It’s been known for many years that breast cancer progression is associated with inflammation. It wasn’t clear as to how that happened but it was known that an enzyme called cyclooxygenase-2, which makes prostaglandins in human tissue, could mediate some of the inflammatory activity, and it was also known that prostaglandins which derive from COX-2 could promote breast cancer proliferation and angiogenesis. Those were the facts back in 2000 or so when we began to think about this trial. It was also known about that time that there were a few studies indicating that drugs like aspirin could maybe have some preventive effect, particularly in colorectal cancer as well. So there was quite a bit of clinical and preclinical evidence to suggest that a trial looking at a cyclooxygenase-2 inhibitor would be interesting.
We began to recruit patients about 15 years ago and the study started, but shortly after it started there was a big crisis in America around celecoxib and other COX-2 inhibitors. They were said to be promoting heart attacks and all sorts of problems clinically and in fact the US study that had been started was abandoned because of these early fears. We stopped our study, we stopped recruitment for a while, and then when some of the concerns proved to be unfounded we restarted. In the end we recruited 2,600 patients and it’s now been five years of median follow-up.
Essentially, the bottom line is that overall it doesn’t do anything at all to either time to relapse of breast cancer or overall survival. But when we examined the subsets of patients we found a signal in the patients, which numbered about 660, who had not received chemotherapy. So about 25% of the patients didn’t have chemotherapy and those patients appeared to benefit from the drug. It’s only a signal, it’s a subset analysis, so we need a prospective study to validate that. The second feature that came out of the study was how non-toxic the drug really was. We didn’t see any cardiac side effects at all in any of the women, we didn’t see any of the gastrointestinal effects which people were worried about. Instead, what we saw was an improvement in what we call arthralgia – aches and pains, arthritis-like symptoms in patients in the study.
In summary, we do have a signal in people who’ve not had chemotherapy, it needs to be confirmed. We do have an indication that it could help some of the common side effects of endocrine therapy like arthralgia. We also have collected all the breast cancer samples from 95% of the women who entered the study. I think the next years are going to be very important, we need to try and find markers for COX-2 sensitivity, a bit like oestrogen receptor or HER2, in these tumour blocks and then carry out further analyses to see if we have defined a subgroup of patients with a COX-2 signature who would benefit more that those that don’t.
If you look at the history of adjuvant therapy breast cancer you can see that before oestrogen receptor was discovered there was a big debate about the effectiveness of endocrine therapy and then when they suddenly discovered that actually a third of the patients wouldn’t benefit anyway, then the results began to become much more meaningful. I think the jury is still out, and hopefully this time next year we’ll have a better result.
If it made it to this phase III trial and nothing happened, how promising were the earlier indications that there could be some celecoxib activity or significance, which then led to the construction of a phase III trial which then resulted in these negative results?
I think until we have done the further analysis I think it’s impossible to say. The whole of this conference has been filled with talks trying to explain to people that breast cancer is not one disease, that you have different subtypes, there are different immune cells that interact with breast cancer cells in different populations. I think what we’re going to find is that there’s going to be a subset of cancers whose progression is dependent on enzymes like cyclooxygenase-2.
Briefly, you mentioned the aspirin repurposing projects that have been going on with their COX activity. It’s something that a lot of authors publishing with the ecancer journal have shown interest in as well - the cancer ReDO Project, we’ve had articles from them. I was wondering if the arthralgia you mentioned, the pain relief in joints, aching, stiffness, if that could be something that there’s overlap in terms of aspirin being used for pain relief?
Yes, I think so. The problem is that aspirin has got more gastrointestinal toxicity and a lot of patients can’t tolerate it for that reason. But aspirin, as you know, inhibits COX-1 which has a different spectrum of downstream effects than COX-2. It’s tempting to think one should be combining the two agents; perhaps low-dose aspirin could have all sorts of other benefits to women along with the celecoxib, but I don’t know yet.