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Aspirin Reduced Risk of CRC Recurrence for Patients With PI3K Alterations


Anna Martling, MD, PhD, Karolinska Institutet, Stockholm, Sweden, discusses the results from the ALASCCA study, which found that adjuvant aspirin reduced the risk of colorectal cancer recurrence among patients with PI3K alterations. The study met its primary end point, demonstrating that for patients with mutations in the PI3 kinase pathway, 160 mg aspirin daily for 3 years resulted in a more than 50% reduction of recurrence.

Dr Martling concluded these results “should change the way we treat patients accordingly.”

These results were first presented at the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

Transcript:

My name is Anna Martin. I'm a professor of surgery at the Karolinska Institutet in Stockholm, Sweden.

Thank you for giving me the opportunity to present a little bit about the ALASCCA trial. The background is, first of all, colorectal cancer is one of the most common cancer diagnoses in the world. About 2 million people do get colorectal cancer each year globally. Despite the advancements in new treatment strategies, new diagnostic tools, it's still the second leading cause of cancer-related death. Meaning that there is a large unmet need to improve new treatment strategies, find out new predictive biomarkers, etc.

Aspirin, which is the drug I will come back to that we have studied in this randomized controlled trial, is one of the most well proven drugs we have on the market. It's been on the market for more than 120 years, mostly for painkilling effects, fever reduction, but also later in the cardiovascular field. But actually, it was already a thousand years ago, it has been told that human beings chewed white willow bark for salicylic acid for painkilling effects. So, it's been used for many years apart from studies in the cardiovascular field, designed for other causes.

What’s interesting for the background of our study, it has been shown that people on aspirin for other causes do have a lower risk of getting colorectal cancer. And it has also been proven in randomized control trials that aspirin reduces the number of polyps, and the size of polyps, in patients with high risk of developing polyps and cancer in the bowel. Interestingly, also in large, non-selective retrospective, but with observational design, it has also indicated that it might not only lower the risk of getting cancer, but also lower the risk of getting the cancer back if you have had been treated for colorectal cancer. And it might also be shown in retrospective studies that this effect of aspirin is explained by a predictive biomarker, a genetic biomarker called PIK3CA.

But before you can implement that kind of strategy in the population, you have to have more robust firm evidence. And that is the background to the randomized control trial that we launched in 2016 in four Nordic countries, including 33 different study sites. The ALASCCA trial is the first biomarker-driven randomized study on aspirin in patients with colorectal cancer, which has fulfilled 3 years and now we present the final data, 3 years follow-up data.

The design was that we screened 3500 patients in the Nordic countries, 33 sites, and we screened them for the PIK3CA mutations, but also for other mutations in the same signal pathway, because we thought that it might not be only the mutation, it might be the signal pathway that is of interest actually. So there are 2 groups: patients that had either of those mutations were either in the PIK3CA arm, or in the group outside the hotspot PIK3CA mutations, but same signal pathway. And there was 37% of the patients did have any kind of mutation in the signal pathway. So a large proportion of stage II to III disease in colon and rectal cancer. Those patients then went on in the trial and were randomized to 160 mg aspirin or placebo, once daily for three years. The primary endpoint was time to recurrence in group A. in the PIK3CA mutated group.

What we now have shown is that the primary end point was met, 160 mg aspirin did reduce the risk of recurrence in group A with PIK3CA mutations by more than 50%. But also, interestingly, in the explorative arm, with the other mutations, it was even a larger, almost up to 60% reduction in recurrence rate, meaning that we have expanded the targetable population substantially to almost 40% gaining benefit from aspirin.

The effect was also seen in the overall survival, not significantly for group A, probably a power thing, but significantly in group B and in the combined cohort, which was significantly reduced. And what is also interesting is that the data seems to be very robust. Although the study was not designed for subgroup analysis, we could see the effect in all subgroups no matter what kind of mutation you had, if you had the colon or rectal cancer, if you were on neoadjuvant/adjuvant treatment —almost 50% of the rectal cancer patients did get neoadjuvant in addition to the study drug and colon cancer, 50% had adjuvant therapy inadditional to the study drug. And you can see they also gained from it, but also those that didn't receive another treatment and also in both groups had success. So, it's a robust data.

The side effects were as expected. This is a very well-known, we know probably all side effects of this drug. It’s very inexpensive and available as study drug, and it was as expected, so the toxicity is quite low.

To conclude, it was a positive study, the primary end point was met. We have shown that patients with mutations in this PI3 kinase pathway that get with 160 mg aspirin for 3 years did have a more than 50% reduction in recurrence. And I think it should change the way we treat patients accordingly.

We have proven that the very available, well-studied inexpensive drug is effective and it's quite remarkable effect actually on a subgroup of patients. But of course, to identify that subgroup of patients, you have to have genomic testing available. And that is something to think about for equality reasons, and in a global matter. This is not the case all over, and that is quite expensive to have this upfront genomic testing. On the other hand, there's a one-time cost, and to have a local recurrence is also very expensive.

The development in healthcare today is driven by the diagnostics. You might have a more costly diagnostic procedure, but on the other hand, you will save money somewhere down the road and you can perhaps avoid some treatment in some patients. But also you have an effective, very inexpensive treatment at hand that you can use that could prevent recurrences. Of course, you can discuss if you should give it to everyone. You will not have the same effect on the population, of course, but you will know that 40% of the patients will actually gain without the test. So that is something interesting. And we are planning to do health economy analysis afterwards, to study this and also the risk benefit analysis in that aspect as well.

We can fine tune probably to see if there are other groups that could be included, how long you need to be on the treatment, when you should start, etc. We started postoperatively immediately. Meanwhile, they also had their other treatment. The doses, of course, there are effects in both men and women. The effect is even stronger in women, and that is interesting. It might be related to the dose, which has been studied before in the cardiovascular field. There are a lot of things to do fine-tuning. But we have proven that it works with 160 mg, but then you can of course adjust that. A lot of good, much more research is needed, but I think we shouldn't wait for the results before we implement this because there's so much other literature indicating this effect, but it hadn’t been proven before.


Source:

Martling A, Lindberg J, Hed Myrberg I, et al. Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial. Presented at ASCO Gastrointestinal Cancers Symposium; January 23-25, 2025. San Francisco, CA. Abstract LBA125

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