Roundtable Discussion: Gradishar Considers Impact of Brain Metastases on HER2-Targeted Therapy in Breast Cancer

Case-Based Roundtable Meetings Spotlight, Case-Based Roundtable Meetings Spotlight June 2021: Solid Tumors,
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Strategies for treating patients with HER2-positive breast cancer and metastatic brain lesions was a topic discussed between William J. Gradishar, MD, and a group of peers during a Targeted Oncology Case-Based Roundtable event.

Strategies for treating patients with HER2-positive breast cancer and metastatic brain lesions was a topic discussed between William J. Gradishar, MD, of the Maggie Daley Center for Women’s Cancer Care and Robert H. Lurie Comprehensive Cancer Center at Northwestern University and a group of peers during a Targeted Oncology Case-Based Roundtable event.

GRADISHAR: Is there anything about this case as it’s framed that strikes you as unusual or just not what you typically see, or is it in keeping with what you experience in your own practices?

KOKO: The part that I find unusual is that she had achieved complete pathologic response [pCR] and then progressed so quickly.

GRADISHAR: Yes. We typically think of these patients as being home free, but of course we know that a fraction will develop disease recurrence. The other aspect of this, too, is whether one would revisit H-trastuzumab] and P [pertuzumab] after having received it preoperatively and achieving a pCR. Oftentimes we say if it was a short interval between the completion of HP and then the recurrence, that may be a situation where somebody goes on to T-DM1 instead of something like the CLEOPATRA [(NCT00567190) regimen of] THP again. But it was 3 years [later], so I don’t think that was crazy.

Anybody else think this is a little bit atypical in their own experience, or is it not so far afield from what you see?

CHOWDHERY: Yes, I agree with Dr Koko. This is pretty aggressive for having a pCR.

GRADISHAR: Yes, it’s disappointing, to say the least. Again, it highlights the manifestations of brain disease being a problem in this population of patients.

GRADISHAR: So in this case, there’s a strong embrace of the HER2CLIMB [NCT02614794] regimen, with 100% of people viewing that as the best option in this situation. The issue would be that this patient clearly had brain metastases, was treated with radiation therapy, [and] has remained relatively stable but now has progressive disease systemically. The question would be: Are you obligated to use a tucatinib [Tukysa]-based regimen, or could you use something else?

TAJUDDIN: Can you reuse [tucatinib] after a break, after you have gone through other lines of therapy? Would you see benefit in brain metastases with that?

GRADISHAR: If they’ve already received tucatinib once? Well, I don’t think there’s, to the best of my knowledge, any experience that is reported on that in any meaningful way. So I simply don’t know. I think what people might be more inclined to do is go to a different TKI [tyrosine kinase inhibitor], possibly neratinib [Nerlynx] or something else. I’m not aware of any, at least, substantive data—anymore than anecdotal, 1 or 2 patients—where we have any guidance at this point.

RAMADAS: In asymptomatic patients that are progressing, are you now doing brain MRIs for everyone?

GRADISHAR: I think there [are] 2 issues. One is now that we have a therapy, I think people are going to start doing more MRIs. I don’t routinely do it in every patient. Certainly, anybody that has symptoms, if their systemic disease is progressing, I would probably get a brain MRI; it might influence my decision-making regarding therapy. I think the way people responded to the question highlights that—and that is, if somebody had brain disease, would that be viewed as very important in making a decision? And everybody thought it was at least important, if not very important.

I think that you will find more MRIs being ordered than in the past. But if a patient is stable and they’re clinically doing fine, I don’t feel like you have to get MRIs constantly in those patients. With that said, we’ll see what utilization looks like a year from now. I’m willing to bet there’s going to be a marked uptick in the use of brain imaging.

I think [from the question, it’s clear that the presence or absence of disease above the neck, in the CNS [central nervous system], is an issue.

GRADISHAR: [Based on an understanding of] the toxicity profile of both the HER2CLIMB regimen— which is more GI [gastrointestinal events], maybe a little bit uptick in liver function test abnormalities— and then with respect to trastuzumab deruxtecan [Enhertu], with a fraction of patients getting interstitial lung disease, how does that play into your decision-making about treatment?

REMO: If a patient had severe lung disease or chronic obstructive pulmonary disease with oxygen dependence already and had stable brain metastases, I think that would impact or at least play a role in the decision in choosing between the trastuzumab deruxtecan or tucatinib, given the risk of pulmonary toxicity.

GRADISHAR: How about the issue of 3 drugs versus 1? Does that raise any concerns in your mind about reliability, adherence, those sorts of things—particularly as it relates to things like capecitabine and tucatinib, which are going to be oral and multiple pills per day, versus coming in once every 3 weeks to get an intravenous regimen?

KALAKOTA: That’s concerning for me, especially [since for] a lot of the patients that I treat, sometimes health literacy is a huge issue, so I think taking a combination of oral medications, having to pick them up, time it, would make me have some pause about their adherence to it. So when they don’t have brain metastases, if they don’t have underlying lung disease, I think it is easier to have patients come in once every 3 weeks for an infusion versus giving them a 3-drug regimen.

TAJUDDIN: The insurance coverage is also a big issue when you have, especially with oral drugs, the high deductibles and copays. Sometimes, we’re able to find some foundation to cover some that. On the other hand, intravenous medication, intravenous chemotherapies, are much easier to get approval and provide coverage for.

KOKO: I’ve used both regimens, and it’s been easier to administer and for patients to tolerate the trastuzumab deruxtecan. One of my patients developed pulmonary toxicity. But it was very easy to manage, and she was back on the treatment with dose reduction after treatment with steroids. The same patient is currently on the other regimen, and she’s having difficulty tolerating the 3-drug regimen, but she’s still on it. So it was easier for her to take the trastuzumab deruxtecan.

SHAH: I agree with Dr Koko. I had a patient with pneumonitis and pulmonary toxicity with the trastuzumab deruxtecan. This patient that I treated didn’t recover as well. Pneumonitis is something I’m very concerned about and have a healthy respect for because some patients completely recover [but in other patients], whether it’s this drug or another drug, it lingers. So I am more prone to, and I have a couple patients that are responding very nicely to, the [capecitabine (Xeloda), trastuzumab], and tucatinib combination. I’m more prone to go with that combination in the third line. That’s just my personal opinion.

GRADISHAR: Diarrhea is one of the things I think we’re pretty familiar with managing, not only in breast cancer but, in a variety of other diseases, and my guess is that many of you deal with other malignancies [in which] this is not uncommon. So do you view the tucatinib regimen, where GI symptoms are a bit more problematic, as so offsetting that you would avoid it, or this is something in your wheelhouse? If you know how to manage diarrhea, is it not a big issue?

KOKO: I think it’s not a big issue. A lot of the patients have probably been exposed to capecitabine previously and have developed diarrhea with it, so I think they are quite familiar with managing the diarrhea toxicity. My patient didn’t have any problem with it. She knew what to do.

GRADISHAR: Yes, and I think, relative to the experience with neratinib, tucatinib is easier to tolerate. I think we’ve learned, probably, with managing GI symptoms in those receiving neratinib, that this, for the most part, is an easier drug.

I’d just make one other comment about the pneumonitis: When they’ve gone back collectively and looked at many of the other drugs we use in breast cancer, including CDK4/6 inhibitors and everolimus [Afinitor], etc, there are a fraction of patients [based on reported] clinical experiences that will develop pneumonitis.1 It’s not restricted only to trastuzumab deruxtecan. I think we just have to have a reasonably high sensitivity to the possibility that it can occur. Certainly, in the setting of trastuzumab deruxtecan, be ready to stop it or institute steroids if we have a suspicion.

GRADISHAR: We work as a team, generally. I don’t think we’re cowboys out there, doing things all by ourselves. Do you guys all interact with your colleagues in radiation oncology, particularly as it relates to pneumonitis, and so forth? Because sometimes it can be a challenge to draw a distinction [based on] findings on imaging between whether it is disease related versus a pneumonitis.

RAMADAS: I work over in Northwest [Cancer Center], and I think we’re always in communication, luckily, with our radiation colleagues to be able to come up with a plan [and] also with the pulmonologist, locally, to first stop the drug and see how they recover and what we can do moving forward.

So I think it’s pretty seamless that way, not only in breast cancer in multiple other cancers that we follow.

GRADISHAR: Yes, and one of the issues we’ve talked about right at the outset, when we were describing scenarios, is CNS progression versus visceral progression. Any progression’s a bad thing—nobody wants to deliver bad news to patients—but brain metastases can often be a fairly devastating thing. When you start getting to the brain, patients process that, in some ways, differently than saying, “You have some changes in your lung or liver." So I’m just curious if that’s your experience as well, or [is it] something different?

KALAKOTA: Yes, of course, and I think it’s also harder to treat. Now we have tucatinib that does have efficacy in brain metastases, but prior to that, once you’ve had radiation, whether it’s radiosurgery or whole brain, some of the options became more limited. So I think it’s always a little scarier for patients and for providers to manage progressive brain metastases for those reasons.

CHENNAMANENI: I agree...since we have the option of tucatinib, [I’m not] that much concerned. Otherwise, in the past, we only used radiation, either the stereotactic or whole brain. I think with [having] more options, we can probably avoid radiation.


Hackshaw MD, Danysh HE, Singh J, et al. Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2020;183(1):23-39. doi:10.1007/ s10549-020-05754-8