OncoDefender-MMR

The OncoDefender-MMR test helps physicians assess the prognosis for individual colorectal cancer (CRC) patients; OncoDefender-MMR helps physicians decide which treatment strategy is required based a patient’s individual prognosis.

Recent advances in molecular diagnostics and genomics have revealed that colorectal cancer is not a single disease but in fact consists of three very different types of colorectal cancer disease.  Independent of whether colorectal cancer is diagnosed at stage 1, 2, 3 or 4, the type of colorectal cancer a patient has is of enormous medical importance in defining tumor aggressiveness, determining aggressiveness of each type way each type that exhibit chromosomal instability (CIN), microsatellite instability (MSI), or CpG island methylation, (Ogino and Goel 2008), with overlap between the groups.

The Mismatch Repair System (MMR) is responsible for the detection and correction of insertion/deletion mutations of short tandem repeat sequences and single base pair mismatches that occur during cell division. Failure of the MMR system may result from an inherited mutation in an MMR gene, a somatic mutation in an MMR gene, epigenetic suppression of MMR gene function, or a combination of the above any of which leads to microsatellite instability (MSI-H).  Several studies1 have shown that MSI-H tumors have a more favorable prognosis and are less prone to lymph node and systemic metastasis.1

MSI-H status has been shown to correlate with CRC patient survival. A meta-analysis of 7,642 CRC patients from 32 studies, including 1,277 MSI-H patients, revealed that MSI-H tumors were associated with better prognosis than MSS tumors (hazard ratio for overall survival was 0.65)2.

  • MSI-H was an independent prognostic marker associated with a favorable outcome in CRC and these tumors were less prone to lymph node involvement and systemic metastases.
  • Several studies support this further by confirming that only 4% of MSI-H tumors exhibit metastatic disease vs. 15-17% of MSS tumors.
  • CRC tumors harboring a V600E BRAF mutation are associated with an unfavorable outcome. While MSI-H CRC without an associated BRAF mutation has a favorable prognosis, patients showing MSI-H and a BRAF mutation have a prognosis similar to MSS CRC.

 


Footnotes:

1,2 College of American Pathologists, Prognostic Uses of Microsatellite Testing, May 12, 2011

Additional References:

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  • American cancer society. Estimated new cases and deaths from colon and rectal cancer in the United States in 2009. Online at www.cancer.org
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  • Umar et al. Revised Bethesda Guidelines for HNPCC (Lynch Syndrome) and Microsatellite Instability. J Natl Cancer Inst 2004; 96: 261-268.
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  • Ribic CM et al. Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer. N Engl J Med. 2003;349(3).
  • D. J. Sargent, et al. Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): A pooled molecular reanalysis of randomized chemotherapy trials. J Clin Oncol 2008; 26 (May 20 suppl; abstr 4008).
  • P L Barratt et al. DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet 2002; 360: 1381–91.
  • Kerr et al. A quantitative multi-gene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in 4 large studies and results of the independent, prospectively-designed QUASAR validation study. J Clin Oncol, 2009 ASCO Annual Meeting Proceedings. 2009;27(15S): 4000.
  • PR Newswire. Genomic Health's Oncotype DX Colon Cancer Test Predicts Individualized Recurrence Risk for Stage II Colon Cancer Patients. March 14, 2009. http://www.cancercompass.com/cancer-news/1,15698,00.htm
  • Bertagnolli MM et al., Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol, 2009;17(11).
  • Marcus VA, Madlensky L, Gryfe R, Kim H, So K, Millar A, et al. Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair deficient tumors. Am J Surg Pathol 1999;23:1248–55.
  • Lindor NM, Burgart LJ, Leontovich O, et al: Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol2002;20: 1043-1048.
  • Boland CR, Thibodeau SN, Hamilton SR et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58(22):5248-57.
  • Palomaki GE, Mc Clain MR, Melillo S et al: EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch Syndrome. Genetics in Medicine, 2009: 42(11).