Colorectal Cancer Information

1. Epidemiology

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in both men and women in the US. The American Cancer Society estimates that approximately 141,210 new cases will be diagnosed in 2011. Approximately 72% of cases arise in the colon and 28% in the rectum. More information on colorectal cancer statistics is available via the following links:

2. Genetics

Colorectal cancer develops slowly over as many as 20–40 years, progressing from benign to malignant lesions with the potential to spread to other tissues, with liver being the most common metastatic site. It is characterized by the accumulation of defects in genes that control the growth and differentiation of epithelial cells, leading to genomic instability and widespread loss of DNA integrity (1, 2). Two pathways that lead to genomic instability have been identified in the progression from precancerous to malignant lesions—a tumor-suppressor pathway and a mutator pathway (1, 3). Approximately 85% of sporadic colorectal cancers originate via the suppressor pathway and have typical genetic profiles characterized by chromosomal abnormalities leading to mutations and loss of function of tumor suppressor genes such as APC, p53, and DCC (3). Deactivating mutations in APC occur in approximately 70% of sporadic colorectal cancers, and it is believed that these mutations play a pivotal role in initiating these cancers (2). Other mutated genes include members of the Ras family of small-G proteins, KRAS, NRAS, and HRAS. Also, up to 20% of sporadic colorectal cancers display loss of expression of PTEN.

Normal mucosal cells have an inherent DNA repair mechanism that replaces any mismatched bases incorporated during replication. However, 10–20% of sporadic colorectal cancers have defective DNA mismatch repair mechanisms caused primarily by hypermethylation of the mismatch repair genes, hMLH1 and hMSH2, resulting in the accumulation of DNA mutations, usually 100- to 1000-fold more than in normal cells (1, 3, 4). These mutations often occur in the repetitive regions of genes such as TGFβRII, EGFR, APC, or BAX. The mutator pathway is predominant in the hereditary disease Lynch Syndrome which comprises approximately 2–4% of colorectal cancers. However, in Lynch Syndrome, defects in the mismatch repair mechanism are caused by inheritable germline mutations in the mismatch repair genes (3).

It is generally believed that cancers that derive from the mutator pathway are associated with a good prognosis (1, 3). However, on visual examination, these tumors may appear identical to other subtypes that may have different prognoses and different responses to treatment. The use of molecular markers is an effective means of distinguishing between tumor types to help select the appropriate therapy for the specific subtypes of colorectal cancer. Therapies can also be targeted at cancers bearing the relevant mutated gene.

3. Diagnosis

With proper screening, colorectal cancer can be detected before symptoms develop, when it is most curable. Routine physical examinations rarely detect colon polyps or cancer, but rectal examinations may reveal a mass in patients with rectal cancer. A fecal occult blood test (FOBT) may detect small amounts of blood in the stool, which could suggest colon cancer. However, this test is often negative in patients with colon cancer. For this reason, a FOBT should be combined with an imaging exam such as colonoscopy or sigmoidoscopy. A newly-developed fecal immunohistochemical test is replacing the FOBT test in many settings (5). Blood tests for colorectal cancer include tests for CEA. If colorectal cancer is diagnosed, further tests are performed to determine if the cancer has spread. CT or MRI scans of the abdomen, pelvic area, chest, and brain may be used to stage the cancer.

Much progress has been made by researchers in the discovery of biomarkers to enable the development of new, improved molecular tests for colorectal cancer. New genetic tests, such as tests for detecting mutations in the KRAS oncogene, help predict response to therapy. Mutations in KRAS and BRAF are frequently found in human cancers, including colorectal cancer. Knowing the mutation status of a cancer is important because the presence of a mutation can influence the effectiveness of a therapy. For example, patients with certain KRAS mutations do not benefit from therapies targeted at the epidermal growth factor receptor (EGFR) (6-9); therefore, the FDA recommends against using anti-EGFR therapies for the treatment of advanced stage colorectal cancer with KRAS mutations.

Molecular tests are now available to help predict outcome and response to therapy and to detect inherited colorectal cancers..

For more information on laboratory tests click on any of the links below:

4. Treatment

5. Guidelines

6. References

1. Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist 2010;15:699-731.
2. Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol 2011;6:479-507.
3. Moran A, Ortega P, de Juan C, Fernandez-Marcelo T, Frias C, Sanchez-Pernaute A, et al. Differential colorectal carcinogenesis: Molecular basis and clinical relevance. World J Gastrointest Oncol 2010;2:151-8.
4. Stratton MR. Exploring the genomes of cancer cells: progress and promise. Science 2011;331:1553-8.
5. Potack J, Itzkowitz SH. Practical advances in stool screening for colorectal cancer. J Natl Compr Canc Netw 2010;8:81-92.
6. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008;19:508-15.
7. Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26:374-9.
8. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66:3992-5.
9. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408-17.

7. Additional Resources