“What you now see is that every cancer is a rare cancer.”
So says Emile Voest, professor of medical oncology at the Netherlands Cancer Institute, who was writing in the journal Nature. Voest was highlighting a revolutionary change in cancer treatment over the past decade: the advancement of genomics.
Genomics is the study of how genes interact with one another and the environment. It has already had a massive impact in oncology. For example, Voest notes that 12 years ago, lung cancer was classified as either small cell or non-small cell. Today, it’s identified by nearly 30 genomic mutations or changes.
Identifying specific mutations in patients marks a radical shift from one-size-fits-all treatment towards more personalised therapy. For example, it could provide treatments for colorectal cancer with mutations in the so-called KRAS gene, which don’t respond to some standard therapies. Likewise, acute myeloid leukaemia carries mutations that make it resistant to drugs known as isocitrate dehydrogenase inhibitors; genomics could offer answers.
A complex battle
Cancer is far more complex than even the most visionary of scientists ever imagined.
Twenty years ago, for example, researchers speculated that germ cell testicular cancer might be attributable to a single gene. However, a team led by Professor Clare Turnbull of the Institute of Cancer Research in London has found more than 40 genomic variants associated with the disease.
Small wonder, then, that so many experts see such importance in genomics. And there has been significant progress. For example, Turnbull was clinical lead on the 100,000 Genome Project, which sequenced 100,000 genomes from more than 80,000 NHS patients with cancer or a rare disease. This yielded potential research leads in nearly half the cancer patients taking part.
To understand why all this is so remarkable, it’s important to understand the context. The initial sequencing of the full human genome took more than 10 years and cost in excess of £2 billion. Using a blood sample, an individual’s genome can now be sequenced in a day for less than £700.
Genomic medicine is already saving lives in a multitude of ways. Take DYPD, a gene mutation carried by roughly 10% of the UK population that can make chemotherapy harmful to the bone marrow, potentially killing the patient. Genomics advances mean doctors can now test patients for the mutation at a cost of £50 each, saving lives and cutting costs for the NHS, notes Andrew Beggs, professor of cancer genetics and surgery in the Institute of Cancer and Genomics Sciences at the University of Birmingham.
Lack of awareness
However, Beggs worries about a lack of public and even professional awareness about the scope for cancer prevention. For example, Lynch syndrome is a genetic condition that can increase the risk of bowel cancer by up to 80%. It also increases the risk of ovarian, womb and other cancers. Beggs, who runs a Lynch syndrome clinic, says it’s a relatively common condition, affecting about 1% of the UK population, but most are not aware of it.
One reason for this is cultural. Most people think of the NHS as an institution they turn to when they are feeling sick, but genomic medicine points to a future when there will be an ever bigger emphasis on preventive medicine. Increasingly, families with a history of genetically linked cancers will be asked to undergo testing and any necessary treatment to prevent the cancers developing at all. But Beggs says that some patients fear screening because they do not want to face up to the idea that they could be at risk from a fatal disease.
“Most people want to find out if they are at risk, but the people who don’t want to know tend to be in their late teens and early 20s. You can understand this. They are young and believe it will never happen to them. But some are scared,” he explains.
The answer, he says, lies in education of both healthcare professionals and patients. GPs have a critical role to play in identifying families at risk.
There are advantages to the NHS too. A single round of chemotherapy in a private hospital can cost up to £3,000, while cancer drugs cost the NHS more than £2bn a year. While a single genomic treatment could cost up to £20,000, that’s cheaper than “putting a patient through hospital admissions with say five or six rounds of chemotherapy that don’t work and that cause significant side effects”, Beggs notes.
Oncology used to be like sharp-pointed sticks and rocks. We now have more finesse and have moved to the medical equivalent of a scalpel
Statins, the widely prescribed cholesterol-lowering drugs, are another example of a cheap therapy that has been found to have a beneficial effect in genomic treatment. Costing as little as four pence per tablet, statins have been shown to reduce levels of P53, a tumour suppressor gene. P53 mutations can cause cancer cells to grow and spread.
Statins are an example of repurposed drugs – old medicines used in new ways – that have long-established safety records. They can avoid the need for expensive new medicines. About 25,000 new substances are tested for every marketed medicine that makes enough money to pay for its development.
Genomic drug testing is also changing clinical trial design. Traditional trials usually compare one drug with another, with patients divided into treatment groups. They remain on the trial from the start to the end – perhaps for several years – irrespective of whether it is helping them.
The ongoing National Lung Matrix Trial could change this. Through the trial – which is based on 11 treatment arms using different drugs – University of Birmingham researchers match various treatments to different groups of lung cancer patients according to genetic changes in their cancers. If a particular drug isn’t working, that treatment arm is closed and a new one may be introduced. If a patient doesn’t respond to drug “A”, they can be switched to drug “B”. They may be in and out of the trial within two months.
“In a traditional trial, patients receive broad spectrum chemotherapies that don’t work half the time,” Beggs says. “Oncology used to be like sharp-pointed sticks and rocks. We now have more finesse and have moved to the medical equivalent of a scalpel.”
Kinder treatment
Thirteen regional genomic centres are now operating in England. One of their goals is to identify the patients who may benefit most from from genomic testing. Another is to ensure more effective use of medicines, not just in cancer, but in all health care. The NHS medicines bill was about £17 billion a year. However, 50 per cent of medicines are not taken as prescribed and one in 15 hospital admissions occur because of adverse drug reactions according to a recent report in the Pharmaceutical Journal.
What is also disturbing is that the effectiveness of drugs overall ranges between 30 to 50 per cent. Advances in cancer genomics is explaining why so much conventional chemotherapy fails – it does not target the right mutations. Hopefully, genomics will also lead to kinder treatments. Severe side effects arising from cancer therapy are all too common.
There is, of course, still a long way to go before the genomic revolution meets its full potential, but the success so far would have been unimaginable just a few years ago.
