Exercise and Breast Cancer

I was alerted today to an interesting new paper in the Journal of the National Cancer Institute that looked at the effect of exercise on tumour blood supply and the response to chemotherapy in breast cancer. Now this is a topic which is worth paying attention to – there is lots of evidence that daily exercise can reduce breast cancer recurrence, have positive effects on physical status and may even improve overall survival in women with breast cancer. With that in mind, what does this new paper tell us?

Firstly, it’s important to note that this isn’t a study in people – this is a study in mice. But these are mice with intact immune systems and they are bearing mouse tumours. It means that although this is an animal model we can trust the evidence a bit more than we can when dealing with immune deficient mice implanted with human tumours. Secondly we should note that these mice were not forced to do exercise – so there was no additional stress involved and there were no enforced amounts of exercise that had to be performed. Basically the mice were given an environment which gave them an exercise wheel they could use, whereas the comparison group didn’t have the opportunity to exercise. Finally, some of the mice had ER+ and some ER- tumours, matching human tumours in hormone responsive and non-responsive sub-types.

What the study showed was that the mice doing the exercise had a reduced the tumour growth rate, an increased the rate of cancer cell death (apoptosis), increased the maturity of the tumour blood vessels, increased tumour blood flow and reduced the areas that were starved of oxygen (hypoxia). These are all things which are positive and which we definitely would want to achieve clinically. Basically these results show that exercise normalises the tumour blood supply. This is a good thing.

Normally the tumour blood supply is chaotic – vessels are immature, leaky, misconnected. This chaotic blood supply has a number of downsides. Firstly it means that the drugs we give cancer patients to kill the tumour often don’t make it into the interior of the tumour – not good because if they don’t in they won’t work. Secondly the chaos causes areas of the tumour to become starved of oxygen and nutrients – this in turn causes the cancer cells to become more aggressive and dangerous as they adapt to these harsh conditions.

So, normalising the blood supply means that tumours are not forced to become more aggressive and, as we see in these results, this can lead to a slower growth rate. It also means that when drugs are administered they can make it into a greater portion of the tumour. And this is where the second lot of results come in. Mice treated with the chemotherapy drug cyclophosphamide had greater response if they were exercising compared to the sedentary mice. Interestingly, mice who did exercise alone (no chemo) showed a similar response to mice treated with chemo alone. But the best response came from mice who had chemo and did exercise.

These are positive results but we do have to keep in mind that this is in mice. However, it backs up what we know from evidence in humans and suggests reasons for why we’ve seen these results. The take home from this is that exercise has a positive effect in breast cancer – and most likely in other cancers too. It doesn’t have to be running a marathon every week either – a study in women with breast cancer back in 2005 found that walking at an average pace for 3 – 5 hours per week had positive effects on survival.

Bisphosphonates in non-bone tumours

Bisphosphonates are a class of bone-targeted drug that act to slow the turn-over of bone (bone resorption). These drugs, including zoledronate, ibandronate and others, are standard treatments for osteoporosis and other bone diseases. And, as I have mentioned previously on this blog they have increasingly found use in cancer treatment to help control bone-related problems - both from metastatic disease to the bone and in primary bone tumours. There is also increasing evidence that as well as controlling bone pain and reducing fractures, these drugs have some very positive effects on overall survival. For example there is now evidence that zoledronate (also called Zometa or zoledronic acid) gives a survival advantage even in early stage breast cancer. Now this is something of a surprise because the effects are there even when there are no bone metastases, so the drug must be acting on non-bone tumour tissue - how is this possible?

New light has been shed on the matter by some recent work that convincingly shows that zoledronic acid is taken up by cancer associated cells outside of bony metastases. Some clever lab work has shown that zoledronic acid attaches itself to tiny crystals of calcium (microcalcifications) outside of the bone. These microcalcifications are then eaten up by tumour associated macrophages, immune cells that actively encourage and support tumour growth. Once these macrophages have swallowed the microcalcifications with the zolderonic acid attached the drug can get to work and interfere with their function. In other words, the drug doesn't affect tumour cells directly, it affects the cells that provide some of the life-support that tumours require. The lab work on mice was also confirmed on a tumour sample from a breast cancer patient.

Osteosarcoma - A Proposal for Reducing the Relapse Rate

As has been mentioned on this site before, there has been little progress in the treatment osteosarcoma – the disease that killed my son,George – in the last twenty-five to thirty years. The actual figures vary by country, but generally the five year disease free survival is around 60% - 70%, though in the UK the last published figures were an absolutely appalling 43%. But these figures mask what’s really going – osteosarcoma of the extremities (the long bones in the arms and legs) has a much higher disease free survival rate than osteosarcoma at other sites. So the figures for England show that the rate is 48% for osteosarcoma of the extremities and only 16% for other sites. And, regardless of site, the prognosis for relapsed disease (whether it’s a local recurrence or a distant metastasis) is truly grim.

Looking at the patterns of relapse however shows us something really interesting and, hopefully, significant. The vast majority of relapses occur within 18 months of surgical resection (and in osteosarcoma the only way for definitive cure is to surgically remove the tumour). What is more, most of these relapses take the form of distant metastases, the majority appearing as new tumours in the lungs. This begs the question as to why this pattern? It suggests that there’s something systemic going on – and it’s a similar pattern to the relapse/recurrence of breast, lung, head and neck and other cancers. 

One possible mechanism involves the surgery itself. The body responds to the trauma of surgery by releasing different growth factors, cytokines and other inflammatory responses. This is necessary for wound healing, but it also creates an environment that is conducive to cancer growth – there are pro-angiogenic growth signals, immune suppression and so on. It all adds up to an environment that gives any microscopic pockets of cancer cells the chance to expand and grow into new tumours, particularly in the lungs.

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.

Losartan - High-Blood Pressure Drug Helps Fight Cancer

We treat cancer with the most vicious, toxic and carcinogenic drugs available to science in the form of chemotherapy. But the fact is that the chemotherapy drugs are brutally effective at killing cells - at least initially, and at least when they can get to the cells we want to target. But, as we all know, most chemotherapy drugs are not easily targeted and end up killing plenty of non-cancerous cells. Not only that, cancer cells are also able to find various methods of shielding themselves from the poisonous brew or they mutate and become resistant. This means that no matter how good chemo drugs are at killing cells, if tumour cells are able to hide or adapt then that killing power is ultimately useless (not to say downright dangerous to the rest of the body). The upshot of this is that finding ways of getting more chemotherapy to more cancer cells is a hugely useful strategy if we can do it.

One mechanism by which cancer cells cells are shielded from chemotherapy (and other treatments, including radiotherapy), is through the decreased blood supply inside solid tumours. As tumours develop they constrict blood vessels into the interior of the tumour, stopping nutrients and oxygen getting to the cells deep inside the mass. With the vessels so constricted it's also the drugs carried in the blood supply - like chemotherapy drugs - which are cut off from the cells at the heart of the tumour. Furthermore, in response to this restrict supply of food and oxygen, the cancer cells adapt and become more aggressive and able to cope with the harsh conditions that surround it. These adapted cells are also more likely to form metastases, spreading the cancer to other parts of the body where conditions are easier, at least initially.

One possible way to stop this is to look at 'tumour vasculature normalisation' as a therapeutic strategic. The idea behind this is that by reducing the constriction of blood vessels into the tumour, then blood, oxygen and blood-borne drugs can make it into the heart of the tumour. In this way there is a reduced push towards more aggressive mutations, reduced risk of metastases and of course a greater delivery of cancer-killing drugs like chemotherapy. It seems counter-intuitive to want to make it easier for tumours to have a blood supply, but sometimes it's the counter-intuitive ideas that work the best in practice.

Q & A With Dr Patrice Forget: Ketorolac and Breast Cancer

In the previous article on this site I wrote about recent work that showed that the use of a cheap, safe and generally available anti-inflammatory pain killer (ketorolac) had the potential to massively reduce the incidence of cancer relapse following surgery. This extraordinary result was discovered by a Belgian anaesthesiologist Dr Patric Forget and colleagues. Now working on a clinical trial to put this finding under test, Dr Forget kindly agreed to respond to a short interview to give us more of background to his research.

PP: What prompted your initial investigations - did you expect to find the results that you found?

PF: The diverse long term effects of anaesthetic techniques and analgesic medications have been suspected for many years. Discrepancies exist about the effect on outcome in humans. Concerning opioids, many data exist, but results are inconsistent. Concerning NSAIDs, animal data are consistent, but no human data are available. Therefore, we investigated it in the prospective patients listing existing in our Cancer Centre. Nevertheless, the magnitude and the repetition of the NSAIDs data were relatively unexpected.

PP: What are the clinical factors that influence the choice of ketorolac versus other medications?

PF: The anaesthesiologists have to make choices for which there are not always evidence-based guidelines. This is the case with single NSAIDs dose in the perioperative period. The usefulness of this single dose in terms of analgesia improvement is still matter of debate. The American Society of Anesthesiology has no definitive recommendations about it. Consequently, in many centres, including ours, some anaesthesiologists use it systematically, and others not.

PP: Your findings suggest that other interventions - such as taking a surgical biopsy - could also have a negative influence on cancer outcomes. What is your view on this?

PF: Inflammatory pathways are implicated in the development of cancer. It is probable that the degree of tissue injury during surgery is associated with cancer outcome. Nevertheless, whether  this effect is mediated by an influence on tumours cells, tumours cells spreading and/or immune suppression is not clear. In all cases, many arguments exist to limit as far as possible the extent of tissue attrition and surgical procedures in cancer patients.

PP: Although the emphasis of your work is on breast cancer, there is evidence that a similar bimodal pattern of relapse occurs in other cancers. Do you think that peri-operative ketorolac can have a similar reduction in relapse in these cancers?

PF: Yes. We have done the same observation in non-small cell lung cancer (NSCLC) (Forget et al, Ann Surg Oncol 2013). In NSCLC, the bimodal pattern of relapse was shown by Demicheli et al. Out data shows that the NSAIDs effect is also present. In contrast, in prostate cancer, no NSAIDs effect was observed (Forget et al, Eur J Anaesthesiol 2011). Concommitantly, no bimodal patter of relapse was shown, in my knowledge, arguing for a different pre-, intra- and/or postoperative cancer pathophysiology.

Ketorolac and Breast Cancer

Most cancer papers, even the ones with really interesting and important results, are not exactly an easy read. Aside from the technical content, they’re written in a deliberately dry and unemotional style that suggests objectivity and cautiousness. Which is why the paper ‘Promising development from translational or perhaps anti-translational research in breast cancer’, published in the journal Clinical and Translational Medicine stands out from the crowd. It’s an open access paper available here: http://www.clintransmed.com/content/1/1/17. If you only ever read one cancer paper make it this one. It’s written a highly accessible style, raises key questions and contains a result that, if confirmed, could reduce breast cancer mortality by 25% - 50%. That would be a massive step forward, truly massive.

And what is this finding that holds the promise of reducing breast cancer deaths by such a massive amount? It’s not a new drug, not a new form of therapy not even a new type of treatment. It’s simple, cheap and easily available and, best of all, easy to slot into place in existing treatment protocols. The starting point for all of this is the observation that the pattern for cancer recurrence following mastectomy occurs in two waves (it’s bimodal in stats jargon). The first wave happen in the immediate period (the first four years), and then there is a second peak of relapses that happens much later, around six years and stretching out to 10 – 15 years. This pattern of relapse has been confirmed in numerous countries and studies now, and seems to also be common in some other cancers, including prostate, lung, and pancreatic cancer, as well as osteosarcoma and melanoma.

This pattern of relapse could not easily be explained by existing theories of cancer growth. In fact, it was a down-right inconvenient finding with huge and controversial implications. Chief among these was that it suggested that surgery to remove the primary tumour was often triggering spurts of metastatic disease. To quote from the paper directly: Between 50% and 80% of relapses result from surgery initiated growth. That is a truly shocking result. It means that many breast cancer deaths are caused by the surgery meant to remove the initial small tumours.