ATM Germline-Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics, and Potential Therapeutic Implications.

BACKGROUND: Gastroesophageal junction (GEJ) adenocarcinoma is a rare cancer associated with poor prognosis. The genetic factors conferring predisposition to GEJ adenocarcinoma have yet to be identified. METHODS: We analyzed germline testing results from 23 381 cancer patients undergoing tumor-normal sequencing, of which 312 individuals had GEJ adenocarcinoma. Genomic profiles and clinico-pathologic features were analyzed for the GEJ adenocarcinomas. Silencing of ATM and ATR was performed using validated short-interfering RNA species in GEJ, esophageal, and gastric adenocarcinoma cell lines. All statistical tests were 2-sided. RESULTS: Pathogenic or likely pathogenic ATM variants were identified in 18 of 312 patients (5.8%), and bi-allelic inactivation of ATM through loss of heterozygosity of the wild-type allele was detected in all (16 of 16) samples with sufficient tumor content. Germline ATM-mutated GEJ adenocarcinomas largely lacked somatic mutations in TP53, were more likely to harbor MDM2 amplification, and harbored statistically significantly fewer somatic single nucleotide variants (2.0 mutations/Mb vs 7.9 mutations/Mb; P < .001). A statistically significantly higher proportion of germline ATM-mutated than ATM-wild-type GEJ adenocarcinoma patients underwent a curative resection (10 [100%] vs 92 [86.8%], P = .04; Fisher's exact test.), A synthetic lethal interaction between short-interfering RNA silencing of ATM and ATR was observed in the models analyzed. CONCLUSIONS: Our results indicate that germline pathogenic variants in ATM drive oncogenesis in GEJ adenocarcinoma and might result in a distinct clinical phenotype. Given the high prevalence of germline ATM-mutated GEJ adenocarcinomas, genetic testing for individuals with GEJ adenocarcinomas may be considered to better inform prognostication, treatment decisions, and future cancer risk.

Moving beyond PARP Inhibition in ATM-Deficient Prostate Cancer.

DNA repair defects are found in primary and metastatic prostate cancer. Alterations in the ATM gene are the second most common defect after BRCA2, but their sensitivity to PARP inhibitors has been questioned by recent clinical literature. The work by Rafiei and colleagues in this issue of Cancer Research now supports this observation with genetically engineered cells and quantitative responses. ATR inhibitors have not yet found a clear role in the clinic, but the new work suggests that ATM-deficient cancers may be more vulnerable to ATR inhibition rather than PARP inhibitors, which is a testable hypothesis for clinical trials.See related article by Rafiei et al., p. 2094.

A new role for a tumor-suppressing protein.

In addition to its role in preventing tumors, the protein p53 appears to participate in a DNA repair process known as the replication-stress response.

Estimate of the impact of FDG-avidity on the dose required for head and neck radiotherapy local control.

BACKGROUND AND PURPOSE: Although FDG-avid tumors are recognized as a potential target for dose escalation, there is no clear basis for selecting a boost dose to counter this apparent radioresistance. Using a novel analysis method, based on the new concept of an outcome-equivalent dose, we estimate the extra dose required to equalize local control between FDG-avid and non-avid head and neck tumors. MATERIALS AND METHODS: Based on a literature review, five reports of head and neck cancer (423 patients in total), along with an internal validation dataset from our institution (135 oropharynx patients), were used in this analysis. To compensate for the heterogeneity among multi-institutional patient cohorts and corresponding treatment techniques, local control data of the cohorts were fit to a single dose-response curve with a clinically representative steepness (γ50=2), thereby defining an 'outcome-equivalent dose' (OED) for each institutional cohort. Separate dose-response curves were then determined for the FDG-avid and FDG-non-avid patient cohorts, and the ratio of TD50 (tumor dose required for 50% of control) values between the high- and low-FDG-uptake groups (TD50,high/TD50,low) was estimated, resulting in an estimated metabolic dose-modifying factor (mDMF) due to FDG-avidity. RESULTS: For individual datasets, the estimated mDMFs were found to be in the range of 1.07-1.62, decreasing if the assumed slope (γ50) increased. Weighted logistic regression for the six datasets resulted in a mDMF of 1.19 [95% CI: 1.04-1.34] for a γ50 value of 2, which translates to a needed dose increase of about 1.5Gy per unit increase in the maximum standardized uptake value (SUVm) of FDG-PET [95% CI: 0.3-2.7]. Assumptions of lower or higher γ50 values (1.5 or 2.5) resulted in slightly different mDMFs: 1.26 or 1.15, respectively. A validation analysis with seven additional datasets, based on relaxed criteria, was consistent with the estimated mDMF. CONCLUSIONS: We introduced a novel outcome-equivalent dose analysis method to estimate the dose-response modifying effect of FDG uptake variation. To reach equal response rates, FDG-avid tumors are likely to require 10% to 30% more dose than FDG-non-avid tumors. These estimates provide a rational starting point for selecting IMRT boosts for FDG-avid tumors. However, independent tests and refinements of the estimated dose-modifying effect, using high-quality prospective clinical trial data, are needed.