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

Thomas Pavelitz, Lindsay Renfro, Nathan R Foster, Amber Caracol, Piri Welsch, Victoria Valinluck Lao, William B Grady, Donna Niedzwiecki, Leonard B Saltz, Monica M Bertagnolli, Richard M Goldberg, Peter S Rabinovitch, Mary Emond, Raymond J Monnat Jr, Nancy Maizels, Thomas Pavelitz, Lindsay Renfro, Nathan R Foster, Amber Caracol, Piri Welsch, Victoria Valinluck Lao, William B Grady, Donna Niedzwiecki, Leonard B Saltz, Monica M Bertagnolli, Richard M Goldberg, Peter S Rabinovitch, Mary Emond, Raymond J Monnat Jr, Nancy Maizels

Abstract

Purpose: Colon 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 methods: Cancer 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.

Results: Of 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.

Conclusions: Analysis 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 registration: ClinicalTrials.gov NCT00003835.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Consort diagram.
Figure 1. Consort diagram.
Outline of CALGB 89803 randomized trial which generated the 625 samples tested.
Figure 2. Genomic PCR assay of MRE11…
Figure 2. Genomic PCR assay of MRE11 intron 4 T11 tract.
(A) Diagram of the MRE11 intron 4/exon 5 junction, showing the T11 tract in intron 4, flanking sequence and primers. Contraction of the T11 tract impairs the lariat formation step in mRNA splicing and leads to skipping of exon 5. The resulting mutant mRNA encodes a truncated MRE11 polypeptide with potentially dominant negative effect on protein function . MRE11 is essential for cell viability, and the MRE11 mutations that occur in MMR-D CRC are not null alleles but reduce expression and activity of the MRE11 protein. (B) Sequence traces of the region of MRE11 intron 4 that carries the T11 tract in four tumor samples. Lengths of tracts in nt shown at left.
Figure 3. Tumor MRE11 status is significantly…
Figure 3. Tumor MRE11 status is significantly prognostic for DFS and OS.
(A) Disease free survival for dMRE11 (n = 70; events = 24); 5-yr rate: 67% (95% CI: 56–79%) vs. pMRE11 (n = 555; events = 240); 5-yr rate: 59% (95% CI: 55–63%). (B) Overall survival for dMRE11 (n =  = 70; events = 23); 5-yr rate: 68% (95% CI: 58–80%) vs. pMRE11 (n = 555; events = 194); 5-yr rate: 71% (95% CI: 67–75%).
Figure 4. Assessment of tumor MRE11 status…
Figure 4. Assessment of tumor MRE11 status as predictive of benefit from FU/LV and IFL.
(A) Top: Disease free survival for dMRE11 vs. pMRE11 treated with FU/LV [n = 320; dMRE11 n = 31; events = 11; 5-yr rate: 67% (95% CI: 52–86%); pMRE11 n = 289; events = 122; 5-yr rate: 61% (95% CI: 56–67%)] or with IFL [n = 305; dMRE11 n = 39; events = 13; 5-yr rate: 67% (95% CI: 53–83%); pMRE11 n = 266; events = 118; 5-yr rate: 57% (95% CI: 51–63%)]. Bottom: Overall survival for dMRE11 vs. pMRE11, treated with FU/LV [n = 320; dMRE11 n = 31; events = 10; 5-yr rate: 70% (95% CI: 55–89%); pMRE11 n = 289; events = 98); 5-yr rate: 73% (95% CI: 68–79%)] or with IFL [n = 305; dMRE11 n = 39; events = 13; 5-yr rate: 67% (95% CI: 53–83%); pMRE11 n = 266; events = 96; 5-yr rate: 69% (95% CI: 63–75%)]. (B) Top: Disease-free survival for IFL vs. FU/LV treated dMRE11 [n = 70; IFL N = 39; events = 13; 5-yr rate: 67% (95% CI: 53–83%); FU/LV n = 31; events = 11; 5-yr rate: 67% (95% CI: 52–86%)] or pMRE11 (n = 555; IFL n = 266; events = 118; 5-yr rate: 57% (95% CI: 51–63%; FU/LV n = 289; events = 122; 5-yr rate: 61% (95% CI: 56–67%)]. Bottom: Overall survival for IFL vs. FU/LV-treated dMRE11 [n = 70; IFL n = 39; events = 13; 5-yr rate: 67% (95% CI: 53–83%); FU/LV n = 31; events = 10; 5-yr rate: 70% (95% CI: 55–89%) or pMRE11 [(n = 555; IFL n = 266; events = 96; 5-yr rate: 69% (95% CI: 63–75%); FU/LV n = 289; events = 98; 5-yr rate: 73% (95% CI: 68–79%)].

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