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|Ref Type||Journal Article|
|Authors||Pitter KL, Casey DL, Lu YC, Hannum M, Zhang Z, Song X, Pecorari I, McMillan B, Ma J, Samstein RM, Pei IX, Khan AJ, Braunstein LZ, Morris LGT, Barker CA, Rimner A, Alektiar KM, Romesser PB, Crane CH, Yahalom J, Zelefsky MJ, Scher HI, Bernstein JL, Mandelker DL, Weigelt B, Reis-Filho JS, Lee NY, Powell SN, Chan TA, Riaz N, Setton J|
|Title||Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy.|
|Journal||Journal of the National Cancer Institute|
|Date||2020 Jul 29|
|Abstract Text||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.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.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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ATM inact mut||Advanced Solid Tumor||predicted - sensitive||Radiotherapy||Clinical Study||Actionable||In a clinical study, treatment with radiotherapy resulted in greater therapeutic efficacy in advanced solid tumor patients harboring an ATM inactivating mutation (n=177) compared to those who harbored an ATM variant of unknown significance (n=180), demonstrating a significantly decreased 2-year cumulative incidence of irradiated progression, 13.2% versus 27.5% (p=0.001), respectively, and the greatest clinical benefit was observed in tumors with bi-allelic ATM inactivating mutations (PMID: 32726432).||32726432|