Loss of ataxia-telangiectasia mutated (ATM) protein has been associated with worse prognosis in resected gastric cancer (GC), and may predict sensitivity to drugs targeting DNA damage pathways. Microsatellite instability (MSI) is prognostic in surgically treated GC patients (pts) and may be negatively prognostic in perioperative chemotherapy (chemo) treated GC. We examined the effect of ATM and MSI on overall survival (OS) for pts randomised to surgery alone or perioperative ECF chemo in the MRC MAGIC trial.
ATM was assessed using anti-ATM antibody (clone Y170) on 4 µm TMA sections. ATM negative (neg) tumours had >90% cells neg for nuclear ATM. MSI was assessed using Promega MSI System. MSS tumours had all markers stable; MSI-L had only 1 unstable marker; MSI-H had at least 2 unstable markers. Trial arms were analysed independently.
39 of 225 evaluated pts (17%) were ATM-neg. Pts with/without ATM data had similar OS. Clinicopathological characteristics were similar between ATM-neg and positive (pos) pts. 217 pts had MSI and ATM status available: MSI and ATM status were highly correlated (ATM-neg/MSS n = 27, ATM neg/MSI-H n = 10, ATM-pos/MSS n = 175, ATM-pos/MSI-H n = 5, p
In MAGIC, ATM status was not prognostic for OS in either treatment arm. ATM loss was much more common in MSI-H pts. In this relatively underpowered analysis, chemo treated MSS-ATM-neg pts had encouraging OS. In chemo treated pts, prognosis was poor for MSI-H patients independent of ATM status. Further evaluation of ATM, MSI and chemo outcomes may be justified.
Clinical trial identification
Legal entity responsible for the study
Medical Research Council
Cancer Research UK grant C20023/A7217
E. Smyth: Honoraria for advisory role: Five Prime Therapeutics, Bristol-Meyer Squibb. C. Peckitt: Honoraria for consulting or advisory role from Sanofi. W. Allum: Honoraria from Nestle and Lilly. D. Cunningham: Research funding: Amgen, AstraZeneca, Celgene, MedImmune, Merck Serono, Merrimack, Sanofi. All other authors have declared no conflicts of interest.