WHAT’S NEXT WHEN TREATMENT FOR TRIPLE-NEGATIVE BREAST CANCER STOPS WORKING?

Treatment for triple negative breast cancer has advanced significantly, but challenges remain when in some cases, the disease returns after treatment. In this episode, we sit down with Dr Belinda Yeo to explore treatment options for triple negative breast cancer patients whose cancer has relapsed.

Dr Yeo discusses the challenges that clinicians face when deciding what treatment to offer next, emerging therapies showing promise, and the critical role that clinical trials continue to play in improving outcomes for people with triple negative breast cancer.

“I think triple negative breast cancer gets a worse rap than it really deserves, to be honest. Most triple negative breast cancer does respond to treatment and I’m very pleased to see that we do cure most early triple negative breast cancer.”

“And that might be different if you’re looking at data from say 20 years ago. It’s not driven by the usual things we think about with breast cancer, like oestrogen in the other hormones.”

“But at the same time, it can often be very sensitive to chemotherapy. And given we’ve had immunotherapy in this setting for a few years in Australia, immunotherapy is certainly adding to curing patients with triple negative breast cancer. I do think it gets much worse wrap than it really deserves.”

“But nonetheless, with our current best standard of care, we still find that there is a proportion, maybe one in five patients who do relapse. And, the question is, for those patients who have some kind of resistance to the treatments we’re giving, you know, what else can we do for them?”

“KEYNOTE-522 was a clinical trial looking at combining immunotherapy and chemotherapy for patients with triple negative breast cancer in this early breast cancer setting. And these were patients who needed to start treatment before surgery, and we call that neoadjuvant treatment.”

“Most people think of chemotherapy given before surgery and certainly in this KEYNOTE-522 trial, there is a lot of chemotherapy, which goes for up to six months. But the key thing about KEYNOTE-522 is the addition of immunotherapy with a drug called pembrolizumab started before surgery.”

“And that’s really key to increase the likelihood that firstly the cancer was completely dead when surgery came 6-7 months later, but also, and really importantly, for any study we do in early breast cancer that we increase the chance of cure with that combination regime.”

“It is a lot of treatment to have, and many patients will be well aware of that. It is, I would argue, our most intensive chemotherapy regime I give in breast cancer and obviously it does have the extra complications of giving immunotherapy, which brings its own nuances.”

“That’s KEYNOTE-522, it takes about a bit over a year to give. Sometimes it takes up to a year and a half to give if ready therapy is involved. And in this specific presentation I was looking at the patients who, despite all of that treatment, their cancer still came back later.”

If a patient’s cancer does return after these therapies, what are the biggest challenges clinicians face in deciding what treatment to offer next?

“I think firstly we are trying to understand why did the treatment not work? Which element of this treatment didn’t work for them? Is it the chemotherapy, is it the immunotherapy or is there something else really tricky about this cancer?”

“Has it learnt to evolve despite treatments, which is probably very much part of that story. So, when we’re selecting treatments for patients in this metastatic setting, we’re always thinking about what we can try next.”

“What is something that is very different to the treatments these patients had before? I think something we think a lot about is how long has it been since they completed those treatments in the early setting? And unfortunately for this particular patient population that it’s often not long.”

“We see patients who may have only just finished chemotherapy, not even 12 months ago, and they’re back needing more treatment. And of course, really importantly we are asking how the patient is sick? Are they experiencing a lot of symptoms and do we need to get them under control?”

“Do they have disease in their brain, and should we be thinking about giving them treatments like radiotherapy in combination with drug treatment? So, it’s a really a complicated decision tree for everybody involved in managing this disease.”

Research in the triple negative space is moving quite quickly. As a clinician, what new treatment approaches are emerging therapies that are giving you the most optimism for patients?

“Well, definitely the antibody drug conjugates, which are treatments that are basically fancy ways of giving chemotherapy – they’re actually a lot more complicated than that -but I certainly describe them to patients as we’ve got a really, high dose chemotherapy that we wrap up and try and target to the tumour a bit better than all of our standard chemotherapies, which are not terribly targeted to the tumour.”

“These are antibody drug conjugates. There’s a few we have access to in Australia and there are more coming and there’s some impressive ones, and we’ve seen early and not so early phase data presented at some meetings around the world.”

“I think these are the things that are changing the face of metastatic triple negative breast cancer. I think smarter immunotherapy options need to be there. I can’t see that they’re helping the majority of patients in this specific setting.”

“And then of course, we still want targeted treatments that are not chemotherapy. Wouldn’t it be great not to give chemotherapy? There are some targets in triple negative breast cancer that mean if you give this drug because the patient’s cancer has a certain problem with it, you will get a better outcome.”

“And maybe the best example of that is the PARP inhibitors for patients with a BRCA1 or BRCA2 gene mutation. But definitely from the data we’ve seen in the specific population of these patients who have been treated with early breast cancer and then relapse, you know, having a BRCA mutation and then having a cancer relapse is actually not that common anymore.”

“And I think that’s because our treatments in the early setting have got so much better. So, there’s a there’s a way forward, which is great.”

How important is participation in clinical trials for patients facing relapse? And what questions are researchers hoping to answer next?

“I think they’re absolutely vital. And I can tell you every single patient who is in the position of having relapse after KEYNOTE-522, is always looking for a clinical trial.”

“What is really disappointing in the data that we’ve seen is that the majority of the patients who have been in this position from the data that we have in Australia have not been eligible for the trials open at the time.”

“And that’s mainly because the trials have been strict about how long it can be since your last treatment. And I’m begging those trialists, those companies and any groups that are designing clinical trials for the patients who relapse, to really think more broadly and let patients in because it’s the patients who relapse quickly after chemotherapy that really need novel therapies.”

“But it is because of clinical trials that we are gaining access to newer drugs in this setting. And I suspect in 12 months’ time I’ll be telling you something different, which is great.”

What would be your key message to people affected by triple-negative breast cancer?

“The first thing I would say is absolutely don’t lose hope. I think this idea that triple negative disease doesn’t have any targeted treatments, is just not true. And I think making sure that you can get the best team around you, and the best support that you can is really important.”

One other thing is that breast cancer feels urgent, like when you’re diagnosed with it, you need to start treatment tomorrow. And I understand why patients feel that way, but as a clinician treating breast cancer, I want to make sure I get the treatment right. And sometimes knowing the right treatment takes us a bit longer to work out.”

“And as hard as it is, if we can support you through what might be short weeks, hopefully not months, to make the best treatment decision for you, ultimately our goal is to give you the very best outcome and obviously to keep you well throughout these treatments because we haven’t talked about it, but the treatments obviously come with their problems and their toxicities. So, it’s important that we manage these things too.”