From the Guidelines
Colorectal cancer (CRC) is a significant global health burden with substantial mortality and morbidity, ranking as the third most common cancer worldwide, with the most recent data indicating an estimated 106,590 new cases of colon cancer and 46,220 new cases of rectal cancer in the United States in 2024 1. The pathogenesis of CRC typically follows a sequential progression from normal colonic epithelium to adenoma and eventually to invasive carcinoma, known as the adenoma-carcinoma sequence. This process involves accumulation of genetic and epigenetic alterations, including mutations in the APC gene (initiating event), KRAS mutations, loss of chromosome 18q, and p53 mutations. Approximately 70-80% of CRC cases develop through this pathway. Other pathways include microsatellite instability, characterized by defects in DNA mismatch repair genes, and the serrated pathway involving BRAF mutations and CpG island methylation.
Risk Factors
- Age (increasing after 50)
- Family history
- Inflammatory bowel disease
- Lifestyle factors such as diet high in red/processed meats, obesity, smoking, and alcohol consumption Risk factors for CRC are multifactorial, including both genetic and environmental components. The most significant risk factor is age, with the majority of cases occurring in individuals over 50 years old. Family history, particularly in first-degree relatives, also plays a crucial role. Inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, increases the risk of developing CRC. Lifestyle factors, including a diet high in red and processed meats, obesity, smoking, and alcohol consumption, have also been linked to an increased risk of CRC.
Screening and Early Detection
Early detection through screening programs significantly improves survival rates, with 5-year survival exceeding 90% for localized disease but dropping below 15% for metastatic cases. The most recent guidelines recommend screening for CRC in average-risk adults between the ages of 50 and 75 years, with the selection of screening test based on a discussion of benefits, harms, costs, availability, frequency, and patient preferences 1.
Treatment Approaches
Treatment approaches include surgery, chemotherapy, radiation, and targeted therapies based on molecular profiling, highlighting the importance of understanding CRC's molecular pathogenesis for developing effective personalized treatment strategies. The incidence of CRC has been decreasing in recent years, with improvements in screening and treatment modalities contributing to this trend. However, the incidence of CRC in younger adults has been increasing, with unknown causes, and screening strategies need to be updated for appropriate screening and timely diagnosis in this population 1.
From the Research
Impact of Colorectal Cancer
- Colorectal cancer is the third most common cause of cancer mortality worldwide, with over 1.85 million cases and 850,000 deaths annually 2.
- The age-standardized rate of colorectal cancer increases by over 10-fold before the age of 50 up to ≥85 years, with men having ~50% enhanced risk compared to women 3.
- The number of worldwide deaths for colorectal cancer has been estimated at 0.88 million in 2018, representing ~1.4% of all-cause and ~8.9% of cancer-related deaths 3.
Pathogenesis of Colorectal Cancer
- Colorectal cancer originates from either the colon or rectum, and its pathogenesis involves the interaction of various cells in the tumor microenvironment to promote growth and proliferation of tumor cells 4.
- The disease progression usually takes between 7-10 years and can be asymptomatic, making early detection and diagnosis difficult 4.
- The leading risk factors for colorectal cancer include familial history, pre-cancerous conditions, tall stature, physical inactivity, overweight, large intake of alcoholic beverages, high consumption of red or processed meat, as well as modest intake of dairy products and foods containing wholegrains or dietary fibre 3, 5.
Treatment and Prevention
- The primary treatment for unresectable metastatic colorectal cancer is systemic therapy, including cytotoxic chemotherapy, biologic therapy, immunotherapy, and their combinations 2.
- Genomic profiling to detect somatic variants is important in identifying effective treatments, and targeted therapies such as cetuximab and panitumumab can extend median survival by 2 to 4 months compared to chemotherapy alone 2.
- Prevention is the most effective method for controlling colorectal cancer, and primary prevention includes determining and avoiding modifiable risk factors, as well as increasing protective factors such as physical activity and aspirin 5.
- Detection and removal of precancerous colorectal lesions is also an effective strategy for controlling colorectal cancer, and health policymakers should consider the best decision in identifying the starting age and selection of the most effective screening strategies for the target population 5, 6.