In this interview, Imogen Locke (The Royal Marsden NHS Foundation Trust, UK) discusses the evolving role of stereotactic ablative radiotherapy (SABR) in oligometastatic and oligoprogressive breast cancer.
Locke explains the distinction between these two clinical scenarios, how timing and patient selection influence treatment decisions, and emerging evidence around metastasis-directed radiotherapy for ER-positive, HER2-negative patients on CDK4/6 inhibitors. Additionally, Locke walks us through a patient case study and highlights key radiotherapy trials seeking to answer the most pressing questions in breast cancer radiotherapy.
Can you give a brief overview of your talk at the Royal Marsden Breast Cancer Meeting?
I’ve been asked to give a talk on updates and clinical dilemmas in adjuvant radiotherapy. There’s almost so much to talk about in that space that I thought I would talk about something different that’s very live for me as a clinical issue at the moment, which is the management of oligometastatic breast cancer. This is breast cancer that’s spread or has progressed in a very limited way. We’re seeing new drugs coming through like CDK4/ 6 inhibitors, which are less toxic and more effective. Patients are living longer and they’re living long enough to start to develop resistant breast cancer clones and develop metastases in a very limited way.
And the questions are, if we use metastasis-directed therapy, so that could be surgery or it could be ablation but in my world, that’s SABR. The question is, by ablating those resistant oligometastases, do we prolong patients’ survival? Do we give them longer on the same less toxic drug therapy? This is an unanswered question.
My talk will review what we know so far from prospective trials on oligometastatic disease and also a variant of that, which is oligoprogressive disease. I’m going to present the evidence that we have so far and ask the question: what is SABR adding? How should we select patients? I’m going to finish up by presenting a couple of patients who’ve come through my clinic doors in the last couple of months.
How do you approach the timing and sequencing of radiotherapy for oligometastatic patients?
It varies between oligometastatic disease and oligoprogressive disease. Oligometastatic disease is usually defined as being five or less metastases. They can appear at the time of primary diagnosis, and we call that synchronous oligometastatic disease.
Then there is metastases that develop sometime after the primary diagnosis, and we call that metachronous oligometastatic disease. At the moment in England, it’s only the latter scenario where SABR, is actually commissioned because it’s felt if there’s a prolonged disease-free interval before the development of metastases, then it’s more likely that ablation will have a role.
We generally like to see a patient established on systemic therapy for a number of months to be absolutely sure that they’re in a true oligometastatic state before we would bring in stereotactic radiotherapy.
It’s even more nuanced when looking at oligoprogressive disease, which is where there is more widespread metastatic disease. These patients have commenced on systemic therapy, which controls their disease for a period of time. Then you see the emergence of some resistant clones, so progression in a limited number of sites. Again, we would usually consider that to be four or five or less metastases. In this situation, it’s much more difficult to know when to time ablative radiotherapy treatment.
Also, there’s much less certainty about what we’re achieving. In trials, so far, it hasn’t been demonstrated that ablative therapy prolongs overall survival or even that it gives a progression- free survival advantage. Though there is starting to be a signal that perhaps in selected patients, those with ER-positive HER2-negative disease who are well controlled on a CDK4/6 inhibitor, may have some benefit from ablative radiotherapy in terms of treating disease that’s progressing, which can allow them to stay on that low-toxicity systemic treatment for longer.
So, the paradigm is different. In oligometastatic disease, we’re usually looking to ablate the disease in the hope of achieving a progression-free or overall survival advantage for the patient. Whereas in the oligoprogressive setting, the paradigm is much more about obtaining more value out of the systemic treatment that they’re on, which is largely working well with low toxicity. And we hope to stop having to switch their systemic therapy to something that’s more toxic.
Is toxicity a challenge you face when delivering radiotherapy to this patient group?
With stereotactic radiotherapy, the metastasis that you’re ablating can be anywhere in the body. It can be in a bone, it could be in the lung, for example, and the toxicities will be different. But what is fundamental about stereotactic radiotherapy is that it’s a very focused treatment.
So, whilst the metastasis gets a very high dose of radiotherapy, that dose of radiation falls off very quickly. So, in general, this is an extremely well-tolerated treatment and toxicity is not usually an issue at all.
Could you talk us through a SBRT case study?
The case that I’m going to present today is of a woman who presented with node-positive TNBC and had a very turbulent time with her chemotherapy.
She had an enormous amount of toxicity and so the treatment had to be stopped early. She then had adjuvant radiotherapy and a period where she was on no systemic therapy. Within a few months, she developed oligometastatic disease.
I was asked to see her in clinic because she had one lesion in her lung that was progressing. I looked at the natural history of her disease. I’m always quite cautious in TNBC.
I think what you have to remember with stereotactic radiotherapy is what’s your treatment goal? What are you trying to achieve for the patient? The other challenge is that sometimes radiology underestimates the burden of disease. For example, on a CT scan or a PET scan, you might see one solitary nodule or hotspot. But we know that there may be more widespread microscopic disease that we can’t see.
In these situations, I sometimes do an interval image to get a feel for what’s happening. In this woman’s case, I did a PET scan 2 months after the one that she’d had before and sadly, she’d developed widespread liver disease.
In hindsight, if I treated that one nodule that was hot on the PET scan, it would have done her absolutely no good because she actually didn’t have true oligoprogressive disease. So, I think the challenge for us is defining that oligoprogressive state better. That’s probably going to be through more sophisticated imaging modalities, looking at the disease trajectory and perhaps things like circulating DNA will have a role, where we’ll be able to better select patients for ablative therapies by looking at whose ctDNA mutation burden falls with systemic therapy.
Are there currently ctDNA tests for determing oligometastatic or oligoprogressive disease?
No, we don’t use them routinely in the clinic. ctDNA mutation burden was measured as part of the CURB trial, which was a trial in oligometastatic disease, looking at ablative radiotherapy in a population of both breast cancer patients and lung cancer patients. This trial showed that for lung patients who saw a progression-free survival benefit from radiotherapy, this was matched by a fall in ctDNA burden, whereas in the breast group where we didn’t see that benefit in the primary endpoint, the ctDNA didn’t change. So, it may well emerge to be a useful part of the picture in defining true oligoprogression, but it’s not live in the clinical setting at the moment.
What do you see as the most pressing research questions or unmet clinical needs in breast cancer radiotherapy?
I think we’re lucky in the UK to have an absolutely fantastic portfolio of trials going on. The question that is really live at the moment in breast radiotherapy is: can every single patient having adjuvant breast radiotherapy be treated in just 1 week? We know that 70% of women who have breast radiotherapy after surgery at the moment are treated in 5 fractions over one week. But there are still some groups, for example, those having radiotherapy to their internal mammary lymph nodes, or those patients who are having a tumor bed boost, who currently are treated in 3 weeks.
From a practical point of view, the FAST-forward trial, which is ongoing, will answer that question. And I can see a very promising future where all breast radiotherapy for all patients in the adjuvant setting is done in 1 week.
Also, the limits of hypofractionation is a really interesting question. We have recruited fully to the PARABLE trial, which is the trial of protons for the adjuvant breast radiotherapy. It will be really interesting to see what niche role, if any, protons have for breast radiotherapy.
We have a whole array of trials looking at auxiliary treatment and the potential de-escalation of how much we treat the axilla.
As part of FAST-forward, we will answer the question surgeons keep asking us, which is whether five fractions of treatment is bad for oncoplastic surgery. We’d like to be able to give them the evidence to say, no, it’s fine.
For radiotherapy sequencing, we’ve got the PRADA2 trial opening, which is looking at giving radiotherapy before DIEP reconstruction and looking at cosmetic outcomes.
So that’s another question. There are a lot of unanswered questions, but we’re lucky to have a lot of trials led in the UK that are going to answer them.
It sounds really exciting; we’re on the cusp of answering those questions.
Breast radiotherapy, has changed so much in the time that I’ve been a consultant. When I started as a consultant, it was routine that all patients had 5 to 6 weeks of radiotherapy.
Now, for the vast majority of patients, they’re having 1 week of radiotherapy and it has much less impact on their life and less toxicity. Now, I think the real unanswered question, and the one where we do need trials around, is how we personalize radiotherapy more to the biology of the disease.
That will be the next thing. We’ve got a lot of translational studies going on. So, each of those trials that I just talked about has a translational question attached to it as well.
Being able to personalize the radiotherapy to the underlying biology of the cancer and of the person will be the next focus. I think all the trials coming through in the future will need to be incorporating that kind of translational question. And also, as you mentioned earlier, incorporating ctDNA routinely into trials, will be the next big thing to do.
The opinions expressed in this article are those of the author and do not necessarily reflect the views of Oncology Central or Taylor & Francis Group.
Disclosures:
Interviewee profile:
Dr Imogen Locke has both a private and an NHS practice at The Royal Marsden.
The service offers a comprehensive range of cutting-edge radiotherapy treatments including Intensity Modulated Radiotherapy (IMRT), Image Guided Radiotherapy (IGR), stereotactic radiotherapy and brachytherapy. She specializes in the treatment of breast and lung cancer.
She qualified at St Bartholomew’s Hospital, London (UK) in 1994 and her subsequent oncological training was in London. She undertook research at The Institute of Cancer Research London, UK) between 2003 and 2006, and was awarded an MD in 2008. Her research focused on the role of ductal lavage in the molecular risk assessment of women carrying germline mutations in the BRCA1 and BRCA2 genes who are at increased risk for developing breast cancer.
Her current interests include the development of heart-sparing radiotherapy techniques for the treatment of breast cancer, stereotactic radiotherapy for the treatment of early-stage lung cancer and quality improvement activity.