Colorectal cancer (CRC) is the third most commonly diagnosed type of cancer in men and women worldwide. An estimated 148,810 new cases of colon/rectum cancer were forecast to be diagnosed in the U.S. in 2008 [1
], while 376,400 cases were forecast to be diagnosed in Europe in 2004 [2
]. In addition, CRC continues to be one of the most common fatal types of cancer.
CRC develops slowly over several years and progresses through cytologically distinct benign and malignant stages of growth ranging from single crypt lesions through adenoma to malignant carcinoma with the potential for invasion and metastasis [3
]. Colorectal carcinogenesis is characterized by the successive accumulation of mutations in genes controlling epithelial cell growth and differentiation leading to genomic instability whereby widespread loss of DNA integrity is perpetuated [5
]. The development of genomic instability is an important event in the multistep progression of colorectal carcinogenesis. Two apparently independent pathways of genomic instability have been identified. The suppressor pathway is found in the majority of cancers (85%) and these tumors have a molecular profile characterized by specific chromosomal amplifications and transformations, aneuploidy, and loss of heterozygosity (LOH). Cancers originating from the mutator pathway have a defective DNA mismatch repair mechanism (MMR), which allows mutations to be accumulated at many times the normal rate. This inability to repair DNA mismatches can easily be demonstrated because it results in cell-to-cell variability in the length of DNA microsatellites, called microsatellite instability (MSI) [6
]. Colorectal malignancies demonstrating MSI have a very heterogeneous histological appearance, better prognosis, and altered response to chemotherapy and radiotherapy; see further below [7
]. In addition, in recent years, it has become apparent that promoter methylation is as important in shutting down tumor suppressor genes, as are the various mechanisms of somatic mutation. More than half of the tumor suppressor genes that are involved in familial cancer syndromes, because of germline mutation, have been found to be silenced in sporadic colorectal cancer by promoter hypermethylation. Careful characterization of the epigenetic factors, particularly promoter sequence methylation, has led to the definition of CpG island methylator phenotype (CIMP) cancer, which is proposed as a novel, third pathway [9
Treatment of CRC consists of complete surgical removal of the primary tumor and the regional lymph nodes [10
]. At the time of resection, approximately 30%–40% of patients with CRC are diagnosed with stage II disease [11
]. Despite improvements in surgical techniques and the dosing and scheduling of adjuvant and neoadjuvant therapy, the 5-year survival rate for patients with early-stage CRC, that is, without invasion or lymph node metastasis, is about 90%, but this falls of to 65% for tumors with regional spread and to 10% for late-stage disease in which the cancer has metastasized to distant sites [12
]. Prognostication relies on the stage or anatomic extent of disease based on the International Union Against Cancer tumor–node–metastasis (TNM) and American Joint Committee on Cancer staging classifications. The function of TNM staging has expanded from predicting prognosis to aiding in the choice of treatment [10
]. Accordingly, all node-positive cases (T3/4NposM0, stage III) receive adjuvant therapy while, despite several large randomized trials (Intergroup trials, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colorectal Cancer; Immediate Preoperative Arimidex®, Tamoxifen, or Combined with Tamoxifen; Surveillance, Epidemiology, and End Results; and National Surgical Adjuvant Breast and Bowel Project trials) conducted over the past decades, the value of adjuvant therapy for node-negative cases (T3/4N0M0, stage II) is controversial [10
]. There may well be a subgroup of patients with stage II CRC who would benefit from adjuvant chemotherapy [14
]. Patients with stage IIB (T4N0M0) CRC have a worse prognosis than patients with stage IIIA (T1–2N1M0) CRC, although the latter are usually treated with adjuvant therapy. The predictive value of TNM staging is limited because even the outcome within each stage group is not homogeneous.
Indeed, CRC should be regarded as a heterogeneous, multipathway disease, an observation sustained by the fact that histologically identical tumors may have neither a similar prognosis nor a similar response to therapy [12
]. Therefore, particularly in stage II CRC, there is a need for markers capable of selecting those patients with aggressive disease that might benefit from adjuvant chemotherapy [16
With recent developments in gene sequencing, molecular diagnostics, and targeted therapies, cancer treatment is beginning to move from the traditional “trial and error” approach to a position involving a personalized approach. There is clearly a need for strong and independent prognostic markers that can reliably differentiate patients into subgroups for which different treatment options, including the possibility of no adjuvant treatment, are appropriate. In addition, markers to prospectively predict response or resistance to specific therapies and markers to identify patients who are likely to develop severe toxic side effects from these specific treatments are warranted [16
]. However, in practice, the distinction between prognostic and predictive factors is not straightforward, and many factors are a mixture of the two [17
Consequently, in recent years a huge amount of research has been devoted to the study of new biological prognostic/predictive markers (). Several criteria must be met to ensure that a biomarker is clinically useful. In addition, evidence needs to be derived from multiple independent studies, which ideally should include a prospective trial. Most importantly, the marker concentration or status must be able to affect patient management [16
]. Although hundreds of these markers have been proposed in the last two to three decades, the current reality is that no molecular marker, other than the KRAS
gene in the case of epidermal growth factor receptor (EGFR)-targeted therapy for metastatic disease, has made it into clinical practice [16
Summary of tissue-based prognostic/predictive markers most studied in colorectal cancer
The aim of this review is to provide an update of the most recent data on biological prognostic and or predictive markers in patients with CRC that show promise in the clinic.