HER2+ Metastatic Breast Cancer: Unmet Needs and Future Directions in Care


Closing out their review of the HER2+ metastatic breast cancer treatment landscape, expert oncologists look forward to future evolutions in the paradigm.


Sara Tolaney, MD:It’s been a wonderful discussion thinking about all the progress we’ve made in HER2 [human epidermal growth factor receptor 2]–positive disease. Before we close, I’d love to hear from our panelists about what unmet needs you think are in this area and where we’re headed in the future. Ayal, I’d love to start with you.

Ayal Aizer, MD:Radiation has come a long way, and each year it gets better. Every year there are advances that weren’t present the year before, and it’s been nice to offer our patients better treatment. At the same time, there are some unmet needs, particularly in the HER2 population. Retrospective data suggest that patients with HER2+ brain metastases, as opposed to breast cancer of other subtypes, may be more resistant to radiation. They still respond, but they tend to recur more often and earlier. In those patients, more effective radiation is needed. One approach that our institution [Dana-Farber Cancer Institute] has taken is to look at radiation sensitization, in this case through a gadolinium-based nanoparticle. The gadolinium is the same as the MRI contrast but is linked to a nanoparticle, which hopefully will make the radiation more effective. That’s 1 way we hope things will get better going forward.

The other advance that we need is to mitigate toxicity, specifically with whole-brain radiation. Thankfully, there have been some improvements there with hippocampal-sparing techniques, which tend to preserve memory function relative to traditional techniques. In the SRS [stereotactic radiosurgery] realm, I’ll also add memantine, which is a neuroprotective drug that can help with cognitive function of the whole brain. In the SRS realm, necrosis is the big toxicity that we need to reduce the incidence and severity of. There are some very early trials looking at that, but more needs to be done.

Sarah brought up surgery, which undoubtedly plays a vital role for patients with bulkier symptomatic brain metastases. About 6% to 10% of our patients will have surgery, and then the tumor will disperse and cling to the packing meninges, the lining of the brain and form multifocal nodular recurrences. This situation approaches, at times, the severity of leptomeningeal disease. It’s not leptomeningeal disease. It’s a pachymeningeal phenomenon, and it’s softer. It’s a leptomeningeal-light situation, and that can be a big factor to consider when sending patients to surgery. Trying to manage it is something that we all struggle with.

One intriguing approach to minimize the risk of pachymeningeal seeding related to surgery is to give the radiation before surgery. Instead of treating the cavity, give the radiation up front, and then the patient can go to surgery. That’s similar to models in other disease sites outside the brain. We don’t know if that’s a good strategy , but we should know very soon if it is. There are at least 4 ongoing randomized trials asking the question of pre-op vs post-op stereotactic radiation in patients who need to go to the OR [operating room] for brain metastases. Hopefully, we’ll know if treating the tumor before they go to the operating room reduces the likelihood of surgical seeding. We’ve come a long way and have more to do, but thankfully some promising advances are on the horizon.

Sara Tolaney, MD:That’s great. Wonderful to hear. How about you, Ada? What are your thoughts in this area?

Adrienne Waks, MD:There’s a very long list of responses to this question, but I’ll pick the low-hanging fruit and say prevention. There are a lot of exciting changes happening in how we manage early stage HER2+ breast cancer. We’re increasingly de-escalating or individualizing the treatment approach we take for patients with early stage disease, which is wonderful and absolutely on point. It’s going to be extremely important to look carefully at CNS [central nervous system] recurrences in the early stage setting, understanding how de-escalation and escalation can impact the likelihood of patients recurring in the CNS.

The trial that was referenced earlier looks at the addition of tucatinib in the adjuvant setting. It will be interesting to look at those data and understand if that’s something that’s able to prevent recurrence, specifically in the CNS. It’s interesting and somewhat disappointing when we look at the results of the CATHERINE trial, which showed that adjuvant T-DM1 [trastuzumab emtansine] for patients with residual disease outperformed trastuzumab in terms of preventing metastatic recurrence or recurrence in general. We didn’t see much of it in terms of the CNS recurrences. That CNS end point will be important and should be looked at when we think about how we design and look at recurrence outcomes from early stage trials.

Sara Tolaney, MD:Excellent point. It is good to see that there are some studies trying to work on that prevention aspect of things. How about you, Sarah?

Sarah Sammons, MD:You stole my answer.

Adrienne Waks, MD:I’m sorry.

Sarah Sammons, MD:I’m kidding. We need prevention for brain metastases. The holy grail is a biomarker to determine who will develop brain metastases. Who with de novo metastatic disease is going to develop brain metastases? Who in the early stage setting is going to be in that 6% who have isolated brain relapse? There are some companies looking into this, and that would be fantastic because then you could utilize that population to do a primary prevention trial. One of my interests is secondary prevention. Once you develop a brain metastasis and have it treated, preventing subsequent brain metastases with systemic therapy is in that area, which could use some attention.

Sara Tolaney, MD:That’s a great point there. You’re actively involved and trying to think about this secondary prevention aspect with active trials. That will be important to see. How about you, Nancy?

Nancy Lin, MD:I agree with the prevention comments. But despite the advances with tucatinib and T-DXd [trastuzumab deruxtecan], which are both very good drugs, most patients ultimately progress. We still need late-line HER2-targeted therapies for patients with HER2+ metastatic breast cancer. For people interested in drug development, there’s definitely still space and clinical need for treatment advances in that refractory setting. We haven’t solved HER2+ metastatic breast cancer. For people who are developing studies in that space, the longer somebody lives with HER2+ metastatic breast cancer, the more likely they are to have brain metastases. Trying to actively include patients with brain metastases in early drug development in that refractory space is crucial. Otherwise, we’re excluding almost half the patient population, which means we’re not doing a good job developing drugs for patients who need them.

Taking a step back, Heather Parsons and others in our group are involved in efforts to raise the bar and understand whether we’re at a point in patients with de novo metastatic breast cancer that we could shoot for the moon. We could try to cure patients with metastatic breast cancer with escalated regimens. That’s going to be an important area of research moving forward, trying to be more ambitious now that we have such good drugs.

Sara Tolaney, MD:It’s nice that we’re heading in that direction. You said it well: we’ve made tremendous strides in improving outcomes for patients with HER2+ disease, but there’s room for improvement. Obviously, lots of important work is ongoing, so hopefully we’ll get there.

I’d like to thank my excellent colleagues for joining me today. Thank you, Dr Lin, Dr Sammons, Dr Waks, and Dr Azar, for this excellent discussion on treatment for patients who have breast cancer and brain metastases. This was brought to you by Cancer Network®. Thank you to our viewing audience. We hope you found this interactive discussion to be informative and beneficial to the treatment of your patients with HER2+ metastatic breast cancer.

Transcript edited for clarity.

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