Colorectal Carcinoma and Emerging Targeted Therapies

Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in the U.S. ^1-3 Only 40% of cases are diagnosed in a localized stage with an estimated 5-year survival of 90%, whereas 20% of cases present with metastatic disease with a 5-year survival of about 12.5%. ¹ With recent advances in cancer genetics and immunology as well as approval of targeted agents by the FDA, different treatment options are now available, even for progressive disease.

This article presents a brief review of CRC with a special focus on targeted therapies in metastatic CRC (mCRC). Colorectal cancers exhibit certain mutations, which affect the tumor responsiveness to various treatment options. This article describes the role of targeted therapies in various well-established mutations.

Epidemiology

The most common tumor location is the proximal colon (42%), followed by the rectum (28%). More than 90% of patients with CRCs are aged > 50 years at diagnosis.
Women have a higher percentage of proximal tumors compared with men (46% vs 38%) and a lower percentage of rectal tumors (24% vs 31%).ŽAmong both sexes, incidence and mortality are highest in African Americans and lowest in Asian/Pacific Islanders. The estimated 5-year survival is slightly higher for rectal cancer (66.5%) than for colon cancer (64.2%), although the stage-specific survival is similar. The difference in 5-year overall survival (OS) is attributed to the higher percentage of rectal tumors diagnosed at a localized stage (44% vs 38%). Patients aged < 65 years have higher 5-year survival rates than do those aged • 65 years (68.9% vs 62.0%). ¹

Risk Factors

Like most human cancers, multiple genetic and environmental factors are believed to play a role in the development of colorectal carcinomas, with environmental factors playing the dominant role. ⁴

Environmental risk factors include a low-fiber diet, ⁵ red and processed meat intake, ⁶ a high-fat diet, ⁷ smoking, ⁸ heavy alcohol consumption, ⁹ obesity, ¹⁰ physical inactivity, ¹¹ alteration in intestinal flora, ¹² and chronic inflammation. ¹³ Aspirin (at doses > 300 mg/d), nonsteroidal anti-inflammatory drugs, and folic acid are believed to protect against colon cancer. ¹⁴

Some of the genetic factors involved in colorectal cancers include (1) the loss of tumor suppressor genes, such as APC (most common tumor suppressor mutation), p53, SMAD4 pathways, or TGF-ß pathways; (2) DNA mismatch repair defects: mutations in MLH1, MSH2 in hereditary nonpolyposis colon cancer or methylation of MLH1 in sporadic cases; and (3) CpG island methylation (CIMP pathway), methylation of MLH1, MINT1, MINT2, MINT3 ; and (4) activation of oncogenes such as RAS and BRAF.¹⁵

Pathogenesis

The colonic mucosa consists of epithelial cells arranged in cylindrical structures called crypts. The human colon contains about 10 millionŽcrypts. The cellular proliferation and migration in each of the crypts is believed to be tightly regulated, with the majority of cells arising from a small number of stem cells (around 4-6) at