By Andrew Tutt, PhD, as told to Susan Bernstein
When you develop HER2-negative breast cancer, you still have a risk of life-threatening recurrence despite the best treatments that we have available. Many patients will do really well. But sadly, a significant percentage succumb to recurrent breast cancer despite our best efforts with surgery, radiotherapy, chemotherapy, and hormone therapy. So, if we could design a new treatment approach that targeted the special nature of their genetic cancer, we could add another step for them that would further reduce their risk of recurrence.
In the laboratory, we have shown that what causes the breast cancer -- this genetic fault in BRCA1 and BRCA2 -- creates a weakness in the cancer that we could specifically target. It’s a kind of Achilles’ heel. And for that, we have worked with a biopharma firm to develop a drug targeting it called a PARP inhibitor. One of these was olaparib.
The impetus for this trial, the OlympiA study, which involved 1,836 people with high-risk, early, HER2-negative breast cancer, was to say, “OK, we have this approach and this new drug, which we had earlier shown could delay the progression to advanced, incurable breast cancer.” We had a signal that said that this drug does something effectively and it is tolerable. It helps people live longer and better in the metastatic setting. Could we take this drug and give it to patients with an earlier stage of genetic breast cancer and cure more of them? Can we reduce life-threatening recurrence? That’s the question we asked: “Could we stop more women from developing a life-threatening recurrence of their breast cancer?”
We know that breast cancer is more than one disease. We know that success can come in targeting a particular biology, not just treating all patients as if they have only one form of cancer. What’s unique here is that for this genetic form of the disease, which can be one of the more aggressive forms, you can say, “Well, at least I have a targeted approach to add to the other treatment approaches.”
That is special. That doesn’t mean these patients wouldn’t benefit from hormone therapy or chemotherapy if they need that. But there is a special element to this treatment.
When you design a trial like this, you have a target that you’d like to achieve. We set a goal of a 30% reduction in the rate of invasive or life-threatening recurrence. We thought it would take a bit longer to reach that bar. In fact, what was surprising was that the independent data monitoring committee recommended that we stop the trial early. They had a set date to look at the results and see if we needed to stop early because we already had an answer, and that’s when they told us we should fully analyze the data because we did already have an answer. That was a surprise.
The other thing is that we were targeting a reduction of 30%. In fact, what we got early was a 42% reduction. Not surprising in that we had a pretty powerful effect that we were testing, but it was nice to achieve this.
Thankfully, most women in an early breast cancer setting will do very well with the normal treatments we give, such as surgery and radiation therapy. But you have to be very honest with women about the side effects of treatment, and we look very carefully for these side effects. People don’t want to take something that makes them feel bad. Compliance is a big issue. There’s no point in giving a treatment to someone who only takes it half the time because of the way it makes them feel.
There are side effects with this drug in this trial. It’s not a sugar pill. But those side effects were both tolerable and manageable. It is a drug that can cause sickness, tiredness, and anemia, and cause some effects on immunity, or white blood cells. There was nothing surprising about these side effects, and compared to some of the things we put people through with cancer treatments, it doesn’t seem so bad. This wasn’t a comparison with chemo, because all of these patients have already had chemo. It was a comparison with placebo in people who had already had their other cancer treatments.
Clearly, this result has already had an impact on the breast cancer treatment guidelines, which is fantastic. That is an important message.
What are our remaining questions? Trials are being designed to look at them, including: Could we actually use this approach with people with lower risks of disease recurrence to de-escalate treatment? Could we use this drug in people with genetic risk of breast cancer to replace the more aggressive treatments like chemotherapy, using less chemo and more of these drugs instead? These are just questions. We don’t have the answers. It’s not we could, but could we?
With this group of patients who have a genetic risk -- they know they carry a faulty copy of BRCA1 or BRCA2 -- could giving this drug in some way prevent them getting breast cancer? That’s where you must be super careful that you have a really safe drug. You don’t want to cause healthy people without cancer to become ill.
We need to follow up this study to know more about the safety in the long term. That’s ongoing. We were recommended to report the results of this trial, but that doesn’t mean that we stop looking at the data and following up on these questions about profiles in long-term safety. If we’re going to do a prevention trial, we really need to know that the drug is safe. This is really reassuring so far, and this has raised the question of how we might look at prevention.
The lovely part of this story is that it goes right into the cause of this cancer -- one that only occurs in 5% of breast cancers -- but a clearly identifiable group of women with a common disease. As a community, we’re going to find out why it happens, inform people of their risk, and try to help them manage their risk, but also work out how to treat their disease better.
We’re bringing the power of molecular biology to tackling this problem. We’re working very hard to address the fact that these drugs don’t work as long as we’d like in some people, and in other people, they don’t work at all.
Now, in the oncology clinic, we know that there’s a good reason to identify the type of breast cancer you have, because it can tell us how to treat you differently. We have shown there’s a reason to do that. This trial’s results have shown us that, and we have changed the guidance. Now, everyone is going to want to know whether or not they have a genetic form of breast cancer. Once you know you have this community of women with this definable genetic risk of this type of breast cancer, we can really start to find ways to help them and treat them more effectively.”
