OncoSelector

Individual colorectal cancer (CRC) patients respond very differently to available chemotherapeutic drugs.  OncoSelector helps physicians select the specific chemotherapy which a colon cancer patient is likely to best respond to and tolerate the side-effects associated with a particular chemotherapy.

Microsatellites are repetitive sequences distributed throughout the genome which are frequently copied incorrectly when DNA polymerases cannot bind efficiently. The Mismatch Repair System (MMR), consisting of several proteins including MLH1, MSH2, MSH6 and PMS2, is responsible for the surveillance and correction of these errors.

Microsatellite Stability (MSS) is a hallmark of a properly functioning surveillance and correction MMR system. Patients with MSS are less likely to suffer from MMR defects.

Microsatellite Instability (MSI) is the hallmark of a defective mismatch repair (MMR) system and generally occurs because of a germline mutation in one of the MMR genes or methylation of the MLH1 promoter. Patients with MSI are more likely to suffer from MMR defects.

Implications for chemotherapy selection in CRC patients; current data suggests that1:

  1. In colon cancer patients identified by OncoSelector with MSS, these patients are likely to better respond to and tolerate 5-FU therapy
  2. In colon cancer patients identified by OncoSelector with MSI, these patients may be more responsive to irinotecan than patients identified as MSS
  3. Patients identified as MSI do not benefit (and might actually be harmed by) 5-FU therapy

 

 

Additional References:

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

Additional References:

  1. Klump B, Nehls O, Okech T, et al. Molecular lesions in colorectal cancer: Impact on prognosis? Original data and review of the literature. Int J Colorectal Dis2004; 19:23-42.
  2. American cancer society. Estimated new cases and deaths from colon and rectal cancer in the United States in 2009. Online at www.cancer.org
  3. Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev 2004, 23:11-27.
  4. Umar et al. Revised Bethesda Guidelines for HNPCC (Lynch Syndrome) and Microsatellite Instability. J Natl Cancer Inst 2004; 96: 261-268.
  5. Popat S, Hubner R, Houlston RS. Systematic Review of Microsatellite Instability and Colorectal Cancer Prognosis. J Clin Oncol 2005; 23(3):609-618.
  6. 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).
  7. 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).
  8. 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.
  9. 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.
  10. 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
  11. 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).
  12. 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.
  13. Lindor NM, Burgart LJ, Leontovich O, et al: Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol2002;20: 1043-1048.
  14. 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.
  15. 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).