinical practice have been achieved in metastatic colorectal cancer (mCRC), even if only few of them (such as RAS and BRAF mutational status or microsatellite instability [MSI]) are endowed with clinical relevance. Because of the consistent prevalence of ATM mutations in CRC (7% in non-hypermutated cases)[14] and their potential crucial role as biomarker of chemosensitivity to platinum salts and topoisomerase inhibitors, ATM mutations would characterize mCRC patients with a more favourable outcome, at least when eligible for combination chemotherapy. Moving from this background, we performed a translational study aimed at assessing the prognostic relevance of ATM mutational status in mCRC patients
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