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 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.

The Impact of Durvalumab on Local-Regional Control in Stage III NSCLCs Treated With Chemoradiation and on KEAP1-NFE2L2-Mutant Tumors

“…These data suggest that local-regional control can be substantially affected independent of radiation dosing. Furthermore, although there has been a greater understanding in how tumor and host genetic factors affect radiation sensitivity, 23,24 the impact of durvalumab should also be computed in future strategies personalizing radiation dose. Moreover, the striking impact of durvalumab on local-regional control found herein suggests that one potential underlying mechanism by which durvalumab improves patient survival is through its direct actions on local-regional disease.…”

ATM Variants in Breast Cancer: Implications for Breast Radiation Therapy Treatment Recommendations

“…28,29 Given that patients with AT are at increased risk of radiation toxicity, patients who are carriers of ATM variants may also be at increased risk. While the incidence of AT is relatively rare (approximately 1 in 40,000), the carrier rate for pathogenic ATM variants (mono-allelic carriers or ATM heterozygotes) is much higher, at an estimated frequency of 0.5-1% (approximately 1-2.4 out of 200) of the general population 30,31 (Fig. 1).…”

“…However, heterozygous inheritance is much more common, with approximately 2.4 in 200 individuals harboring 1 copy of a variant allele. 31 Recent evidence suggests these individuals have a higher risk of developing breast cancer. Additionally, somatic variants are more common, affecting 1 in 40 tumors.…”

GARD is a pan-cancer predictor of radiation therapy benefit

“…Further, that this heterogeneity is at least partly driven and influenced by changes in the tumor genome is now accepted -indeed, large-scale classification efforts have been performed to understand these differences. [1][2][3] There have also been several efforts to understand surrogate genomic metrics for individual patient's resistance to radiation 4 , as well as imaging-based studies. 5 None of these efforts, however, considers the explicit relationship between intrinsic tumor genomics and RT dose -the most fundamental parameter in radiation therapy.…”