What is CAR-T therapy and why did NICE recommend against it?

You might have seen in the news today that NICE has denied patients access to a ‘pioneering’, ‘breakthrough’, ‘revolutionary’ treatment.

But what actually is this treatment?

CAR-T

CAR-T therapy is a type of immunotherapy that takes advantage of the cell killing capabilities of cytotoxic T cells. This particular type of T cell is an important part of the human immune system which for many years, researchers have hoped might be useful in treating cancer.

Cytotoxic T cells surround a cancer cell
Cytotoxic T cells surround a cancer cell (taken from NIH)

The problem is, cancer cells are derived from your own cells so your immune system has no reason to target them for destruction. That’s where CAR-T therapy comes in. In CAR-T therapy, the T cells of the patient are taken from the blood and genetically modified so they express a chimeric antigen receptor (CAR). A CAR is basically a signalling molecule on the surface of the T cells that allow them to recognise cancer cells as worthy of destruction. These genetically modified T cells are then put back into the patient’s blood to target and kill cancer cells.

Because we know that different types of cancer typically have different types of signalling molecule on their surface, we can then use different types of CARs to help draw the cell killing T cells to the cancer cells. For example – nearly all types of B cell acute lymphoblastic leukaemia (ALL) have a protein called CD19 on the surface of cells so researchers have been working on CARs that specifically target cells which have CD19 on them.

B cell lymphoma cell is recognised by a T cell which has a CAR protein expressed on it
Modified from here.

Yescarta

The specific therapy that NICE has reported on this week is one called Yescarta from a company called Kite Pharma. Yescarta consists of taking T cells from the patient then using a system hijacked from retroviruses to genetically modify the cells. The genetically modified cells are then reintroduced to the patient in a single dose.

Clinical Trials of Yescarta have been initially promising. A phase II single-arm trial found that of 101 patients treated with Yescarta, 54% had a complete response and 52% survived over 18 months. All of these patients had refractory large B-cell lymphoma – that means they had a type of blood cancer that had already failed treatment and the patients had an average expected life expectancy of 3-4 months. While the trial showed that all patients had significant adverse events related to Yescarta, only 3% of patients died from the treatment itself.

Yescarta logo

Based largely on this trial the FDA approved Yescarta for certain types of lymphoma late last year and the European Commission granted Marketing Authorisation for the treatment this month.

Why not recommend it?

But NICE had some concerns. Firstly, they were concerned that the clinical trials for Yescarta, while promising, were insufficient to allow recommendation of the drug. While this particular type of lymphoma doesn’t have a standard therapy, yet, most patients are treated with scavenger chemotherapy and the Yescarta clinical trials haven’t proven that Yescarta is better than scavenger chemotherapy. The two therapies haven’t been compared side by side. This is quite a significant concern because, without side by side comparison, we can’t be sure that diverting patients from one treatment type to the other is actually beneficial for the health and life expectancy of those patients.

NICE aren’t saying no to Yescarta, they’re saying “not yet”.

The second concern NICE has is that the treatment is currently very expensive. The cost to the UK has not been made available, but in the US the treatment can cost $373,000 per patient. And this is something that NICE has to weigh up in its cost-benefit analysis. So far, Yescarta has been shown to prolong life by approximately 14 months in around 50% of patients. Is it justifiable to divert so many funds to a treatment that only works 50% of the time and we can only say extends life by a year (so far)?

A woman standing at a laboratory bench facing away from the camera and wearing a lab coat

The company that makes Kite Pharma was bought by Gilead Sciences last year, just two months before Yescarta was approved by the FDA. Last year Gilead Sciences had a revenue of $30.4 billion and a free cash flow of $15.9 billion. Gilead Sciences spent $12 billion in order to acquire Kite Pharma and its marketable therapy Yescarta. NICE perhaps has reason to be cautious.

Any other concerns?

If Yescarta were approved for the use in the UK, it would be the first of its type to be approved. There are potential concerns we need to consider when introducing both genetically modified cells into patients and playing around with the immune system in patients. In his article for McGill, Jonathan Jarry pointed out that “Autoimmunity is when our immune system improperly responds to something that belongs to us” and in the case of Yescarta we’re actively training the T cells to recognise cancer cells derived from our own cells. In fact CD19 isn’t just expressed on cancerous B cells, it’s found on all B cells – even the healthy ones. In the case of terminal cancer this might be a price worth paying but it has to be taken into consideration. Sudden activation of T cells in the body is such a strong response that patients can get very sick and even die from a condition called cytotoxic release syndrome.

We must also consider the reproducibility of the initially promising clinical trials. There is evidence that when repeated, less than 50% of clinical trial results are reproducible and many negative clinical trials go entirely unpublished which means a high likelihood of false positives, it seems prudent to take care when making decisions based on single clinical trials.

Conclusion

NICE - national institute for health and clinical excellence logo

While many patients were hoping for the approval of Yescarta by NICE, the limitations have proved too high at this stage. I don’t think this decision should be used to criticise NICE or the NHS, rather to encourage further research using reliable controls and a focus on bringing down the prices of promising new treatments. It also highlights an example where the novelty of new treatments can overtake scientific sense and lead to approving treatments which might currently be lacking sufficient clinical evidence supporting their use.

Meanwhile, the NHS will not withdraw funding for any patients already undergoing Yescarta therapy and will reconsider their decision given further research or reduced costs.

 

 

Is Cannabis a Cure-all?

You might have seen in the media lately a lot of coverage about the use of cannabis to treat epilepsy and other conditions. It all started with the case of a young boy with severe epilepsy who was using cannabis oil to manage his seizures, with apparently great effect. Until, that is, his mother was unable to bring his treatment into the UK and his medication was seized at the airport.

These stories raise three questions:

  • What does UK law regulate in the case of medications based on cannabis
  • What is a cannabis oil?
  • Can cannabis treat any medical condition?

UK Law

In the UK, cannabis is a Class B drug – you aren’t allowed to possess or supply it and doing so can result in jail-time. This is a regulation under the Misuse of Drugs Act 1971, however cannabis is also regulated by The Misuse of Drugs Regulations 2001 which control the therapeutic use of drugs. Under this legislation, cannabis is regulated as a Schedule 1 drug which means it is not available for medical purposes and possession and supply are prohibited unless the Home Office approves.

cannabis plant seedlings

Cannabis: the sum of its parts

Cannabis refers to a group of plants which produce compounds called cannabinoids. Cannabis plants contain 113 different cannabinoids – so what exactly are we talking about when we talk about cannabis oil?

The two important cannabinoids to consider are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main part of cannabis that gives its psychoactive effects. It’s the compound that will make you feel ‘high’ if you smoke marijuana although this response is mediated by other cannabinoids too. It also stimulates release of the hunger hormone, ghrelin, which explains why people have an increased appetite when they take cannabis. It does this by binding to a specific receptor on the surface of cells in the brain.

CBD is non-psychotropic and it acts in a very different way to THC. But it might also enhance THC activity by increasing the number of receptors available for THC to bind to. It might also increase the levels of those natural endocannabinoids in the body.

In the UK, CBD is legal which means cannabis oils containing only CBD are legally available whereas THC is not legal.

four brown glass unlabelled bottles containing oil

Can cannabis treat disease?

In the UK, there are already two cannabinoid based treatments licensed for prescription. Nabilone is used to treat nausea and vomiting in people undergoing chemotherapy. There are other conditions it has been indicated for including IBS, fibromyalgia, chronic pain and parkinson’s disease however in the UK it is only permitted to help treat the side effects of chemotherapy.

The second cannabinoid based treatment available in the UK is Sativex which is used to treat the symptoms of multiple sclerosis including neuropathic pain and spasticity. Sativex is a cannabis extract which contains both THC and CBD.

Cannabis for epilepsy

When it comes to epilepsy – there is considerable evidence that THC can control convulsions through regulation of neuronal excitability and inflammation. But because it can make you high – it’s not an ideal avenue for therapeutic exploration.

Research into CBD for treating epilepsy is relatively new but initially promising at least for certain types of epilepsy and there is a drug awaiting FDA approval which can treat Lennox-Gastaut syndrome and Dravet syndrome, two severe forms of epilepsy. But this might not be sufficient in all cases – some patients may require different mixtures of THC and CBD to see an effect.

Cannabis for cancer

Cannabis can be useful in managing cancer-associated side effects in patients. It can act as both a pain reliever and a way to reduce nausea and enhance appetite. But there is early research that it might also kill cancer cells and stop them growing. In these cases researchers have looked at highly purified THC and CBD. Some trials have shown that combining chemotherapy with cannabis might have some promise. However, we have insufficient evidence to support its use as a cancer treatment either due to small study sizes or the research predominantly taking place in cells in the lab which is just not a good representation of what would happen in humans. We don’t know which types of cannabinoids are most useful, what doses are needed, what types of cancer respond, how to take them effectively and whether they should or shouldn’t be combined with other treatments.

Cannabis research

If cannabis is so promising, why don’t we do more research on it to bring it to clinical trial? Cannabis is a Schedule 1 regulated drug, it can only be used in research with Home Office approval. Schedule 1 drugs are so classified because they are not deemed to have medical usefulness. But researchers like Professor David Nutt are concerned that the medical usefulness of cannabis cannot be proven if research is prohibited.

Importantly, the recent media interest in cannabis use as a medical treatment has been useful in encouraging a UK government review on the therapeutic value of medications based on cannabis. This review will be undertaken by the Advisory Council for the Misuse of Drugs and may lead to a change in the legal status of cannabis and cannabinoids with regards to their use in medicine.

A woman standing at a laboratory bench facing away from the camera and wearing a lab coat

Alternative medicine

In the meantime, it is important to remember that while cannabis holds some promise as a potential therapy for many conditions, it is crucial to always follow professional medical advice when considering medical treatments. The research supporting cannabis use is limited and there are many questions about safety and efficacy that remain unanswered. For many conditions that cannabis might be useful for, we already have good medical treatments that can be used before considering an as-yet, unproven treatment. Cannabis oils are poorly regulated and might have wildly variable levels of cannabinoids and may even contain ingredients that are harmful. It is never advisable to buy medical treatments online or take medical advice from someone other than a qualified medical professional.

 

I talked more about this on my podcast, Skeptics with a K – on this episode. You can follow me on Twitter @AliceEmmaLouise for more.

Is sunscreen bad for you?

The weather has been glorious here in the UK, which means out come all the warnings to apply sunscreen copiously and frequently. It also means out come all the warnings that chemicals in sunscreen are dangerous.

But what does the science say?

Types of sunscreen

There are two main types of sunscreen: chemical or mineral. Chemical sunscreens contain chemical UV filters such as octinoxate and oxybenzone and some have retinyl palmitate added to them. Mineral sunscreens contain mineral compounds like titanium dioxide and/or zinc oxide. Chemical sunscreens absorb UV light and convert it whereas mineral sunscreens are reflective and act as a physical barrier. This means mineral sunscreens are often thicker and have a less pleasant texture on the skin and they leave your skin a little ghostly.

image of a person's knee with white sunscreen and a hearth drawn into the sunscreen

Chemical sunscreen – The warnings

When we see warnings about the dangers of sunscreen it tends to be related to three things:

  • Does chemical sunscreen cause skin problems such as contact dermatitis?
  • Does chemical sunscreen cause cancer?
  • Does chemical sunscreen cause birth defects?

So what are these concerns based on?

Contact dermatitis

Some people have skin reactions to chemical sunscreens – this occurs in less 1% of users and can be a response to fragrances, preservatives or the UV absorber itself. Sensitivity can develop after using a particular formulation for a long time. If you have a sensitive reaction to sunscreen you can try switching formulations, or you can switch to mineral sunscreen which is less likely to cause a reaction. And of course, see your doctor if you’re worried.

Causing cancer

Some studies suggest that oxybenzone can cause hormonal changes in cells grown in the lab. These hormonal changes have been confirmed in animals like mice but have not been reliably shown to occur in humans. Hormone changes can cause cancer so some people believe that oxybenzone can cause cancer. To date this has not been shown to be the case. Oxybenzone has not been shown to cause the DNA mutations needed to cause cancer and hormonal changes are not always linked to cancer. This evidence is insufficient to prove any link between oxybenzone and cancer.

an image of a small white mouse standing on a white background

Retinyl palmitate is sometimes found in sunscreen. Retinyl palmitate is derived from retinol or vitamin A and it acts as an antioxidant. Retinol generates reactive oxygen species (ROS) when exposed to UV radiation and ROS are able to damage DNA. This is the basis for the concerns that Retinol will cause cancer. Studies in mice did not show that retinol combined with UV radiation causes cancer. There is no data published in humans to suggest that retinyl palmitate causes cancer.

A recent meta-analysis confirmed that there is no evidence supporting an increase in cancer risk caused by sunscreen use.

Causing birth defects

There is evidence that medicinal retinol pills can cause birth defects however this has not been shown to be the case with topical retinol application. Still, as a precautionary method it is advisable that pregnant women do not use a sunscreen containing retinols for the duration of their pregnancy.

The context

It is important to note that while there may be some evidence suggesting some level of risk associated with chemical sunscreen risk – this must be taken within the wider context.

Skin cancer

There are two main types of skin cancer – melanoma and non-melanoma skin cancer. Non-melanoma skin cancer includes basal cell carcinoma and squamous cell carcinoma and is largely treatable if it’s caught early. Non-melanoma cancers are the most common type of cancer. Melanoma skin cancer is an invasive form of cancer that is the 5th most common and at late stages is usually considered incurable. At early stages it is highly treatable but this form of cancer can progress rapidly and requires early intervention.  Both types of skin cancer are on the rise in the UK and this is linked to increasing sun and sunbed exposure. UV light exposure accounts for 86% of all melanoma cases, in the UK. Studies in Australia have shown a reduced rate of melanoma with regular sunscreen use.

A white sunhat with a black ribbon on a table with a pair of blue lensed sunglasses

Does sunscreen prevent cancer?

There is evidence that regular sunscreen use reduces pre-cancerous conditions and prevents skin cancer. However, the research into the efficacy of sunscreen is highly variable. This is partly because people are prone to using sunscreen in order to extend their time in the sun and misunderstand the most effective ways to use sunscreen. Chemical sunscreens should be applied to the skin 30 minutes before going into the sun and should be reapplied every two hours or more often if you are perspiring or swimming. Even waterproof sunscreen will be removed by towelling down after a swim. Sunscreen does prevent sunburn however research shows that people who only rely on sunscreen to protect themselves from UV damage burn more often than people who also practice sun avoidance habits. A person who has suffered sunburn more than twice in their life is twice as likely to get melanoma.

So what should you do?

While there is evidence that chemical sunscreens can have some detrimental effects on the body – the evidence is overwhelmingly clear that over-exposure to UV light causes skin cancer. Not only that, the research shows that the benefits of using sunscreen far outweigh the risks. Unless you are completely avoiding any UV light exposure then in my opinion, using sunscreen is a risk worth taking. In addition to wearing sunscreen and reapplying regularly, you should aim to avoid direct sunlight during the hottest hours of the day or wear clothing that covers your skin. And don’t forget, you might not burn through glass but you can still get UV skin damage through glass!

Extra reading:

https://www.skincancer.org/prevention/sun-protection/sunscreen/sunscreens-safe-and-effective

https://www.consumerreports.org/cro/sunscreens/buying-guide/index.htm

https://www.popsci.com/sunscreen-harmful#page-2

 

Kitchen cupboard “cures” – number one: turmeric

Wouldn’t it be great if we could cure all our ills with ingredients we can find in our kitchen cupboard? Plenty of people claim that it can be done and with the popularity of ‘natural’ medicines it’s not just your Nana who recommends it because that’s what her Nana taught her.

Kitchen cupboard remedies have become so mainstream that they become potentially dangerous when recommended for life-threatening diseases such as cancer. In fact, just a few months ago the Express asked “Can turmeric really cure cancer? Woman says benefits of golden spice ‘cured’ her disease”.

the express
Headline from the Express: “Can turmeric really cure cancer? Woman say benefits of golden spice ‘cured’ her disease”

But sometimes we wonder, if so many people believe it, maybe there’s really something in it?

In this series I will cover kitchen cupboard “cures” to investigate the claims made, and what the science really says. The series begins with the tasty Indian spice turmeric.

Turmeric

Turmeric is often reported as some sort of wonder spice. People who promote its use claim turmeric is anti-inflammatory, reduces cholesterol, treats diabetes, prevents Alzheimer’s disease and both prevents and cures cancer.

glass jar of orange coloured ground turmeric on a tea towel with a wooden spoon on the worktop next to it and turmeric on the spoon and counter

But actually, while this seems like a bizarre old wives’ tale, there is evidence supporting some of the claims for turmeric. The active ingredient in turmeric is curcumin or diferuloyl methane. Experiments in the lab show that curcumin alters the expression of genes in cells and some of these genes are related to specific pathways. For example, curcumin alters the expression of proteins related to inflammation in rat liver cells in a petri-dish and also alters the production of cholesterol in cells. Curcumin supplementation might also help manage some of the side effects of diabetes but only in conjunction with standard therapy. There is even some early evidence from mice with Alzheimer’s disease that curcumin can slow cognitive decline.

However, the science is also quite complicated. When it comes to cancer there is some evidence that curcumin can slow the growth of cancer cells in the lab but plenty of things slow cancer growth in the lab and never go on to prove useful therapies. Having said that, some clinical trials have shown that curcumin might one day prove useful as an adjunct to some cancer treatments in some cancer patients with some types of cancer.

The Express article above did discuss a case of a woman with myeloma, a type of blood cancer. This article was based on a single case published in British Medical Journal Reports in which a patient who had been on conventional treatment for many years suffered a relapse and was advised that there was nothing else doctors could do to help treat her cancer. The patient decided to take 8g chemical curcumin in tablet form per day in the hope it would treat her cancer. Her cancer has subsequently stabilised. This is a potentially interesting case – however it is only one single case that has been observed. Subsequent studies have not been done to investigate why this patient stabilised and there is insufficient evidence that it was the turmeric that was responsible. In fact, there are rare cases in which cancers such as myeloma can go into spontaneous remission without treatment and doctors believe this might be due to the patient’s own immune system targeting the cancer cells.

Important caveats

It would seem that the early research is fairly promising, however there are some very important caveats to remember here. So far, these studies are largely done in cells in a petri-dish or animals like mice or rats. We are not yet able to translate the findings to humans and we’re a long way from finding useful therapies using this compound.

Importantly, the studies use chemical curcumin rather than dietary turmeric and usually have specific measured doses. If curcumin becomes a useful therapy, the dose will change between different diseases and different patients. There is no evidence supporting the use of turmeric in isolation to treat disease. In all studies it is used as a supplement to standard therapy.

Clear capsules with orange powder inside

Medical treatments should always be managed by a medical professional. Any ‘herbal’ remedy has the risk of interacting with conventional drugs. In the case of curcumin research has shown that the chemical can inhibit some cancer treatments so it is important we understand the role curcumin plays in reacting with other medications before using this to treat patients.

It is because of this risk of interaction with other medications that it is really important patients taking any herbal remedy supplements speak to their doctors about whether these supplements might harm themselves or the efficacy of their treatments. It is important to note that many supplements are not fully regulated and therefore may contain ingredients that cause harm. For example, some curcumin supplements have been shown to contain anti-inflammatory drugs which can cause liver damage if taken in excess.

Summary: while there is some early evidence the active ingredient of turmeric might one day prove a useful supplement to conventional therapy we’re a long way from this being clinically useful. We need much more research to confirm the efficacy of curcumin and to establish which compounds work best and at which doses.

Next week I’ll be writing about Rosemary. If you have any specific requests for a Kitchen Cupboard “Cure” for me to cover, please leave a comment or send me a tweet @AliceEmmaLouise.

For more information on turmeric and cancer you can see CRUK’s review.

Sources:

 

 

 

Skincare, anti-aging (and cancer)

The world of skincare is not a place for the faint-hearted. It is such a dizzying mix of advice and recommendations, advertising and ‘science’ that any wander through this world leaves you feeling like you are not doing enough for your health or appearance. The only way to make yourself feel better, it would seem, is to spend sometimes hundreds of pounds on products you will use religiously for a few weeks before you end up exhausted by all the time you’re spending slathering on potions, oils and creams.

Why do we do it?

There are a range of reasons we feel we have to invest time, money and energy into our skin. One of the main reasons seems to be to maintain a youthful appearance for longer. Anti-aging is a huge part of skincare marketing and people (women especially) are targeted from an early age to start protecting their skin from the effects of aging.

The science of aging

There are two types of aging – intrinsic and extrinsic.

Intrinsic aging is the type that is genetically accounted for. It happens naturally pretty much no matter what you do. This is the kind of aging that leads to changes in skin elasticity. This type of aging is also called chronological aging and is the one you cannot really do much to change.  The characteristics of intrinsic aging include smooth, unblemished skin with a loss of elasticity, fine wrinkles and paling of the skin. The skin gets thinner and the small blood vessels in the skin reduce in quantity.

In addition to the natural course of aging, we also have extrinsic aging. This is the one our behaviour has a say in. By far, the two biggest factors which cause extrinsic aging are smoking and exposure to UV light.

Smoking reduces the elasticity of skin and reduces collagen levels in the skin. This means the skin gets hardened, slack and rough. We have evidence from multiple studies over a number of years showing that smokers have increased wrinkling compared to non-smokers. The evidence is consistent and overwhelming – smoking tobacco increases skin aging.

Photoaging

Exposure to UV light from the sun is thought to account for up to 90% of visible skin aging. UV light causes an increased level of specific proteins in the skin called enzymes. The enzymes that are increased in skin exposed to sunlight are responsible for degrading important connective tissue. After repeated exposure the skin starts to sag and to form wrinkles. Sunlight exposure increases the production of reactive oxygen species (ROS) and free radicals in the skin. ROS and free radicals damage the DNA which increases your risk of skin cancer, but they also increase the levels of those degrading enzymes even more. In addition to all of that, UV radiation interferes with the immune system and may even prevent cell death in sun-exposed skin which can also contribute to an increased risk of skin cancer. The characteristics of photoaged skin include nodular, leathery, blotchy skin with coarse wrinkles and furrows. The skin has irregular pigmentation and obvious marking on the skin and the elasticity is severely damaged. Blood vessels become dilated and there is pronounced inflammation.

What works?

It should be clear, now, that the two most useful ways to prevent visible skin aging are to minimise intake of cigarette smoke and to minimise skin exposure to damaging UV rays.

Sunscreen

To protect your skin from UV damage, applying a daily sunscreen with a high factor SPF and high-quality UVA protection (4 stars or above). SPF protects your skin from burning and from the damage associated with that but it does not protect against UVA radiation. UVA damage is invisible, although it does cause darkening of pigmentation, and is very deeply penetrating. You need a sunscreen that protects against both UVA and UVB damage.

image of a person's knee with white sunscreen and a hearth drawn into the sunscreen

Topical Retinoids

While most skincare products have very little evidence supporting their use in preventing or reversing the signs of aging, there is one active ingredient that does seem to help.

Retinoids are a family of chemicals which include retinol (vitamin A) and similar compounds. The potential of retinoids in treating aging was discovered in the 1980s when scientists treating photoaged mice noticed repair of the skin and reduction in wrinkling. We now know that retinoids encourage cell growth and can reverse some of the effects seen in photoaged skin and you can buy skincare products which have retinoids in them. There are two downsides to using retinoids on your skin – firstly, retinoids can cause some sensitivity making the skin red and sore which means some people cannot use it at all and most people need to build up their usage from a low dose (0.1%) used infrequently (1-2 times per week). Retinoids can also make your skin more sensitive to UV damage. This means if you are using retinoid skin products you need to be extra careful about staying out of the sun.

Prevention is better than cure

Ultimately, the best thing you can do for your skin to prevent visible aging is to protect it from harmful damage caused by smoking or sun damage. Of course, if you enjoy the relaxation of using different products on your skin, then go right ahead. But the best way to protect your skin is to use a decent sunscreen and to refrain from smoking.

You will also be doing wonders for your risk of lung and skin cancer!

Sources:

Read more about skin cancer here:

http://www.cancerresearchuk.org/about-cancer/skin-cancer/about-skin-cancer 

 

 

 

A list of alternative cancer therapies and a Good Thinking Society

Recently I worked on an interesting project with the Good Thinking Society.

The Good Thinking Society are a great charity who are small in size but are making great waves. The charity was founded by Simon Singh and their goal is “to encourage curiosity and promote rational thinking”.

One thing the Good Thinking Society does excellently is working in the medical field – they have been fundamental in changing the environment of NHS funding for treatments which lack scientific support for their use.

In 2010, The House of Commons Science and Technology Committee reported that homeopathy is no better than placebo. Despite this, this scientifically implausible treatment continued to be funded on the NHS to the tune of three to five million pounds per annum. This is a figure that the Good Thinking Society determined after working systematically through each CCG in the UK to identify which of them continued to fund homeopathy and how much they spent. Good Thinking Society supported many of those CCGs still funding homeopathy in reviewing their funding policies and succeeded in initiating the removal of this funding in many areas across the UK. They have also been instrumental in NHS England calling for homeopathy to be added to the NHS Blacklist of items which cannot be prescribed by GPs.

Good Thinking Society have some excellent resources on specific alternative therapies which you can find under their heading ‘Good Thinking About’. In particular they have an excellent primer on Gerson Therapy, a ‘treatment’ promoted as a cure for cancer which I have discussed here before.

Recently, I helped the Good Thinking Society compile a list of treatments which might be offered by alternative practitioners to vulnerable cancer patients. The list brings together a summary of the evidence for each treatment and outlines some of the potential risks and dangers of those treatments.

Here is a sample from this list:

Cancer list

Go take a look at their website and the list of alternative cancer treatments. And while you’re there – donate to their cause. They exist on donations and they need your support.

How many mutations does it take to create a cancer?

Last week I wrote a post all about how we understand cancer to arise. I explained how mutations in certain genes for certain proteins can drive cancer and I explained some of the important families of proteins such as oncogenes and tumour suppressors.

But even that complicated post was an over-simplification. Sure, a single mutation in a single gene for a single protein might cause cancer, but actually we know that many cancers have several mutations. Sometimes, several hundred mutations.

Several hundred mutations

many mutations per cancer
Image adapted from this paper. A graph showing a number of non-synonymous mutations per tumour against tumour types ranging from colorectal cancer to glioblastoma. (See the text for some example figures).

The above is an image which shows just a few examples of some cancer types and the number of mutations you might expect to find in them. Recognise the word non-synonymous from last week? Non-synonymous mutations are those which cause a change in a protein. Whereas synonymous mutations are effectively “silent” (they don’t change a protein) so we tend to focus on non-synonymous ones when it comes to disease. You can read more about them here.

From the image you can see that some types of cancers can have several hundred mutations per tumour – colorectal cancer for example can have between 500 and 1200 mutations. Lung cancer can have between 100 and 200 (interestingly this is much lower for lung cancer in the “never-smoked” category which has a considerably smaller number of 25) and breast cancer between 25 and 100 mutations per tumour.

The problem

What this means is that when it comes to understanding what drives cancer we need to know how many of these mutations are actually relevant to the disease. Do they all contribute to “driving” cancer or are some of them “passenger” mutations? If only a few contribute, then how many?

Often, we treat cancer by designing drugs which target specific proteins. If we suspect a cancer is “driven” by an overactive protein then we can treat patients with an inhibitor of that protein – something that blocks the protein’s function. But for us to do this, we need to know which mutation, potentially hundreds, is actually relevant. It’s like trying to find a needle in a haystack.

The study

The paper published in October 2017 in Cell is an analysis of 7,664 tumours across 29 different tumour types. They looked at all of the mutations each of those tumours had and focussed on the non-synonymous ones, the ones that actually change the proteins inside the cell. But they knew that even with protein changes, not all of the mutations present actually cause cancer. They wanted to establish how many might be responsible for the disease.

“Normal” cells acquire mutations all of the time but this happens at random so sometimes it will affect proteins and sometimes it won’t –  we get a reliable mixture of non-synonymous and synonymous mutations that are all mostly harmless even if there is a change in a protein. This is useful information because we can establish an “expected” ratio between the two. In cancer cells, the mutations that change proteins and allow a cell to survive and grow more than it should (i.e. the mutations that drive cancer) are passed on to more cells as the cancer cells replicate. This means you get a skewed ratio in cancer cells – more non-synonymous mutations than synonymous ones. By figuring out how many more mutations there are than we expect from the “normal” cells we know that those are the ones allowing cells to replicate in an uncontrolled way – therefore those are the ones that are driving the cancer.

And that’s exactly what the authors of this study did.

What they found

What they found was that although some cancer cells have hundreds of mutations, only a few of those actually drive the cancer. The average number of cancer drivers per cancer type is just four and the numbers only range from one to ten. So, we can narrow our focus to between one and ten mutations per tumour. We just need to figure out which ones.

This is phenomenally useful information because we can then build further on this knowledge to understand which mutations are the common driver mutations and focus our drug development on those specific mutations. We have a significantly smaller haystack and we can start to really get very specific with our cancer therapies! The better our understanding of how cancer really works, the more complete our understanding of all of the complicated processes involved, the better able we are to design clever therapies that really benefit patients.