Dr. Hurvitz: Welcome to The ASCO Post Roundtable Series on Updates in Breast Cancer. I'm Dr. Sara Hurvitz, Professor of Medicine, and Director of the Medical Oncology Program for Breast Cancer at the University of California Los Angeles Jonsson Comprehensive Cancer Center. And joining me today are two of my colleagues, Bill Gradishar and Sara Tolaney. I'll let each of them introduce themselves. Bill?
Dr. Gradishar: Hi, I'm Bill Gradishar, a breast medical oncologist, and Professor of Medicine at Northwestern University.
Dr. Hurvitz: Welcome Bill. Sara?
Dr. Tolaney: And I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston.
Dr. Hurvitz: Thanks for being here, Sara. Today we'll be discussing recent updates in breast cancer, including data presented at the 2021 ASCO Annual Meeting, and integrating these new developments in four patient case studies. Our fourth installment will focus on treatment options for hormone receptor–positive, HER2-positive metastatic breast cancer.
Let's turn to a case. We have a 34-year-old woman who is diagnosed with de novo metastatic, ER-positive, PR-positive, HER2-positive by IHC breast cancer, that is metastasized to the liver, bones, and lungs. She has mild shortness of breath, as well as some back pain. What first-line treatment therapy do you recommend for this particular patient? Sara, can you take us through how you would address this sort of decision?
Dr. Tolaney: She's such a young person who's coming in now with visceral involvement, bone involvement, and pain. Generally, my first-line approach for metastatic HER2-positive disease is usually to use the CLEOPATRA regimen, so to use a taxane with trastuzumab and pertuzumab. I personally tend to use paclitaxel with the HP regimen. And really this is because we saw in CLEOPATRA that adding pertuzumab to a taxane and trastuzumab really added dramatic benefit where we saw about a 16-month improvement in overall survival. And really that has established this as a standard in the first-line setting.
I tend to start the taxane now with HP, really treat them until I see a really nice response or until I start to see some toxicity emerge. Sometimes people start to get a little neuropathy and then I'll drop the taxane. I'll leave them on the HP maintenance. And then in this case, because she's ER-positive, I would then add on endocrine therapy to her HP treatment as a maintenance regimen.
Dr. Hurvitz: I completely agree with you. I would always add on the endocrine therapy in the case of hormone receptor expression during maintenance phase. It's interesting that that wasn't done in the CLEOPATRA trial. I wonder why not, because it would be interesting to see whether or not the survival was even longer with the addition of endocrine therapy.
Bill, the fact that this woman has ER-positive breast cancer, are there any patients that you would omit chemotherapy and just utilize endocrine therapy in combination with HER2-targeted therapy?
Dr. Gradishar: It would be a very unique situation. I think you would have to be looking at the patient with respect to comorbidities and other issues. Because we have the survival benefit from CLEOPATRA, it would be not a very common thing. But if the patient refused chemotherapy, if the patient had some contraindication to chemotherapy, you could consider it, but it wouldn't be my first choice.
Dr. Hurvitz: Sara, there are a few clinical trials that have addressed the use of endocrine therapy–based approaches and HER2-positive breast cancer. We've got the ALTERNATIVE trial PERTAIN and then earlier TAnDEM and another study looking at lapatinib. Can you briefly summarize sort of your take from these clinical trials?
Dr. Tolaney: I think some of the early trials were really trying to say if we add HER2-directed therapy to an endocrine agent, are we going to make that endocrine therapy work better for HER2-positive patients? And I'll say in truth, I thought the benefits that we're seeing from doing this were pretty modest. In TAnDEM, it took you from about two and a half to almost five months, but not dramatic outcomes and benefits that we were seeing.
It does seem like using dual HER2-directed therapy with endocrine therapy is better than single HER2-directed therapy. And so you can see this in the ALTERNATIVE study where they looked at doing lapatinib in addition to trastuzumab, adding it to an AI, and you can see when they added both HER2-directed drugs, numerically, you see a larger difference when compared to the AI/trastuzumab arm.
And then in PERTAIN, they looked at sort of giving an AI with trastuzumab compared to the AI, trastuzumab, and pertuzumab. And they did see that there was greater benefit with the pertuzumab treatment. This trial was a little complicated because they did allow induction therapy with chemotherapy. And so almost half the patients had gotten chemo prior to this phase of being randomized. But I think all of this data, in my mind, point to the fact that if you're going to use endocrine therapy, it tends to work better when you're using dual HER2-directed therapy with it, rather than just one HER2-directed agent.
Dr. Hurvitz: That's a great summary. It was interesting that PERTAIN did have a PFS that looked strikingly similar to that of CLEOPATRA around 18 months. You can't actually extrapolate or compare the two trials, but it is kind of interesting to me.
Bill, you are well aware of the data relating to SYSUCC, just presented at ASCO, looking at a head-to-head comparison of chemo with HER2-targeted therapy versus endocrine therapy plus trastuzumab. Can you give us the highlights of that data and what your take is on this?
Dr. Gradishar: This was an interesting trial and one that needed to be done, but you might ask, maybe it should have been done many years ago before we had dual HER2 targeting, which Sara alluded to. It was a comparison as you pointed out between endocrine agents, either tamoxifen or an AI with trastuzumab versus a choice of chemotherapies with trastuzumab. The reason I had that introduction is because it's not dual HER2 targeting.
If you look at the CLEOPATRA study compared to this study, you can see some distinctions. Being a noninferiority study, it looked like the endocrine trastuzumab option was not so bad. And the way that I thought about this study when I discussed it was that if you had that kind of patient where you were trying to avoid chemotherapy, whatever the medical reason or patient wishes might be, this could be an option. But if you do what you're not supposed to do and put the survival curves next to one another and look at CLEOPATRA compared to this trial, you're going to see that it seems one doesn't have as good of an outcome.
And secondly, in the absence of dual HER2 targeting, which would be viewed as contemporary therapy, I just think the outcomes are going to be not as ideal. So it was an interesting trial, but I don't think it really informs us, at least in the US, with the options we have available today.
Dr. Hurvitz: I would agree with you completely. I was so excited to see that the study was being done, but as I dove in a little bit and saw the details of the trial, I agree with you, there were some design flaws. I think that had they been different, might've been able to address this question a bit more. I would have loved to have seen both arms ultimately get endocrine therapy because that's what we do in practice, and really establish how much more we're buying by doing the several rounds of induction chemo. So it's an opportunity lost, but I agree, the data does support that there is benefit for patients if they're not good candidates for chemotherapy.
Sara, do you have any other takes from this trial? It was sort of a highlight of ASCO. There was a lot of talk around it. Any other points you'd like to make?
Dr. Tolaney: I think Bill did a great summary. I think it is intriguing that you see a very similar PFS with endocrine therapy and trastuzumab compared to chemo/trastuzumab in a very select patient population. Again, these patients are picked less metastatic disease. Most of these patients, about half, are de novo patients. So it's a very select group of patients. But that being said, the challenge, as you alluded to, is it wasn't with dual HER2-directed therapy and it's not currently how we are treating people. And so knowing their survival benefit with THP, it's hard for me to think about switching over to endocrine therapy with HER2-directed therapy lapatinib, but again would reserve it for the select patient who's not a great chemo candidate.
Dr. Hurvitz: And another point I would make is that we're not sure the proportion of patients who received taxane-based chemo or vinorelbine or SERMs versus AI. So I think there's some unanswered questions that hopefully when the publication comes out, we'll have a little bit more information to work with.
That brings us to the end of this section. I will just provide a few key clinical takeaways. First-line standard therapy remains THP for approximately six cycles or until best response, with T being taxane and then maintenance trastuzumab/pertuzumab. If the patient has hormone receptor co-expression on the tumor, then the use of endocrine therapy is accepted by many as standard. And during the maintenance HP, if the patient has hormone receptor–positive, HER2-positive breast cancer, and chemotherapy contraindications, one could consider using HER2-targeted therapy and endocrine therapy as an approach. And I think many of us would utilize dual HER2 targeting with HP if we're going to take that approach in that situation.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in breast cancer or visit ASCOpost.com. Thank you very much to my colleagues and thank you for listening.