Colorectal cancer (CRC) is considered the third most common types of cancer globally. It is estimated that around 75% of CRC cases are sporadic suggesting environmental and genetic as contributing factors while 25% is the result of inheritance. Most of CRC develop on the inner lining of the colon or rectum starting as polyps and the chance of it developing into cancer is based on the type. The two main types of polyps are; adenomatous polyps also known as a precancerous condition with the potential to develop into cancer and hyperplastic polyps and inflammatory polyps that are more common but are not considered precancerous.
Most of the colorectal cancers are adenocarcinomas accounting for 96% which develop in the cells that produce mucus for the lubrication of the colon and the rectum. Some of the lesser common types of colorectal cancers include carcinoid tumors, gastrointestinal stromal tumors, lymphomas and sarcomas. In a majority of the cases, cancer remains undiagnosed until it has reached an advanced stage. Although the overall incidence of colorectal cancer for individuals over the age of 50 has decreased, according to the American Cancer Society, the trend of individuals younger than 50 years developing colorectal cancer has risen. Therefore, the American Cancer Society has now revised the guideline for screening for colorectal cancer at 45 years of age.
As colorectal cancer may not present any symptoms in the initial stage of the disease, the visual examination of the stool is important to detect the abnormality. Some of the symptoms associated with CRC include rectal bleeding, blood in the stool, changes in bowel habits such as constipation or diarrhea, abdominal pain, fatigue and weight loss. Although the current availability of chemotherapies and biologics has increased the survival of the patients, research is continuing to identify novel treatments to target the tumor.
According to a recent study conducted by the Indian Institute of Science, Education and Research, colorectal cancer can be detected with a simple test devised to identify the abnormal imbalance in the special AT-rich binding proteins. This can help with the early diagnosis of cancer and to help initiate an early treatment.
‘It is for the first time we found that any variation observed in the two types – SATB1 and SATB2 protein levels reported in cancer patients – can actually indicate the stage of colorectal cancer. Importantly, it can provide an estimation of the survival of patients,” Sanjeev Salande, lead investigator of the study told media.
Microsatellite Instability (MSI)
Microsatellites are the repeated stretches of DNA of the human genome and are prone to the high mutation rate. Microsatellite instability occurs because of a defective DNA mismatch repair system and it is used diagnostically for the tumor identification and classification. As MSI is a genetic marker for CRC which can be used for prognosis and the prediction of which chemotherapeutic treatment works, it can be detected indirectly by immunohistochemical (IHC) staining and by PCR-based amplification of specific microsatellite repeats. Also, the colorectal tumors with MSI tend to have a better prognosis than the other MSS forms of tumors. The three chemotherapeutics used for CRC treatment include antimetabolites, alkylating agents and topoisomerase inhibitors.
Colorectal Cancer Screening Guidelines from the American Cancer Society
In the United States, colorectal cancer is the second leading cause of death from cancer. The screening is associated with a significant reduction in the incidence of colorectal cancer and with the timely removal of precancerous lesions. According to the recommendation, adults aged 45 and above with the risk of CRC should undergo regular screening either by a visual examination or a high-sensitivity stool-based test and any positive result should be followed up with a colonoscopy. However, a strong recommendation is suggested for individuals over the age of 50 and above and for those aged between 76 and 85, screening should be based on the individual’s preference, health status and prior screening history. The screening options include fecal immunochemical test annually; multitarget stool DNA test every 3 years, computed tomography colonography every 5 years and flexible sigmoidoscopy every 5 years.
Advancing Colorectal Cancer Immunotherapies
With immunotherapy becoming the standard of treatment for several cancers, colorectal cancer has remained resistant and its efficacy has remained limited with a small percentage of patients with microsatellite instability-high. The Cancer Research Institute and Fight Colorectal Cancer convened to develop a blueprint for research and guideline development for the advancement of immunotherapy as treatment of colorectal cancer. In a clinical phase II trial, the use of pembrolizumab resulted in the stability of the disease among MSI-H patients which has resulted in the approval for pembrolizumab in all MSH-H cancer. Also, the advances in the taxonomy of colorectal cancer have resulted in the understanding of the pathways that are potential immunotherapeutic targets. Various studies investigated radiation or chemotherapy in colorectal cancer and some explored the effects of combining them with immunotherapy. However, several questions still remain which may be answered by performing deep immune phenotyping. Further studies are required that analyzes the genomic profiles of the patients which could help understand why some individuals respond well to immunotherapy while others don’t.
New Treatments approved by FDA
FDA recently approved the use of a combination of immunotherapeutics such as ipilimumab (Yervoy) and nivolumab (Opdivo) for certain individuals with colorectal cancer. The microsatellite instability-high colorectal cancer has shown responsive to the immunotherapeutic treatment by removing the brakes off immune cells called T cells. In May 2017, FDA approved the use of pembrolizumab for the treatment of metastatic solid tumor identified to be microsatellite instability-high or mismatch repair-deficient colorectal cancer and in August 2017, FDA approved nivolumab also. However, on July 2018, nivolumab in combination with ipilimumab was approved for metastatic colorectal cancer positive for microsatellite instability-high that had progressed following the treatment with cytotoxic chemotherapy. This approval was based on phase II clinical trial showing that 46 percent of the patients treated with the combination therapy presented partial or complete tumor shrinkage.