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Understanding the genetic 'patchwork' of ovarian cancer will lead to more effective treatments.

Cancer is not one disease, but a multitude.

We often say that there are more than 200 types of cancer – lung, prostate, bowel, breast and all the rest – but this is a fairly broad definition, based on the rough number of different principal cell types in the body.

Thanks to advances in gene-reading (sequencing) technology over the past few years, we now know that each person’s cancer is as unique as they are. And as cancers grow and spread, the cells within them evolve and change in different ways. This means that within a patient’s body, individual tumours or groups of cells within a single tumour can be genetically distinct, even though they all started from the same place.

Scientists use the term tumour heterogeneity to describe this patchwork made up of clusters of different cancer cells. In fact, it’s been known about for many years, but it’s only recently that we’ve been able to look in detail at the genetic threads that create it.

Knowing about heterogeneity helps to explain why cancers are so difficult to treat successfully once they’ve spread through the body. Cancer drugs or radiotherapy may kill some of the cancer cells, but others will have gained genetic changes that make them resistant. And once the vulnerable cells have been picked off, any remaining resistant ones can just keep on growing.

So understanding this patchwork is vital if we’re to make meaningful progress in treating advanced cancers and save more lives. And a new study from scientists at our Cambridge Institute, published in the journal PLoS Medicine, reveals what’s going on in a type of ovarian cancer, paving the way for new approaches for treatment.

Starting out

James Brenton

Dr James Brenton is unpicking the genetic patchwork of ovarian cancer

To find out more, we spoke to Dr James Brenton, who led the research. As a doctor working in Addenbrooke’s Hospital in Cambridge, he treats women with ovarian cancer every day. And although fewer women are getting ovarian cancer nowadays, survival from certain types has changed little over the years. One such form of the disease is high-grade serous ovarian cancer.

“The problem here is that most women with this type of cancer already have advanced disease when they’re diagnosed,” says James. “We think that this type of tumour probably starts in the fallopian tube, but by the time it’s detected it’s just a big mess, and the cancer cells are all over the place in their abdomen. The other thing is that these cancers often have a fault in a gene called TP53, which makes the p53 protein that normally protects us against cancer – so they grow and spread very quickly.”

Back in 2010, James and his team published a paper looking at the genetic makeup of high-grade serous ovarian cancer in cells growing in the lab that had been taken from tumours before and after treatment with carboplatin – the main drug used for the disease.

“What we found is that when the cancer comes back after treatment, it’s genetically very different from when it’s originally diagnosed. So we wanted to see if the same thing was happening in patients, rather than cells growing in the lab.”

The other thing James and his team wanted to do was question a common assumption: that the more pieces making up the genetic patchwork of a patient’s disease, the worse their outcome.

In many ways this is a sensible idea – the more different clusters of cells there are, the greater the chance that some of them will evolve resistance to treatment. But it’s not that simple.

“It could be different between cancers,” James explains. “Also we know that some ovarian cancers have faults in their BRCA1 or BRCA2 genes, which reduce their ability to repair DNA damage caused by the treatment. So, counter-intuitively, that might actually mean they respond better to therapy.”

Recently we’ve seen several studies looking at tumour heterogeneity in a range of different types of cancer, some of which we’ve helped to fund (for example, lung, bowel and kidney cancers). But what James and his team wanted to know was not just whether there were genetically different cells in a patient’s cancer, but to put some numbers on exactly how different they were.

Mapping the patches

To do this, James enlisted the help of Florian Markowetz and Roland Schwarz at the Cambridge Institute, both experts in using computer software to analyse genetic relationships. Together, they trawled through DNA sequences of 135 separate tumour samples from 14 women who had been diagnosed with high-grade serous ovarian cancer, taken from various places the disease had spread to inside their body, both before and after carboplatin treatment.

This allowed them to get an idea of the degree of heterogeneity in each woman’s cancer – whether it was a patchwork of a few large blocks of closely-related cancer cells, or an intricate collage of many genetically different groups.

Then they looked to see how this variation was related to how the women had fared after being treated with the disease.

“The bottom line is the more detailed the patchwork is – in other words, the more heterogeneity there is – the higher the chances that the cancer will come back quickly, and that the patient will die from the disease,” James explains.

These ovarian cancers had extraordinarily chaotic DNA. “You see big chunks of DNA being copied or lost. Each of these changes could potentially encompass hundreds of genes, so now we need to work out which are the important ones that are driving the cancer to grow and become resistant to treatment,” says James.

The team also compared the genetic makeup of cancer samples taken early on, before women were given carboplatin, to later cancer cells that had developed resistance to the treatment and were continuing to grow. In doing so, they shed light on a long-standing puzzle: the origins of drug resistance.

James and his team noticed that certain gene faults, previously linked to treatment resistance, were present in tumours before treatment started, but only in a very small proportion of the cancer cells. One example is a gene called Neurofibromin-1 (NF1). Mistakes in NF1 are often found in advanced high-grade serous ovarian cancer, and it seems to play a role in making cancer cells grow again after treatment.

“We found that the later drug-resistant tumours have a high proportion of cells carrying a faulty version of NF1. But when we looked carefully, around five per cent of the cancer cells prior to treatment had it too. And it was even there in the original tumour sample from the fallopian tube, but only in a few cells.”

This suggests that the genetic seeds of resistance are already present at the very earliest stages of cancer, and that the population of cells carrying them expands and grows over time.

Unfortunately, it’s very difficult to test patients for these rare gene faults when they’re first diagnosed, although there is a technique that might help: so-called ‘liquid’ biopsies, which can detect DNA shed from tumours into the bloodstream (and which we’ve written more about here). Can the early signs that groups of cells carrying particular genes faults are starting to grow, be spotted in the blood?

“We want to be able to use this technique to monitor patients in real-time as they have their initial treatments, and see what is changing in their cancer at a genetic level,” James tells us. “Clearly, if we could see changes occurring earlier, we might be able to do something to make treatment more effective – such as switching to a different drug if it looks like the cancer is becoming resistant. But we need to be able to pick up on these changes quickly, while there’s still a chance to make a difference.”

At the moment, it’s not possible to measure the amount of heterogeneity and put a precise prediction on survival – but James is hopeful that he’ll get there.

“While we’ve shown that there definitely is a relationship between the amount of heterogeneity and survival, we can’t put precise numbers on it yet as we don’t have enough data,” he says. “But I think this kind of approach will eventually allow us to make those correlations. High grade serous ovarian cancer is a disease where there are extraordinary genetic changes, and it’s very complex to figure it all out. Now we need to work out ways we can do this on a larger scale, over hundreds of patients.

“We did this study looking at a lot of samples from a few patients, but we want to know if we can develop methods where we just need a couple of samples from many women.”

From patchwork to plan

From a scientific point of view, this is fascinating. But what we really need to do is turn it into more effective treatments. This is still very much a work in progress, and something that the Cambridge team is now turning its attention to, although there are a few exciting ideas in the pipeline.

James says: “We need to be thinking about how we schedule chemotherapy and other treatments to make it very unfavourable for these resistant cells to grow – we need to make life very uncomfortable for them.”

He thinks it’s important to look at the ways doctors give drugs to patients, and whether tweaking the dosing or timing could be beneficial for patients with lots of heterogeneity in their cancer.

“Is it such a good idea to give big doses of drugs every few weeks, or might it be better to give smaller doses more regularly?” James asks. “We need to think about how to schedule chemotherapy in different ways, whether we can use the immune system to tackle cancer as well as drugs, and even if we can alter the evolution of the disease in the body.”

Research like this is enabling scientists to reveal the genetic landscape of cancer within the body for the first time, and it should lead to urgently-needed improvements in the way that women are treated for ovarian cancer. And by agreeing to take part in studies like James’s, it’s these women who will ultimately lead to advances for future patients.

“I’m not sure how much they know about tumour heterogeneity,” he says, “They just want something to make the cancer go away and make them feel better. But they all really want to help our research.”

Kat

References:

Cooke S.L. et al.(2010). Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma., Oncogene,    PMID: http://www.ncbi.nlm.nih.gov/pubmed/20581869

Schwarz R.F. et al. (2015). Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis., PLoS medicine,    PMID: http://www.ncbi.nlm.nih.gov/pubmed/25710373

Comments

Kat Arney May 8, 2015

Hi,
The majority of cervical cancer cases are linked to HPV, an infection passed on by skin-to-skin contact, including through sex. The evidence shows that if a woman has never been sexually active then her risk of developing cervical cancer is very low indeed, although it’s not possible to say that it’s an absolutely zero risk. If you’re worried about anything please do go and talk to your doctor, as we can’t give medical advice on the blog.
Best wishes,
Kat

Letlole Gontse May 2, 2015

Hi
From the symptoms that I read, I can’t find anything to do with having cervical cancer if you are not sexually active. Does it mean that you can’t have cervical cancer.?

Kat Arney April 27, 2015

Hi Nuala,
Thanks so much for your feedback – glad you found it interesting.
Best wishes,
Kat

Gaughan, Nuala April 25, 2015

I found this information very clear and informative and the quilt image very helpful to a non medical person given the concept of a quilt where each piece could have a distinct image.
Nuala gaughan

Kat Arney April 20, 2015

Hi Leon,
Letotle is correct – there are many different types of cancer, each with different treatments and chances of recurrence and survival depending on the stage at which it is diagnosed. But it’s important to remember that every patient is an individual, and it’s hard to predict exactly how someone’s cancer will respond to treatment. Our researchers are working hard to understand more about why some cancers come back after therapy and how to treat the disease if it does return. You can explore the survival statistics for different types of cancer on our website: http://www.cancerresearchuk.org/cancer-info/cancerstats/survival/ and you may also be interested to read this recent blog post about our scientists’ research into understanding how cancers grow and change within the body: http://scienceblog.cancerresearchuk.org/2015/04/15/from-snapshot-to-family-tree-writing-the-evolutionary-rule-book-of-cancer/
Best wishes,
Kat

Kat Arney April 20, 2015

Hi,
I’m sorry to hear about your pain. There’s information about cervical cancer on our website here: http://www.cancerresearchuk.org/about-cancer/type/cervical-cancer/about/cervical-cancer-symptoms but the best thing to do is always to see a doctor if you’re worried.
Best wishes,
Kat

Letlole G.K April 16, 2015

Hi, I have this pain on my cervical region towards the fallopian tubes do you think it might be a cervical cancer symptom? I have had this pain since 13 and nothing can seem to fix it. When I’m on my periods it becomes worse.
Thanks

Letlole G.K April 11, 2015

Hi
I think that it depends on the type of cancer and it is not always guaranteed that it might come back. Am I right kat?

Leon H April 11, 2015

Hi
Does it mean that if I have cancer and it is treated it will come back?

Letlole Gontse 15043976 April 11, 2015

Cancer is such a great hider that some of the information about it is also not known to people.

Kat Arney April 7, 2015

Hi,
It depends on the type of cancer. For some cancers, including the three that we have screening programmes for here in the UK (breast, bowel and cervical cancer), they can be detected at early stages before they have spread. In some cases, particularly cervical cancer, screening can detect pre-cancerous cells before they even become dangerous. But for other types of cancer, early diagnosis is more difficult.

We are funding research into tests that could detect other types of tumour at an earlier stage, including ovarian, oesophageal and prostate cancer, and are working on developing new approaches such as blood or urine tests that could pick up the earliest signs of cancer. We also run public awareness campaigns encouraging people to go to the doctor if something doesn’t seem normal for them, which can also help to ensure people are diagnosed at an early stage, before cancer has spread. You can read lots more about diagnosing cancer early on our website: http://www.cancerresearchuk.org/cancer-info/spotcancerearly/
Best wishes, Kat

rebaone April 6, 2015

Hi kat
so is it possible to detect the cancer before it spreads or does it only show after spreading?

Kat Arney April 2, 2015

Hi,
Great questions! Thanks to research, survival from cancer has doubled over the last 40 years, and one in two people now survive at least ten years following their diagnosis. For some people, their cancer will not come back in their lifetime or lead to their death, especially if it was diagnosed early – this can be considered to be a cure. There are some types of cancer where the chances of being cured are very high, such as testicular cancer where nearly all men are now cured. But for other types of cancer the long-term survival is less good, especially if cancer has spread through the body.

We are working hard to find cures for all types of cancer, especially those where survival is still very low, such as oesophageal, pancreatic and lung cancers, as well as brain tumours. To see some of the work we’re doing, take a look around the blog and also on our website here: https://www.cancerresearchuk.org/our-research

Finally, you cannot “catch” cancer – it is not an infectious disease in humans. However, there are a few viral and bacterial infections that increase the risk of developing cancer. You can read more in our extensive 5-part series on cancer and infections: http://scienceblog.cancerresearchuk.org/series/cancer-and-infections/

Kat

Letlole G.K March 31, 2015

Hi
Thanks for your last response kat. I would like to understand that cancer is believed to be curable, but to date is not and research on it cure is still being conducted? And is it possible to prevent yourself from being infected with cancer?

Lisa J. Davis March 17, 2015

I would love these folks to test me. I’ve never had cancer, but have the BRCA2 genetic mutation. But the interesting thing is I am highly resistant and/or allergic to many antibiotics, so I am wondering if there is a connection and if I also have a fault in Neurofibromin (NF1)… it would be interesting to know, and also find out what can be done about it, if anything.

Kat Arney March 17, 2015

Hi,
Thanks for your comment – you raise an important point. It’s becoming increasingly clear that each person’s cancer needs to be thought of according to its individual genetic makeup. We’ve written about this new era of cancer science in detail in this post:
http://scienceblog.cancerresearchuk.org/2013/10/15/a-new-age-of-cancer-classification-and-treatment/
You may also like to read our blog post about the METABRIC study, which showed that breast cancer is ten distinct subtypes, each with a particular genetic ‘signature’ and needing different treatment:
http://scienceblog.cancerresearchuk.org/2012/04/18/increasing-the-resolution-on-breast-cancer-the-metabric-study/
And this study showing that there are four distinct types of pancreatic cancer:
http://scienceblog.cancerresearchuk.org/2015/02/26/pushing-unstable-pancreatic-cancers-over-the-edge/

With regard to your second question, cancer comes back after treatment because cancer cells in the body can change and evolve to become resistant to treatment. Our researchers are putting a lot of effort into understanding how and why this happens, in order to find more effective ways to treat the disease. Here are a few posts about cancer evolution and research into it that you may find interesting:
http://scienceblog.cancerresearchuk.org/2012/03/07/on-the-origin-of-tumours/
http://scienceblog.cancerresearchuk.org/2012/01/26/expert-opinion-why-are-some-cancers-so-difficult-to-treat/
http://scienceblog.cancerresearchuk.org/2013/04/08/watching-cancers-evolve-using-liquid-biopsies/
http://scienceblog.cancerresearchuk.org/2013/07/18/a-new-era-in-lung-cancer-research-the-tracerx-study/
http://scienceblog.cancerresearchuk.org/2014/10/09/lung-cancer-evolution-a-journey-through-space-and-time/

Best wishes,
Kat

Letlole G.K March 15, 2015

This has really been enlightening for me ,but it raises more questions. I would like to know since the cancer of different people is also different does it mean that the patients cannot be treated the same even if they are suffering from the same type of cancer? Why does cancer come back after treatment and why is it more stronger than before treatment?