TY - JOUR
T1 - Pathogenic ATM Mutations in Cancer and a Genetic Basis for Radiotherapeutic Efficacy
AU - Pitter, Kenneth L.
AU - Casey, Dana L.
AU - Lu, Yue C.
AU - Hannum, Margaret
AU - Zhang, Zhigang
AU - Song, Xinmao
AU - Pecorari, Isabella
AU - Mcmillan, Biko
AU - Ma, Jennifer
AU - Samstein, Robert M.
AU - Pei, Isaac X.
AU - Khan, Atif J.
AU - Braunstein, Lior Z.
AU - Morris, Luc G.T.
AU - Barker, Christopher A.
AU - Rimner, Andreas
AU - Alektiar, Kaled M.
AU - Romesser, Paul B.
AU - Crane, Christopher H.
AU - Yahalom, Joachim
AU - Zelefsky, Michael J.
AU - Scher, Howard I.
AU - Bernstein, Jonine L.
AU - Mandelker, Diana L.
AU - Weigelt, Britta
AU - Reis-Filho, Jorge S.
AU - Lee, Nancy Y.
AU - Powell, Simon N.
AU - Chan, Timothy A.
AU - Riaz, Nadeem
AU - Setton, Jeremy
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102657399&partnerID=8YFLogxK
U2 - 10.1093/jnci/djaa095
DO - 10.1093/jnci/djaa095
M3 - Article
C2 - 32726432
AN - SCOPUS:85102657399
SN - 0027-8874
VL - 113
SP - 266
EP - 273
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 3
ER -