What we need to know before chemotherapy or radiotherapy?

I recently joined one of the Wigwam cancer support group forums (i) with Dr Peter H Kay who introduced us to the idea that our genetic profile can significantly influence whether chemotherapy or radiotherapy will be helpful or harmful. For example studies into chemotherapy have shown that about 25% of patients die or have a shortened life because of this form of treatment.

The information that Peter shared in the forum made it one of the most important talks I’ve heard about conventional treatment. It is complicated. The language alone is enough to give me a headache. Yet as I grappled with the science it became increasingly clear that this information should be in the hands of more people. Indeed why are the NHS not routinely testing in the way Peter suggests?

In the talk Peter, who is an Australian trained Molecular Pathologist, Immunopathologist and Cancer Specialist, discussed the significance of some of the more important genetic aspects to be considered to optimise the effectiveness of chemotherapy. Considerations include reference to the genes that encode the proteins p53 and CYP2D6 as well as a gene called MDR1. The gene MDR1 encodes a protein that causes multidrug resistance. He also spoke briefly about the importance of oxygen in radiotherapy. I will introduce them in more detail below.

TP53

The gene TP53 encodes a protein called p53. The protein p53 plays a very important role in many aspects of development, progression and treatment of cancer. It is a type of tumour suppressor protein that inhibits the development of tumours. It has been called “the guardian of the genome,” and when inactivated, it permits the growth and spread of cancer. Around half of all cancer cells have developed a mutant form of the TP53 gene.

Broadly speaking it seems there are two types of mutations; germline and somatic. Germline mutations are heritable. These mutations are present from birth and affect every cell in the body. Genetic tests are now available and folks can check for several germline mutations that increase cancer risk, such as mutated BRCA1 and 2 genes. Germline mutations in the TP53 gene are not common. Indeed it should be noted that less than around 7% of all cancers are due to germline gene mutations. Most cancers are associated with a somatic mutation.

Somatic mutations are acquired. They are not present from birth but come about from the process of a cell becoming a cancer cell. In contrast to germline mutations there are a wide range of cancers that are associated with somatic mutations in the TP53 gene including most lung cancers and 20-40% of breast cancers. Somatic mutations are only present in cancer cells and not in other cells in the body.

Damage to the TP53 gene can be due to cancer-causing substances in the environment (carcinogens) such as cigarettes but often the toxin leading to the mutation is unknown. Mutations are also caused by exposure to radiation and ultraviolet light and viruses. Somatic mutations also occur when DNA repair genes are faulty.

Recent studies have shown that the presence of mutant forms of TP53 may reduce the benefits of chemotherapy and radiotherapy.

DNA sequencing tests can easily be done on DNA samples isolated from a blood sample or a cheek swab to identify germline mutations. Somatic mutations however can only be identified by sequencing DNA or RNA isolated from the cancer cells themselves, usually requiring a biopsy.

If a cancer is found to have a somatic TP53 mutation, other forms of treatment, other than chemotherapy or radiotherapy, may be more suitable

CYP2D6

Many chemotherapeutic drugs are administered in an inactive form called a pro-drug. When pro-drugs are absorbed into the bloodstream, they need to be activated by certain enzymes within the cytochrome P450 enzyme system   before they can be of help. CYP2D6 is a key pro-drug activating enzyme that is encoded by the CYP2D6 gene mainly in the liver. It plays a key role in the metabolism and elimination of the drugs and toxins we ingest.

We inherit different functional forms of cytochrome P450 family members such as CYP2D6. Some people inherit CYP2D6 enzymes that work very poorly. These people may not activate pro-drugs adequately for drugs to be effective. Others inherit CYP2D6 enzymes that are highly active. These people may activate pro-drugs too quickly leading to an overdose effect. Most drugs are designed to work best in those who have inherited a CYP2D6 enzyme with intermediate activity.

An example that is currently being researched is Tamoxifen. This treatment can reduce a woman’s risk of developing a second primary breast cancer, but there is substantial variability in response to treatment. Some of this may be attributed to germline genetic variation because Tamoxifen is a pro-drug activated by CYP2D6.

MDR1

Many cancer patients develop resistance to the very chemotherapy drugs designed to kill their cancer. Even more problematic, it seems that once a patient’s tumour is resistant to one type of chemotherapy, it is much more likely to be resistant to other chemotherapies as well. This is known as multidrug resistance. Once patients reach this point, the prognosis is often poor.

Several genes are recognized as playing a role in multidrug resistance in cancer; key amongst these is the multidrug resistance-1 gene (MDR1). MDR1 inhibitor drugs have sadly not been successful in clinical trials with cancer and it is now thought the reason maybe because it impacts on our natural immune responses (ii).

Development of multidrug resistance by cancer cells is the greatest obstacle against efficacy of chemotherapy. Multidrug resistance is often referred to as the “Oncologist’s nightmare”. Knowing the extent of MDR1 gene expression in cancer cells would be useful in determining further chemotherapy or not. If multidrug resistance is present in cancer cells, then other treatment options such as immune based therapies should be considered.

Tests for the presence of multidrug resistance require a sample of the cancer cells usually by way of a biopsy.

Oxygen and radiotherapy

Radiotherapy is about using shaped beams of high radiation energy, light or particles to induce cell death in tumour cells, whilst sparing healthy cells; up to 60% of cancer patients will receive radiotherapy in the course of treatment.

Yet we don’t get to hear about oxygen and the key role it plays in the replication of cells and growth of tumours. Research has shown that oxygen deficient tumours create their own networks of blood vessels to sustain themselves and develop their capacity to metastasise (ie spread the cancer to other parts of the body).

Oxygen also plays a key role in radiotherapy; a well oxygenated tumour responds up to three times better than those with less oxygen. Knowing this opens up huge possibilities for cancer treatment, one very promising example being researched is to have hyperbaric oxygen before having radiotherapy. There seem to be similar benefits from this approach with chemotherapy.

Good news story

Recently work is being done around the widely used fluoropyrimidine chemotherapy drugs such as 5-fluorouracil (5-FU). This powerful class of drugs is proving useful in the treatment of many cancers.

The fluoropyrimidine class of drugs are usually administered intravenously in an active form.  They are metabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) enzyme encoded by the DPYD gene. The problem is that around 5% of people have a genetic deficiency of DPD and less than 0.1% of people have a complete deficiency. This means they are unable to break down the chemotherapy agents and in a small number of cases it will lead to rapid life threatening toxicity.

The good news is that some NHS hospitals, like Manchester, have started to save lives by screening for the DPYD genotype prior to fluoropyrimidine treatment (iii). When will they also start to look at other genetic tests?

Where can we get tests done?

In view of the benefits of genetic testing for germline and somatic cell mutations, it is possible that oncologists, clinicians and general practitioners will have access to helpful genetic tests locally within the NHS system (iv). You should seek these tests from them.

Other approaches

In recent times, new immune based treatments like CAR-T cell therapy and immune checkpoint therapy and the use of monoclonal antibodies have been developed by harnessing elements of the immune system. These immune based treatments avoid many of the problems associated with chemotherapy and radiotherapy. Let us hope these and other treatments will provide more answers and ways forward.

It is also worth mentioning epigenetics. We may not be able to change our genetics but we are not a victim of them. What we can change is the expression of our genes – and that’s what epigenetics is about. Some of the epigenetic changes may have a serious impact like cancer, but it is clear that these can still be modified by lifestyle choices and environmental influence.

Understanding our genetics can play a key role in choosing conventional treatments like radiotherapy and chemotherapy – but also adding support like lifestyle and complementary approaches. It would be great to have access to these important genetic tests on the NHS. Having access to this information could have a significant impact on the quality of lives; avoiding for example, harsh chemotherapy treatments that have no benefits.

Course on offer

Peter has prepared a course based on past and present advances to provide a wide range of genetic, biochemical, metabolic and immunological information. It is aimed at patients, practitioners and students of the health sciences to enable them to understand many aspects of the development, progression and treatment of cancer. The normal charge for the course is £200, however, if interested, members of Wigwam support groups can take the course for £100. For details and further information contact Dr Peter H Kay at: peterhkay@gmail.com

Notes

Philip would like to note his thanks to Dr Peter H Kay for the talk and acknowledge that this blog is based on his understanding gained from Dr Kay. Philip also notes that of course people should consult their cancer specialist before making any decision that could affect their treatment.

(i) For Wigwam Forums see: https://www.wigwam.org.uk/forums-and-webinars

For a video of Peter’s Forum with Wigwam register on the Wigwam website in top right hand corner to get access to the talk:

https://www.wigwam.org.uk/resources

You can also hear Peter in a Yes to Life Radio Show: https://www.ukhealthradio.com/blog/episode/critical-information-molecular-pathologist-and-cancer-specialist-dr-peter-kay-wants-people-considering-chemotherapy-to-be-aware-of-genetic-tests-that-could-save-their-lives/

(ii) https://www.sciencedaily.com/releases/2020/04/200417114440.htm

and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915407/

(iii) https://mft.nhs.uk/dpyd/

(iv) Genelex in USA offer CYP2D6 and DPYD typing. See  https://www.genelex.com/test-menu/