Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy

Abstract

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 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided.

Results: Among 357 pan-cancer patients who received 727 courses of RT, 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 variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors.

Conclusions: We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT.

Figure 1.

Genetic inactivation of ATM  is common and is associated with clinical benefit from radiation therapy across cancer histologies. A) Distribution of loss-of-function (LoF) ATM mutation frequency by cancer type. Black bars represent the number of cases of each cancer type in the overall cohort, red bars represent ATM mutational frequency within each cancer type. B) Cumulative incidence of irradiated tumor progression by ATM genotype for all histologies. ATM LoF associated with decreased incidence of tumor progression (P = .001; Fine-Gray competing risk regression with clustering). C) Forest plot of irradiated tumor progression for ATM LoF tumors (vs variant of unknown significance [VUS]), stratified by histology or cancer type. All statistical tests were 2-sided. CI = confidence interval; RT = radiotherapy.

Figure 2.

Clinical outcomes stratified by TP53 genotype and loss of ATM heterozygosity. A) Cumulative incidence of irradiated tumor progression stratified by ATM genotype among TP53 wild-type tumors. B) Cumulative incidence of irradiated tumor progression stratified by ATM genotype among TP53 mutant tumors. ATM loss-of-function (LoF) was associated with decreased tumor progression for TP53 wild-type tumors (P < .001) but not TP53 tumors (P = .26; Fine-Gray competing risk regression with clustering). C) Cumulative incidence of irradiated tumor progression stratified by ATM allelic status. D) Kaplan-Meier overall survival analysis from time of radiation stratified by ATM allelic status (P = .72). All statistical tests were 2-sided. VUS = variant of unknown significance.