I first published this blog on the Yes to Life website here following a great Forum put on by Yes to Life's Wigwam Cancer Support Group - in that we heard Dr Peter H Kay talk about genetics and more (i). It does seem extraordinary that this issue is not being more considered by the NHS? I would hugely welcome any feedback from others about their experiences? Is this something patient groups should be campaigning on?
Genetics is more than complicated to get my head around. Some regular blog readers might have seen my earlier blogs looking at the role of p53 and my own cancer here and the key role of epigenetics here. Well in thsi blog Peter kindly cast an eye over it before I published so hopefully this will make sense to folks.
What we need to know before chemotherapy or radiotherapy?
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Dr Kay on Zoom
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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.
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Reading lots to try and understand!
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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.
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See my blog & film re hyperbaric oxygen here
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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 metastasis (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/
