This study is about… the research question behind it is actually could a widely used, very safe, old, inexpensive drug be used to reduce recurrence in patients with colorectal cancer using a specific genetic biomarker. So that was the question behind it. The unmet need, if you look at colorectal cancer it’s one of the most common cancer forms in the world, globally two million people are diagnosed each year. There is still, despite the advancement in new strategies, new diagnostics, new treatment regimens, it’s still the second leading cause of cancer death, actually. So there is a large unmet need of identifying new treatments but also new biomarkers to improve prognosis in those patients.
The story of aspirin is fascinating, I would say. Actually it has been on the market for more than 125 years, I think. It is described that it was used already thousands of years ago by humans chewing white willow bark, and that contains acetylsalicylic acid, for pain relief and so on. That was the indication from the beginning – pain relief, fever reduction and then later on in the cardiovascular field. But then more recently, during the last years, it has been proven that it actually reduces the number of polyps and the size of polyps in patients with hereditary syndromes for polyps with a high risk of getting colorectal cancer. So that is well known in randomised controlled trials. It has also been shown in non-selective observational studies, mainly retrospective studies that were designed for other courses, mainly in the cardiovascular field, that it also might reduce the incidence of colorectal cancer.
What is interesting for this specific study is that it has also been indicated but needed more firm evidence that it might also reduce the risk of getting the disease back once you have had a colorectal cancer. Then there is an indication, and that is also from retrospective studies, that PIK3CA, the genomic marker we are using, might be a predictive biomarker and could explain the slight effect you see on reduced recurrence. That was the hypothesis and the background beyond when we decided to start this Nordic study.
What was the study design?
The study was a randomised controlled study. We did the power calculation on the PIK3CA, the well-known biomarker, and then we needed 300 patients in that arm. But we thought that we also should study other mutations in the same signal pathway because it might not be the specific mutation, it might be the pathway that is involved in tumorigenesis. So we also had another group, another arm, with other mutations in the same signal pathway which haven’t been studied before. So that’s an exploratory arm, quite new, so we added that. Then we screened 3,500 patients, a little bit plus, for those mutations and about 37% of the patients did have any of those mutations and went into the trial. They were randomised to 160mg aspirin or placebo once daily for three years. So one arm with PIK3CA and one arm with the other mutations, so to say, and randomised in both arms. Then they have been on medication for three years and we had then the final three-year result which I will present tomorrow in the ASCO GI meeting, the results of that trial.
What were the key findings?
Well, it’s actually extremely interesting. The trial met the primary endpoint, so we showed that low dose aspirin for three years in patients with PIK3CA mutations did reduce the risk of recurrence by more than 50%. And also what is also super-interesting is that in addition to that also in the exploratory arm with the other mutations in the same signal pathway we had the same effect, even actually a stronger effect – 58% reduction – and that has never been shown before. It is also extremely important because it expands the [??] population to almost 40% of the patients with stage 2 and 3 disease in colorectal cancer.
Also we have done subgroup analyses but the study is, of course, not powered for those. But we can see that the effect is in all groups, no matter if it’s colon or rectal cancer, if it’s stage 2 or 3 disease, both [??], if they have had neoadjuvant or adjuvant treatment or not. So it’s a very consistent result in all groups which is also very encouraging, showing that all patients in that stage 2 and 3 do have an effect of aspirin.
What could be the clinical significance of these results?
I think this will actually change practice globally. This is a very inexpensive drug available with no practical adverse events. We use a genetic biomarker and that, of course, will need to have that at hand to be possible to analyse the genomic biomarker. On the other hand, we know that taking that cost could save a lot of money. In the end it’s more costly to have a recurrence than to make a proper diagnosis beforehand and using this extremely inexpensive drug. For one year of consumption once daily the cost of aspirin is €20 or US$20 so compared to all other expensive oncological drugs. So, in that respect it will be possible to use globally, also in low-income countries, and you could discuss if you could do it unselectively without genomic testing, of course, in low-income countries, knowing that 40% will have an effect. But on the other hand that would need to be weighed because it’s safe but it’s not without any risks, so you have to weigh that with the risk you have of bleeding etc.
Anything else to add?
Yes, I think it’s also an example of precision medicine, another way of precision medicine. You’re using a predictive biomarker and then you can repurpose another drug that is used for other indications, a very cheap one. So precision medicine is not only about the new drugs and the new latest treatment, it’s also about using the already existing drugs. So that is also something good with this. I think it’s super-exciting, especially from a global perspective also and I think it will change practice, hopefully. That will be the next step, of course.
