 Michelle, you touched on this a little while ago, but I want to unwrap this concept just a bit more, which is for patients who present with large breast masses and maybe have oligometastatic disease, what is the role of going back and trying to completely rid any sites of disease in these women? And how aggressive should we be?

 As I mentioned, the standard thinking, at least in my institution with the surgeons based on the randomized clinical trial data, is that there is no survival benefit from surgery in a patient who has de novo metastatic disease. And even when they looked at different subsets in various trials, the only group that seemed to benefit was the ER [estrogen receptor]-positive, HER2-negative with a single or isolated bone metastasis. But that has not been my experience. We have sort of broken the rules many times, largely based on patient preference, as I said, these women had a large breast mass. Oftentimes it will shrink away in the neoadjuvant setting. We do, as Dr Geyer said earlier, we treat these sort of aggressively, these oligometastatic patients, trying to treat them with curative intent, giving them a CLEOPATRA-like regimen. Sometimes I will even add the carboplatin in as if it were a true neoadjuvant patient and get a really good response. And then you have no metabolically active disease anywhere, and typically our pattern is we take them off the chemotherapy, keep them on dual HER2-targeted therapy. Or in the case of someone who has triple-positive disease, we might add hormone therapy, an aromatase inhibitor [AI] if they’re postmenopausal, OS plus AI plus Herceptin and Perjeta [HP] if they’re premenopausal, and then wait 4 to 6 months and make sure that everything stays stable.

That’s what our surgeons have demanded in terms of wanting the patient to demonstrate that their disease is going to be quiet everywhere else in the body before taking them to surgery. But there’s always this discussion about, do you go for broke, and do you do a lumpectomy plus sentinel node plus/minus full axillary node dissection? Because these women almost always present with clinically node-positive disease, which under the current standard—although that’s changing—would mandate a full axillary node dissection. And then if they have a lumpectomy, do you follow up with radiation, and what’s the radiation field? And then the whole surgical and radiation oncology role of de-escalation, there are a lot of moving parts, and I think that we don’t really have the answer. But I’m curious to hear what my colleagues, what their institutional practices are, because I feel that in the community, I think they’re fearful. They generally will do more than less, and that’s because patients want more, they want that breast mass gone, or even if the breast mass is gone from chemotherapy, they’re constantly feeling their breast wondering, “Do I feel this? Do I feel that?” And I think that having gotten breast-directed therapy, whether it’s a lumpectomy and radiation, or in many cases, these women will want bilateral mastectomies, it gives them hope that they will be cured. I think it’s a psychological measure oftentimes, but it’s an important psychological measure.

 At our institution, not all de novo patients are the same, and so we are really thinking about them in different ways. There’s the patient who has potentially a locally advanced HER2-positive breast cancer and 1 or 2 discrete bone metastases on staging imaging. For those patients our terminology is “curative hope.” We treat them with curative hope, with essentially a curative intent regimen of neoadjuvant therapy, surgery, radiation as needed, and potentially radiation to the oligometastatic sites. That’s one group of patients. Then the other group of patients might present with quite significant liver disease, and they might have a T1 or T2 lesion in their breast. Those patients we generally don’t offer breast surgery, we treat them as we would treat somebody with metastatic breast cancer. The exception to that is occasionally those patients progress only in the breast, and that might be a situation if they’re doing well on HP maintenance that we might offer local therapy to the breast in the hopes that then we could just continue HP maintenance afterward if that’s the only site of progression. But I think we try hard at the beginning to classify patients because patients generally fall into 1 of 2 two categories, and for patients who we’re planning to treat with so-called curative hope, we tend to present those at our tumor board meetings so that there’s a consensus that that’s a reasonable patient to offer that aggressive therapy to.

 Nancy, I love the term curative hope, and I’m definitely adopting that in our practice. I’ll say that the bulk of the data regarding these ideas of the old term of “toilet mastectomies” etc in patients who have metastatic disease are from places like Tata Memorial Hospital in India or Turkey. And if you look at the trial data, they did everything we would do, but the truth is that patients in this country have access to a lot of different tools and a lot of different expertise that is just not available to others. One still wonders if these things are still appropriate in the patients we’re seeing, at least in the United States. And I would argue that until we have definitive homegrown data, that we should still continue to explore these concepts. Chuck, I don’t know if you have a thought on that.

 For me, I always worry about the opportunity lost when you have this. We do adjuvant therapy because we believe it is getting rid of hidden occult metastatic disease. So we’re basically saying that, “If I can see it, then it’s no longer curable.” That’s just magical thinking to me. Clearly as we get increasing sensitivity and look harder, you might see the tumor sticking its head out of the foxhole, but to act like there’s a fundamentally biologic difference there, I’ve never understood that. The other thing to me looking back that we have to remember is, back in the day when our first modality beyond surgery was radiation therapy and we had horrible disease, we learned that it helps with local control, but it doesn’t have a systemic effect, so we didn’t do much radiation. Then a few radiation oncologists, once we were doing adjuvant therapy said, “Maybe we should go back and look at this, maybe it will do something.” Now in the setting of chemotherapy, local treatment, optimal local treatment, improves survival.

We see that, so now do we need a study in this situation, which would be virtually impossible to do? Or should we just be extending it and embracing it as a community? Lajos Pusztai, MD, DPhil, is interested in trying to come up with a study to address this. He’s done a beautiful job of reviewing the literature. The interesting thing is apparently our colleagues in Europe, in ESMO [European Society for Medical Oncology], have sort of taken the position statement that this is a group where we probably ought to do as Michelle is suggesting. So there’s already a sense that looking at a trial here, could you even do it in the HER2-positive space? Probably not, because of what we just heard. Because at my institution too,we treat those patients with curative hope. Once the equipoise goes, you can’t answer it. If you’re going to study it, maybe it’s luminal B patients, I don’t know, but HER2-positive, it’s a tough place to think about that, personally.

 It makes you wonder whether there is the will and the way to do a centralized registry. This is the sort of question that lends itself to a registry that any community-based oncologist or academic-based oncologist could essentially register their patients when they start treatment, so that it’s a fair denominator. And see what happens to patients over time, you’re not assigned treatment, but to understand. If we had data on 100 patients treated with curative hope where we could say, “X percent of patients are off treatment and disease free at 5 years,” that would be practice-changing data. And it wouldn’t require, I don’t think, a randomized trial to show that. I think with the last year and a half, or 2 years now, of COVID-19 expanding our minds in terms of thinking what is possible to do that doesn’t require study visits to an academic center? I think this is the sort of question that would be very well suited to that kind of effort.

 I know SWOG [Cancer Research Network] was exploring exactly that Nancy, prepandemic, and I don’t know where that concept sits right now, but maybe we can revisit it.

Videos

Shared insight on the potential role for surgery in the setting of HER2+ metastatic breast cancer in the context of pharmacologic therapy.

Potential Role of Surgery in HER2+ Metastatic Breast Cancer

 Nancy, there were some small molecule updates as well, maybe you can hit some of those for us.

 I think there is a cautionary note that we saw, which was from the I-SPY 2 trial, that was a neoadjuvant platform trial. What was reported is the tucatinib, paclitaxel, pertuzumab, preoperative arm, so patients got all 4 drugs: tucatinib, paclitaxel, pertuzumab, and trastuzumab. And on the one hand the clinical activity was very high, 15 out of 17 patients had a clinical radiographic response, that’s great. But there was grade 3 and 4 LFT [liver function test] elevation, and even after they dose reduced the tucatinib to 150 mg down from 300 mg, they still saw grade 3 LFT elevations. I think 2 points, one is that I think there is room to develop other tucatinib-based chemotherapy/trastuzumab combinations. Clearly it was an active regimen, but I wouldn’t go doing this in an off-label manner in clinical practice because I think the toxicity was really quite cautionary. To see a very high rate of grade 3 and 4 toxicity even with a 50% dose reduction, I think is really concerning to say, I am not going to be combining tucatinib with other chemotherapies indiscriminately in my clinic.

The other ADC [antibody-drug conjugate] that we didn’t touch on, which I thought would be worth touching on, is ARX788. That’s a HER2-targeted ADC, the payload is a tubulin inhibitor. What was really exciting about that presentation, speaking to Chuck’s point, is that there was activity seen, over 60% objective response rate even in patients with prior HER2 TKI [tyrosine kinase inhibitor], even in patients with prior T-DXd [trastuzumab deruxtecan], prior T-DM1 [trastuzumab emtansine], some sort of prior HER2 ADC. So, I think that’s a very interesting compound. There was ocular toxicity seen and there was ILD [interstitial lung disease] seen, so we are going to have to keep an eye on that, but there is a phase 2 trial that has been launched already, ACE-Breast-03. I think we’re going to see more of that compound going forward.

 Nancy, while I still have you, I think there was a bit of an update from TBCRC049 with Rashmi Murthy, MD, et al, for leptomeningeal disease. Could you comment on that perhaps?

 Sure. This was a study looking specifically at HER2-positive leptomeningeal disease. The study was closed early because essentially 17 patients were enrolled, and then COVID-19 hit, and tucatinib was commercially approved and available, and the accrual basically went down to zero. But despite the small numbers, I think it was really encouraging. The median overall survival, though was only 10 months, is actually very long in comparison to what we see from all population-based studies, where the median survival tends to be less than 6 months. There were responses seen, there was a decent PFS [progression-free survival] that was seen. And I think that it adds a treatment option that’s a systemic option for patients who have leptomeningeal disease, which I think is really very much needed. What was also interesting about the study and already presented at ASCO [American Society of Clinical Oncology annual meeting] was that they were able to measure tucatinib concentrations in the CSF [cerebrospinal fluid], and the CSF-to-plasma ratio was 0.8 at steady state. They were able to also show that tucatinib, we know that it must get into the brain mets [metastases] because of the CNS activity, but there was actually very good penetration into the CSF, which I think was very important to know.

Rounding out their conversation on SABCS 2021, experts discuss small molecule–based treatment strategies for relapsed/refractory HER2+ metastatic breast cancer.

SABCS 2021: Small Molecule Clinical Trials in R/R HER2+ mBC

 Let’s go to the exciting new stuff and frame it in terms of this patient. Michelle, I’m going to start with you. Maybe highlight a couple of San Antonio Breast Cancer Symposium abstracts or things that caught your eye, and we can use that as a launching point.

 In terms of what was presented in San Antonio, a review of things presented at previous meetings, DESTINY-Breast03 was the most powerful presentation. It was interesting. Maybe it’s not so interesting for this community-based audience, because we’re in the United States. But the number of presentations on other tyrosine kinase inhibitors, like ceritinib, got a plenary or was in 1 of the main general sessions, because it’s being developed in China. It’s interesting that 1 of the speakers mentioned, why is this relevant? This drug is being tested in a space where we have many other options in the United States. I thought it was amazing that these drugs that we take for granted—like trastuzumab deruxtecan, or Kadcyla, or even pertuzumab—are not routinely available for people in most of the world. That’s not necessarily the question you asked, but it’s important for us to recognize that we have an embarrassment of riches in the United States with our care.

In terms of other agents that are interesting, no other antibody-drug conjugate [ADC] stood out as being so remarkable, that had me jumping up and down to use it instead. In HER2 [human epidermal growth factor receptor 2], there were data on other combinations. As Nancy mentioned, we’re wondering how we’re going to be combining Kadcyla with tucatinib, trastuzumab deruxtecan with tucatinib—all these combinations of what we have are where we’re moving forward.

Another session I thought was very interesting in San Antonio was the triple positive. We’ve been largely talking about this patient who has ER [estrogen receptor]–negative, 

-positive disease, but some of the more challenging questions are how do we make changes in treatment in a patient who’s ER+, 

+? We have to understand the phenotype of those patients and recognize, are they more HER2 driven or ER driven? That’s not necessarily the case that we’re talking about, but that stood out as questions that folks have in the community.

Another thing about this case is that this patient has progression in the bone. Let’s say that they did this single isolated new lung metastasis. What’s the role of stereotactic radiation, stereotactic body radiation, or isolated radiation to a single site to allow patients to remain on that same second-line therapy? Unfortunately, I can’t say I was jumping up and down about any other agent. I’m curious if I missed something. The questions about the management of this patient come down to how can we maximize, keeping everything we have going and stretching as long as possible?

 Thank you. Chuck, I’ll go to you. There are new molecules that Michelle just mentioned. Anything stick out for you from San Antonio in terms of first in class?

 We’re clearly seeing ADCs revolutionizing in a way we’re treating patients. It’s interesting because we’re getting into seeing more of the heterogeneity and how we’re going to deal with heterogeneity. Then T-DXd [trastuzumab deruxtecan] drops in, and maybe we don’t have to worry as much about the heterogeneity. It’s so active in all these subtypes. That’s a particularly disruptive drug in terms of trying to predict the best way to use it. It’s going to be interesting to sort it out, but even with all the great information on T-DXd [trastuzumab deruxtecan], there are still patients progressing and failing. Now it’s what you do post-antibodies, post T-DXd [trastuzumab deruxtecan], post-tucatinib.

Now we’re talking about a fourth line, so you’re getting into whether it’s lot of heterogeneity. But there were a couple of types of drugs. It looks like there are bispecific antibodies that bind to 2 parts of a single antibody, binding to 2 different points on the extracellular domain of HER2. There were some early studies—in particular, KN026 from a Chinese company Jiangsu Alphamab Biopharmaceuticals—developing this, but they were looking at heavily pretreated patients. They did a quick phase 1/2 study reporting on activity of this antibody on 57 patients in this heavily pretreated population. They had an overall response rate of 28%. The neat thing is they also prospectively planned on looking at the subset where there was coamplification of CDK12. I had to read about this. When I saw those, I thought, “I don’t know what that is. I’ve got to go look.” Apparently this is 1 of the CDK family that is frequently coamplified with HER2 and appears to be a resistance mechanism. So when they looked at that subset, it was a response rate of 50%, so maybe there will be subsets. That seemed to be well tolerated, so I found that to be an interesting abstract.

There was another bispecific antibody that took the next step, giving it with chemotherapy. The name—you have to hear it said a couple of times—is zanidatamab. I love it. It was dealer’s choice with chemotherapy for 20 patients, but they had overall response rate of 38% clinical benefit. It’s remarkable when you get into those patient populations whose tumors have been under so much pressure for many active drugs for many years, but they’re still vulnerable. These are interesting things to keep an eye on and conceptually think about. There are ADCs. There are also antibodies. People are turning to the partner HER3 [human epidermal growth factor receptor 3]. What about monoclonal antibodies and ADCs linked to HER3. To me those are what to look for behind ADCs that might see the light of day. Maybe will be some bispecifics or ADCs targeting the HER3. The studies look that way, but we’re years from the clinic.

 I agree. What’s interesting is that these new bispecifics are being combined with chemotherapy. We’re getting those safety data. I can see these slotting in much earlier lines of therapy, eventually being able to challenge a classic combination like THP [docetaxel, trastuzumab, pertuzumab] with zanidatamab. With a drug like that with combination chemotherapy, you can see that you haven’t enrolled down the road.

Considering data from the SABCS 2021 annual meeting, experts discuss novel combination strategies for relapsed/refractory HER2+ metastatic breast cancer.

SABCS 2021: Combination Strategies Under Investigation for R/R HER2+ mBC

 Nancy, there were great data from this woman named Nancy Lin presented at San Antonio Breast Cancer Symposium. Maybe you could tell us firsthand what you presented?

 We presented an update with additional follow-up of the HER2CLIMB trials, specifically restricted to the CNS [central nervous system] subset. If you recall, HER2CLIMB had about 600 patients enrolled. About 300 of those patients had brain metastases, including 174—so a very substantial portion—who had active brain metastases entering the trail. Updated overall survival data, as well as other end points, were presented. The most striking finding was that there was a further improvement in overall survival as seen from the first initial presentation.

Now the median overall survival delta is over 9 months in the CNS subset, so from 12.5 to 21.6 months. Before it was 12 to 18 months in the overall CNS subset. If you look at the patients with active brain metastases—

 [human epidermal growth factor receptor 2]–positive, prior trastuzumab taxane, pertuzumab, and T-DM1 [trastuzumab emtansine]—the median overall survival went from 11.8 to 21.4 months. These are striking survival differences in a patient population that was previously written off as not fit for clinical trials. You can’t use the excuse anymore that patients don’t survive long enough; therefore, we can’t enroll them in clinical trials. These are patients who are heavily pretreated who had active brain metastases and survived almost 2 years from trial entry. If we’re not going to enroll those patients in trials, we might as well not do any trials of metastatic triple-negative breast cancer, right?

The message is that systemic therapy has the potential to have dramatic survival improvements. If we look at trials of whole-brain radiation vs SRS [stereotactic radiosurgery], there’s no survival difference with whole-brain radiation. To see a 9-month absolute delta is unprecedented in this patient population.

 Nancy, at the meeting there was also talk and interesting signals. We mentioned this earlier, with trastuzumab deruxtecan maybe having actual CNS activity. Maybe you can speak to that as well.

 Historically we’ve thought that ADCs [antibody drug conjugates] don’t work in the CNS [central nervous system] because they’re big and bulky, but that’s been challenged because we have multiple reports that T-DM1 [trastuzumab emtansine] has CNS activity. There’s been a lot of interest in determining whether T-DXd [trastuzumab deruxtecan], which obviously we know is better than T-DM1 [trastuzumab emtansine], also has CNS activity.

That’s been looked at in a couple of different ways. DESTINY-Breast03 looked at it indirectly. Most patients didn’t have active brain metastases; they were treated stable. But in that subset the PFS [progression-free survival] definitely favored T-DXd [trastuzumab deruxtecan]. For what it’s worth, there were CNS responses seen in the T-DXd [trastuzumab deruxtecan] arm. Because it’s a randomized trial, you could compare it with the CNS response rate in the T-DM1 [trastuzumab emtansine] arm, and it was substantially higher. That suggests it’s not just previous radiation because you would imagine those things would be balanced out by randomization. That was very interesting.

There were a number of phase 2 trials or retrospective experiences looking at T-DXd [trastuzumab deruxtecan] in different types of brain metastases populations, all with a very consistent message that CNS objective responses are seen and were fairly convincingly attributable to the T-DXd [trastuzumab deruxtecan]. This is a real paradigm shift, that ADCs as a class are likely active in the CNS. We have data also from Andrew Brenner’s group with sacituzumab preop trial—

 meaning preop to craniotomy, where their group showed therapeutic levels of SN-38 in the CNS with sacituzumab. I believe there’s going to be a class effect of ADCs in the CNS, and we should think about it as we’re thinking about developing other ADCs.

 These studies should heighten the interest in the KATHERINE replacement studies because the issue with a little disappointment on KATHERINE was that it didn’t look like T-DM1 [trastuzumab emtansine], and that potentially curative population was effective in preventing the brain metastases. That was the 1 unmet need in KATHERINE, that it didn’t seem to have impact on brain metastases. For about half the patients with events, brain metastases were part of it. Clearly the CompassHER2 RD [residual disease] study that’s being led by Alliance for Clinical Trials in Oncology…are taking T-DM1 [trastuzumab emtansine] to see how we do with adding tucatinib. Makes a lot of sense; it’s a very interesting study.

The other 1 out there is the DESTINY-Breast05 comparing T-DM1 [trastuzumab emtansine] with T-DXd [trastuzumab deruxtecan]. These are encouraging data that perhaps we’re going to see this unmet need addressed in both trials. It’s encouraging, but people doing clinical trials who have patients with the non–PCR [polymerase chain reaction] ought to be participating in 1 of these trials, because we need to learn this very important information. It’s the last step in the early breast cancers.

+ disease we’re seeing have de novo disease or relapse in their CNS. Those are the 2 most common metastatic populations if we look at newly diagnosed 

+ patients with metastatic disease these days.

A brief review of updated data from HER2CLIMB and discussion on which agents may be best for treating patients with CNS disease.

HER2+ Breast Cancer: Updates on HER2CLIMB and CNS Disease Management

 Chuck, we talked a little about deruxtecan and the DESTINY-Breast03 study. Perhaps you can just remind us about tucatinib and how these recent trials are affecting our thinking on where tucatinib fits, etc.

 Tucatinib is a drug we’ve been interested in for a long time, but it was very challenging for the company to get the trials done. They elected to basically do the HER2CLIMB study, in a very heavily treated patient population. They had to have both antibodies T-DM1 [trastuzumab emtansine]. To their credit, they didn’t run from brain metastases. They embraced brain metastases, so to speak. There’s always been that standard saying, “We’ll let people on the stable on brain metastases.” But the thing about this study that everybody is aware of is that with any brain metastases, you can come in—almost half their patients had brain metastases, and a substantial percentage had disease that was actively progressing after prior radiation somewhere new that had been treated. There’s a lot of information on that trial because it was a large phase 3 about the subsets. Nancy has been active and has shared that information as it’s evolved. The study was designed to look at the efficacy of the drug overall, the IIT [intent-to-treat] studies. The thing that was impressive about it is that everybody was getting an acceptable regimen of trastuzumab capecitabine. For that scenario, with added tucatinib, you saw very impressive hazard ratios for the end points. Progression-free survival [PFS] hazard ratio was 0.54.

When you look at how much the progression-free survival mattered, it was only 5.6 to 7.8 months. But when you start looking at benchmark end points, like who was free or who was still alive at 2 years, you start seeing that there are subsets of patients benefiting from that. The interesting thing about the study is that the benefit is virtually the same when you look at the patients with and without brain metastases and maybe even a little better in the brain metastases population. It’s very striking, and it tells us that this is a drug that clearly has CNS [central nervous system] activity that needs to be considered. The trial was done in that third-line setting, so the big question has been, “What if in your second line, you’ve got brain metastases? Do you bring it forward? Do you use T-DXd [trastuzumab deruxtecan]?” The interesting information on the DESTINY-Breast03 study was the follow-up about their small subset of patients with stable brain metastases. We’re going to hear more about that later. But it certainly encourages us that when we’re using T-DXd [trastuzumab deruxtecan], we’re probably delivering reasonably effective therapy against CNS disease as well.

 Before we return to our case, Nancy, I’m going to come to you for a second. We have a couple of other drugs out there that got extended approvals related to them. All of us are like, “Where do we use these?” For example, neratinib and margetuximab. Quick comments on those?

 Great question. Both of them—neratinib with NALA and margetuximab with SOPHIA—had positive phase 3 trials. But as you point out, the question is, what do you do with them in clinical practice? I think the trials were more important from a proof-of-concept standpoint than for changing our usual second- and third-line regimens. Neratinib was neratinib, and the NALA trial compared neratinib-capecitabine vs lapatinib-capecitabine, and neratinib was marginally better—the hazard ratio was 0.7, and the absolute difference is about 2 months in PFS, with no survival difference. There were some interesting findings out of NALA. Patients who had baseline brain metastases were less likely to progress in their brain.

There were some interesting hints of data in terms of benefit in the CNS. One major takeaway from the study that I took away was that we can develop better HER2 [human epidermal growth factor receptor 2] TKIs [tyrosine kinase inhibitors]. Lapatinib, which Chuck was very involved in developing, can be improved upon. By dialing in CNS activity and also better HER2 inhibition, you can improve upon first-generation HER2 TKIs. But in clinical practice, I’m typically choosing tucatinib over neratinib at least early on because of the toxicity profile and because of the survival data seen in HER2CLIMB, which wasn’t seen in NALA.

There are some big questions. Is there a role for neratinib after tucatinib or lapatinib? Is there a role for switching out the chemotherapy, in the way that we do for trastuzumab? Are we continuing trastuzumab and then switching out multiple types of chemotherapy? The problem is, with the HER2 TKIs, we don’t have a lot of combination data with other chemotherapies, and so we’re stuck with capecitabine. That really interesting. There’s an ongoing study of T-DM1 [trastuzumab emtansine]–neratinib in patients with brain metastases. It’s quite interesting, the potential to overcome T-DM1 [trastuzumab emtansine] resistance. There’s still some room left for neratinib, and there are data in 

Margetuximab is a technically positive study, but the difference was quite marginal. There’s no difference in overall survival, and there was a 1-month or so difference in median PFS. Hazard ratio was very similar to NALA: 0.7 or 0.75. But it’s a proof-of-concept study in the sense that in the FF genotype, there was a benefit seen, and there was proof of concept that you can engineer trastuzumab to be more visible and more promoting of immune activation. The question is, if you use it earlier, before a patient’s immune cells are exhausted, and you tried in the neoadjuvant setting or in earlier lines, could there be a benefit? In routine clinical practice, it’s hard to come up with a major role of margetuximab in the typical 

 Let’s go back to our patient quickly. She had HER2-enriched de novo disease: ER [estrogen receptor]–negative, HER2+. As Chuck pointed out, she does get some variation of THP [docetaxel, trastuzumab, pertuzumab], taxane plus HP [trastuzumab, pertuzumab], presumably even subcutaneously for a while. Then 2½ years later, she completes some more scans, and there are lung metastases and bone metastases. With this in mind, we quickly talked about all these options—standard, clinical trials. Are there any changes in terms of patient factors, disease factors, treatment factors? How would you put all this together? Nancy, bone metastases vs lung metastases—does that change anything for you?

 If we think about, she’s been on THP [docetaxel, trastuzumab, pertuzumab]. Now you’re trying to choose second-line therapy. In general, I’m going to be reaching for trastuzumab deruxtecan because the results of DESTINY-Breast03 were so impressive. There are some exceptions. It’s more toxic than T-DM1 [trastuzumab emtansine], and there’s the ILD [interstitial lung disease] issue. For a patient who has preexisting lung disease, for a patient who may be more frail, for all sorts of more toxicity-based issues, I might still choose T-DM1 [trastuzumab emtansine] over T-DXd [trastuzumab deruxtecan] in the second line-setting. For a patient who has predominantly CNS progression, it’s not clear whether one should choose T-DXd [trastuzumab deruxtecan] or tucatinib, because the T-DXd [trastuzumab deruxtecan] data are a little more limited in terms of CNS. Patients with active CNS disease weren’t included in DESTINY-Breast03. On the other hand, HER2CLIMB wasn’t studied in the second-line setting. It’s a bit of a toss-up, and I base it on where the predominant burden of disease is. If it’s predominantly CNS-burden disease, I tend to reach for tucatinib. If it’s predominantly extracranial disease, even if there’s some CNS disease, I tend to reach for T-DXd [trastuzumab deruxtecan].

Experts discuss the role of novel therapies in relapsed/refractory HER2+ metastatic breast cancer accounting for results from recent clinical trial.

Novel Treatment Approaches to R/R HER2+ Metastatic Breast Cancer

 I’m going to transition us to a different phase of the discussion that’s focused on treatment beyond the first line. Let’s say this patient who we just discussed gets good mileage out of this—3, 4 years of stable time. We’re up to the second line because of some progression event. Maybe we have a ton of agents to talk about in the second line and beyond. I’ll start with Michelle. Can you go through some of the things that have caught your eye? How is KATHERINE affecting what we might do in the second line? Just update us on what we’ve learned from EMILIA and the mechanism actions of some of the things we’ve been doing for years in that second line.

 Obviously, KATHERINE has had 1 of the greatest impacts on clinical practice of early stage 

 [human epidermal growth factor receptor 2]–positive breast cancer since the approval of Herceptin and Perjeta years ago. Everyone knows the structure of this trial: patients who had residual disease after neoadjuvant chemotherapy were randomized to continue on trastuzumab or get T-DM1 [trastuzumab emtansine], and the use of T-DM1 [trastuzumab emtansine] resulted in an 11% reduction in invasive disease-free survival at 3 years. That’s a pretty dramatic outcome and improvement for those patients with 

-positive breast cancer who didn’t achieve a pathologic complete response with their neoadjuvant chemotherapy.

Recognizing that there will be a larger population of 

+ patients who’ve been exposed to T-DM1 [trastuzumab emtansine] or Kadcyla in the post-neoadjuvant and adjuvant setting, we wonder how effective Kadcyla will be in the metastatic setting. Until the last couple of years, the first line would be the CLEOPATRA regimen. Upon progression patients would go on Kadcyla under most circumstances based on the EMILIA trial, which randomized Kadcyla to lapatinib and capecitabine and found that Kadcyla was superior with about a 4-month advantage in terms of progression-free survival.

Now we have the data that compares Kadcyla and HER2 with trastuzumab deruxtecan in the second-line setting, showing that trastuzumab deruxtecan has phenomenal efficacy with the median time to progression and progression-free survival not reached. This is going to be a game changer in our practice. It’s going to get harder and harder to identify patients for these trials because if we carry things out, and we expect that we’re going to get 2 to 2½ years of stability with first-line treatment. In the second-line treatment, the new standard is likely going to be trastuzumab deruxtecan. Those patients may get another 2 to 3 years.

What’s next? To leave some other trials to talk about the data on tucatinib and HER2CLIMB. Going back to what Nancy said before, it’s about the role of CNS [central nervous system] imaging for these patients. In my experience, where we fail—at least in the CLEOPATRA taxanes and dual HER2-targeted antibodies—is in the brain. That’s often a good first line of progression. We’re very excited about the potential for trastuzumab deruxtecan to have some CNS activity. We know that tucatinib does, but it’s going to be a big question: how do we image the brain other than having a very low threshold, as Nancy mentioned? I have a bunch of patients who are really pushing, they want their brain MRI every 6 months, and I usually acquiesce. I’ve had patients who are percolating along, doing great, and then they call in with slight dizziness. I had someone last week with a 5-cm brain metastasis who showed up with her only presentation—a little dizziness. My staff wanted to give her some meclizine and tell her she had an inner ear infection. I was like, “No, you have to get an MRI.” I have a very low threshold. That’s where challenge like remains.

 It’s amazing how variable symptoms are between patients with different volumes of disease in those cases, and that’s what’s so concerning about it. You’ll have people come in with relatively minimal symptoms. It’s like, “Ha.” When you’re doing that every 6 months, Michelle, are you talking about your patients once they develop recurrent disease? Even if they’re systemic only and it’s looking good, you’re still saying you check the MRI every time? I don’t think that’s unreasonable at all.

 It’s obviously not guideline driven. Nancy mentioned this trial in Toronto. We’re going to pick up more brain metastases, and then that’s going to set people out on a screening every 2 to 3 months. It’s not going to be very cost-effective, but it may improve people’s quality of life to not have to go through, obviously, whole-brain radiation or to have a big brain metastasis resected. I’m not dogmatic about it, but I have 5 or 6 women who have prolonged stable disease systemically on HER2-targeted therapies, and I order it at intervals of about every 6 months. Of course, as Nancy said, there’s a very low threshold to order a brain MRI on any 

+ patient and triple-negative patient that shows up with a subtle neurological symptom.

Shared insight on the roles of trastuzumab emtansine and trastuzumab deruxtecan in relapsed/refractory HER2+ metastatic breast cancer.

HER2+ mBC: Impact of T-DM1 and T-DXd Beyond the Frontline Setting

 This is going to dovetail on what we were just talking about: defining these patients. How are we monitoring them? How do we define a patient who might be progressing? The big topic now is do we screen for brain metastases in patients whose baselines maybe don’t have them, but they’re on therapy? Nancy, maybe you can comment on this and about circulating tumor DNA [ctDNA] and what role that might have.

 In terms of extracranial imaging, we generally do CT scans as our go-to. Occasionally we’ll move to PET [positron emission tomography] scans if there’s some issue on the CT—a patient can’t tolerate IV [intravenous] contrast, there’s imaging of bone-only disease, or there are other circumstances for which we might use PET instead of a regular CT. As far as brain screening, it’s a good question. We don’t do it as standard of care, and the guidelines don’t recommend it. That’s because of a lack of evidence as opposed to evidence of no benefit, and that’s a different situation.

Through an ASCO [American Society of Clinical Oncology] CDA [Career Development Award]—is running a randomized trial of screening or no screening in patients who are starting or who are on chemotherapy for 

 [human epidermal growth factor receptor 2]–positive disease or ER [estrogen receptor]–positive disease. Patients with triple-negative disease are also screened in this trial, but it’s not randomized. The end point is neurological functions—a quality-of-life end point, because it took a long time to think about what the right end point might be. There’s an 8-minute brain MRI-screening protocol, so it will be nice if it pans out. But there are other trials. There’s a trial in Canada that’s similar. This is a question on the minds of a lot of patients. I certainly have an extremely low threshold to order brain a MRI for my patients with 

With respect to ctDNA, I’m not using it to monitor disease response. I’m not using it in a quantitative way. It’s something that Dr. Heather Parsons, as part of the STOP-HER2 trial, will be testing to see whether we can use minimal residual disease and exceptional responders to pick out patients who can stop therapy. But that’s very investigational. I do use liquid biopsies to look at alternative genetic alterations, but I don’t use them in 

+ patients. I tend to use them in in ER+ or triple-negative patients, where you’re more likely to see something that might ultimately affect the treatment you prescribe. For 

+ patients, I’m not using liquid biopsies in any way in clinical practice.

A brief review of patient monitoring and screening practices in the setting of HER2+ metastatic breast cancer.

Monitoring Patients With HER2+ Metastatic Breast Cancer

 We have a little more information on this patient. We find out from the breast biopsy that she’s got 1 of these HER2 [human epidermal growth factor receptor 2]–enriched phenotypes. She’s hormone receptor–negative for estrogen and progesterone, but 

-positive 3+ by immunohistochemistry. On top of that, the nodule is also similar in 

+, presumably by FISH [fluorescence in situ hybridization], in this case as well. With that information, any changes in your thinking? I imagine not, correct?

 With that in mind, we have a first-line patient, a virgin tumor that hasn’t seen a lot of therapy. Chuck, because you were just sharing some information with us, what’s your approach? Has this changed in recent years with all the new data?

 With first-line untreated metastatic cancer, these patients need dual HER2-targeted therapy with a trastuzumab-pertuzumab with chemotherapy. We’re tracking this. We’re trying to do a first-line metastatic trial looking at atezolizumab, NRG-BR004. What we’re seeing is that 80% of patients are presenting with de novo disease. Some have very advanced disease. It’s a surprise because the liver disease is dominant. Others are presenting, like this patient, with mammographic abnormality and some axillary nodes. When we get to staging—they’ve got relatively small volume—I don’t know if we can call it oligometastatic. But this is an area where there are some interesting questions out there, because broadly speaking there’s the idea that metastatic disease isn’t curative and that we should approach this in a palliative manner.

+ space, I question that rigid thinking. But you do see it, and it’s 1 of these things that seems to be guideline driven. People say, “The guidelines say this is the regimen, so I’m going to use it.” I tend to be a bit more aggressive with my chemotherapy when I have a patient with newly diagnosed cancer in the breast with small-volume oligometastatic disease. I tend to use neoadjuvant regimens with HP [trastuzumab, pertuzumab] and try to make it all go away. If I have a pathologic complete response in the breast and the nodes, and the disease in the lungs disappears, that’s a good place to get a patient. Is there evidence based for this? This is always the challenge we have.

There’s a limit to what you can generate in prospective randomized studies, and this is the increasing challenge as we move forward with more agents. There’s a point where you can’t generate level 1 evidence for every question we’re seeing in clinic. This is 1 area. It’s clear that they need HP [trastuzumab, pertuzumab]. They need chemotherapy. But there are oligometastatic questions about this.

 I’m glad you brought up the atezolizumab trial. I put a gentleman on that study this week.

 It raises a great point: we have fewer patients with recurrent 

+ metastatic breast cancer. The patients we see more and more have de novo disease, and that’s a really important point. There are first-line trials out there that don’t wait to refer patients for clinical trials until their nth line. There’s the NRG-BR004 study with atezolizumab. There’s the DESTINY-Breast09 study randomizing THP [docetaxel, trastuzumab, pertuzumab] vs Enhertu or trastuzumab deruxtecan. There are good first-line trials out there. Between the NRG-BR004 trial and DESTINY-Breast09, there’s fairly good coverage across the United States. I’ll put in a plug that there are definitely trials in the early line setting.

To Chuck’s point, there’s a lot of interest in trying to determine whether there’s a subset of patients with 

+ metastatic breast cancer who can be cured. Some have already been cured, and we just aren’t brave enough to stop their trastuzumab. That’s going to be the subject of a trial through the Translational Breast Cancer Research Consortium looking at exceptional responders that will be led by my colleague Heather Parsons. There’s also the question of whether we should purposely escalate people’s therapies à la an adjuvant regimen using non-cross-resistant treatments, switched not because of progression but because it’s a fixed regimen. I’m not doing something so escalated outside a trial with the exceptions of what Chuck has mentioned, which is those oligometastatic patients. But it’s an interesting question, and hopefully that will become a study that opens in 2022, because this may be the first group of patients that we can attempt to cure with metastatic disease.

 If you look at CLEOPATRA, you’ve got the tail on the curve. We do see subsets of patients who are free from progression 8 years out, but that subset grew with the addition of pertuzumab. The 

+ space, particularly when you’re starting with relatively small-volume disease, is a little different. It’s more about the volume. You’ll see patients who didn’t realize they had it—they’re a little nauseated, and they come up with loaded liver metastases. That’s a different patient from what we’ve got. I guess this is what we’re losing a little. The guidelines get set up based on clinical trial cohorts that you need to define to try to get your study done. But not everybody is fitting those cohorts that well. There are some things that we need to—particularly as we’re getting all these amazing therapeutics in this space. NRG-BR004 is struggling with approval in part because we don’t see as many of these patients as we used to.

Taking into account a patient case of HER2+ metastatic breast cancer, experts review current frontline treatment options.

Patient Case: Frontline Treatment Options for HER2+ mBC

 Let’s go ahead and move through. We have a few cases that are going to spark some conversation. I’ll start with the first 1. A 62-year-old woman who from the current mammogram identifies a new mass, 1.5 cm, in her right breast. She has 2 adult children. Menopause at age 47. No known or particular family history for cancers. Our imaging reveals a 1.9-cm regular mass in the right breast with suspicious adenopathy. MRI bone scans seem to be negative. PET [positron emission tomography]–CT shows the axillary nodes and some pulmonary nodules, unfortunately. The breast mass, lymph node, pulmonary nodules are all biopsied and sent to pathology. Her PS [performance status] is 0. At this point, let’s focus on some of the diagnostics. Michelle, you can tell me some of the additional tests beyond those imaging diagnostics you might order in this patient.

 The twist to this case, as happens not infrequently, is the presence of a possible metastasis based on PET–CT scan. That’s another topic of discussion: the use of imaging studies in higher-risk disease, who gets it, who doesn’t, and how that impacts the treatment of these patients. In this case, she did have the PET scan. It shows these nodules. The case doesn’t present how big they are, but we’d want to try to determine whether these were possible to be biopsied. Once that’s determined, then for the breast mass itself, we’d send it for the standard receptor studies: ER [estrogen receptor], PR [progesterone receptor], and HER2 [human epidermal growth factor receptor 2]. With HER2, we’d want to test with both IHC [immunohistochemistry] and FISH [fluorescence in situ hybridization], given that we’re not talking about 

-positive in the conventional way of 3-plus IHC and FISH-positive, but we’d also want to know the IHC if it was 1-plus or 2-plus to define the HER2-low population. And then of course the receptor studies, ER/PR, to know down the road the role of endocrine therapy.

The biopsy of the lung is critical because if it’s positive, then that puts the patient into a particular bucket of disease. If her disease is triple-negative and she has metastatic disease, then we need to know the PD-L1 status. However, if the biopsy of the lung is negative and we have a locally advanced high-risk triple-negative breast cancer, then we can treat with immunotherapy-chemotherapy combination without knowing the PD-L1 status. If the patient ends up having a biopsy-proved metastatic disease in the lung, there’s a question about the role of next-generation sequencing to look at actionable mutations. That’s a whole other conversation, a bag of worms about the value of performing NGS [next-generation sequencing] as first-line therapy, to guide first-line therapy. I know many centers do it on every patient.

Given the circumstances, if we know the patient is 

+, we’d treat them with metastatic disease under 1 very defined pathway. If they’re 

-negative, triple-negative, it would be another pathway. I’m not sure the role of next-generation sequencing in selecting the first line of therapy for 

+ and triple-negative. It has more value in ER+, where the course isn’t as defined. I’m curious to hear what my colleagues think in terms of biomarker selection and what needs to be done with the tissue.

 I would think there’s 1 exception to the last point you made about doing genetic testing on the tumor itself for somatic mutations: if we had clinical trials.

 Yes, and I often set it even in the first-line setting, even if it’s not going to affect my first-line regimen, because there’s a turnaround time associated with the test. We see a lot of patients as consultations. It takes awhile to get outside tissue in for us to send it out for testing. At the time of progression, you don’t want to wait 6 or 8 weeks to get the tissue, get it sent out, get a turnaround time, get the result. We have sent it off when we first see patients, more for practical reasons—it’s not necessarily going to affect first-line therapy. Certainly, in ER+ patients, we routinely sendoff NGS because we want to know the PIK3CA status of the tumor. Obviously, there are some interesting data about TMB [tumor mutational burden], so could we offer some subset of patients with ER+ disease immunotherapy? I agree with Michelle that for 

+ disease, with the exception of looking for potential clinical trials, we’re not translating the results into clinical practice from NGS.

 Keeping in mind a community audience, for community practitioners, the next-generation sequencing isn’t at all a standard. It isn’t that you’re undermanaging your patient if you don’t do that with the newly diagnosed cases. There clearly are situations where you need to be thinking about it sooner than later that are appropriate subsets and clinical situations. But it’s different in the academic centers, working in a very different environment from a community doctor for sure.

Centered on a patient presentation of breast cancer, panelists consider optimal biomarker testing strategies to inform their treatment approach.

Patient Case: Biomarker Testing in Breast Cancer

 Hi, my name is V.K. Gadi. I’m the director of medical oncology in the division of hematology-oncology in the department of medicine at the University of Illinois College of Medicine in Chicago, Illinois. Welcome to this 

® program titled “Changing Treatment Paradigm for 

+ Metastatic Breast Cancer.” Joining me are my colleagues Dr Chuck Geyer from Houston Methodist Cancer Center in Houston, Texas, Dr Nancy Lin from Dana-Farber Cancer Institute in Boston, Massachusetts, and Dr Michelle Melisko from the University of California, San Francisco UCSF. Panelists, say a few words about yourselves. I’ll start with Dr Geyer. Chuck, go for it.

 I’m a breast medical oncologist at the Mary and Ron Neal Cancer Center at Houston Methodist Hospital. I serve as breast committee chair for the NSABP [National Surgical Adjuvant Breast and Bowel Project] Foundation and also the medical oncology cochair for NRG Oncology. I’m happy to be participating.

 Thank you very much. Nancy, you’re up.

 Hi, I’m Nancy Lin. I’m a medical oncologist at Dana-Farber Cancer Institute. I lead our metastatic breast cancer program, and I’m the associate chief of our breast oncology division.

 I’m Michelle Melisko. I’m a breast-focused medical oncologist at UCSF. My research interests are in metastatic disease, primarily CNS [central nervous system] disease, and then also quality of life, patient-reported outcomes, and survivorship issues.

 Thank you very much. As the title suggests, we’re going to overview the landscape that’s changing and evolving for 

 [human epidermal growth factor receptor 2]–positive MBC [metastatic breast cancer]. We’ll look at the latest research, focused on the San Antonio Breast Cancer Symposium that just concluded, and how these trials are changing how we manage women and men with breast cancer. With that, let’s get going with the first topic. This is to level-set where we all are in our own practices and the current state of MBC with 

+ disease in your practices. I‘ll call on you sequentially. What are you seeing in terms of the incidence of each type of breast cancer? Is it changing in your practices? Michelle, I‘ll start with you.

 Because I’m at an academic center, we tend to see a population of younger women presenting with more aggressive disease. We end up seeing more triple-negative breast cancers, perhaps more 

+ breast cancers, and less of the run-of-the-mill older ER [estrogen receptor]–positive 

-negative breast cancers. We also tend to see more of the rare, unusual subtypes like metaplastic or things like that. But it’s definitely enriched for younger and more aggressive disease.

 Before I leave you, Michelle, can you highlight 1 or 2 emerging challenges you’ve identified in your recent population?

 Of course, we’re very interested in pursuing clinical trial research. With all the optimistic and fantastic breakthroughs, the approval of pembrolizumab in triple-negative disease, and the approval of Enhertu in 

+ metastatic disease, we have a lot of good treatments. Not necessarily the best treatments. But 1 of the challenges we face is trying to convince women that it’s worthwhile to participate in clinical trials, that there’s still work to be done because there are a lot of unknowns with trial participation, particularly in the face of COVID-19 and the extra work that’s involved. In terms of other challenges in managing patients, CNS disease still remains a tremendous challenge, particularly in the triple-negative and ER+ populations. We have some breakthroughs in the 

+ space, but we need work in the other areas as well.

 Thank you. Chuck, from your perspective, what’s your practice looking like? What are a couple of challenges you’ve noticed?

 We’re a very broad health care system, so we have more of a mix. We have a large primary care group that feeds into the cancer center, so we see some older patients with mammographically detected ER+. We seem to have few older patients, 80 or 90 years old. We do because we do the clinical trials. Jenny Chang’s interest in triple-negative breast cancer. We get that element of that younger, more aggressive subtype coming to our practice as well.

In terms of the challenges, this is something we’re facing. We have a large hospital and cancer center downtown, but we have a community network with regional hospitals. We’re interested in extending our clinical research efforts out, making that available as everybody is. But there’s always the challenge of the increasing productivity, RBE [relative biological effectiveness] pressures balanced with the time it takes to consent the patient and then monitor and document everything. There’s extra work to clinical research that takes time. That’s a big challenge that we’re all going to be seeing more as payments are “adjusted” moving forward to maintain the ability to do this, because it’s phenomenal what we have before us in terms of opportunity.

 Nancy, if we can hear from you about the same issues with same questions. What is your practice looking like?

 In our early stage breast cancer population, I haven’t seen a tremendous shift 1 way or the other in terms of subtype distribution or age distribution over last multiple years. Where we have seen a shift is in people with metastatic breast cancer, and we’re certainly seeing the effects of better adjuvant therapy for 

+ metastatic breast cancer than we did 10 or 20 years ago, and that makes it challenging in a way that wasn’t the case before. It’s a good thing to accrue to HER2+ metastatic breast cancer trials. We also have a large group of patients who are living many years with ER+ or 

+ metastatic breast cancer and reaching for nth-line therapy more often in a way that we didn’t before. In terms of challenges, triple-negative breast cancer remains a major challenge, particularly in the metastatic setting. Even with the improvements with pembrolizumab and sacituzumab, patients still don’t do as well as patients who have other subtypes of metastatic disease. In ER+ disease we struggle with what to do in endocrine-refractory patients because after 1 or 2 lines of chemotherapy, patients tend not to respond to nth-line therapy in the ER+ metastatic space. As Michelle alluded to, CNS disease remains a major problem across all 3 subtypes of breast cancer. Although in HER2, we have options that we don’t in some other subtypes. It’s also very frequent in 

+ disease. We have patients who’ve exhausted our systemic therapy options for CNS metastasis, and there’s still a clinical need to develop better treatments in that space.

Expert perspectives on the current treatment landscape of metastatic breast cancer and the unmet needs prevalent across various subsets of disease.

VK Gadi, MD, PhD

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