Li Fraumeni Syndrome - A New Hypothesis

In the last year or so I have been working on developing some new ideas on cancer development in Li Fraumeni Syndrome. The results so far are a paper in a peer-reviewed oncology journal (Cancer Cell International), and a follow up article (aimed at clinicians rather than researchers) in Oncology News. Both of these are open access publications:

My paper is available here: http://www.cancerci.com/content/13/1/35

And the less technical version is here:: http://www.oncologynews.biz/pdf/20%20ONJA13/88_JA13_Li%20Fraumeni%20Syndrome.pdf

But this isn't the end of the story - I am continuing to develop these ideas and follow up on the clinical implications.

Omega 3s and cancer - confusing results

I had been planning on writing a follow up to the last article on omega 3s and chemotherapy with a piece on new research that looked at a protective effect of omega 3s on breast cancer. However, the big news of the moment is the result of a study that found that an increased risk of prostate cancer from omega 3s. So what gives? For those wanting to know whether to increase or decrease omega 3 intake, these conflicting results are just down-right confusing and a bit scary too.

Let’s deal with the prostate cancer results first. The paper in question is called ‘Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial’ and was published in the Journal of the National Cancer Institute (unfortunately not an open access publication). The abstract is available here: http://www.ncbi.nlm.nih.gov/pubmed/23843441. The authors looked at the relative percentages of different omega 3s fatty acids in blood samples from men with and without prostate cancer who had been enrolled in the Selenium and Vitamin E Cancer Prevention Trial. Men were ranked into four groups according to relative plasma omega 3 content and then the group with the lowest 25% were compared with the highest 25%. The results of this analysis showed that the men in the highest group had greater risk of prostate cancer than those in the lowest group. This was true for total omega 3 measurement as well as for individual omega 3s (e.g. DHA, DPA and EPA). On the face of it this looks like a pretty solid finding. But there are some puzzling things about this result. The first and the most obvious is that there’s no causal mechanism offered to explain a result that the authors themselves admit is puzzling and contrary to expectations. Omega 3s have many different effects in the body, for example they are strongly anti-inflammatory, but none of them known to be pro-carcinogenic or pro-tumour. Stranger still, the study found that some omega 6 fatty acids, which are known to be pro-inflammatory and often associated with being pro-cancerous, were associated with lower cancer incidence in this study.

Book Review: Mammography Screening: Truth, Lies and Controversy

Keywords: Cancer, screening, medicine, public policy, science Title: Mammography Screening: Truth, Lies and Controversy Author: Peter C. Gotzsche Publisher: Radcliffe Publishing Ltd ISBN: 978-1846195853

Buy US Buy UK

On the face of it the case for increased breast cancer screening is clear. Cancers caught sooner are easier to excise or to treat with chemotherapy. Earlier diagnosis means a lower likelihood of metastases, which are the real killers in cancers of all kinds. So who could argue against increased screening? Unfortunately this simple picture, seductive though it is, is just too simplistic and obscures a bitter controversy that has raged across the medical literature but which barely registers in public consciousness.

Peter Gøtzsche, a Danish medical researcher, Professor of Clinical Research Design and Analysis and the director of the Nordic Cochrane Centre, is a key player in the controversy and is highly sceptical of the value of breast screening in the general population. As an expert in clinical trial design and results analysis he came to the topic with no real experience of breast oncology, chemotherapy or surgery. But it was from this position of independence that he looked at the data from the studies that had been performed on breast screening and decided, based on the evidence that he and his colleagues uncovered, that far from being an unalloyed good, there were real and significant harms being perpetrated on women taking part in breast cancer screening programs.

As Gøtzsche outlines in considerable detail in this book, his findings were not greeted with open arms by breast screening advocates, the medical establishment and numerous well-placed political and academic figures. In fact the reaction was extremely hostile and remains so to this day, many years after his initial research findings. Gøtzsche and his colleagues were attacked from all sides for straying from the 'consensus' view that screening saved lives. His results, methods and motives were all attacked and continue to be attacked, though few seem to actually dispute the core of what he has found.

And what is it that makes Gøtzsche and a few others like him dispute the simple narrative that regular screening saves women's lives? The fly in the ointment is simple - over-diagnosis. If you go looking for cancer then cancer is what you'll find. Mammography screening will find all kinds of lumps and abnormalities. Some of these will become invasive and dangerous cancers, many will not. The difficulty is that at this stage we don't know which will melt away and which will turn into killers. Given that we can't tell the difference the only thing to do is to aggressively treat all the tumours that we find. And, let's be honest, this treatment is often brutal - mastectomy, radiotherapy and chemotherapy.

In analysing the data Gøtzsche focuses on overall all-cause mortality. And his key finding is truly shocking - while some women might be saved by early diagnosis and treatment, others will die from over-diagnosis and the results of over-treatment. In their latest advice, Gøtzsche and his co-workers state that:

Screening produces patients with breast cancer from among healthy women who would never have developed symptoms of breast cancer. Treatment of these healthy women increases their risk of dying, e.g. from heart disease and cancer.

This is not a trivial finding it's a scandal that ought to have anti-cancer activists up in arms. Unfortunately many activists are so wedded to the idea of mammography being the panacea that they campaign for increases in screening rather than wanting to subject the programs in place to the critical scrutiny they deserve.

For those of us familiar with that other science war - climate-change - some of what Gøtzsche describes will be eerily similar: well-entrenched 'consensus' science subjecting sceptical voices to attack, subversion of peer review, ad hominen attacks, endless dissimulation and the knocking down of strawman arguments that sceptics do not make. The parallels between this and what goes on in 'climate science' are strong, obvious and depressing. Even more depressing is the fact that Gøtzsche himself seems to have fallen for the party line when it comes to climate change, not realising that scientists sceptical of the 'consensus' view of man made climate disaster are also subject to subverted peer review, ad hominen attack, accusations of working for commercial interests etc. Where he is accused of killing patients, anthropogenic global warming sceptics are accused of wanting to kill the planet.

Gøtzsche describes in great detail the many controversies and arguments that have ensued since going public with his results. There is a degree of repetition throughout the book, but at its core is a simple story based not on complex statistical analysis or mathematical modelling but on the raw data of what happens to women taking part in screening programs.

Where he comes back again and again to the inevitable fact of over-diagnosis, the advocates of screening focus on the fact that earlier diagnosis leads to improved outcomes for the women diagnosed. Both these things are true. But in terms of women in general, it means that large numbers of women are being turned into cancer patients unnecessarily, and that some of these will die because of the treatment they receive.

This isn't to say that screening is a bad idea per se. For women with genetic predisposition, with family histories of breast cancer or who are in other high risk groups then screening make sense. However, for the vast majority of women who are not at high risk, especially younger women, screening does not make sense and will lead to harm to a number of them. In fact Gøtzsche and the Nordic Cochrane group have published a leaflet for women, setting out the benefits and risks of screening, leaving it to women to make up their own minds based on a clear exposition of the data. It can be downloaded here: http://www.cochrane.dk

And, despite the accusations of his opponents, Gøtzsche is not alone. For example, Michael Baum, who worked for 30 years as a surgeon specialising in breast cancer, and is now professor emeritus of surgery at University College London, recently stated:

If we stopped screening today, the incidence of breast cancer would fall at a stroke by about 25 per cent.

In the end Gøtzsche's book is like the cancer version of Andrew Montford's 'The Hockey Stick Illusion'. Both books look at contentious areas of science. Both books cut through often obscure statistical arguments to get to the core of the issue. And both books describe a situation where you have tightly knit and entrenched groups of scientists with institutional backing, political support and significant funding doing their level best to lock out those who refuse to bow down to a 'consensus' that is not grounded in solid science.
Or as Gøtzsche puts it:

The screening literature has been polluted to an extraordinary degree by statistical modelling of raw data, often combined with wishful thinking and the use of favourable, but unrealistic assumptions for variables that cannot be measured. This has helped conceal inconvenient facts and has yielded results people wanted to see.

To conclude, this is essential reading for everyone interested in science, medicine and public health policy. Most of all it is essential reading for women being emotionally blackmailed into taking part in screening programs without being given all the facts.

Omega 3 Fish Oils and Chemotherapy

While chemotherapy remains the mainstay of treatment for most types of cancer, there will be a need to improve what’s called the ‘therapeutic index’. Simply put this is a measure of the good a drug does versus the bad. Chemotherapy causes all kinds of toxic side effects while killing cancer cells, and generally it could kill more if given at a higher dose, but to do so ends up causes a lot more damage. One way of improving chemo is through the use of new generation drugs that target tumour cells rather than the indiscriminate slaughter of the older drugs.

Another way to do this is to find ways of protecting normal cells in some way and/or making cancer cells more susceptible to the effect of the existing chemo drugs. Can this be done safely? According to some researchers the answer is a qualified yes. And the magic drugs that can spare normal cells but make cancer cells more susceptible to chemo are…omega 3 fish oils. There is mounting evidence that omega 3 fish oils, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can indeed work in this way.

A new paper ‘Selective sensitization of tumours to chemotherapy by marine derived lipids: A review’, published in the journal Cancer Treatment Reviews (abstract here: http://www.ncbi.nlm.nih.gov/pubmed/22850619), goes over the evidence from cell cultures, animal experiments and clinical trials. And there is a lot of evidence to go over. The authors summarise it quite nicely, showing that the positive effect is there across many tumour types (including breast, prostate, colon, lung, lymphomas and more), and across chemo types (nearly all of the main classes of chemotherapy drug are listed).

One very encouraging aspect of this story is the number of active clinical trials looking at this now. The pre-clinical results and first analyses from those human trials that have taken place have all been positive. And when you factor in the other positive effects of EPA and DHA, such as helping to cope with stress (http://www.anticancer.org.uk/2012/02/omega-3s-stress-and-cancer.html), or a reduction in side effects (http://www.anticancer.org.uk/2012/08/peripheral-neuropathy-and-chemotherapy.html), then it really does begin to seem as though high dose omega 3s should be the one supplement that every cancer patient takes.

Cancer research - Surrey University

Interesting news on cancer research can come from all sorts of unexpected sources (and I don't mean the daily press or the BBC...). One recent example comes from 'Forever Surrey', the magazine for alumni and supporters of Surrey University (where I did my PhD in computer science). The latest issue carries a few interesting snippets on cancer research at the university.

First up is news of a new urine test for prostate cancer. Current testing for the test is geared around Prostate-Specific Antigen (PSA), which is produced by all prostate cancer cells, not just cancerous ones. This means a high PSA value may not necessarily be connected to cancer but be caused by other conditions. It's better than no test at all, but it's not ideal. It also makes it hard to distinguish between slow-growing prostate cancers that can be safely let alone or monitored over time, and those that are fast-growing, aggressive and have to be treated immediately. Professor Hardev Pandha, a professor at the university and a consultant oncologist at the Royal Surrey County Hospital, and his team have come up with a new test that is much more cancer-specific.

Targeting a protein called Engrailed-2 (EN2), which is produced by prostate cancer cells and present in urine, they have developed a test that is much more specific, faster and easier to use. For starters this is a urine test rather than a blood test (which is what the PSA test is), and the researchers are working on a version of the test that can be done using a dipstick (like a pregnancy testing kit). A more faster and more accurate test that can really pin-point cancer rather than just generic prostate problems would be a great step forward.

But it's not just a new and improved biomarker test that's being developed at Surrey. The same research team are also working on a new treatment for prostate cancer. Dr Richard Morgan, one of Professor Pandha's team, has been working on a drug that targets a protein called HXR9 which is only active in cancer cells. By being able to switch off this protein with a new drug it can safely treat prostate cancer - without the damaging side-effects of existing treatments.

Interestingly, the same drug seems to have activity in a range of other cancers, including ovarian, breast and melanoma. This is definitely one to keep an eye on in the future...

George - Second Anniversary

One of the many doctors who treated George described him as a miracle child. And it was true. He had survived a rhabdomyosarcoma diagnosed at two and which was aggressively treated for about a year, followed by a few months in remission. When the disease recurred it was treated hard again but the last scan showed there was still evidence of disease. With no options left on the table we were sent home to prepare for the worst. George was just four years old. We refused to accept the news, and he was just a kid who wanted to play. And play he did, for the next eleven years. He really was a miracle child. But when he was fifteen he was diagnosed first with a basal cell carcinoma and then, a little later, with osteosarcoma. For us the miracle ended two years ago, when the osteosarcoma finally defeated our wonderful, lovely child, after the hard years of battle.

On this second anniversary it’s time to take stock of where we are with the Trust formed in his name. One of the things we wanted to focus when we started was on encouraging more research in Li Fraumeni Syndrome. We never imagined that we would be responsible for some of that research, but that is precisely what has happened. Over the last year I have developed a new theory about cancer initiation in LFS, one that is subtly different from the mainstream view. The first test of a new theory is to see if it can stand the peer review process and be published in a reputable peer-reviewed scientific journal. I am happy to report that the paper ‘Li Fraumeni Syndrome, cancer and senescence: a new hypothesis’ has been published in the journal ‘Cancer Cell International’. There will be more to say in the coming weeks and months about this paper, but for now it’s available for download at the journal’s website.

Ablation of bone tumours

For patients with advanced cancer bone tumours, (whether from primary bone cancers like osteosarcoma or metastases from other types of cancer, such as breast or prostate), can be a cause of persistent and hard to treat pain. A standard treatment in many such situations is radiotherapy, which can have unpleasant side-effects, and, in the case of Li Fraumeni Syndrome patients, might also have long-term implications regarding further cancers. Additionally, treating cancer pain with opiate-based pain-killers, such as morphine, can also be problematic given the evidence that opioids can cause further cancer progression (though this can be reversed with the use of naltrexone).

In which case there’s some encouraging news being reported at the 29th Annual Meeting of the American Academy of Pain Medicine. A group of French clinicians have reported on treating patients with tumour pain, including bone tumours, with micro-wave ablation (MWA).

One of the doctors, Adrian Kastler of the Centre Hospitalier Universitaire, in Besançon, France, is reported as saying:

"This technique may be applied to any patient suffering from bone tumour pain, mainly in patients suffering from bone metastases, refractory to conventional therapies. The main advantage of ablation techniques is the fast pain relief obtained - immediately after the procedure - as opposed to delayed pain relief obtained with radiation therapy… Our research showed that the use of MWA in bone and soft-tissue tumours is feasible and effective concerning pain palliation. However, MWA needs to be studied in order to apply the same procedure in a curative intention." 

The last point is certainly one that needs urgent attention. Bone tumours are notoriously hard to treat, so any new treatment that shows signs of being effective needs to be researched as a matter of priority. And, given that primary bone cancers are often unresponsive to chemotherapy, any physical treatments that can be used alongside surgery are urgently needed.