Synapse - Pathogenic ATM mutations in cancer and a genetic basis for radiotherapeutic efficacy

Pathogenic ATM mutations in cancer and a genetic basis for radiotherapeutic efficacy Journal Article

Authors:	Pitter, K. L.; Casey, D. L.; Lu, Y. C.; Hannum, M.; Zhang, Z.; Song, X.; Pecorari, I.; McMillan, B.; Ma, J.; Samstein, R. M.; Pei, I. X.; Khan, A. J.; Braunstein, L. Z.; Morris, L. G. T.; Barker, C. A.; Rimner, A.; Alektiar, K. M.; Romesser, P. B.; Crane, C. H.; Yahalom, J.; Zelefsky, M. J.; Scher, H. I.; Bernstein, J. L.; Mandelker, D. L.; Weigelt, B.; Reis-Filho, J. S.; Lee, N. Y.; Powell, S. N.; Chan, T. A.; Riaz, N.; Setton, J.
Article Title:	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. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Journal Title:	JNCI: Journal of the National Cancer Institute
Volume:	113
Issue:	3
ISSN:	0027-8874
Publisher:	Oxford University Press
Date Published:	2021-03-01
Start Page:	266
End Page:	273
Language:	English
DOI:	10.1093/jnci/djaa095
PUBMED:	32726432
PROVIDER:	scopus
PMCID:	PMC7936050
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85102657399&doi=10.1093%2fjnci%2fdjaa095&partnerID=40&md5=59f374798f3d42d665dc2af257cbc49d
Notes:	Article -- Export Date: 1 April 2021 -- Source: Scopus