 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.

Videos

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

Articles

Monitoring Patients With HER2+ Metastatic Breast Cancer

Patient Case: Frontline Treatment Options for HER2+ mBC

Patient Case: Biomarker Testing in Breast Cancer

An Overview on the Current State of Metastatic Breast Cancer