PI3K-Mutant Metastatic Colorectal Cancer

Transcript:Richard Kim, MD: PI3K mutation is a potential biomarker that has been studied in colon cancer in patients who are receiving EGFR drugs. We know that EGFR drugs activates two pathways. One is the KRAS, the RAS-RAF-MEK pathway, which has been studied extensively. And the other pathway, is the PI3K-AKT-PTEN pathway. Now, PI3K is one of the biomarkers that has been looked at. It’s been sort of controversial in terms of the prognostic nature of this marker. However, in terms of the predictive value, it’s been looked at in two areas. The hot spots are exon 9 and exon 20, and it occurs in about 20% of the patients with advanced colon cancer. And there’s some data that if you have mutations of both exon 9 and exon 20, it’s actually a poor prognostic feature. But, in terms of the predictive value of being resistant to EGFR drugs, the data currently out there are mixed in terms of the nature of the value.

However, when they looked closely at the exon 20 mutations, they found out that patients with PI3K exon 20 mutations are the patients that are actually resistant to EGFR drugs, most likely because it is independent of RAS binding. However, the patient with exon 9 mutation, with PI3K exon 9 mutations, those patients actually were not resistant to EGFR drugs because the PI3K exon 9 mutations are dependent upon the RAS binding. Having said that, the numbers of PI3K exon 20 mutations are very small, in 2% to 3% range, therefore we need larger studies to be done to validate this finding and its clinical implication.

Charles S. Fuchs, MD: The PI3K gene, an important gene in a variety of cancers, is mutated somewhere in the range of 15% to 20% of metastatic colon cancer. There have been many drugs under development to target the PI3K gene in a variety of malignancies, but so far those drugs aren’t working for those patients with PI3K-mutated tumors. We need better drugs. The gene is important. It’s a major driver in colon cancer, but we haven’t been able to effectively target it. What is interesting is that there have been some studies to suggest that if your patient’s tumor is mutated in PI3K, you may be less responsive to EGFR antibodies. That’s controversial, but it has been suggested, and more needs to come out there.

The other thing is we have a study from our center where we found that patients with earlier-stage disease, who took aspirin, seemed to do better. If they took aspirin in conjunction with their standard therapy, they had a better outcome. Aspirin appears to have an antiproliferative effect on colon cancer. What was interesting from our study, published in the New England Journal of Medicine about a year ago, was that if your patient’s tumor had a PI3K mutation, you had a significant, even greater benefit if your patient took aspirin in conjunction with their therapy. Now, that’s one study. It needs to be confirmed. It was a large study, but it’s interesting, and maybe that might be one area, at least today, where knowing the status may inform what is a very inexpensive and easy addition to therapy; namely taking an aspirin.

Daniel G. Haller, MD, FACP, FRCP: For PI3-kinase, there’s not a lot of agreement among different studies on its exact interaction with EGFR agents and development of resistance. The most exciting data that exists for PI3-kinase is in the use of COX-2 inhibitors and aspirin to either prevent cancer, or to prevent recurrence of cancer, or to prolong survival, even in patients with metastatic disease.

At ASCO last year, there was a very large study done from Norway, where they have very good long-term data on their entire population, looking at aspirin use in patients who had colon cancer stages 1 through 4. And, so they didn’t differentiate. What was seen was exactly what was seen in the health professional study in the US, the Nurses’ Health Study with aspirin use, that overall survival was improved. And no one quite knows why this is true, although aspirin is a COX-2 inhibitor and there is data also for the nonsteroidal anti-inflammatory drug (NSAID) COX-2 inhibitors in improving survival. But these data, nicely discussed by Andy Chan from Harvard, stand in complete agreement with at least 15 prior studies.

Now all of these are retrospective studies, but the data are pretty profound where people not only have better survival overall, but they have better colorectal cancer survival. People develop fewer tumors, altogether. Then, when they get colon cancer, they do better. One would ask the question, why not use something simple and cheap like aspirin if it’s good for you in this regard?

Well, a number of groups in Great Britain and the US had discussed this thoroughly and have come to different conclusions. People worry that bleeding rates, vis-à-vis the use of aspirin versus colorectal cancer, or cardiac benefits. And the difference is not so much a qualitative one. Everyone agrees that it should be useful. What they disagree on is the number of patients who might have a bleeding event versus the number who might benefit; the number needed to treat.

I have to tell you when I look at the numbers, I take aspirin. That’s my answer, that’s what I do. One further thing in regard to PI3-kinase, the people who seem to benefit, almost all are those who have PI3-kinase mutations, which is 15%. All of these studies, when they go back retrospectively, and have the tissue available to do it, show that there’s no benefit if you don’t have the PI3-kinase mutation, and a huge benefit if you do. There are about five aspirin-intervention trials underway. Only one of them is collecting the PI3-kinase mutations upfront. They’re collecting tissue, but they’re only collecting it upfront. And they’re not randomizing patients with or without, whether they have the mutation or not.

So that’s a good part, we have prospective trials underway. The bad part is that it will be at least 15 years before we get the data from these studies because we’re looking at large numbers of patients who need to be treated. The studies will take at least 5 years to accrue, and then one needs at least 5 to 10 years of follow-up to see who’s benefitting.

For the moment, when I finish adjuvant therapy in a patient, I don’t tell them that their treatment is over because there are so many other things that Charlie Fuchs and his colleagues at the Dana Farber Cancer Institute have told us about how also to prevent recurrent beyond chemotherapy. One of them is diet, one of them is exercise, and one of them is vitamin D. And finally, one of them could be aspirin, especially for those who have PI3-kinase mutation. More people will be looking for that in their practices, looking for this mutation, to select people who are at low risk for bleeding and potentially high risk of benefit from aspirin.

Transcript Edited for Clarity