Emerging Prognostic Markers in Colon Cancer 


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Patients with stage II colon cancer generally have a favorable prognosis, with about 80% of patients surviving 5 years after surgery and the majority of these long-term survivors presumed to be cured. Clearly though, some patients are destined to recur after surgery, and there is an urgent need to develop reliable prognostic markers to identify these high-risk patients.

Until now, no prospective randomized clinical trials have clearly identified a role for adjuvant chemotherapy in patients with stage II colon cancer. The most recent ASCO guideline on this issue, published in 2004, recommended against the routine use of adjuvant chemotherapy and that patients be encouraged to participate in well-designed clinical trials.1 At the time this guideline was published, the most widely used prognostic factors in stage II colon cancer were T stage (ie, depth of tumor invasion), histologic grade, presence or absence of lymphovascular or perineural invasion, number of lymph nodes sampled, evidence of colonic obstruction or perforation, and preoperative serum carcinoembryonic antigen level.

Mismatch Repair Genes

In more recent years, a number of molecular prognostic markers have emerged that appear to be useful in refining the prognosis of patients with stage II colon cancer. Perhaps the most powerful of these are markers of DNA mismatch repair deficiency in the tumor cells, detected as either the absence of immunohistochemical staining for the proteins encoded by the DNA mismatch repair genes (MLH1, MSH2, MSH3, MSH6, etc) or the presence of small fragments of DNA known as microsatellites detected with molecular analysis.

The commonly used nomenclature is cumbersome and confusing, but tumors characterized as mismatch repair–deficient or microsatellite instability high, representing about 15% of colon cancers, are now known to have a more favorable prognosis, with a 40% to 50% relative improvement in overall survival compared with stage II tumors that are mismatch repair–proficient. Some data also suggest that these patients do not benefit from adjuvant chemotherapy with fluorouracil.2 Thus, many clinicians will now routinely obtain a test for microsatellite instability status in newly diagnosed patients with stage II colon cancer to help inform discussions regarding prognosis and the advisability of adjuvant treatment.

Recurrence Score

Several gene expression profiles have also been introduced recently that offer prognostic information. The Oncotype DX colon cancer recurrence score test is now commercially available in the United States. This test is based on the relative expression of 12 genes (7 recurrence and 5 reference genes) and is reported as a recurrence score that is associated with the risk of tumor recurrence.

The recurrence score is an independent risk factor in multivariable analyses that include microsatellite instability status, T stage, histologic grade, lymphovascular invasion, and number of nodes examined and thus appears to offer incremental information on risk. The test has now been extensively tested and validated in several large clinical trials, some of which, including CALGB 9581, were performed exclusively in patients with stage II disease.3

The major limitation of the Oncotype DX assay is limited dynamic range. For example, in the CALGB 9581 study, low recurrence score patients had a risk of recurrence at 5 years of approximately 12% and high recurrence score patients had a 5-year risk of approximately 18%.4

The test may have its greatest utility in refining prognosis of patients with T3, mismatch repair–proficient tumors, in whom the risk of recurrence was 13% for low recurrence score patients and 21% in high recurrence score patients. Thus, before ordering the test, clinicians may wish to consider whether the test results will truly be useful in guiding discussion with patients regarding prognosis, keeping in mind that, even in high-risk patients, there is no conclusive evidence that adjuvant chemotherapy is beneficial.

Other Prognostic Biomarkers

The Oncotype DX colon cancer test is one of only several gene expression signatures that have been developed to assess prognosis in patients with early-stage disease. All such tests are complicated to perform and interpret, and there are few overlapping genes among the signatures used in these tests, raising some question as to their biologic relevance.

Other emerging prognostic biomarkers in colon cancer include presence of BRAF mutations in the tumor5 and the expression of microRNA 21.6 We can be encouraged that ongoing research will likely produce other biomarkers that will help guide clinical decision-making for patients with early-stage colon cancer. ■

Dr. Schilsky is Chief Medical Officer, American Society of Clinical Oncology.

Disclosure: Dr. Schilsky had a consultant or advisory role with Foundation Medicine and stock ownership of Foundation Medicine and Universal Oncology; however, at the present time he has no relationships to disclose.

References

1. Benson AB III, Shrag D, Somerfield MR, et al: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22:3408-3419, 2004.

2. Sargent D, Marsoni S, Monges G, et al: Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:3219-3226, 2011.

3. Gray RG, Quirke P, Handley K, et al: Validation study of a quantitative multigene reverse transcriptase polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol 29:4611-4619, 2011.

4. Venook AP, Niedzwiecki D, Lopatin M, et al: Biologic determinants of tumor recurrence in stage II colon cancer: Validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol March 25, 2013 (early release online).

5. Ogino S, Shima K, Meyerhardt JA, et al: Predictive and prognostic roles of BRAF mutation in stage III colon cancer: Results from intergroup trial CALGB 89803. Clin Caner Res 18:890-900, 2011.

6. Schetter AJ, Leung SY, Sohn JJ, et al: MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425-436, 2008.


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SIDEBAR: Mismatch Repair Genes

Mismatch repair genes are involved in numerous cellular functions, including the recognition and correction of errors in DNA replication. Germline mutations of mismatch repair genes have been shown to be involved in various types of cancer. ■


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