Image: DNA sequencing autoradiograph - coloured. Credits: Michele Studer. Attribution 4.0 International (CC BY 4.0)
A gene test already used routinely in the NHS can guide use of chemotherapy in people with bowel cancer by predicting whether or not they will benefit.
The test could allow doctors to select patients whose cancers are likely to be sensitive to chemotherapy – and spare others who will not respond from unnecessary toxicity and debilitating side effects.
Scientists hope their findings, published in Nature Medicine, will enable the first routine use of a genetic test to predict how patients’ cancers will respond to chemotherapy in bowel cancer.
The gene test is already used as part of standard of care in the UK and worldwide to predict patients’ responses to other targeted cancer drugs, meaning doctors could apply it to guide chemotherapy straight away.
The research was a joint effort between scientists from The Institute of Cancer Research, London, Imperial College London and the Netherlands Cancer Institute. It was funded by The Institute of Cancer Research (ICR), Imperial and the Oncode Institute.
Harnessing genetic markers
Patients with late-stage bowel cancer receive a series of chemotherapies and targeted medicines to treat their cancer, but eventually cancers adapt and evolve to become resistant to each treatment.
The chemotherapy trifluridine/tipiracil is a last-line treatment available on the NHS for patients who have exhausted most other therapies. It is made up of two drugs trifluridine and tipiracil and is taken as tablets.
Responses to trifluridine/tipiracil vary greatly between patients – with some patients showing good, long-term responses, and other patients seeing no benefits.
The researchers looked at data from three sources to understand whether genetic markers could help to explain the differences in survival.
Personalising chemotherapy
First, researchers profiled the entire genomes of 37 patients with advanced bowel cancer, who had been treated with trifluridine/tipiracil.
The researchers found that a specific mutation in the KRAS gene called KRASG12 was linked to poor survival in treated patients and confirmed this in data from a further 960 patients from 36 centres across the UK.
Next, they looked at data from a clinical trial called RECOURSE, and were able to unravel the impact of treatment on survival for patients with different KRAS mutations.
Patients with a mutation in the KRAS gene called KRASG13 – 8 per cent of those on the trial – saw their median survival triple from 2.9 months without treatment to 8.7 months with the treatment.
This was compared to no benefit from treatment in patients with KRASG12 mutations – both patients who received placebo, and patients who received the treatment survived for an average of six months.
For patients without mutations in KRAS, also called wildtype KRAS, survival improved by approximately 2 months in patients treated with FTD/TPI compared to placebo.
Overall, the findings suggest that patients with KRASG12 mutations – accounting for around 28 per cent of all patients with bowel cancer – do not benefit from trifluridine/tipiracil, and should avoid unnecessary toxicity. Instead, they could take part in clinical trials.
But patients without mutations in KRAS may benefit from trifluridine/tipiracil, and those with a KRASG13 mutation are likely to do very well on the treatment.
Patients with advanced bowel cancer already receive gene tests which look for mutations in KRAS as part of standard NHS care, to select those who would benefit from targeted medicine called cetuximab.
Doctors could immediately apply the same test to direct treatment with trifluridine/tipiracil based on this evidence.
The researchers are calling for regulators to rapidly incorporate the findings into guidelines so that using the test to direct treatment with trifluridine/tipiracil becomes standard of care.
Immediate impact on patient care
Professor Nicola Valeri, Honorary Professor of Gastrointestinal Oncology at The Institute of Cancer Research and Imperial College London, said:
“This is the first time we have a genomic marker already used in the clinic that can tell us whether a patient’s cancer will be sensitive or resistant to chemotherapy. We hope doctors will use this data to improve care for patients with advanced bowel cancer without delay.”
“It will be difficult for some patients to find out that this last-line drug will not benefit them, but this test will mean they are able to avoid unnecessary side effects and have a better quality of life with advanced cancer. Fortunately, our findings also reveal a group of patients who see substantial benefits from taking this type of chemotherapy.”
Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:
“Treating cancer well is not just about allowing people to live for longer, but also about giving them the best possible quality of life. Although chemotherapy can be very effective for many patients, it can also have debilitating side effects – and so it is important to have as much information as possible about how likely treatment is to work.
“This is an exciting advance for genomic medicine – showing that genomic tests are not just useful for guiding treatment with targeted therapies, but also chemotherapies. The study could have a big impact for people with advanced bowel cancer, by potentially giving them a more suitable treatment.