Thanks to advances in research over the years, we know more about cancer than ever before, with new discoveries being made all the time. In some cases this knowledge has led to life-saving new treatments. In others, it causes frustration and head-scratching until more pieces of the puzzle fall into place.
For example, why do some patients with the same type of cancer respond to a treatment but others don’t? And what makes some cancers grow and spread aggressively while others are less dangerous?
Thanks to research, answers to these questions are coming. Much of this progress hinges on the use of new technology to analyse the faulty genes in cancer cells, enabling researchers and doctors to characterise the molecular fingerprint of an individual person’s cancer and select the most appropriate treatment.
As an example, last year our scientists showed that, based on the genetic makeup of each patient’s disease, breast cancer can be divided into at least ten distinct subtypes, each with different outlooks and responses to treatment.
Now it’s bowel cancer’s turn under the spotlight, as researchers at our Cambridge Institute – along with colleagues in the Netherlands and Oxford – have discovered a new subtype of bowel cancer, which has a worse outcome than other types and is resistant to current targeted treatments.
Published in the journal Nature Medicine, their results have big implications for patients and future research.
Deciphering the signature
The researchers analysed the activity patterns of thousands of genes in tumour samples from 90 patients with what’s known as ‘stage II’ bowel cancer – where the cancer has just started spreading out of the bowel into the surrounding organs. They found that the patterns fell into three broad groups, which they call CCS1 (for Colon Cancer Subtype 1), CCS2 and CCS3. We’ll refer to them here just as Group 1, 2 and 3 to keep it simple.
The scientists then narrowed down a set of just 146 genes that could accurately distinguish between the three types – essentially a molecular fingerprint for each type of the disease.
Using this, they worked out that nearly half of the patients had Group 1 tumours, while roughly a quarter were affected with Group 2 and a quarter with Group 3. The team confirmed their findings by looking at the patterns of gene activity in tumour samples from a larger group of just over 1,000 bowel cancer patients.
So far, so interesting. But what do these different subtypes actually mean?
It turns out that the tumours in Group 1 and 2 are already familiar to bowel cancer researchers. Group 1 cancers are known as “chromosomal instable” tumours, which we recently wrote about, that have a lot of broken and messed-up chromosomes. By contrast, Group 2 tumours are called “microsatellite instable” and have changes in the lengths of short repeated sequences of DNA known as microsatellites – it’s a kind of genetic ‘fuzziness’.
The newly discovered Group 3 tumours are different. They don’t have chromosome or microsatellite instability, and they’re more likely to have faults in specific genes (such as BRAF and KRAS) than the other types.
When the researchers compared how long each group of patients had survived, people with Group 3 cancers generally had a worse outlook. Many had more aggressive tumours that grew and spread faster than those in the other groups. And in more than half of all cases, the cancer came back within two years.
And there’s more. The scientists found that the Group 3 tumours were much more likely to be resistant to treatment with cetuximab (Erbitux) – a commonly-used drug targeted against a molecule called EGFR (which our scientists helped to discover) on the surface of bowel cancer cells.
Putting it all together, this is a hugely important discovery. Not only have the researchers revealed a whole new subtype of bowel cancer that was previously elusive, it also looks like these tumours are more aggressive, harder to treat and have poorer survival than other types.
On the surface this sounds like bad news, but, as we’ll see below, it opens the door to much more effective approaches for identifying and treating patients with these types of tumour in the future.
Going back to the roots
There’s one more important question that the researchers needed to answer – where do these Group 3 tumours come from?
To find out, they compared the genetic fingerprints of different types of precancerous bowel lumps (lesions) to the signatures of the different subtypes of bowel cancer. They discovered that Group 3 cancers shared their genetic makeup with lesions known as serrated adenomas, which develop in a different way from the precursors of Group 1 or 2 tumours.
The researchers also found that genes linked to aggressive growth and cancer spread were more active in Group 3 tumours. And they spotted rogue activity patterns of genes that switch cells from being a well-behaved part of the lining of the bowel to becoming ‘free agents’ that can invade nearby tissues.
Significantly, they noticed that many of these genes are already active in precancerous serrated adenomas, suggesting that they’re somehow primed to spread from an early stage – something that usually happens much later for other subtypes of bowel cancer. The researchers think that this may be due to the particular type of cell in the bowel that these Group 3 tumours start from, but more work needs to be done to figure out exactly what’s going on.
Again, this finding is highly significant as it tells us that there’s a group of patients whose tumours have the capacity for aggressive growth ‘hardwired’ into them practically from the start. The major challenge now is to work out which patients have these tumours, and find ways to treat them more effectively.
There’s still a way to go before this knowledge can be applied to bowel cancer patients on a widespread basis, but there are some clear ways forward.
For a start, the team’s findings need to be confirmed in a larger number of patients, to make sure they hold up. Another important step will be to develop a reliable test that can identify which patients fall into which groups – something that should be possible in the not-too-distant future.
As part of this research, the team showed that an FDA-approved gene test called Oncotype DX, which looks at the activity levels of 21 genes and costs thousands of dollars, could distinguish patients with Group 3 tumours. But this test, and others like it, are designed to help doctors predict whether individual patients are likely to have a good or poor outlook (prognosis), not identify the specific gene faults that underpin their cancer (which would be important for selecting the most appropriate treatment).
To solve this problem, the team developed a ‘mini-classifier’ panel of just four genes that could accurately distinguish between the different bowel cancer subtypes at a biological level, rather than just giving a “good or bad” read-out. Developing this kind of approach into a simple, cheap test that can be validated in a large number of patients could help doctors identify patients with more aggressive Group 3 cancers and help guide treatment decisions.
This research also has big implications for research into bowel cancer, as it turns out that current lab models of the disease are based on Group 1 and 2 tumours. Group 3 cancers are relatively unexplored territory, scientifically speaking, so much more work needs to be done to understand where they come from and how best to treat them.
By understanding the faulty genes and molecular pathways in these cancers, researchers will be able to develop more effective therapies specifically targeted at these aggressive tumours, which could save many lives in the future. One particularly exciting avenue is the TGF-beta pathway (which we’ve talked about before), which seems to be hyperactive in Group 3 tumours, so drugs that block TGF-beta (which are already in development) or related molecules might be useful, but this still needs to be investigated.
April is bowel cancer awareness month, and although we can’t control when our researchers publish their scientific papers, this new discovery is a timely reminder that research is the best weapon we have for beating this disease that claims more than 15,000 lives in the UK every year. And, one day, we will get there.
De Sousa E Melo F. et al (2013). Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions, Nature Medicine, DOI: 10.1038/nm.3174