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.

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.