Dr. Sara Tolaney:
Welcome to this ASCO Post Roundtable on Evolving Paradigms in the Treatment of Hormone Receptor–Positive, HER2-Positive Metastatic Breast Cancer. My name is Sara Tolaney and I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston. And today, I'm joined by my two very esteemed colleagues, Dr. Ian Krop, who is Professor of Medicine at Yale School of Medicine and Dr. Mark Pegram, who is Professor of Medical Oncology at Stanford University.
So, welcome and thank you so much for joining us today.
Dr. Ian Krop:
Thank you for having us.
Dr. Sara Tolaney:
We're just going to dive right into our first case, which is focused on de novo metastatic hormone receptor–positive, HER2-positive breast cancer. So this is a 62-year-old woman who presented with a right breast mass with an palpable ipsilateral axillary node. The breast was biopsied and came back as a high-grade invasive ductal carcinoma that was strongly hormone receptor–positive, so ER 95%, PR 95% and was also HER2 IHC 3+.
The axillary node was FNA’ed and also came back consistent with having malignant cells in it. And because she had a node-positive, HER2-positive cancer, it was decided to do staging studies, and there was evidence of a single liver metastasis. And this was biopsied and was consistent with her original breast primary, so also hormone receptor-positive and HER2 IHC 3+.
And so this, in essence, is a case of a woman who has de novo metastatic disease that just has one isolated site of metastatic disease. So I think this question comes up, and I think it's a challenging one where patients will often ask, "Well, should I go to breast surgery in this case? And is there any role for local therapy?"
So maybe, Mark, I'll start with you. And how do you think about these cases when you see them? Are you trying to treat to curative intent or not?
Dr. Mark Pegram:
Well, there are randomized trials looking at overall survival as the primary endpoint when comparing surgery for the primary, vs not, for stage IV metastatic breast cancer. And those trials were negative for the OS endpoint.
But significantly, in my opinion, in some cases, the trials were positive for local regional control, which is not necessarily to be dismissed in some cases, because some patients have very difficult problems with inflammatory breast changes, et cetera. And even in the setting of stage IV disease, that could be very problematic. So sometimes, local control is important.
Moreover, those studies did not have a high fraction of HER2-positive patients. So there's no detailed information on HER2-positive disease.
And the one exception that I think about in HER2-positive disease are the so-called exceptional responders. There are some patients with stage IV disease, HER2-positive, who are apparently cured 10, 20 years later, from systemic treatment with, usually, combination chemo and HER2 antibodies, et cetera.
And consequently, this gives me enthusiasm in this case to maybe think about giving her systemic therapy first. Mind you, I wouldn't go to surgery first in this case, and then see what happens in the liver. If you have a clinical CR in the liver, then my enthusiasm for considering locoregional treatment would go up, because the clinical CRs, in particular have a higher probability of these long, disease-free intervals, in some cases, apparent clinical cure.
Dr. Sara Tolaney:
That's a really good point. I think it's so hard because, as you point out, some of these randomized trials were not done in the so-called modern era, right, not everyone was getting the best HER2-directed therapies. And as you point out, even in E2108, I think there are only like 70-some patients with metastatic HER2-positive disease. And so, it is hard to know definitively if we, maybe, would see survival benefit from local therapies because, again, they weren't done in this current setting with the drugs that we have available.
So Ian, if you were seeing this patient, one, I'll ask you, too, would you ever think about local therapy? And then, two, what systemic treatment would you initiate in this particular patient?
Dr. Ian Krop:
Yeah, no, I think it's a good question. And I think Mark pointed out all the ambiguity of how to approach patients with de novo HER2-positive disease because of the lack of real definitive data, particularly in this subtype, which is obviously less common than other breast cancer subtypes.
Personally, I think, given, as Mark said, the very impressive results we're seeing with systemic therapy in which it looks like 15 to 20% of patients actually seem to be cured or have very long remissions. I think that tells us that the systemic therapy works very well. And I'm not sure that means that going back and doing surgery or local therapy is going to make a difference in those patients because the patients in those trials didn't get additional local therapy and still did very well. But it's clearly an open question.
And at Dr. Tolaney's institution, they're leading a study of multiple, highly-effective systemic therapies in patients with de novo HER2-positive breast cancer in a curative intent type of approach, which I think should be very interesting what the results for that are. There are other studies now looking specifically in HER2-positive disease, or at least trying to get off the ground, looking at the role of local therapy in these patients. Again, trying to provide more definitive data in this world where we have incredibly effective systemic therapy.
So, I think more to come. Personally, I generally don't typically recommend local therapy in these patients, whether they have a very good response or not. Obviously, if they start having evidence of local progression, then that's a different story and we do want to certainly jump on that to prevent local complications.
So for a patient like this, I would typically give, as my first-line therapy, a taxane, I typically use weekly paclitaxel, along with trastuzumab and pertuzumab, given the really impressive data we've seen from the CLEOPATRA trial with that regimen.
Dr. Mark Pegram:
The real question in my mind, Sarah, is what to do in a case like this if they have a clinical PR in the liver, but not a CR. But even in those cases, we have a multidisciplinary panel that adjudicates these difficult cases. And there's so many different things now you can do for solid tumor metastasis to liver, from cryoablation, to chemoembolization, to surgery, to stereotactic radiation, there are a number of things that can be done. So all these are on the table for a balanced discussion with the patient if some of these ideas are technically feasible in selected cases.
Dr. Sara Tolaney:
Yeah, that is a-
Dr. Mark Pegram:
“Curative intent,” perhaps, for oligometastatic disease.
Dr. Sara Tolaney:
Clearly, very controversial about if there really is survival benefit from those approaches.
So maybe another controversial question is, again, this patient had ER-positive, HER2-positive disease. And Ian, you mentioned you'd start off with taxane-based therapy. Do you ever consider not using chemotherapy-based approaches in a patient like this, such as using endocrine therapy with HER2-directed therapy? And do you think there's a role for that type of approach? So maybe I'll start off with Ian and then maybe we'll get Mark's thoughts, too.
Dr. Ian Krop:
Yeah, no, it's a good question. And actually, I meant to talk about that, or ask you more questions about the patient, but I got too excited about the oligometastatic question aspect of it.
So, I think the role for a taxane/HP is, given the data, I think most patients that makes the most sense. But there are select patients who, either because they're very averse to chemotherapy, or they have comorbidities that make chemotherapy more challenging or more likely to cause significant problems, that in a patient like this who's triple positive, we have pretty convincing data on the combination of endocrine therapy with trastuzumab and pertuzumab. We also have some data with tyrosine kinase inhibitors and endocrine therapy.
But the data, particularly with HP and endocrine therapy are quite, to me, compelling as a first-line therapy for these triple positive patients. The PFS in those patients, my recollection was in around 21 months for the patients who did not get any upfront chemotherapy and just got trastuzumab, pertuzumab, and endocrine therapy. So, I think if you have a patient who you don't think the chemotherapy is appropriate, I think you can tell that patient that they're likely to do very well with that endocrine HP regimen.
Dr. Sara Tolaney:
How about you, Mark? Do you ever take that approach?
Dr. Mark Pegram:
I'm reminded of a provocative study that was presented at ASCO a few years ago, I think about 2021 or so. It was a Chinese study, SYSUCC-002, and it was a comparison of chemo-trastuzumab vs chemo-endocrine therapy for HER2-positive HR-positive first-line metastatic breast cancer patients. And the study met its noninferiority endpoint with statistical confidence.
Now, it's provocative, it's prior to the pertuzumab era, so I don't know what that study means in the modern era or in the West. However, it begs the question, have we gotten it wrong in HR-positive, HER2-positive therapy all along, whereas in HER2-negative breast cancer, we would never think about starting with chemo anymore. And it begs the question, should we be doing the same thing all these years with HER2-targeted therapies in hormone receptor–positive disease? There's synergy between anti-estrogens and HER2-targeted therapies that we published at UCLA back in 1995.
And since then, there's been the TAnDEM trial with trastuzumab and AI, the PERTAIN trial that did incorporate pertuzumab in a phase II randomized trial. There's the ALTERNATIVE trial with lapatinib plus trastuzumab endocrine therapy. And then there's the GSK-30008 study that we published leading to the FDA approval of letrozole lapatinib back in 2010.
So, all those are on the table for patients to hear about, especially if they have any reluctance to take chemotherapy or medical contraindication to chemo. And some patients, as you know from practice, refuse chemo, even weekly paclitaxel. Some patients refuse it just because of alopecia. And this would be an interesting option for those patients.
Dr. Sara Tolaney:
It is, it's tricky. I will say this got brought up in our internal discussions about coming up with our pathways and what we should be recommending physicians do in the first-line, HER2-positive setting. And I will say it was a debate that not everyone felt comfortable saying you should give an alternative to, say, endocrine therapy/HP, simply because as you point out in the SYSUCC trial that it wasn't using modern-era dual HER2-directed therapy. And we don't have clean, randomized data in a way that we would feel comfortable saying it's equivalent, in essence, to taxane-based therapy. But clearly, I think most of us tend to do it. And someone who may have a contraindication to chemotherapy, or as you point out, also maybe refuses chemotherapy. So, it is, I think there's more to come here. And as you point out, maybe we have gotten it wrong and it does definitely deserve further investigation.
Yeah. So I think, thank you guys for this discussion because I think what I've learned, at least, is there isn't a clear role for local therapy in patients who have oligometastatic HER2-positive breast cancer. Certainly, the randomized trials haven't definitively told us we need to do that, we don't have proven survival benefit. However, they were done at a time when we weren't treating patients in the modern era. They weren't powered specifically just in the HER2-positive subset. And so it does remain an unknown question. And the people who maybe have had prolonged disease control, certainly local therapy can be considered or in some of those locoregional progression, certainly.
And right now, I think the standard still remains chemotherapy induction, followed by HP maintenance, and adding endocrine therapy, I think is what most of us do. And we'll talk more in other cases about newer data that's evolving on that strategy. But endocrine-based therapy could be considered an alternative, particularly in someone who may be averse to chemo or contraindicated to chemotherapy.
So really nice to have these discussions with you guys. So thank you so much.
This brings us to the end of this case, and so please see the other segments for further discussion about the latest research in metastatic hormone receptor–positive, HER2-positive breast cancer, or visit ascopost.com.
Thank you.
