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. 2009 Sep-Oct;3(5):191–196.

Adjuvant Chemotherapy for Stage II Colon Cancer: The Role of Molecular Markers in Choosing Therapy

Patrick Chun 1, Zev A Wainberg 1,✉
PMCID: PMC2806802  PMID: 20084160

Abstract

The optimal adjuvant treatment for stage II colon cancer remains controversial. While chemotherapy is often recommended for high-risk stage II disease, many low-grade tumors with similar histopathologic features will recur and ultimately cause cancer-associated mortality. The development of molecular markers that predict clinical outcome or response to therapy in stage II colon cancer is an important tool that could give clinicians added information in discussions regarding the role of adjuvant chemotherapy. While many potential molecular biomarkers have been investigated, to date none have been validated in prospective clinical trials. Among the most promising molecular markers to be studied are microsatellite instability and 18q and 17p loss of heterozygosity, both of which are currently being evaluated as prognostic indicators in a large prospective clinical trial (Eastern Cooperative Oncology Group 5202). This review focuses on potential molecular biomarkers being evaluated for their prognostic value in stage II colon cancer and their potential role in clinical decision-making regarding the use of adjuvant chemotherapy.

Colorectal cancer is the third most commonly diagnosed cancer in both men and women in the United States, and despite advances in treatment, colon cancer remains the second-leading cause of cancer death in the United States.1 Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve progression-free (PFS) and overall survival (OS), and is currently recommended as standard therapy.2–6 The value of adjuvant chemotherapy for patients with stage II disease (T3 tumors extending through the muscularis propria or T4 tumors directly invading organs or other structures or visceral peritoneal perforation, but without lymph node involvement or metastases) is controversial, with available data leading to differing conclusions.7–12

Although surgery alone is usually curative for stage II colon cancer, approximately 20% to 30% of these patients develop tumor recurrence and ultimately die of metastatic disease.13 Further complicating the issue is the fact that most available data on stage II colon cancer are derived from subgroup analyses of larger studies that have included both stage II and III patients and therefore lack the statistical power to demonstrate significant differences. As a result, there is no standardized approach to determining which (if any) stage II colon cancer patients should receive adjuvant chemotherapy. Current National Comprehensive Cancer Network (NCCN) guidelines for treatment of stage II colon cancer, which suggest a discussion with the patient regarding the risks and benefits of adjuvant chemotherapy in addition to clinical risk assessment (using number of lymph nodes analyzed, tumor stage, etc.) reflect this uncertainty.14

Because many patients with stage II colon cancer are at increased risk for recurrence, it has been assumed that, as in lymph-node–positive disease, some of these patients may be cured with adjuvant chemotherapy. However, the observation that stage II patients are clearly a heterogeneous group (with 5-year OS rates ranging from 84.7% for stage IIA to 72.2% for stage IIB15), has made defining patient subgroups most likely to benefit from adjuvant chemotherapy an elusive goal. Several clinical risk factors (T4 tumors, lymphatic or venous invasion, obstruction, perforation, poorly differentiated histology and <10 lymph nodes examined) have been identified in an attempt to stratify certain stage II patients as “high risk.”9,16–20 Although current data suggest that some of these clinically high-risk patients may have improved outcomes with adjuvant chemotherapy, 21 many of these risk factors remain predictive without being clearly prognostic.22

MOLECULAR MARKERS AND ADJUVANT CHEMOTHERAPY

Recent advances in the understanding of tumor biology have led to the discovery of new and potentially useful molecular markers that may help to define better those high-risk groups who stand to benefit from adjuvant chemotherapy. The identification of accurate and validated predictive and prognostic markers will help guide the clinician in making informed decisions regarding the appropriate use of adjuvant chemotherapy in patients with stage II colon cancer.

Microsatellite Instability

The molecular marker with the most available data in stage II colon cancer is the measure of deficient DNA mismatch repair. Microsatellite instability (MSI) is a change in the length of DNA microsatellites due to the insertion or deletion of repeating units (usually 1–5 nucleotides long) caused by defects in mismatch repair genes (MLH1, MSH2, or MSH6, and others) or methylation of the MLH1 promoter.23 While MSI is found in many different types of cancer, numerous studies have demonstrated a relationship between MSI and improved prognosis in colon cancer.

Most cases of familial colorectal cancer, and approximately 15% of sporadic colon cancers, show high-frequency MSI (defined as instability of ≥40% of MSI loci), while the remaining 85% of sporadic colon cancers are thought to develop from the chromosomal instability pathway characterized by aneuploidy, allelic losses, amplifications, and translocations.24 Tumors with MSI are more frequently proximal, poorly differentiated, mucinous, and show marked lymphocyte infiltration.25 While colon cancers exhibiting high-frequency microsatellite instability (MSI-H) have been associated with larger primary tumors, they have also been associated with more favorable stage distribution.26,27 Patients with MSI-H colon cancers have been shown to have longer OS and less tumor recurrence than stage-matched patients with microsatellite-stable (MSS) colon cancers.25,26,28,29

A retrospective analysis of the prognostic value of MSI in 142 stage II colon cancer patients by Parc et al in which patients underwent curative resection without adjuvant treatment showed 17% of the patients had MSI tumors, and these patients had significantly prolonged recurrence-free survival compared to patients with MSS tumors (P = .02).30 Similarly, a meta-analysis by Popat et al analyzed 35 studies of over 7,000 patients with colorectal cancer and concluded that patients with MSI-H tumors had a significantly improved prognosis as compared with MSS tumors.24

Ribic et al retrospectively analyzed 570 tissue specimens from patients with stage II or III colon cancer (collected from patients enrolled in five randomized trials of 5-fluorouracil [5-FU]–based chemotherapy) and showed that among the 287 patients who received no adjuvant chemotherapy, those with MSI had greater 5-year OS than those with MSS disease (hazard ratio [HR] 0.31; 95% confidence interval [CI] 0.14–0.72; P = .004).31 However, among patients receiving 5-FU–based adjuvant chemotherapy, 5-year OS did not differ based on MSS status (HR 1.07; 95% CI 0.62–1.86; P = .80), suggesting that 5-FU–based chemotherapy may only benefit MSS tumors.

In contrast to these results, analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) C01-4 trials demonstrated no prognostic correlation and no trend between high-degree MSI and OS (P = .67).32 Most recently, Sargent et al demonstrated that among stage II colon cancer patients with deficient DNA mismatch repair (MMR), those treated with 5-FU–based therapy had a worse overall survival than those patients who were untreated (P < .03).33

While the prognostic value of MSI after resection in stage II colon cancer has been demonstrated in several retrospective studies, it has not been prospectively tested and it remains unclear if MSI status predicts response to combination chemotherapy such as FOLFOX (folinic acid/5-FU/oxaliplatin). Topoisomerase I inhibitors have been shown to be effective in MSI tumor cells with mismatch repair deficiency in vitro;34 however, similar to the use of MSI in disease prognosis, prospective studies are needed to define the role of chemotherapy in MSI tumors.

Mutations in transforming growth factor-β (TGF-β), a potent negative regulator of epithelial cell growth, have been found to occur in up to 61% of stage III colon cancers in a study by Watanabe et al.35 This study showed a correlation between 5-year survival rates for patients with high-frequency MSI tumors and a mutation in TGF-β receptor II and response to 5-FU–based adjuvant chemotherapy, indicating that this mutation may be useful in combination with MSI status as a prognostic marker for adjuvant therapy.

More recently, MSI has been linked to genomic regions that contain a high frequency of CpG (Cytosine–phosphate–Guanine) sites known as CpG islands, which frequently occur near the promoter regions of mammalian genes.37 The CpG island methylator phenotype (CIMP) is a tumor-suppressor inactivator that has wide-spread promoter methylation function and is a distinct epigenetic phenotype thought to be an important mechanism in colon cancer carcinogenesis.37–39

Promoter hypermethylation is regarded as a critical mechanism for tumor-suppressor gene silencing, and inactivation CpG island hypermutation (CIMP-high) colorectal tumors appear to have a distinct molecular profile, and clinically are associated with female sex, proximal tumor location, poor differentiation, and MSI.40–44 As aberrant CIMP-high does not occur in nonmalignant, normally differentiated cells, it has been suggested that methylated DNA in the circulation may be used for tumor detection and as a prognostic indicator.45 Some data have shown that CIMP can be detected in the serum of patients with cancer,46 and that it may have some prognostic value,47 though the wider clinical usefulness of CIMP-high has yet to be fully determined.

Loss of Heterozygosity of 17p and 18q

It has been reported that allelic deletions involving chromosomes 17p and 18q occur in over 70% of colorectal cancers.22 These deletions are thought to signal the existence of a tumor-suppressor gene in the affected region. The tumor suppressor gene p53 is located on 17p and is mutated in 40% to 60% of colon cancers,34 yet despite its central role in the detection and prevention of genomic mutations, its role as a prognostic and predictive marker in colorectal cancer remains unclear.

The long arm of chromosome 18 (18q) contains several genes thought to be important in colorectal cancer tumorigenesis (SMAD-2, SMAD-4, CABLES1, and DCC). Among these, the DCC (deleted in colon cancer) gene is perhaps most relevant, as it encodes for a cell adhesion molecule that has been implicated in enhanced tumor growth and metastatic potential.48 The product of DCC is the netrin-1 receptor, which guides the migration of neuronal axons and loss of DCC as a result of del(18q) triggers impaired apoptosis. 49 Loss of the 18q region is thought to contribute to the inactivation of the DCC tumor-suppressor gene, though this remains controversial.50 Although most studies have agreed that del(18q) and decreased mRNA expression of DCC are associated with poor survival, estimates of the prognostic value have varied considerably.51

Chromosome 17p and 18q allelic loss or loss of heterozygosity (LOH) has been demonstrated to be a prognostic factor independent of histologic stage.52 The prognosis of patients with stage II colorectal cancer with 18q LOH is similar to that of patients with stage III tumors receiving adjuvant chemotherapy; conversely, patients with stage II tumors with no allelic loss have comparable survival to patients with stage I disease.53 The value of 18q LOH as a poor prognostic sign was best validated by Watanabe et al in patients with stage III colon cancer,35 though several conflicting studies54 have not observed a statistically significant correlation between chromosome 18q allelic loss and prognosis of patients with either stage II or stage III tumors. Thus, the true prognostic and predictive value of 18q LOH is currently unknown and warrants further exploration.

GENE-EXPRESSION SIGNATURES

Due to the uncertainty of benefit of adjuvant chemotherapy in patients with stage II colon cancer, microarray-based gene expression profiling might be a useful strategy to provide both prognostic and predictive value. These signatures offer the potential of a complementary approach to clinical and/or pathologic evaluation. Wang et al demonstrated that a genetic signature derived from microarray gene-expression analysis and classification methods could be a valuable prognostic marker in patients with stage II colon cancer.55 The 23-gene signature identified by gene-expression profiling in this study successfully predicted poor clinical outcome in patients with stage II disease, with an overall performance accuracy of 78% (OR 13, 95% CI 2.6–65; P = .003). However, due to significant technologic and methodologic differences between different platforms and concerns about reproducibility/comparability of experimental results, gene-expression microarrays have yet to find wider clinical application.

Most recently, Kerr et al presented a multigene reverse transcription polymerase chain reaction assay based on several large prospective trials.56 This study evaluated 1,436 paraffin-embedded stage II tumors culled from the Quick and Simple and Reliable (QUASAR) study group and attempted to develop and validate a multigene expression assay that would be of independent clinical value compared to other measures (such as T stage and MMR/MSI). The assay, optimized for fixed, paraffin-embedded colon tumor tissue, attempts to improve treatment decisions for patients with stage II colon cancer by providing an individualized assessment of recurrence risk following surgery and identifying patients with differential 5-FU/leucovorin benefit.

The recurrence risk groups were placed in three categories—low risk (12% risk of recurrence), intermediate risk (18%), and high risk (22%)—and associated with statistically significant values for both PFS and OS. This recurrence score, based on seven suspected recurrence genes, was validated as a predictor of recurrence in stage II colon cancer patients following surgery (HR for high-risk vs. low-risk recurrence 1.47, P = .046). However, this recurrence score was not a predictor of benefit from chemotherapy, and a separate score based on a distinct set of six genes was not shown to be predictive of treatment with 5-FU and leucovorin. Because this assay had a narrow spectrum of recurrence rates between the low- and high-risk groups and no predictive value for 5-FU–based chemotherapy, it appears to have limited clinical value. While this was the first demonstration that a prospectively defined gene-expression assay can independently predict recurrence in colon cancer patients, further research is needed to identify a prognostic and predictive gene set with practical clinical utility.

ANTIANGIOGENESIS AGENTS

Tumor-associated angiogenesis is an important feature in tumor development, progression, and metastasis.57 Targeted agents such as bevacizumab, the monoclonal antibody that binds to human vascular endothelial growth factor (VEGF), have significantly increased the efficacy of chemotherapeutic regimens in the setting of metastatic colorectal cancer,58 and are being evaluated for clinical value in the adjuvant setting.59

The recent results of NSABP protocol C-08 investigating the role of bevacizumab in the treatment of adjuvant colon cancer has made the addition of antiangiogenic agents in this setting an unlikely prospect in the future.60 In this study, the addition of bevacizumab to FOLFOX chemotherapy did not meet its prespecified statistical end point of disease-free survival (DFS), which was statistically insignificant (3-year DFS 77.4% vs. 75.5%, HR 0.89, P = .15). Looking at the stage II cohort alone, 3-year DFS was 87.4% vs 84.7% (HR 0.82, P = .25), which also did not demonstrate statistical significance.

An additional study, the AVANT trial, enrolled 3,450 patients who were randomized to FOLFOX4, FOLFOX4 plus bevacizumab for 1 year, or XELOX (capecitabine/oxaliplatin) plus bevacizumab, with a similar goal of evaluating the role of bevacizumab in the adjuvant setting. The results of this study have yet to be presented. While polymorphisms in VEGFR-2, epidermal growth factor receptor, and interleukin-1β have been identified as potential prognostic markers in stage II disease,61 larger independent prospective trials will be needed to validate the prognostic value of these molecular markers.

OTHER MARKERS

KRAS Mutation

The KRAS gene mutation has been studied extensively in colorectal tumors, and is thought to accompany the conversion of small adenomas to large adenomas. The mutation has been reported to occur in 30% to 40% of sporadic colon cancers, and it is presumed that mutations in KRAS develop early in the progression of adenoma to carcinoma.62–65 However, it is unclear how mutations relate to other histologic and clinical factors, and the prognostic significance of KRAS mutation remains controversial.

Almost all data reported to date with KRAS relates to patients with metastatic disease. A Southwest Oncology Group study showed that after adjustment for treatment and clinical variables, patients with stage II colon cancer whose tumors had KRAS mutations had shorter survival times than patients whose tumors had wild-type KRAS (HR 4.5, 95% CI 1.7–12.1).66 In that study, however, no benefit to adjuvant chemotherapy was demonstrated, regardless of the mutational status, and data remain insufficient to recommend the routine clinical use of KRAS mutations as a prognostic marker in stage II colon cancer. While mutations in KRAS can clearly be considered a negative predictor marker for the use of anti-EGFR therapies, the value of KRAS as a prognostic marker has not been validated.

Thymidylate Synthase

Thymidylate synthase (TS), the sole denovo source of intracellular thymidine and the primary target for inhibition by the chemotherapeutic agent 5-FU, has been implicated as a potential prognostic marker for response to chemotherapy with fluoropyrimidines. Studies have shown that intratumoral levels of TS vary among tumors and that the response to 5-FU–based chemotherapy regimens are related to intratumoral TS protein expression.67 Kornmann et al demonstrated that overexpression of TS was correlated with a better prognosis in patients with stage II and III tumors receiving 5-FU–based adjuvant chemotherapy.68 A meta-analysis by Popat et al showed an HR of 1.35 (95% CI, 1.07–1.80) for OS comparing low TS expression vs. high TS expression.69 Although the data on TS as a prognostic factor in stage II disease are promising, it has yet to be validated as a clinically useful marker.

DNA Ploidy

Given that chromosomal instability (characterized by loss of heterozygosity events and aneuploid DNA content) is found in 85% of colon cancers, DNA-ploidy analysis has been suggested as a potentially useful independent prognostic factor. Aneuploid tumors have an abnormal balance of chromosomes and represent cell populations with more or less DNA than normal diploid cells, which leads to asymmetric chromosome segregation at each mitosis and “chromosome error propogation.”70 However, given the lack of standardized methods for measuring ploidy, it is difficult to interpret studies using DNA ploidy as a prognostic marker, and consequently the American Society of Clinical Oncology (ASCO) Tumor Marker Expert Panel concluded that the literature did not support the use of DNA-ploidy analysis as a prognostic marker.71

DISCUSSION

The value of adjuvant chemotherapy in patients who undergo successful surgery for stage III colon cancer has been clearly demonstrated.72,73 However, the role of adjuvant chemotherapy for stage II colon cancer is still unclear. Subpopulation analyses from the principal studies, such as the Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, have lacked the power to demonstrate statistically significant differences in what is clearly a heterogeneous population of patients.21 Traditional clinical indicators such as tumor grade, venous invasion, obstruction or perforation, or other clinical indicators attempting to stratify stage II colorectal cancer patients as “high risk” (and therefore more likely to benefit from adjuvant chemotherapy) have had limited success in identifying patients at increased risk for recurrence. In addition, many tumors with similar histopathologic features show significantly different clinical outcomes, making the identification of robust molecular prognostic markers to supplement conventional pathologic staging highly desirable.74

As we learn more about the complex pathways that drive disease progression, it is becoming increasingly clear that one single marker is unlikely to be able to predict progression of disease with sufficient accuracy and precision. Studies using molecular markers to date have been too small in sample size, too heterogeneous, or too lacking in standardization to be able to draw any conclusions about the validity of using the markers clinically. This is reflected in the 2006 ASCO Guideline for the Use of Tumor Markers in Gastrointestinal Cancer, which reviewed the data assessing the use of tumor markers in screening, treatment, and surveillance of colorectal cancer. It concluded that to date, there is insufficient evidence to recommend the routine clinical use of p53, TS, dihydropyrimidine dehydrogenase, thymidine phosphorylase, KRAS, 17p and 18q LOH, and MSI as prognostic molecular markers in stage II or III colorectal cancers.75 At present, the influence of such molecular markers on treatment has yet to be revealed in clinical trials.

In the future, microarray technology with increased resolution and customizable chips may emerge as the preferred method of genotyping cancers. The goal of individualized cancer treatment based on the molecular characteristics of the tumor will be aided by novel therapeutics in combination with new screening tools and the discovery and validation of predictive and prognostic molecular markers. It is hoped these advances will enable clinicians to tailor adjuvant chemotherapy to patients most likely to benefit from such treatment.

FUTURE DIRECTIONS

The current ongoing prospective randomized controlled clinical trial, Eastern Cooperative Oncology Group (ECOG) 5202, is attempting to address whether MSI and 18q LOH status can be used to determine which patients with high-risk stage II colon cancer stand to benefit from adjuvant chemotherapy. This phase III trial randomizes patients with stage II colon cancer based on their MSI and 18q LOH status to observation vs. adjuvant chemotherapy (FOLFOX or FOLFOX/bevacizumab) with the intention of prospectively determining the prognostic value of MSI and 18q as molecular markers.76 A significant limitation of the ECOG 5202 trial, however, is its lack of a true control group. A direct comparison between patients stratified to adjuvant chemotherapy according to MSI/18q status vs. patients with MSS/18q-stable phenotype treated with adjuvant chemotherapy would be required to establish the true prognostic value of MSI and 18q LOH.48 Furthermore, the lack of surgical standardization (no requirement of 12 sampled lymph nodes) suggests that many patients on this trial will have stage migration and may in fact have stage III disease.

Despite steady movement toward being able to predict which patients will recur and which are likely to benefit from chemotherapy, it is worth noting that adjuvant chemotherapy itself is somewhat of a moving target. Revisiting prior clinical indicators of “high-risk” disease may yield improved prognostic utility in some cases. In addition to considerations of when to treat stage II disease, we must also consider the importance of whether or not many of these patients actually have stage III disease. Thus, better and more accurate staging methods must go hand in hand with molecular analysis. Although the National Quality Forum, the Commission on Cancer, ASCO, the American College of Surgeons, and NCCN have endorsed 12 as the minimum number of lymph nodes evaluated to be considered adequate, there continues to be controversy regarding the actual number needed for adequate evaluation, technique of sampling, and assessment of lymph nodes.

Improved lymph node mapping and targeted nodal evaluation may improve staging accuracy in conjunction with more detailed pathologic analysis differentiating micrometastases from isolated tumor cells, though this has yet to be proven. A large, prospective, multicenter study supported by the National Institutes of Health (2RO1CA090848) will address whether micrometastases represent a high-risk group in the absence of chemotherapy, as well as integrating primary tumor characteristics and gene signatures to develop a more comprehensive staging system.

Acknowledgments

Supported in part by the National Cancer Institute, Grant Number: 2RO1 CA090848-05A2.

Footnotes

Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

  • 1.American Cancer Society . Cancer Facts & Figures. Atlanta: American Cancer Society; 2008. 2008. p. 4. [Google Scholar]
  • 2.IMPACT investigators Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995;345:939–944. [PubMed] [Google Scholar]
  • 3.Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993;11:1879–1887. doi: 10.1200/JCO.1993.11.10.1879. [DOI] [PubMed] [Google Scholar]
  • 4.Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouaracil and levamisole, and fluorouracil, leucovorin and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project protocol C-04. J Clin Oncol. 1999;17:3553–3559. doi: 10.1200/JCO.1999.17.11.3553. [DOI] [PubMed] [Google Scholar]
  • 5.O’Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997;15:246–250. doi: 10.1200/JCO.1997.15.1.246. [DOI] [PubMed] [Google Scholar]
  • 6.André T, Colin P, Louvet C, et al. Semimonthly vs. monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol. 2003:2896–2903. doi: 10.1200/JCO.2003.10.065. [DOI] [PubMed] [Google Scholar]
  • 7.IMPACT B2 investigators Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999;17:1356–1363. [PubMed] [Google Scholar]
  • 8.Figueredo A, Charrette M, Maroun J, et al. Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site Group. J Clin Oncol. 2004;22:3395–3407. doi: 10.1200/JCO.2004.03.087. [DOI] [PubMed] [Google Scholar]
  • 9.Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004;22:1797–1806. doi: 10.1200/JCO.2004.09.059. [DOI] [PubMed] [Google Scholar]
  • 10.Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B vs. Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project Adjuvant Studies (C-01, C-02, C-03 and C-04) J Clin Oncol. 1999;17:1349–1355. doi: 10.1200/JCO.1999.17.5.1349. [DOI] [PubMed] [Google Scholar]
  • 11.Sakamoto J, Ohashi Y, Hamada C, et al. Meta-Analysis Group of the Japanese Society for Cancer of the Colon and Rectum; Meta-Analysis Group in Cancer: Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol. 2004;22:484–492. doi: 10.1200/JCO.2004.04.065. [DOI] [PubMed] [Google Scholar]
  • 12.Gray RJ, Barnwell J, Hills R, et al. QUASAR: a randomized study of adjuvant chemotherapy (CT) vs. observation including 3238 colorectal cancer patients. 2004 ASCO Annual Meeting Proceedings. J Clin Oncol. 2004;22:14S. (abstr 3501) [Google Scholar]
  • 13.Benson AB, III, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22:3408–3419. doi: 10.1200/JCO.2004.05.063. [DOI] [PubMed] [Google Scholar]
  • 14.Principles of Risk Assessment for Stage II disease. NCCN Clinical Practice Guidelines in Oncology. v.2.2009
  • 15.Burke HB. Outcome prediction and the future of the TNM staging system. J Natl Cancer Inst. 2004;96:1408–1409. doi: 10.1093/jnci/djh293. [DOI] [PubMed] [Google Scholar]
  • 16.Compton CC, Fielding LP, Burgart LJ, et al. Prognostic factors in colorectal cancer: College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124:979–994. doi: 10.5858/2000-124-0979-PFICC. [DOI] [PubMed] [Google Scholar]
  • 17.Le Voyer TE, Sigurdson ER, Hanlon AL, et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of Intergroup trial INT-0089. J Clin Oncol. 2003;21:2912–2919. doi: 10.1200/JCO.2003.05.062. [DOI] [PubMed] [Google Scholar]
  • 18.O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 2004;96:1420–1425. doi: 10.1093/jnci/djh275. [DOI] [PubMed] [Google Scholar]
  • 19.Steinberg SM, Barkin JS, Kaplan RS, et al. Prognostic indicators of colon tumors: The Gastrointestinal Tumor Study Group experience. Cancer. 1986;57:1866–1870. doi: 10.1002/1097-0142(19860501)57:9<1866::aid-cncr2820570928>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  • 20.Wolmark N, Wieand HS, Rockette HE, et al. The prognostic significance of tumor location and bowel obstruction in Dukes B and C colorectal cancer: Findings from the NSABP clinical trials. Ann Surg. 1983;198:743–752. doi: 10.1097/00000658-198312000-00013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Hickish T, Boni C, Tabernero J, et al. FOLFOX4 as adjuvant treatment for stage II colon cancer: subpopulation data from the MOSAIC trial. 2004 ASCO Annual Meeting Proceedings. J Clin Oncol. 2004;22:14S. (abstr 3619) [Google Scholar]
  • 22.Blanke CD. Perforation and stage-II colon cancer: is it always high risk? Gastrointest Cancer Res. 2008;2:103–104. [PMC free article] [PubMed] [Google Scholar]
  • 23.Wilson PM, Ladner RD, Lenz HJ. Predictive and prognostic markers in colorectal cancer. Gastrointest Cancer Res. 2007;1:237–246. [PMC free article] [PubMed] [Google Scholar]
  • 24.Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–618. doi: 10.1200/JCO.2005.01.086. [DOI] [PubMed] [Google Scholar]
  • 25.Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumour spectrum, and pathology of hereditary non-polyposis colorectal cancer: An updated review. Gastroenterology. 1993;104:1535–1549. doi: 10.1016/0016-5085(93)90368-m. [DOI] [PubMed] [Google Scholar]
  • 26.Gryfe R, Kim H, Hsieh ETK, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77. doi: 10.1056/NEJM200001133420201. [DOI] [PubMed] [Google Scholar]
  • 27.Halling KC, French AJ, McDonnell SK, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst. 1999;91:1295–303. doi: 10.1093/jnci/91.15.1295. [DOI] [PubMed] [Google Scholar]
  • 28.Lukish JR, Muro K, DeNobile J, et al. Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg. 1998;227:51–56. doi: 10.1097/00000658-199801000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Bubb VJ, Curtis LJ, Cunningham C, et al. Microsatellite instability and the role of hMSH2 in sporadic colorectal cancer. Oncogene. 1996;12:2641–2649. [PubMed] [Google Scholar]
  • 30.Parc Y, Gueroult S, Mourra N, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371–375. doi: 10.1136/gut.2003.019190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–257. doi: 10.1056/NEJMoa022289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Kim GP, Colangelo LH, Wieand HS, et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol. 2007;25:767–772. doi: 10.1200/JCO.2006.05.8172. [DOI] [PubMed] [Google Scholar]
  • 33.Sargent DJ, Marsoni S, Thibodeau SN, 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. 2008 ASCO Annual Meeting Proceedings. J Clin Oncol. 2008;26(May 20 suppl) (abstr 4008) [Google Scholar]
  • 34.Nash GM, Gimbel M, Shia J, et al. Automated, multiplex assay for high-frequency microsatellite instability in colorectal cancer. J Clin Oncol. 2003;21:3105–3112. doi: 10.1200/JCO.2003.11.133. [DOI] [PubMed] [Google Scholar]
  • 35.Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344:1196–1206. doi: 10.1056/NEJM200104193441603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Ahuja N, Mohan AL, Li Q, et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res. 1997;57:3370–3374. [PubMed] [Google Scholar]
  • 37.Issa JP. CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004;4:988–993. doi: 10.1038/nrc1507. [DOI] [PubMed] [Google Scholar]
  • 38.Jass JR. Serrated adenoma of the colorectum and the DNA-methylator phenotype. Nat Clin Pract Oncol. 2005;2:398–405. doi: 10.1038/ncponc0248. [DOI] [PubMed] [Google Scholar]
  • 39.Laird PW.Cancer epigenetics Hum Mol Genet 14 Spec No 1:R65–R76.2005 [DOI] [PubMed] [Google Scholar]
  • 40.Hawkins N, Norrie M, Cheong K, et al. CpG island methylation in sporadic colorectal cancers and its relationship to microsattelite instability. Gastroenterology. 2002;122:1376–1387. doi: 10.1053/gast.2002.32997. [DOI] [PubMed] [Google Scholar]
  • 41.Samowitz WS, Albertsen H, Herrick J, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 2005;129:837–845. doi: 10.1053/j.gastro.2005.06.020. [DOI] [PubMed] [Google Scholar]
  • 42.van Rijnsoever M, Grieu F, Elsaleh H, et al. Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands. Gut. 2002;51:797–802. doi: 10.1136/gut.51.6.797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies a sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–93. doi: 10.1038/ng1834. [DOI] [PubMed] [Google Scholar]
  • 44.Whitehall VL, Wynter CV, Wash MD, et al. Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res. 2002;62:6011–6014. [PubMed] [Google Scholar]
  • 45.Wallner M, Herbst A, Behrens A, et al. Methylation of serum DNA in an independent prognostic marker in colorectal cancer. Clin Cancer Res. 2006;12:7347–7452. doi: 10.1158/1078-0432.CCR-06-1264. [DOI] [PubMed] [Google Scholar]
  • 46.Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3:253–266. doi: 10.1038/nrc1045. [DOI] [PubMed] [Google Scholar]
  • 47.Lecomte T, Berger A, Zinzindohoue F, et al. Detection of free-circulating tumor associated DNA in plasma of colorectal cancer patients and its association with prognosis. Int J Cancer. 2002;100:542–548. doi: 10.1002/ijc.10526. [DOI] [PubMed] [Google Scholar]
  • 48.Khine K, Smith DR, Goh HS. High frequency of allelic deletion on chromosome 17p in advanced colorectal cancer. Cancer. 1994;73:28–35. doi: 10.1002/1097-0142(19940101)73:1<28::aid-cncr2820730107>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  • 49.Lurje G, Zhang W, Lenz HJ. Molecular prognostic markers in locally advanced colon cancer. Clin Colorectal Cancer. 2007;6(10):683–690. doi: 10.3816/CCC.2007.n.037. [DOI] [PubMed] [Google Scholar]
  • 50.Gryfe R, Swallow C, Bapat B, et al. Molecular biology of colorectal cancer. Curr Probl Cancer. 1997;21(5):233–300. doi: 10.1016/s0147-0272(97)80003-7. [DOI] [PubMed] [Google Scholar]
  • 51.Popat S, Houlston RS. A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer. 2005;41:2060–2070. doi: 10.1016/j.ejca.2005.04.039. [DOI] [PubMed] [Google Scholar]
  • 52.Andre T, Afchain P, Barrier A, et al. Current status of adjuvant therapy for colon cancer. Gastrointest Cancer Res. 2007;1:90–97. [PMC free article] [PubMed] [Google Scholar]
  • 53.Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med. 1994;331:213–221. doi: 10.1056/NEJM199407283310401. [DOI] [PubMed] [Google Scholar]
  • 54.Halling KC, French AJ, McDonnell SK, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst. 1999;91:1295–1303. doi: 10.1093/jnci/91.15.1295. [DOI] [PubMed] [Google Scholar]
  • 55.Wang Y, Jatkoe T, Zhang Y, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol. 2004;22:1564–1571. doi: 10.1200/JCO.2004.08.186. [DOI] [PubMed] [Google Scholar]
  • 56.Kerr D, Gray R, Quirke P, et al. A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study. 2009 ASCO Annual Meeting Proceedings. J Clin Oncol. 2009;27:18S. (abstr 4000) [Google Scholar]
  • 57.Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82:4–6. doi: 10.1093/jnci/82.1.4. [DOI] [PubMed] [Google Scholar]
  • 58.Giantonio BJ, Levy DE, O’Dwyer PJ, et al. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-flurouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol. 2006;17:1399–1403. doi: 10.1093/annonc/mdl161. [DOI] [PubMed] [Google Scholar]
  • 59.Fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab in treating patients who have undergone surgery for stage II or stage III colon cancerAvailable at: http://www.clinicaltrials.gov/ct/show/nct00096278
  • 60.Wolmark N, Yothers G, O’Connell MJ. A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08. 2009 ASCO Annual Meeting Proceedings. J Clin Oncol. 2009;27:18S. (abstr LBA4) [Google Scholar]
  • 61.Lurje G, Schultheis AM, Hendifar AE, et al. VEGF and VEGF receptor-2 (VEGFR2) gene polymorphisms predict tumor recurrence in stage II and III colon cancer. 2007 ASCO Annual Meeting Proceedings. J Clin Oncol. 2007;25(18 suppl):164s. (abstr 4004) [Google Scholar]
  • 62.Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85:692–696. doi: 10.1054/bjoc.2001.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst. 1998;90:675–684. doi: 10.1093/jnci/90.9.675. [DOI] [PubMed] [Google Scholar]
  • 64.Chiang JM, Chou YH, Chou TB. K-ras codon 12 mutation determines the polypoid growth of colorectal cancer. Cancer Res. 1998;58:3289–3293. [PubMed] [Google Scholar]
  • 65.Yamagata S, Muto T, Uchida Y, et al. Polypoid growth and K-ras codon 12 mutation in colorectal cancer. Cancer. 1995;75:953–957. doi: 10.1002/1097-0142(19950215)75:4<953::aid-cncr2820750409>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  • 66.Ahnen DJ, Feigl P, Quan G, et al. Ki-ras mutation and p53 over-expression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res. 1998;58:1149–1158. [PubMed] [Google Scholar]
  • 67.Pullarkat ST, Stoehlmacher J, Ghaderi V, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1:65–70. doi: 10.1038/sj.tpj.6500012. [DOI] [PubMed] [Google Scholar]
  • 68.Kornmann M, Schwabe W, Sander S, et al. Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression levels: predictors for survival in colorectal cancer patients receiving adjuvant 5-fluorouracil. Clin Cancer Res. 2003;9:4116–4124. [PubMed] [Google Scholar]
  • 69.Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol. 2004;22:529–536. doi: 10.1200/JCO.2004.05.064. [DOI] [PubMed] [Google Scholar]
  • 70.Holliday R. Chromosome error propagation and cancer. Trends Genet. 1989;5:42–45. doi: 10.1016/0168-9525(89)90020-6. [DOI] [PubMed] [Google Scholar]
  • 71.Bast RC, Jr, Ravdin P, Hayes DF, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865–1878. doi: 10.1200/JCO.2001.19.6.1865. [DOI] [PubMed] [Google Scholar]
  • 72.Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:399–401. doi: 10.1056/NEJM199002083220602. [DOI] [PubMed] [Google Scholar]
  • 73.Moertel CG, Fleming TR, Macdonald JS, et al. Fluorouracil and levamisole as effective adjuvant therapy after resection of stage III colon carcinoma. Ann Intern Med. 1995;122:321–326. doi: 10.7326/0003-4819-122-5-199503010-00001. [DOI] [PubMed] [Google Scholar]
  • 74.Bendardaf R, Lamlum H, Pyrhonen S. Prognostic and predictive molecular markers in colorectal carcinoma. Anticancer Res. 2004;24:2519–2530. [PubMed] [Google Scholar]
  • 75.Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24:5313–5327. doi: 10.1200/JCO.2006.08.2644. [DOI] [PubMed] [Google Scholar]
  • 76.Oxaliplatin, leucovorin, and fluorouracil with or without bevacizumab in treating patients who have undergone surgery for stage II colon cancer; Eastern Cooperative Oncology Group 5202. ClinicalTrials.gov Web siteAvailable at http://clinicaltrials.gov/ct/show/NCT00217737 Accessed: May 4, 2009.

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