Thursday, 3 April 2014

Guest Post - Genetic Alliance UK: The My Condition, My DNA Project

 My Condition, My DNA

Would you be willing to take part in a research study to help us understand what patients affected by genetic conditions and their families think about the use of genomic sequencing in the NHS?

When the first person had their entire DNA sequenced as part of the Human Genome Project back in the 1990s, it took over 12 years. Today it is possible to have your entire genome sequenced in just a matter of weeks. A new technique has been developed which means it is faster and cheaper to do this, and as a result has the potential to dramatically change the way that conditions may be diagnosed and treated.

The aim of this research is to find out what patients and families think about genomic sequencing. This will involve exploring the ethical, societal and practical issues raised by the NHS using genomic sequencing to collect large amounts of an individual’s genetic information with the view to improving healthcare. As the ease of genomic sequencing and its potential uses becomes greater, people working in the NHS and other healthcare providers will be thinking about these issues and making decisions. By being a part of this research, you can help to bring the perspective of patients into the decision making process and form a key part of shaping how genomic sequencing could be used in UK healthcare to benefit patients.

What is the purpose of this project?

To help patients and their families understand what genomic sequencing is and how it might be used in a healthcare setting; and to understand from them their opinion of the ethical, societal and practical issues raised by using genomic sequencing in the NHS.

Who can take part?

If you or a member of you family has a diagnosed or suspected genetic condition we would like to hear from you. We are particularly interested in having families take part. This may include children under the age of 18, although an individual under 18 cannot take part without a parent or guardian.

Friday, 28 March 2014

The Medical Innovation Bill

What happens when you reach the end of the road with the standard cancer protocols? A patient starts with first-line treatments, usually a combination of chemotherapy, surgery and radiotherapy, depending on diagnosis and disease staging. If the response to that first-line isn’t positive, the disease continues to spread, then there’s a second-line and possibly a third-line treatment, depending on the type of cancer and how the patient responds to these often toxic treatments. And if the disease is still there at the end of this gruelling process? At this point the prognosis is pretty grim. What happens then?

At this point I should say that I’m speaking from direct personal experience with my son, George, who died almost three years ago from metastatic osteosarcoma that resisted every treatment thrown at it. And from the experience gained in the years following his death in trying to help other people in a similar situation, often also suffering from Li Fraumeni Syndrome as George did.

What happens? In the first instance the lead oncologist will often look for a clinical trial, hopefully a Phase II or Phase III trial. But often the patient will have already been on a trial and come out the other side with the disease still active. In practice if there are trials available, and often they are not, it will be a Phase I trial. The aim of a Phase I trial is to find the right dose to use in a Phase II trial, which is looking to see how well a drug works. Efficacy – how well the drug works – isn’t normally the primary outcome from a Phase I trial.

And if there’s no trial, or you don’t want to go on a Phase I trial with a new drug that might have toxic side effects and no effect on your disease? Then you are in the realm of palliative care. If there’s no standard treatment and there’s trial, then the emphasis is on trying to keep a lid on the symptoms and trying to preserve what quality of life you have given the advanced state of the disease.

But what if there’s something that doctors are using in another country? What if there’s a drug that has been shown to have some effect in your type of disease? What if there are other options that aren’t covered by the standard protocols?

Thursday, 13 March 2014

Curcumin - Bioavailability Results

I have written before about curcumin, the yellow pigment from the spice turmeric, and its anti-cancer properties. In the lab there is ample evidence from petri dishes and test tubes, and evidence too from animal experiments aplenty. It seems to act in multiple ways across a wide range of different cancer cell types. On paper at least, it's one of the most promising of the food-derived agents and there are lots of people who are convinced that by itself it can act to protect from the toxicity of chemotherapy and radiotherapy, to act directly against the inflammation implicated in cancer-initiation and as a drug to kill established tumours. The reality is somewhat less impressive than all of the lab work suggests and the clinical trials to prove one way or another are mostly still in progress or not on the drawing board.

One trial that is in progress I have written about previously (www.anticancer.org.uk/2011/12/curcumin-trial-in-uk.html). It's a UK trial looking at curcumin combined with standard chemotherapy for inoperable colorectal cancer. The same team behind the trial have published some interesting results on one of the main issues in the use of curcumin as an anti-cancer drug: bioavailability. Like many other polyphenols with anti-cancer properties, such as resveratrol or quercetin, curcumin suffers fom low levels of bioavailabilty. This means that to get a therapeutic level a person has to take an awful lot of the stuff, and even then it's often doubtful how much gets through digestion and metabolism and into the tissues to do any good. In this trial patients took 5 × 470 mg (2.35 g total) tablets of Curcumin C3 complex for two weeks. This is a relatively low dose compared to some trials where patients took 6 g or even 12 g a day - that's a lot of tablets to take - and the question was whether this dose would even be detectable or not.

The first thing to report is that few patients (six of 24) reported side effects, and these were mild tummy upset, in contrast to studies with higher doses. In this trial only one patient out of 24 reported unpleasant side effects after two weeks of curcumin. The suggests that a good dose for future trials is between 2 and 3 g of curcumin a day. Blood tests revealed that curcumin was detectable in nine of 24 plasma samples, all 24 urine samples, and in the colonic mucosa of all 23 biopsied participants. High levels of topical curcumin persisted in the mucosa for up to 40 hours post-administration.

At the same time this trial asked patients about what they felt about taking curcumin as a treatment. Sixteen participants (67%) stated that they would take curcumin long-term should it be of proven benefit, providing further support for future trials.

While this is a long way from showing that there is a direct clinical benefit from taking curcumin, it's another small step in the right direction. The trial has established a dose that gives detectable levels of curcumin and its metabolites in the colon and has shown that there's some support from patients - with the important proviso that it's shown to be beneficial. And for that we still have to wait.

The results are published as open access here: http://cancerpreventionresearch.aacrjournals.org/content/6/2/119.long

Friday, 21 February 2014

What does significant mean to you?

What does the word significant mean to you? In general usage it's another word for important or substantial, but when it comes to scientific results there's a very different spin to the word. In science results are usually classed as being 'statistically significant', and by science we include medicine and medical research. Very often new results are announced and we are told that these are 'significant', this is particularly the case when these results are announced in the press, especially the popular press rather than the scientific press. The magic phrase 'statistically significant' often gets turned into 'significant', and for the reader not aware of the difference between the two it's normally taken to mean that a result is important or substantial.

Unfortunately 'statistically significant' is just a way of saying that there's only a certain chance that the results could have happened by chance. Normally scientists will talk about a result being statistically significant at a p-level, often p=0.05, which is to say that there's around a 5% (1 in 20) chance that the result could have happened by accident. It doesn't tell us that the result is important, or substantial or even particularly interesting, all it tells us if that you repeated the experiment (or drug trial) you would expect to have to run it 20 times before you got this result by chance.

There are a couple of obvious things to say at this point. The first is to say that p=0.05 sets a pretty low bar. Another way of looking at this is to say that 5 out of every 100 results are just due to chance. Those odds might be fine for the casino or the occasional horse race, but they're way too high for drugs that can kill (or save) people. Surely for medical research we need to be looking at setting the bar higher - we should be looking at results at the p=0.01 or p=0.001 level to make sure that we're not getting spurious results. Even then, a result that is significant at the p=0.001 level means that we're ten times more sure it's not an accident compared to the p=0.01 level, but that's all it means.

Monday, 3 February 2014

LFS - Trial of Metformin

One of the implications of the 'two compartment' hypothesis of Li Fraumeni Syndrome (LFS) is that having a TP53 mutation is not necessarily a guaranteed route to cancer. The theory suggests that there's more to the syndrome than a damaged tumour suppressor gene, and that the 'host environment' is just as important. And what is the host environment in this context? It's the internal state of the body. The theory suggests that cancer risk is a function of damaged TP53 gene and certain conditions which are conducive to cancer. Change those conditions and you reduce the risk of cancer in LFS. In the paper where I introduced the hypothesis I suggested that one possible mechanism to make a positive change to reduce the risk of cancer in LFS is through the well-known anti-diabetes drug metformin. So, late last year the George Pantziarka TP53 Trust put in an application to run a cancer-prevention trial in LFS using metformin. Unfortunately we were unsuccessful in gaining funding for that trial, partly because a cancer prevention trial is actually a hard thing to accomplish, particularly in a rare condition like LFS.

However, a new trial is taking place in the United States looking at the short-term impact of metformin in people with Li Fraumeni Syndrome. The full details of the trial can be accessed here: http://www.clinicaltrials.gov/ct2/show/NCT01981525

The aim of the trial is to track what happens to a range of insulin-related blood markers in LFS patients over a 20 week period, with 14 of the 20 weeks on metformin and with biomarkers checked at regular intervals. The intent of the trial is initially to assess changes in these biomarkers and to assess whether daily metformin is tolerable or not. Now there's no reason to believe that daily metformin would not be tolerable, after all this is a drug that type II diabetes patients take for years on end, but when looking at a specific population of patients like this a trial has to be done. The more important thing is that the trial will be tracking these insulin related markers - specifically plasma insulin, IGF-1 and IGFBP3 - which are associated with increased cancer risk.

As important is the fact that this is that very rare thing, a trial in LFS, and the mechanics of making this happen are important. Being able to recruit and follow patients is a key factor in whether trials go ahead or not. We all need to make sure that this is a trial that is successful so that it can be used as a model for future trials.

So, if you're in the US and you have LFS, then please take a look to see if you are eligible. After all, we can never get to fully-fledged multi-year cancer prevention trials in hereditary cancer conditions like LFS if we can't even make small short-term trials work successfully.

Tuesday, 21 January 2014

Probiotics and Cancer Risk

The link between diet and cancer is complex enough for most people, but add in a genetic predisposition to cancer and the complexities go through the roof. While there are plenty of people out there with healthy diet plans and advice on what to eat to avoid cancer, when it comes to family histories full of cancer, doesn’t genetics trump diet? Is it really possible to reduce your cancer risk in spite of your family history? I am convinced that genes do not rule your destiny. Indeed one of the key things in my two compartment theory of Li Fraumeni Syndrome is that there are ways to massively reduce the risks of cancer even for people with mutated TP53 tumour suppressor genes. The same applies to women with BRCA1 or BRCA2 mutations – while there’s a definite elevated risk of cancer, it does not mean that there’s nothing that can be done to reduce the risks.

Which is why a recent paper published in the International Journal of Cancer makes for such interesting reading.  The title of the paper pretty much says it all:

Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice

Sadly this is not an open access paper that we can all read online. However, the authors of the paper had previously looked at the influence of probiotic bacteria on obesity, and that paper is accessible to all for those who are interested:

Microbial Reprogramming Inhibits Western Diet-Associated Obesity

In that work the authors fed mice a conventional ‘fast food’ diet and monitored the response – a set of obese mice. In contrast mice fed the ‘fast food’ diet but with added pro-biotic yoghurt avoided the onset of obesity, despite eating the same ‘fast food’ diet high in fat, sugar and low in vitamins and fibre. The addition of the yoghurt counteracted the pro-inflammatory effects of the poor diet.

In a detailed set of experiments the authors moved from looking at yoghurt to looking at the probiotic bacteria in the yoghurt, particularly a strain of bacteria called Lactobacillus reuteri. Mice fed the bacteria, in water and without the yoghurt, were still protected from the onset of obesity, and that the immune system was a key component of this positive effect.

In this latest paper the authors again use this beneficial probiotic but in this case they look at cancer development in mice. First they compared cancer development in mice fed the ‘fast food’ diet and those fed a more normal mouse diet. And, as you can probably guess, the ‘fast food’ diet was associated with both obesity and a higher incidence of breast cancer than the control diet. No surprise there. But the addition of probiotics to the diet reduced both cancer incidence and the size and growth rate of tumours that did develop. Now here’s where we get the surprise, because why should adding probiotic to the diet and helping the good bacteria in the gut, have an influence on breast cancer development?

The authors took this work a step further and then used mice with a genetic predisposition to breast cancer and fed one set the ‘good’ diet and the other set the ‘good’ diet with the probiotic. Now in these mice even the good diet led to cancer, though of course there was no obesity involved this time. However, and this is why this is such a great piece of news, the mice who also received the probiotic had lower cancer incidence, slower growing tumours and a longer survival time. In other words in spite of their genetic make-up there was a degree of protection from cancer just with the addition of a probiotic.

The papers go into much more detail on the mechanisms at work, principally to do with different classes of cells in the immune system, but that key result really stands out.

There are the usual caveats about extrapolating from mice to humans, but there is some evidence in people that yoghurt consumption can have a protective effect, both in obesity, metabolic syndrome and cancer. The next step is to take this work to another level and to start thinking about clinical trials. There are lots of ways we can test this out. For example, how about a trial in women with high risk of breast cancer recurrence? Or a trial in women with a genetic predisposition to cancer? And what about some work to see whether this protective effect can apply to other cancer types?

And, of course, there is nothing to stop people adding live pro-biotic yoghurt to their diets, or even taking pro-biotic tablets or drinks if they don’t like yoghurt.

Monday, 6 January 2014

The Promise Of SIGNIFY

One of the good things about writing on cancer is that you get to meet or make contact with people from all walks of life, of all ages and from all over the world. Really, when it comes to cancer, all human life is here (which sounds weird, I know). I wanted to start 2014 with a story of a recent contact via the George Pantziarka TP53 Trust because it’s so positive.

I first wrote about the SIGNIFY trial back in August 2012 (http://www.anticancer.org.uk/2012/08/signify-new-uk-lfs-study.html). This is a trial of a new screening protocol for people with Li Fraumeni Syndrome. Instead of waiting and watching for cancer, the idea is that people are proactively screened using whole-body MRI hoping to catch malignancies before they develop. Recruitment started in early 2013 (http://www.anticancer.org.uk/2013/02/lfs-signify-trial-looking-for-volunteers.html). And just before the New Year I was contacted by a young woman called Lara, who was participating in the trial. Her case epitomises the promise of SIGNIFY.

Lara attended her MRI screening at the Royal Marsden Hospital and was then asked to return for a rescan of the liver and kidneys. She assumed that this was nothing out of the ordinary – she was suffering from no symptoms and felt fine. Instead the scans discovered two primary tumours – one on the liver and another on a kidney. Without the routine scans of SIGNIFY these two tumours might not have been picked up until it was too late to do anything about them. As it is she faces surgery at a time when resection is still possible and is still the best treatment.

As Lara herself has told me:
If I hadn't got tested right when I did I think my story would be a very different one. A year earlier and they may not have been picked up at all, a year later it might have been too late. 
We can but hope that in time the SIGNIFY trial will lead to permanent changes in cancer surveillance for people with LFS. We can hope that it will pick up disease before it becomes life threatening. We can hope that it will save lives. It’s too late for George and Kane and other young LFS sufferers who were diagnosed too late, but we can hope that their stories are not repeated in another generation of young people.

In the meantime I wish Lara, and the rest of the people on the George Pantziarka TP53 Trust forum, the very best for 2014.