The recent passing of actor and role model, Chadwick Boseman, from colon cancer has shocked the nation. This shock seems to not just be because it was the loss of an inspiring performer but also due to his young age. Chadwick was only 43 years old. Many people associate cancer with increasing age and whilst this is generally true, in recent years, cancer incidences have been increasing in younger individuals. The sad loss of Chadwick has made it clear to everyone that anyone can be affected by cancer. Therefore, we felt it necessary to write a summary about colon cancer, including the current treatments.
Background
The colon (large bowel or large intestine) is an organ that forms the final part of the digestive system. It plays a key role in reabsorbing fluids and processing waste products from the body to prepare for its elimination.
Common signs and symptoms of colon cancer include a persistent change in bowel habits (e.g. diarrhoea or constipation), rectal bleeding, abdominal discomfort and unexplained weight loss. For some people, obesity, diabetes, smoking or a family history of cancer may play a role in disease susceptibility. Nevertheless, not all people who develop colon cancer have these risk factors.
Diet in particular has a large influence on colorectal cancer risk and there is a lot of current research looking at the influence of drugs such as antibiotics and their impact on our gut microbiome. A recent study, published in the Journal of Translational Medicine, has depicted the immune microenvironment landscape of colon cancer. Researchers were able to provide further insight into the role of chronic inflammation in colon cancer and its potential use as a prognostic factor. The team found that immunity positively correlated with tumour mutational burden. Applying these highly mutated genes and their correlated signalling pathways may be important for identifying new immunotherapy targets.
Epidemiology
Colon cancer is the second most common cause of cancer death in the UK and third most common in the USA. Surprisingly, a recent report, published in CA: A Cancer Journal for Clinicians, revealed that since the 1990s, colon cancer cases among individuals under 50 have been increasing. The report stated that half of all new diagnoses are from people under 66 years of age.
Evidence has also shown that rates of colorectal cancer cases and death differ among racial and ethnic groups. Rates are highest in Black people. From 2012 to 2016, the rates in non-Hispanic Black people were about 20% higher than the rates among non-Hispanic White people and 50% higher than the rates among Asian-Americans and Pacific Islanders. While the cause for this disparity is multifactorial, a key implication is the obstacle in accessing care.
‘Vogelgram’
Colon cancer first begins with the presentation of polyps which are benign neoplasms. The slow polyp to cancer progression sequence often allows for the detection and removal of polyps early, before they undergo malignant transformation. There are several factors that influence this transformation, including genetic mutations, epigenetic alterations and local inflammatory changes. These alterations allow for initiation and progression of colon polyps into invasive adenocarcinomas.
Fearon and Vogelstein famously modelled the progression of colon cancer in 1990. This model involves a step that initiates the formation of benign neoplasms, followed by a step that promotes the progression to more histologically advanced neoplasms and then a step that transforms the tumours into invasive carcinomas. The model is based on the understanding that colon cancer is the result of a series of genetic mutations in key genes. This includes loss of APC and TP53 and activation of KRAS. Since its initial release, this model has seen many revisions. The true reality of colon cancer progression is much more complex and whilst these changes do occur, they do not occur in such a step wise manner.
Hereditary colon cancer
Of all colon cancer cases, around 5 to 10 percent are hereditary. Lynch Syndrome (also known as hereditary nonpolyposis colorectal cancer) and familial adenomatous polyposis (FAP) are two of the most common inherited colorectal cancer syndromes. Identification of rare germline mutations is critical in developing preventative and screening strategies.
- Lynch Syndrome: Lynch Syndrome is the most common hereditary colorectal cancer syndrome. It accounts for 2 to 4 percent of all colorectal cancers. It is caused by germline mutations in key DNA mismatch repair genes MSH2, MLH1, MSH6 and PMS2. The tumours are often characterised by microsatellite instability. It follows an autosomal dominant inheritance pattern; therefore, the risk of passing it on to potential offspring is 50%. Although not everyone who inherits the variant will develop colorectal cancer, the risk is very high – around 80%. Individuals are also at risk of developing other Lynch Syndrome-related cancers. This includes kidney, ovarian and stomach cancers.
- FAP: FAP is characterised by the presence of hundreds or thousands of adenomatous colon polyps. Most people with FAP will have multiple colon polyps by aged 35. FAP occurs due to mutations in the APC gene, a key tumour suppressor gene. It also follows an autosomal dominant inheritance pattern. FAP accounts for about 1% of all colorectal cancers. People with FAP have an increased risk of developing other cancers, including stomach, small intestine and liver. There are several subtypes of FAP.
Screening
In the UK, the NHS offers bowel cancer screening every two years to individuals aged 60 to 74. This involves a home testing kit, where a small stool sample is collected and sent to a laboratory. The NHS also offers a one-off test called bowl scope screening to individuals aged 55. This test involves a thin, flexible tube with a camera at the end used to detect and remove polyps. Individuals over 74 can request a screening kit every two years if they wish. In the USA, the U.S. Preventive Services Task Force recommends that adults aged 50 to 75 should be screened.
Genetic testing and genetic counselling are available for individuals with family history of colorectal cancer. Counsellors can provide guidance for early detection and prevention strategies.
The five-year survival rate for young individuals for early-stage disease is around 94%. However, for people with late stages of the disease, the survival rate can be as low as 20%. Therefore, early diagnosis can be the difference between life and death.
Treatment
The type of treatment used for colon cancer depends on several factors, including where the cancer is, the stage and the individual’s general health. The main treatments involve surgery and chemotherapy. If the cancer is in very early stages, it may be possible to remove just a small piece of the colon wall (local excision). However, surgeons must perform a colectomy to remove an entire section of the colon if the cancer has spread into the surrounding muscles of the colon. Later stages of colon cancer require combined treatment of surgery and chemotherapy.
Research into the mechanisms behind colon cancer have enabled developments in targeted therapies. These therapies can be used alongside chemotherapy or alone if patients are showing chemoresistance. Evidence has shown that these therapies associate with prolonged survival. With increasing knowledge of cancer pathways, new targets are becoming more prevalent.
Targeted therapy examples include:
- Cetuximab (Erbitux®): The first targeted agent approved for colon cancer treatment. It is an anti-EGFR drug, specifically targeting KRAS mutations. Oncologists often give this agent with chemotherapy.
- Panitumumab (Vectibix®): Panitumumab is also an anti-EGFR treatment approved for use in colon cancer. It specifically targets KRAS-mutated tumours. Oncologists often give this therapy in conjunction with chemotherapy.
- Bevacizumab (Avastin®): Bevacizumab was the first VEGF inhibitor approved for colon cancer.
- Ramucirumab (Cyramza®): Ramucirumab is an anti-VEGF therapy. It is used by oncologists for the treatment of patients with Stage IV metastatic colon cancer.
- Aflibercept (Zaltrap®): Aflibercept is an anti-VEGF agent. It has a stronger affinity to VEGF-A than bevacizumab.
- Regorafenib (Stivarga®): Regorafenib is a multi-kinase inhibitor that affects several signalling pathways, blocking VEGF signalling. Oncologists only use this therapy if all other lines for colon cancer have failed.
There are several immunotherapies for colon cancer in clinical trials. For example, a recent study, involving UCL and UCLH, showed that pembrolizumab more than doubled progression-free survival compared to chemotherapy in patients with a specific subtype of advanced bowel cancer. In addition, researchers have made efforts to develop a colon cancer vaccine to boost immune responses and ensure low toxicity. For example, a Phase I clinical trial last year showed safe and effective immune activation of the cancer vaccine Ad5-GUCY2C-PADRE. A recent study, published in the Journal for ImmunoTherapy of Cancer, showed that alterations to the adenovirus spike protein make GUCY2C-targeting vaccines less prone to being cleared by the immune system.
The Consensus Molecular Subtype (CMS) classification takes into account tumour pathological characteristics and gene expression. Although experts are still developing this system, it may in the future indicate prognosis and help guide in drug development and application.
Conclusion
Increasing awareness and reducing the stigma of colon cancer symptoms is critical to save lives. Colon cancer incidences in younger people are rising. Unfortunately, the time from symptoms to diagnosis for people under 50 is 271 days compared to 29 days for people over 50. Young patients often ignore symptoms, assuming that they will not be affected as they are young. Speaking to a doctor may also seem embarrassing for some individuals. Therefore, it is important that we encourage young individuals to feel comfortable when talking about their health. Another crucial barrier, in countries like the USA, is that many young people or those from deprived areas may not have health insurance.
We must speak out. We must inform and educate. We must end this stigma. We must save lives.
Image credit: By Image Team – canva.com
