Beating the odds

The picture of cancer and how friends and family fare with cancer is often pretty bleak. And yet, there is a hidden element to it that we’re only starting to appreciate now, and that’s a group of patients who beat the odds and surprise everyone, by living much longer than they were expected to. These patients are called exceptional survivors, or exceptional responders. We can learn a great deal about how they manage to achieve something that we’re all striving for in our research: long-term survival.

Ovarian cancer survivors

We’ve been studying a group of patients with ovarian cancer who normally wouldn’t be expected to live more than four or five years, but are still alive ten years later. About half of them appear to be completely free of their disease. We also know that they weren’t cured surgically, or at least a large proportion of them weren’t cured surgically. So, something special has happened in them. This is a programme funded by the Ovarian Cancer Research Program of the Congressionally Directed Medical Research Programs of the US Department of Defense. It’s a funded international consortium here in Australia, in the United States, in Canada and in the UK, but with contributions from about a dozen other countries as well.

Genetics, immunology and lifestyle

We have three major elements of this study. One is to study the genetics and the genomics of cancer patients. By that, I mean the genes that they were born with and the genetic changes that have occurred in their cancer. That part of the programme is led by us, here in Australia. The second part is to study the immunological reaction to the cancer by the patient’s own immune system. That’s led by Brad Nelson in British Columbia, Canada. The third part is to look at the epidemiological associations with long-term survival and diet, lifestyle, medications and so on, and that’s led by Lee Pierce from the University of Michigan and Malcolm Pike from the Memorial Sloan Kettering Cancer Center in New York.

By studying these three aspects of the disease – the genetics, the immunology and the lifestyle – we hope to understand how these patients have beaten the odds. We already know that, in some of the patients, there’s a chance combination of mutations that appear to make the cancer very sensitive to chemotherapy, much more than occurs in most patients and which probably also limits the ability of the cancer to develop resistance to the treatment. This is work that’s led from our lab by Dale Garsed, the senior scientist in the lab, who has discovered that a combination of mutations seems to be associated with this very long-term survival. What we aim to do – by understanding the biology of long-term survival – is to develop therapeutic approaches that will mimic those effects in more typical patients. So, it’s all very well studying these long-term survivors, but what we really need to do is to take that information to more typical patients to improve their survival.

Lifestyle choices

One of the really interesting parts of this study is to understand the effect of diet, lifestyle and exercise. That’s an integral part of the study. In fact, we have a group of long-term survivors who are providing us with their insights in terms of what contributed to their survival. This is very important, because patients want to know about the things that they could be doing that would be contributing to improving their survival. It’s all very well to be thinking about the drugs that could be given and the medical interventions, but what can they do as patients when they go home from the clinic that would improve their chances? That’s why it’s so important to understand how that could influence their outcome.

Silhouette of a group of people standing in front of the sea. By vladgphoto.

Misdiagnosed?

If you talk to any oncologist and ask them whether they have a patient or patients that surprised them in terms of how they survived, they’ll say, ‘Yeah, actually, I do. Mrs Green – she’s amazing. Ten years later, she’s still coming to see me every year. She seems fine. I can’t explain it. She looked exactly like these other patients who have succumbed to their disease.’

For a long time, people thought that these rare patients were actually not what was labelled on the tin – that they had somehow been misdiagnosed, and that they hadn’t had the aggressive type of cancer that people had thought. What we’ve done in the study is we’ve gone back and very carefully documented the fact that they did have that aggressive type of cancer that should have overwhelmed them, and yet they have survived. So, by starting with thousands of patients, we have been able to refine it down to a group who did have the disease but who have survived. It’s those patients that we’re focused on to understand their outcome.

Patients’ contribution to our research

I’ve been fortunate to be head of the Australian ovarian cancer study for the last 20 years. More than 3,000 women with ovarian cancer have generously contributed to the study and allowed us to collect their cancer samples, which were made available during their surgery. This has enabled us to collect information about how the cancer proceeds – what the cancer journey is – so that we can relate the molecular changes that occur in the cancer to how they fare with their disease. It’s been a real privilege to work with these women and to gain knowledge from a very unfortunate event for them.

The other study is a somewhat confronting and powerful one. It’s a study called Cascade – what’s known as a rapid autopsy study. This is where we collect samples from patients in the few hours after they’ve died. We recruit patients to Cascade in the weeks to months before their death, with their participation and consent, and very much with the involvement of their family. Sometimes, patients come to us to see whether there’s an opportunity to donate their body for research after they’ve died. Cascade is an opportunity to really understand the train wreck. What are all the things that have accumulated to ultimately overwhelm the patient? It’s a remarkable chance to collect samples from all over the patient’s body where the cancer is spread, which would simply be impossible, unacceptable, while they are alive.

Democratising information

When people are involved in clinical trials, we need to try to democratise this information, to get it out there to people in an accessible form. A close friend of mine just started a clinical trial last week. I was reading the patient information and consent form – it runs to 15 or 16 pages of dense text – which needs to cover all the eventualities with a trial. It can be very confusing. As scientists and clinicians, we need to engage with the public and try and make this information as accessible as possible. The challenge is that it has its own language. It’s like French or German or Italian. If you don’t speak those languages, it can be very hard to understand. There’s the language of science and molecular biology – with words like CRISPR, genomes, DNA and RNA – and I think that it’s important to try and, by analogy, help people understand what these things mean.

The future of cancer research

Each year, the survival for a cancer improves by roughly 1% to 1.5%. That doesn’t sound like much, but over 10 years, that’s 10% or 15%. That translates to hundreds of thousands of survivors around the world each year – people who might not have survived in the past. The other aspect to appreciate is that, because knowledge is growing exponentially, what is likely to be achieved in the next 5 years is probably the equivalent of what we achieved in the last 10 or 20 years. Things are going faster. The technology is now very sharp. Our ability to understand the code, to know the enemy, has improved greatly. I would expect the future to be one of very significant achievement and improvement in outcome for cancer patients.

Cancer research in a modern lab. By Viacheslav Lopatin.

The polio of our time

Cancer is the polio of our time. It’s the disease that so many fear because it seems to almost strike randomly. Someone that was well last week could suddenly get a diagnosis of cancer. It’s the unpredictable nature of the disease – how it progresses and whether it’ll go into remission – whether you’ll respond to therapy – its capacity to overwhelm our best endeavours – that makes it such a feared disease. We’ve seen that, over the century, the investment of research into these awful diseases has really changed the picture from one that was very bleak and fearful to something that’s managed.

Understanding the enemy

There’s a quote from The Art of War by Sun Tzu, which I love, because I think it typifies what we’re trying to do in cancer research. The quote goes something like this: ‘If you don’t know the enemy and you don’t know your own capabilities, then you will be defeated every time. But if you know the enemy and you know your own abilities, then you will win.’

In the past, you would have said that we didn’t know the enemy and we overestimated our capabilities. Yet now, because we can sequence the code, we can understand the software, and the clouds have parted. Although it’s a formidable enemy and a wily one in its ability to evolve and evaluate our treatment, I feel like we now know the enemy and we have the opportunity to win the war.

Discover more about

exceptional survivors

Saner, F. A. M., Herschtal, A., Nelson, B. H., et al. (2019). Going to extremes: determinants of extraordinary response and survival in patients with cancer. Nature Reviews Cancer, 19, 339–348.

Garsed, D. W., Pandey, A., Fereday, S., et al. (2019). Abstract 2722: The genomic landscape of high-grade serous ovarian cancer in long-term survivors. Proceedings of the AACR Annual Meeting 2019, Atlanta, GA, USA, 79(13).

Beating the odds: ovarian cancer survivors