Mismatch Repair Deficiency, Microsatellite Instability, and Survival: An Exploratory Analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial

Abstract

Importance: Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown.

Objective: To examine the association among MMRD, MSI, and survival in patients with resectable gastroesophageal cancer randomized to surgery alone or perioperative epirubicin, cisplatin, and fluorouracil chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial.

Design, setting, and participants: This secondary post hoc analysis of the MAGIC trial included participants who were treated with surgery alone or perioperative chemotherapy plus surgery for operable gastroesophageal cancer from July 1, 1994, through April 30, 2002. Tumor sections were assessed for expression of the MMR proteins mutL homologue 1, mutS homologue 2, mutS homologue 6, and PMS1 homologue 2. The association among MSI, MMRD, and survival was assessed.

Main outcomes and measures: Interaction between MMRD and MSI status and overall survival (OS).

Results: Of the 503 study participants, MSI results were available for 303 patients (283 with microsatellite stability or low MSI [median age, 62 years; 219 males (77.4%)] and 20 with high MSI [median age, 66 years; 14 males (70.0%)]). A total of 254 patients had MSI and MMR results available. Patients treated with surgery alone who had high MSI or MMRD had a median OS that was not reached (95% CI, 11.5 months to not reached) compared with a median OS among those who had neither high MSI nor MMRD of 20.5 months (95% CI, 16.7-27.8 months; hazard ratio, 0.42; 95% CI, 0.15-1.15; P = .09). In contrast, patients treated with chemotherapy plus surgery who had either high MSI or MMRD had a median OS of 9.6 months (95% CI, 0.1-22.5 months) compared with a median OS among those who were neither high MSI nor MMRD of 19.5 months (95% CI, 15.4-35.2 months; hazard ratio, 2.18; 95% CI, 1.08-4.42; P = .03).

Conclusions and relevance: In the MAGIC trial, MMRD and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy. If independently validated, MSI or MMRD determined by preoperative biopsies could be used to select patients for perioperative chemotherapy.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Smyth reported receiving honoraria from Five Prime Therapeutics for advisory board participation and from Bristol-Myers Squibb for for an advisory role. Dr Allum reported receiving honoraria from Nestlé and Eli Lilly. Ms Peckitt reported receiving honoraria for consulting or an advisory role from Sanofi. Mr Nankivell and Dr Langley reported receiving support from the Medical Research Council Clinical Trials Unit, University College London. Dr Cunningham reported receiving research funding from Amgen, AstraZeneca, Celgene, MedImmune, Merck Serono, Merrimack, and Sanofi. No other disclosures were reported.

Figures

Figure 1.. Overall Survival by Microsatellite Instability (MSI) Status and Treatment Arm in the Study Patients

Patients were dichotomized into 2 groups: high MSI (MSI-H) and microsatellite stable (MSS) or low MSI (MSI-L), which are analyzed separately in each treatment arm. Differences in overall survival were assessed using the Kaplan-Meier method and compared using the log-rank test. The hazard ratios for MSI-H vs MSS or MSI-L were 0.35 (95% CI, 0.11-1.11) for surgery alone (P = .08) and 2.22 (95% CI, 1.02-4.85) for chemotherapy and surgery (P = .04) (interaction P = .01). P < .05 was considered to be statistically significant.

Figure 2.. Overall Survival by Mismatch Repair (MMR) Protein Status in the Study Patients

Patients were dichotomized into 2 groups: MMR deficiency (MMRD) and MMR proficiency (MMRP). The groups are analyzed separately in each treatment arm. Differences in overall survival were assessed using the Kaplan-Meier method and compared using the log-rank test. P < .05 was considered to be statistically significant.