Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy
Menée à partir du séquençage ciblé du génome d'échantillons tumoraux issus de 20 107 patients atteints d'un cancer de stade avancé, cette étude met en évidence une association entre l'inactivation somatique d'ATM et une meilleure efficacité de la radiothérapie
Background : Radiation therapy is one of the most commonly used cancer therapeutics, but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure.
Methods : We analyzed 20,107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1,085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy. Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared to those harboring variants of unknown significance (VUS). All statistical tests were two-sided.
Results : Among 357 pan-cancer patients who received 727 courses of radiotherapy, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs VUS allele, respectively (HR: 0.51, 95% CI = 0.34-0.77, p= .001). The greatest clinical benefit was seen in tumors harboring bi-allelic ATM inactivation (HR = 0.19, 95% CI = 0.06-0.60, p=.005), with statistically significant benefit also observed in tumors with mono-allelic ATM inactivation (HR = 0.57, 95% CI = 0.35-0.92, p=.02). Notably, ATM LoF was highly predictive of outcome in TP53 wild type tumors, but not among TP53-mutant tumors.
Conclusion : We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following radiotherapy. The identification of a radiosensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically-guided radiotherapy.
Journal of the National Cancer Institute , résumé, 2019