Tailor-made treatments: handling colorectal cancer16 February 2018
A team at MD Anderson Cancer Centre, Houston, made a scientific discovery that identified a rare subtype of colon cancer. This can be found in 2.2% of patients and harbours newly identified Non-V600 BRAF mutations, which have very slow tumour growth. Dave Callaghan speaks to the study’s primary investigator, Dr Humaid al-Shamsi, associate professor of oncology at the University of Sharjah, UAE, about how this finding will improve survival rates for patients with advanced colon cancer.
The disease that is commonly known as bowel or colon cancer is most accurately described as colorectal cancer, a major killer that is particularly potent in developed countries. It is the second most common form of cancer in women and third in men, with more than one million people being diagnosed globally every year. Out of these, a shocking 715,000 sadly pass away.
Colorectal cancer develops in the large intestine or rectum, and is usually caused by old age and lifestyle factors, such as smoking, obesity and lack of exercise. Diet can also be identified as a cause, with alcohol, and red and processed meats believed to be contributory factors. Genetics are only attributable to around 20% of cases, with the risk of getting this cancer rising by two or three times for people who have a close relative with colon cancer.
Bowel diseases – including Crohn’s and ulcerative colitis – can also lead to colorectal cancer.
Regularly screening 50–75 year olds helps to diagnose this cancer, especially as early detection is vital for a good prognosis. The removal of benign or cancerous polyps that are found during colonoscopy or sigmoidoscopy examinations is a prevention method that is routinely used in hospitals. Since the introduction of screening in the mid-1980s, death rates from colorectal cancer have fallen in the US and Europe.
For patients with bowel cancer, treatments depend on how advanced the disease is. Unfortunately, some sufferers are diagnosed too late, and the cancer has spread too far, meaning that chemotherapy or an operation are no longer viable – and palliative care is their only alternative. In other instances – for example, cases where the tumour is restricted to the colon – surgical removal can be a cure.
Symptoms include constipation, blood in stools, loss of appetite and weight, nausea and vomiting. Rectal bleeding and anaemia are further signs of colorectal cancer.
Research into the causes and nature of colon cancer has seen a breakthrough with the identification of a less aggressive form of the disease that progresses slower than other types. Treatment for this subtype can be less intrusive and will require milder chemotherapy.
Non-V600 BRAF mutations, as they have been called, are found in 2.2% of colorectal cancer patients. Survival rates for them are typically five or six years – or sometimes eight – whereas sufferers with advanced or metastatic cancer are expected to live for two or three years.
So what are Non-V600 BRAF mutations? BRAF is a human gene that contains a protein called B-Raf, which can mutate and lead to a cancer diganosis. Non-V600 BRAF mutations are a subtype that develop at a slower rate, requiring less aggressive forms of treatment, such as chemotherapy.
Slower growth and a better chance of survival
Prior to becoming an associate professor of oncology at the University of Sharjah, UAE, Dr Humaid al-Shamsi led a research team from MD Anderson Cancer Center at The University of Texas, Houston, US, which evaluated genetic mutations in more than 9,600 patients with colorectal cancer. Nextgeneration sequencing was used to analyse tumour samples and identify thousands of genes. Non-V600 BRAF mutations were found in 208 patients, and researchers identified 22 subtypes – many of which were detected for the first time. One in five of the BRAF gene mutations identified were reported to be in this category.
Patients with a Non-V600 BRAF mutation were more often male than female and also tended to be younger, with the average age being 58 compared with 68 in other sufferers.
“The importance of the identification of this rare subtype is to help physicians who select the best treatment options, given the long survival of this subtype of cancer, which can improve the survival rate of patients,” says Shamsi, the primary investigator.
“The challenge is to try to relate these genetic mutations with clinical care. Targeting the specific mutations can also help treat patients, especially those with advanced colorectal cancer.”
However, there are some limitations to the study’s findings. It is unclear, for instance, how resistant the Non- V600 BRAF mutations are to epidermal growth factor receptor drug treatments compared with cancers that have different mutations. We know that Non-V600 BRAF contain more RAS mutations, which can strengthen resistance to drugs.
While acknowledging the limitations of their findings, the researchers hope that their work will help to inform future clinical trials, as was the case in lung cancer research. They also plan to work with other groups to develop new treatments that will tackle the newly identified mutation.
“We are collaborating with other groups that are conducting basic research to try to identify how we can target the identified gene, which will help patients’ treatment plans and finding specific-target medications for them,” explains Shamsi.
In May 2017, scientists at Queen’s University in Belfast, Northern Ireland, found that by defining gene signatures in colon cancer cells, it is possible to tailor treatment to individual patients. They discovered that doctors can identify diagnoses where chemotherapy would have no effect. This breakthrough could prevent physicians from prescribing chemotherapy, which has serious side effects, to patients who would not benefit from the treatment.
Another development in colon cancer treatment also came in 2017, in the US, where researchers at the VCU Massey Cancer Care Center in Richmond, Virginia, identified a new approach for people with a predisposition to potentially dangerous polyps. By using a drug known as 2-hydroxy-imino phenylpyruvic acid (HIPP), the team found that targeting the CtBP gene in mice enabled them to cut the number of pre-cancerous polyps by half. CtBP suppresses genes that prevent cancer, and promotes others that lead to metastasis, a term for cancer that spreads from where it originated to a different part of the body.
This development could be a breakthrough for patients with the inherited disorder familial adenomatous polyposis, who sometimes need to have parts of the colon removed at a young age to prevent cancer developing. These researchers hope the same treatment may be possible in patients with breast, lung, ovarian, prostate and other forms of cancer.
In October 2017, the Francis Crick Institute announced that it had developed a less toxic drug for treating colorectal cancer. The new medication targets Wnt signalling from antigen-presenting cells (APC) in tumours, without preventing the signalling that is vital in other organs. Previously, drugs have acted generically and caused major problems in different parts of the body. Now, researchers must test if deleting the APC gene, which makes the protein, will prevent cancer in mice, and therefore in humans.
So there are significant steps towards a possible cure for colorectal cancer, as research identifies more sophisticated treatment options and achieves a greater understanding of how the disease develops.
With treatments having such nasty side effects, it is important that medicine does not apply a ‘one size fits all’ approach. Some patients will not benefit from certain treatments because of the type of cancer they have, and their quality of life may be seriously and unnecessarily affected.
Breakthroughs achieved by Shamsi and his team, as well as other research facilities, are extremely helpful. In the case of MD Anderson, discovering a particular subtype of colorectal cancer will allow doctors to tailor treatment packages to patients who have a slow-developing disease, giving them an appropriate level of care that does not necessitate the use of intrusive forms of treatment.
Scientists are playing their part, but it is important that members of the public do what they can to help themselves. Educating people about lifestyle factors that cause colorectal cancer – such as obesity and lack of exercise – is crucial to tackling the disease head on. People need to know how they can improve their life chances and avoid the possibility of developing any type of cancer by choosing healthier options.
Having said that, health authorities can also greatly help by introducing screening programmes for the age groups that are most at risk. For colon cancer, early detection is the key to starting treatments that are likely to actually work. In the Middle East, screening must be seriously considered, not only as a way of prolonging life, but also for avoiding the more expensive treatments that are needed to combat advanced forms of cancer.
They say prevention is always better than a cure, and this is especially true when one does not exist, as is often the case with patients suffering from colorectal cancer.
Colorectal cancer in numbers
- It is estimated that colorectal cancer will cause approximately 50,630 deaths in the US in 2018.
- In the US, one in 22 men and one in 24 women will be diagnosed with the disease during their lifetime.
- Over the past 40 years, the bowel cancer survival rate in the UK has gone from 22–57%, an increase of more than double.
- Colorectal cancer is the third most common cancer in the world.
- It is predicted that by the year 2035, there will be 2.4 million cases of colorectal cancer diagnosed every year worldwide.
Source: American Cancer Society, World Cancer Research Fund International and Cancer Research UK