MRE11-Deficiency Associated with Improved Long-Term Disease Free Survival and Overall Survival in a Subset of Stage III Colon Cancer Patients in Randomized CALGB 89803 Trial

Abstract

PurposeColon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer.Patients and MethodsCancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses.ResultsOf 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed.ConclusionsAnalysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples.Trial RegistrationClinicalTrials.gov NCT00003835

Germline INDELs and CNVs in a cohort of colorectal cancer patients: their characteristics, associations with relapse‐free survival time, and potential time‐varying effects on the risk of relapse

“…In short, Pavelitz et al. examined the MRE11 gene mutation status in stage III colorectal cancer patients and found that the proportionality assumption of the Cox modeling was violated for overall and disease‐free survival times in their patient cohort. These authors then moved on with a statistical approach that we adopted in our analysis, including identification of a time‐point and modeling survival outcome using the Cox regression model with time‐varying coefficients .…”

“…Variants that satisfied the PH assumption were investigated in age‐stratified conventional Cox PH regression models (without the time‐varying coefficients) (Data – Table ). For those variants that violated the PH assumption (i.e., potential variants with time‐varying effects; score test P < 0.05), we first estimated the time‐point before and after which their effects on the RFS changed by following the approach described by Pavelitz and others . In brief, we considered each of the time‐points (and used the survSplit and cox.zph functions in R) starting with t 1 = 0.1 with 0.1 year increments till the end of follow‐up time (10.8 years) in age‐stratified multivariable models.…”

“…In brief, we considered each of the time‐points (and used the survSplit and cox.zph functions in R) starting with t 1 = 0.1 with 0.1 year increments till the end of follow‐up time (10.8 years) in age‐stratified multivariable models. The time‐point at which the model had the largest maximized log partial likelihood was deemed to be the time‐point where the effect of the variants on RFS changed . Score test was again applied to check the PH assumption before and after the identified time‐point for each variant and the coxph function was used to estimate the hazard ratios and confidence intervals for these time periods.…”

High Expression of MRE11–RAD50–NBS1 Is Associated with Poor Prognosis and Chemoresistance in Gastric Cancer

“…The clinical significance of MRE11, RAD50, and NBS1 expression as clinical markers has already been reported. Among them, high MRE11 is associated with poor prognosis and chemoresistance in colon cancer and breast cancer (24,25). Moreover, high tumor NBS1 expression is a poor prognostic factor in breast cancer, prostate cancer, acute myeloid leukemia, and oral squamous cell carcinoma (25)(26)(27)(28).…”

MRE11 and ATM Expression Levels Predict Rectal Cancer Survival and Their Association with Radiotherapy Response

“…Specifically, MRE11 deficiency is associated with improved overall survival (OS) and long-term disease-free survival (DFS) in patients with stage III colon cancer independent of treatment [10], suggesting that MRE11 status has value as a prognostic marker in CRC.…”