Neoadjuvant vs Adjuvant Therapy for Early-Stage HER2-Positive Breast Cancer

In this expert roundtable series, Reshma Mahtani, DO, Miami Cancer Institute, Florida, leads a 4-part discussion on the management of early-stage HER2-positive breast cancer. Participating in the discussion are Terry Mamounas, MD, Orlando Health Cancer Institute, Florida, and Jane Meisel, MD, Winship Cancer Institute, Atlanta, Georgia.

In this video, our experts discuss approaches to neoadjuvant and adjuvant therapy for early-stage HER2-positive breast cancer and the value of achieving a pathological complete response (pCR) from the surgical and medical oncology perspectives.

Watch episode 2 on managing patients with stage 1 HER2-positive breast cancer.

Transcript:

Dr Reshma Mahtani: Welcome to Oncology Learning Network. My name is Reshma Mahtani. I'm the chief of breast medical oncology at Miami Cancer Institute, part of Baptist Health South Florida. It's my pleasure to moderate today's discussion on the management of early-stage HER2-positive breast cancer.

I'm joined today by a distinguished panel of experts in the field, Dr Mamounas, Dr Meisel, would each of you please introduce yourself and tell us a little bit about your background and any specific areas of interest? Jane, do you want to get us started?

Dr Jane Meisel: Sure, I can go first. I'm Jane Maisel. I'm one of the breast medical oncologists here at the Winship Cancer Institute at Emory. I've been here for about 9 years now and really have enjoyed my position. I do breast cancer pretty much exclusively and run a lot of the clinical trials here in breast cancer including several in HER2-positive breast cancer. I've really enjoyed seeing this space expand and how we've been able to really personalize treatment for patients more in the past few years.

Dr Terry Mamounas: I'm Terry Mamounas. I'm a breast surgical oncologist. I'm a medical director of the Comprehensive Breast Program at Orlando Health Cancer Institute in Orlando, Florida. And I also chair the breast committee for NRG Oncology. And I've been practicing breast surgical oncology pretty much my whole career and again, been involved in clinical research for many years as part of the NSABP and now NRG Oncology.

Dr Reshma Mahtani: Wonderful to be with both of you today, and I'm sure we'll have a great discussion. Let's dive right into that discussion, and I'll start with a few opening remarks.

As we start, it’s useful to recognize the progress that we've made in improving outcomes for our patients. We know that overall mortality is declining for our breast cancer patients, and a lot of this is due to the fact that we've made considerable progress in getting the messaging out about the importance of early detection and screening.

But declining mortality is also linked to improvements in novel therapies. I think the treatment of HER2-positive disease is really something that defines that progress, in terms of the number of novel therapies that we have for our HER2-positive patients. For many of our patients, they're doing well, but of course there are patients with higher risk disease and understanding how to tailor treatments is a very important consideration. We hope to dive into some of these factors during today's discussion.

Let’s start with the first section, which is a general discussion on the approach to early-stage HER2-positive breast cancer, neoadjuvant vs adjuvant therapy, and how you both perceive the value of achieving a pathCR [pathological complete response] from the surgical perspective as well as the medical oncology perspective. Dr Mamounas, want to get us started?

Dr Terry Mamounas: Yes, absolutely. And as you mentioned HER2-positive disease is one that we have made pretty much the most progress in the last decade or two because we understand the biology and because of the plethora of drugs that have been developed. Also, came the development of neoadjuvant chemotherapy as a means by which we can first document how the tumor responds to neoadjuvant chemotherapy and use that information to potentially tailor both locoregional therapies as well as systemic therapies. And we have made progress now on both of these fronts and more data are coming to justify this approach.

For example, survival data showing us that we can improve the survival of patients by selecting those that have residual disease after preoperative chemotherapy, plus anti-HER therapy. And also, data that was presented in San Antonio [at the San Antonio Breast Cancer Symposium] looking at de-escalation of radiotherapy for patients that convert positive nodes to negative nodes.

I think for patients that have some recurrence­­¾obviously not everybody may be the best candidate for neoadjuvant therapy and we can discuss the details of that­­¾but for patients with early-stage breast cancer that have some risk for recurrence, and we can define what that risk may be, I think the neoadjuvant approach is very promising and it actually has paid dividends based on what we have found in the last few years.

Dr Reshma Mahtani: Jane, how do you explain this to a patient? You know, a lot of our patients that come in with these smaller HER2-positive tumors are very focused on getting to the OR. And as a medical oncologist, we have to do a lot of education and explaining to them the value, if they do meet criteria, and maybe you can go through that criteria that you use in clinic where you consider offering neoadjuvant.

Dr Jane Meisel: Yeah, I think that we are offering neoadjuvant chemotherapy now to most patients who have a tumor that is 2 cm or greater, or that's node-positive, generally speaking. And there's good data of course to support that approach. The way that I explain that to patients is that of course the desire, once you know you have breast cancer, is “I want to get this thing out.”  But our goal is to cure this breast cancer and that involves both local therapy and systemic therapy.

And depending on the type of cancer you have; we might need to choose to do the systemic therapy first. I talk to them about shrinking the cancer and also seeing what their response is to that treatment and being able to use surgery, as Dr Mamounas said, to then stratify what do they need after surgery.

With HER2-positive breast cancer specifically, especially for those that are hormone negative and HER2-positive, we know that pCR can be a really good predictor of event-free survival and actually overall outcomes. Seeing whether we can get them there can actually really be a prognostic thing.

And then I talk to them about the fact that if we don't do the chemotherapy and anti-HER2 therapy prior to surgery, then we won't really get the information from surgery that allows us to understand, can you continue you with just trastuzumab or trastuzumab plus pertuzumab, or do you need to go onto something like T-DM1 [trastuzumab emtansine]? As we learned this year at San Antonio, with the follow-up data from the KATHERINE study showing that at about 8.4 years, we really do see improved both event-free survival and disease-free survival and more people living longer¾overall survival benefits. This really does pay off to get that information.

And so the patient population over time, especially with all the social media and groups that patients are on for HER2-positive breast cancer, even after diagnosis, I think a lot of patients more now than 5 years ago, I would say, come to the office having heard a little bit about this and not being shocked by the idea of getting neoadjuvant chemotherapy. But it does take some walking back of that innate desire to just go ahead and get to surgery and get it over with.

Dr Reshma Mahtani: Terry, how have you seen the approach from the surgeon's perspective, in trying to convince patients to understand the value of neoadjuvant treatment?

Dr Terry Mamounas: I have found that the last few years our job has gotten much easier. Patients may already go online and look at things and when you proposed this concept a few years ago, several years ago, it was a little foreign to the patients. “What do you mean you're not taking the tumor out?” They seem a lot more accepting nowadays.

And of course, the other barrier was that we said to the patient, “Well, if you get preoperative immunotherapy, you get a pathological response, it’s great, but if you don't, then you have residual disease, which increases your risk.” And we didn't have much to offer in those patients. That makes the patient uncomfortable, makes the oncologist uncomfortable, and the surgeon uncomfortable because now we're dealing with residual disease that we knew about. But if you treat them in the adjuvant setting, you don't have that problem.

On the opposite side of things though, now the data, particularly the KATHERINE data that saw a survival benefit, I think to say to the patient the only way I can actually improve your survival is by giving you this approach where you can find out if you have residual disease. And even with the APHINITY trial, we'll discuss later with pertuzumab, we haven't seen a survival benefit, but we see disease-free survival benefit, but now we have a survival benefit by the approach of combining the APHINITY regimen of TCHP [docetaxel, paraplatin, trastuzumab, pertuzumab], let's say, or AC [doxorubicin plus cyclophosphamide] followed by THP [paclitaxel, trastuzumab, pertuzumab] and then give them T-DM1. I think it is a crucial point now, when we start seeing survival with this approach, I think makes a lot more sense to push for it.

And now, we can talk about the smaller tumors like T1c, which at our institution, we favor neoadjuvant. We don't give pertuzumab because they don't fit the criteria, but we favor the neoadjuvant approach, whatever the neoadjuvant will be either TCH [docetaxel, paraplatin, trastuzumab] or TH [paclitaxel plus trastuzumab] to see can we find a couple bad apples in that good prognosis group that we can then improve their outcomes. Which we lose the chance when you do to the adjuvant. And I'm not saying that everybody needs neoadjuvant, but I think T1c is something that we at least consider here, particularly the high T1c, like 1.8, 1.7 cm tumor, or 1.9. Not so much the 1.1 or 1.2. And so that's kind of how we triage in our institution.

Dr Jane Meisel: I think with those patients it is a little bit trickier, but typically that's the patient population where you're also taking into account age, how strongly HER2-positive, are they even, comorbidities and then, of course, patient preference. But I think, especially now that we have overall survival data in favor of getting that prognostic information and making a change in treatment when we see a non-pCR, it does become even more critical to try to get that information when we can.

And then we'll talk about this potentially a little bit later, but there are also some trials looking at, can we give a little bit less neoadjuvant chemotherapy safely? Like THP for 4 cycles and then use the pCR or non-pCR to guide what we do next. And I think with more personalized approaches like that, it will become easier and easier to think about giving neoadjuvant chemotherapy in patients who maybe have slightly smaller tumors. I think the concern now with some patients is we might be overtreating them if we give them treatment upfront. But if you give them a little less treatment upfront and then still look at pCR as a potential end point, driving your options, then that's all the better.

Dr Reshma Mahtani: Right. I think you bring up a really great point that the chemotherapy that is delivered in the preoperative setting can be challenging for certain patients. And understanding who needs all that chemotherapy vs a de-escalated approach would be really of value.

In the last few minutes that we have of this section, let's turn to a discussion on what type of therapy may be considered, with a focus on single vs dual antibody therapy. And for this discussion maybe one of you can comment on the recent pooled analysis that evaluated event-free survival in patients with a complete response based on the type of HER2-targeted therapy received in the neoadjuvant and adjuvant setting.

Dr Jane Meisel: Sure, I could start with that. This was a paper, a really interesting study, that looked at 5 different HER2-directed therapy studies. Some of these studies, the patients received HP neoadjuvantly and adjuvantly, and some received just 1 antibody therapy. And what was found was that patients that received dual antibody therapy had an improvement in event-free survival vs receiving 1 antibody alone.

They saw also that pCR did translate into longer event-free survival, so those sort of pathologic end points really correlating with clinical end points, which was exciting. And patients with pCR in this study had a 65% reduction in the risk of event-free survival outcomes. Really impressive.

I think that this sort of leads us, especially in node-positive patients, because we know from the APHINITY data that node-positive patients are the ones who seem to benefit from dual antibody therapy, to give more dual antibody therapy in the neoadjuvant setting. I think a lot of us are giving TCHP rather than AC-THP except in select situations, because we also have trial data now showing that for a lot of these HER2-positive patients, we may not really need the anthracycline.

I would say that the majority of my patients, I'm giving TCHP upfront. We do have the Compass [HER2-PCR] trial open at our site, or did, which was looking at THP for 4 cycles, and then looking at pCR as an end point where then, if you got to pCR after THP times 4, you could actually just go on to get HP to complete a year.

I think those kinds of trials, and for patients who may have a difficult time with carboplatin, that don't have trouble de-escalating during neoadjuvant chemotherapy to include some of those cycles with just THP. But that tends to be my general approach to those patients who need neoadjuvant.

Dr Reshma Mahtani: Yes. Terry, anything you wanted to add?

Dr Terry Mamounas: No, no, I agree. And I think that, obviously, de-escalation strategies are important because as we get better antibody therapy, I think we can try to de-escalate neoadjuvant chemotherapy. The challenge sometimes is to actually evaluate the whole strategy.

For example, if the THP and I'm waiting to see what the results of the Compass trial show, but let's say if the pCR rate is not in the 60%, which would be normally with TCHP, it's in the 40% or something, then you have to escalate the post-neoadjuvant therapy with T-DM1 in another 20% of the patients. And it's really difficult to evaluate these 2 strategies. You just can't randomize patients and evaluate what happens after. But you have to do some sort of an analysis to say, what do you gain by doing less upfront? And what did you lose by having to do more afterwards? Because that's what happens for these patients.

But I agree that even based on the approval for patients that have less than 2 cm tumors, clearly dual antibodies are not sort of routinely used or should not be routinely used.  But for those that are at least T2 or node positive, I think clearly they have shown benefit.