'Game-changing' treatment for hereditary breast cancer

Cambridge researchers have found that a new treatment approach for aggressive, inherited breast cancers can significantly improve survival rates and minimise side effects. They've been studying a form of the disease called "triple negative" breast cancer, which is where the tumour cells don't display receptors for the hormones oestrogen or progesterone, or a growth factor called HER2. These cancers can crop up spontaneously, but they can also run in families; in other words they're hereditary: one example are the tumours caused by the BRCA genes, awareness of which shot up when Angelina Jolie announced that she was a carrier. Historically, all of these cancers have been treated identically, usually with chemotherapy up front to shrink the tumour, followed by surgery to resect anything left behind. But many hereditary tumours tend to crop up in younger patients and, for them, the side effects of the chemotherapy can be more severe and even have lifelong consequences. So, what Jean Abraham wondered was whether anything could be done to alleviate this. And a chance conversation over dinner one night gave her the insight to try changing the timings of the administration of the chemotherapy drugs, the idea being to deliver a regular one-two punch to the tumour but with enough time between each punch for the body's healthy tissue to recover sufficiently to minimise side effects and long term damage. And for those people with hereditary tumours, it turns out her findings are a massive game-changer...

Jean - Our trial, which is called PARTNER, we're asking the question, are people who inherit the tendency to get triple negative breast cancer the same as people who spontaneously get this cancer, so without any obvious inherited cause? And we, at the moment, treat them both exactly the same, which means that in our opinion, we thought they were probably getting more side effects and more treatment than they needed.

Chris - How did you structure the trial?

Jean - We recruited over 740 patients who had triple negative breast cancer, either that was non-hereditary or that was hereditary. We decided way back when we designed this that the, what we call the control arm, so what we think the standard treatment would be at the time, was chemotherapy, and it was only chemotherapy. And then we wanted to add in a new drug called Olaparib, and this is a drug shown to be quite successful in people who have the hereditary type of triple negative breast cancer, and it works by manipulating some of the pathways that help us repair our DNA when it gets damaged. So one of the big problems that we were trying to wrap our brains around was how to combine these, because of course all drugs have side effects, and the side effects of the chemo and the side effects of the new novel agent, the Olaparib, overlap. And if they overlap, sometimes it means that you can't give them together, because the side effects are worse than the, you know, so bad that you can't give the treatment. And I was trying to wrack my brain around how to do that when I was at a dinner, at a work dinner in Cambridge, and I sat next to a chap called Mark O'Connor, who was the head of the DNA damage repair unit at AstraZeneca. He'd done some work in the laboratory looking at exactly that question, how can we combine these agents without causing massive damage? And he found that spacing the drugs, so giving the chemotherapy first, and then waiting for 48 hours or more, actually meant that the bone marrow, the place in your body that makes the cells that protect you from infection, doesn't get damaged as much. He'd done this in animal models, and I came back to my team the next day, and I said, okay, scrap the designs, we're going to try this. And so we thought it was such a simple change to make, to just space out the drugs in a different way.

Chris - And what happened? How long did you follow the people up for? And what were the outcomes?

Jean - So we'd planned to recruit over a five-year period, but then unfortunately, we had the COVID-19 problems, and all trials really that were not COVID-19-based were suspended or closed for about two years almost. But actually, in a weird way, it also helped us, because it meant that we'd recruited most of our patients before that shutdown happened. And so all the patients that recruited just accrued time. And so actually, we could not only see if they responded to their surgery, but we could also look at those survival endpoints. And so when we finally came to analyse the two sets of patients, what we found was that there's quite a difference in the results between the two different types of triple negative breast cancer. The people who get triple negative breast cancer, but don't have a strong hereditary component, don't respond any better, either in terms of how much disease is left at the surgical time point, or how long they survive. So actually, the addition of that drug doesn't make any difference. However, in the hereditary breast cancer patients, what we found was that if you space the drugs out correctly, 100% of our patients are alive at three years, in comparison to about 88% in the arm that just got the chemotherapy.

Chris - So this tells you if you know what sort of disease a person is presenting with, then you can put them on either with or without this additional new drug, and you can spare a group of people side effects if they don't need it. That means that you're immediately refining the therapy and improving the outcome for those people.

Jean - Yeah, currently, the standard treatment for both hereditary and non hereditary triple negative patients would be to get chemotherapy. And what we're saying is, that's probably right for the non hereditary triple negatives. But actually, for the hereditary triple negatives, a much shorter course of chemotherapy plus Olaparib can actually achieve as good or better, in fact, survival results, and a lot less toxicity. And actually, Olaparib is a tablet, so you don't have to come in and have an intravenous infusion. So you don't have to be in hospital. So it's time saving. It's bed saving. And it's cost saving. So there's a lot of wins, if we can confirm this.

Chris - And if you scaled this up to the burden that is breast cancer of the type that you're interested in here, how many people will this directly benefit?

Jean - Every year, I would imagine somewhere between 1100 to 1200 patients would benefit from this.

Chris - In just the UK. So if we then extrapolated that worldwide, that's pretty huge .

Jean - It is pretty huge. Yeah, I mean, I think breast cancer in women is the biggest global killer. So yes. And even though that subtype is a smaller percentage than the whole, when you scale it up, it's a lot of people. It's probably over 200,000 people.