Codon-specific mutations in the KRAS gene may predict a patient’s response to harsh chemotherapy, according to a recent study published in Nature Medicine. Testing for these mutations may allow for personalised treatment plans for those with metastatic colorectal cancer, saving patients from harsh treatments that may not ultimately benefit them.
The role of the oncogene
Colorectal cancer often has poor prognosis and is prone to metastasis. Frequently implicated in the development of the disease is KRAS – a well-known oncogene responsible for the conversion of GTP to GDP. The gene is part of the RAS/RAF/MAPK pathway, a signalling pathway that regulates a variety of cellular process such as growth and division. Common KRAS mutations that are associated with colorectal cancer occur at codons 12 and 13 (G12 and G13), and patients are typically tested for these variants at diagnosis. However, despite having distinct biochemical properties, the two mutations are not differentiated in a clinical setting.
A variety of treatments are available for metastatic colorectal cancers, yet positive responses are not universal. A stark example of this is the use of the last-line treatment FTD/TPI – a form of chemotherapy that elicits strong results in some patients, and little to no response in others. The therapy also comes with harsh side effects. As such, it is crucial to determine who may or may not benefit from its use, in order to prevent needless impact on a patient’s quality of life. Therefore, the researchers assessed whether one’s KRAS status was associated with their response to FTD/TPI treatment, in real-life cohorts of metastatic colorectal cancer patients.
Opposing effects
Overall survival in patients who had received FTD/TPI was markedly lower in individuals with the KRAS G12 mutation, a finding initially confirmed via whole-genome sequencing of a small Dutch cohort and replicated in a larger group of 960 patients. Progression-free survival was also shorter in those harbouring the G12 variant.
However, when analysing individuals who had received a placebo drug, those with KRAS G12 mutations exhibited a similar overall survival rate to that of patients without KRAS mutations, whilst patients with a G13 variant had a significantly worse prognosis. Conversely, G13 patients who received FTD/TPI showed a much more positive response to the therapy. This led the researchers to the conclusion that KRAS G13 mutations are associated with worse outcomes in the absence of treatment, but that the tumours respond well to FTD/TPI. On the other hand, KRAS G12 patients do not benefit from undergoing this harsh, toxic therapy.
Improving the standard of care
With KRAS mutations already tested for as standard in the UK, the infrastructure exists to allow for informed decisions regarding personalised cancer treatments. Senior author Professor Nicola Valeri stated in the press release; “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.”
However, as FTD/TPI is a last-line treatment for metastatic colorectal cancer, it is likely that the test would simply prevent the patient from needlessly undergoing the difficult treatment at the end of their life, rather than pointing to an alternative. Despite this, the team are keen for the results to be incorporated into standard cancer care, and for the codon-specific mutations to be viewed as distinct clinical markers. Valeri added; “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.”
