®, which is focused on breast cancer. In today’s presentation, my colleagues and I will review 3 clinical cases. We will discuss an individualized approach to treatment for each patient, and we will review key clinical trial data that impact our decisions. My name is Dr Ruta Rao. I’m a medical oncologist at Rush University Medical Center in Chicago, Illinois. Today I’m joined by Dr Sara Tolaney, who is a medical oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts; Dr Komal Jhaveri, who is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, [New York]; and Dr Evita Sadimin, a pathologist from the Rutgers Cancer Institute of New Jersey [in New Brunswick, New Jersey]. Welcome, everybody.

I will let Dr Tolaney get started with our first case this morning on 

 [human epidermal growth factor receptor 2]–positive early stage breast cancer.

I’ll start with our first case. This is a 42-year-old woman who originally palpated a mass in her right breast and had a mammogram and ultrasound that showed that there was a 2.1-cm mass. She went on to have a breast MRI, confirming this abnormality. On the MRI, the mass was 2.2 cm, but it then showed an additional mass that was 0.9 cm with a larger area of non-mass-like enhancement that extended between the 2 masses. The total area was around 8 by 6 cm. There also appeared to be 1 lymph node that was enlarged.

She underwent a biopsy of the 2.2-cm mass, and this came back as a high-grade ER/PR [estrogen receptor/progesterone receptor]–negative, HER2-positive tumor by IHC [immunohistochemistry]. Given the 2+ staining, she went on to have a FISH [fluorescence in situ hybridization] test done, which came back with a FISH ratio that was over 2; it was 3.8. She had a 

 copy number that was over 4; it was 7. So she was HER2-positive with a high 

 at 30%. She also had an FNA [fine-needle aspiration] of the enlarged lymph node that came back consistent with her breast cancer.

In addition, she had a biopsy of the second site at the 12-o’clock area, which looked just like the first mass: 

-positive cancer and some additional ductal carcinoma in situ. Given the node-positive cancer, she went ahead and had staging studies performed, which revealed that there was no evidence of any distant disease. It appeared that she had a T2N1, high-grade, ER-negative, PR-negative, 

Case 1: Early Stage HER2+ Breast Cancer

Let’s talk about a few points from this case that you presented. This tumor is 

 [human epidermal growth factor receptor 2]–positive by immunohistochemistry [IHC], but 

 amplified by FISH [fluorescence in situ hybridization]. I will start by asking Dr Sadimin to comment on this. How frequently do we see this, and what are the current testing guidelines that speak to this?

Let me start by explaining the difference of testing between IHC and FISH. In IHC, we stain tumor cells on the tumor tissue for the expression of the quantity of HER2 protein in the tumor cells. The scoring is based on the staining that we see, whether membrane staining is present, and then the intensity and the amount of tumor cells that are staining. For the grading, if we have more than 10% of tumor cells that are staining with a strong and complete membrane staining, then we call it 3+ positivity. If we have more than 10% of tumor cells showing weak to moderate complete membrane staining, then we grade it as 2+, which we refer to as equivocal. If the staining is not fulfilling either 1 of those 2, we consider it negative, with grade 1+ having some staining and grade 0 having no staining. As you can imagine, because the grading is the assessment of strength and amount of tumor cells staining, it is somewhat subjective. The strength of the staining itself can also be affected by fixation time and the clone of the antibody being used, with some antibodies being better than others.

On the other hand, doing the FISH test is a more objective process. We count fluorescent signals that correspond to the HER2 gene copy number and the number of the centromere CEP17, the gene copy number. We then take the ratio of the 2 numbers. While it is more objective, the guidelines, as we know, have changed. That refers to the cutoff of the ratio, and it continues to evolve.

The 2007 guidelines were different from the 2013 guidelines, and both were different from the 2018 guidelines. The interpretation of a majority of the cases remains the same, but we do have certain types of cases that fully change. For example, we have a small percentage of cases that, following the 2013 guidelines, we have interpreted as positive. But now following the 2018 guidelines, we have to interpret the case as negative. There is a lot of communication with the clinicians and with the treating team in terms of these results and how they have changed. If we have different results compared with previously, then we will discuss some retesting. If the results are different, it may be the difference of the guidelines that we are using.

Because IHC and FISH are testing different things, we use them together. Some institutions perform IHC first followed by FISH in equivocal cases, and others perform FISH first. The guidelines report as 5 different groups. If it’s a straightforward positive, or group 1 case, or a straightforward negative, or group 5 case, then we don’t do anything. If the results fall into groups 2, 3, or 4, then we refer to IHC. In our institution [Rutgers Cancer Institute of New Jersey], we’re now doing IHC first followed by FISH for equivocal cases. But we used to do FISH first followed by IHC several years ago.

Case 1: Molecular Testing for HER2+ Breast Cancer

Let’s talk about how we would assess this patient’s risk for recurrence.

When we’re thinking about the risk of recurrences, we are taking into account clinical pathological factors and tumor characteristics for the given patient: age, tumor size, nodal involvement, grade, ER/PR [estrogen receptor/progesterone receptor] positivity, and 

 [human epidermal growth factor receptor 2] positivity. In this case, the patient is a young woman with a grade 3 tumor that is at least at 2 cm in size and is multifocal, both biopsy proven as node positive, ER/PR-negative, 

-positive. Those are the criteria that we take into mind. Fortunately, her systemic staging does not show metastatic disease at this point, so we would still treat her for a curative intent in the early stage setting.

Would you recommend neoadjuvant systemic therapy for this patient? Dr Tolaney, would you like to comment?

Yes. We’ve now seen data that show we can improve outcomes for our patients based on adapting therapy, based on response to preoperative therapy. It has shifted our practice so that we are looking to give preoperative therapy to the vast majority of our patients, so we can better understand how they respond in the preoperative setting and then potentially adapt in the adjuvant setting. My preference has been to use preoperative therapy for anyone who has a tumor that is over 2 cm in size or who has clinically node-positive disease. This particular patient would meet those criteria, so I would recommend preoperative systemic therapy. When it comes to making a decision about what to use, I have preferred using pertuzumab-based preoperative therapy for these patients knowing that adding pertuzumab to chemotherapy and trastuzumab is associated with improvements in pCR [pathologic complete response]. I’ve used pertuzumab-based chemotherapy preoperatively.

What about the addition of an anthracycline? Is this something you would consider as 1 of your preoperative chemotherapy drugs?

I trained on the East Coast, and we’ve always had a bias toward the use of anthracyclines over the years. However, I have changed my practices and changed my ways. Over the last 2 to 3 years, I’ve shifted away from use of anthracycline, and the reason is that we initially had some data to suggest that nonanthracycline taxane-based chemotherapy seemed to be as good as anthracycline treatment. This was based on BCIRG 006, where we saw that TCH [docetaxel, carboplatin, trastuzumab] seemed to have similar disease-free survival to ACTH [doxorubicin, cyclophosphamide, paclitaxel, trastuzumab]. Even when I saw those data, I thought that the trial wasn’t powered for that comparison. It’s only 1 study, and we have multiple anthracycline-based trials, so I hadn’t initially fully shifted away from anthracyclines.

At ASCO [American Society of Clinical Oncology Annual Meeting] this year, we also saw updated data from the TRAIN-2 trial, which looked at preoperative anthracycline followed by taxane therapy vs taxane dual anti-

 therapy alone. We had previously seen similar pCRs between the 2 arms, but we now have 3-year disease-free survival, showing that both arms do exceedingly well. Even in the highest-risk patients, when you separated out disease-free survival by nodal involvement, you saw the same benefit, the same disease-free survival with anthracycline vs nonanthracycline therapy. We also saw more toxicity with anthracycline treatment, so there were higher rates of cardiac toxicity, higher rates of febrile neutropenia, and numerically more leukemia cases. In totality, seeing BCIRG 006 and TRAIN-2 again, it is hard to justify using anthracyclines anymore because we’ve been able to escalate our anti-

 therapy to improve outcomes. We need to think about de-escalating the chemotherapy and trying to decrease toxicity for patients. I would not use anthracyclines at this point, and for this particular patient, I would probably give TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin].

Great, thank you. Dr Jhaveri, what about you? Are there any particular patient situations in which you would consider an anthracycline?

No. I completely agree with Dr Tolaney in that I was an avid anthracycline user, and it’s taken a long time for me to convert to thinking about nonanthracycline-based regimens. Having said that, something we do see in practice is with the rates of cardiotoxicity, which is what we talk about with anthracycline-based regimens and leukemia risks that are rare but real with these regimens. The toxicity that we see with TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] is significant as well. We sometimes see our patients struggle with neutropenia, fatigue, and many other adverse effects constitutionally, which can sometimes make even TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] challenging. They both have distinct toxicity profiles.

We have options. We have large bodies of data supporting anthracycline and nonanthracycline-based approaches. Our initial thinking on the East Coast, that every high-risk patient should be treated with an anthracycline, has certainly changed given the body of data that Dr Tolaney beautifully summarized. We had node-positive patients even in the BCIRG 006 trial, where we did not do head-to-head comparisons. But they at least did fairly well even with the highest-risk group in that trial and now with the TRAIN-2 study. These are reasonable options with reasonable toxicity profiles to discuss with our patient and make a patient-physician shared decision-making process. I don’t feel compelled to give anthracyclines anymore.

Case 1: Neoadjuvant Therapy for Early-Stage HER2+ Breast Cancer

You brought up an excellent point about not forgetting about the toxicities that the nonanthracycline regimens contain. Are there any patients for whom you would not recommend neoadjuvant therapy? Dr Tolaney, you touched on your category of patients who fall into neoadjuvant therapy.

My preference has been to take patients to surgery up front if they have tumors that are under 2 cm and clinically node negative, with the idea being that these are clinically likely stage 1 

 [human epidermal growth factor receptor 2]–positive patients. We have some data to suggest that, in stage I patients, adjuvant therapy with paclitaxel and trastuzumab could be an option based on the APT [adjuvant paclitaxel-trastuzumab] data. We also have data from the ATEMPT trials suggesting T-DM1 [trastuzumab emtansine] is highly efficacious in these stage I, 

-positive patients. For patients with clinically stage I disease, I generally take them to surgery up front, confirm that they have stage I disease, and then if so, I give them either adjuvant TH [taxane, trastuzumab] or T-DM1 [trastuzumab emtansine].

Completing our discussion on neoadjuvant therapy for this patient, are there any other disease, clinical, or even patient-related factors that would come into play in making your decision about which therapy to give in neoadjuvant vs adjuvant? It’s always something we have to discuss with the patients, and oftentimes the patients come into us saying that they don’t understand why they have to have therapy before going to surgery. They just want the tumor removed. It’s part of our job to make them understand the importance of the neoadjuvant therapy in these cases.

That’s true. At first, it’s challenging for patients to think that you’re not taking them to surgery first. There is a natural reaction to want to get the tumor out and receive treatment afterwards. You’re right; that it is a real shift. It’s even been a shift for oncologists to move toward giving preoperative therapy. Knowing that we can better understand response to therapy and adapt based on achievement of pCR [pathological complete response] improves patients’ outcomes. It should be the standard of care to give preoperative therapy to stage II/III patients, and you’re right that it is something we need to continue to work on educating our patients about.

Yes. The metanalyses where we’ve seen that pCR [pathologic complete response] rate in 

-positive patients translate into better event-free survivals and overall survival help us support that decision. As you pointed out, Dr Rao, it’s important for us as physicians to highlight to our patients—at least for those patients who are questioning why are we not going for surgery first and getting the tumor out—that we are not only reducing the risk of distant occurrence, which is the goal of any chemotherapy systemically given, but also making an attempt to downstage the tumor both in the breast and the axilla. Understanding the response to therapy and, as Dr Tolaney pointed out, given the data, we now have to be able to adapt for patients who have residual disease and offer them adjuvant therapy based on that and improve their outcomes. It has become a compelling standard to offer these patients with stage II tumors and higher neoadjuvant therapies.

Are there any clinical trials you might consider for this patient at your institutions?

Right now, our institution [the Dana-Farber Cancer Institute] has a trial that’s called the MARGOT trial. It is looking at a de-escalation strategy, and it is randomizing patients to receive THP [paclitaxel, trastuzumab, pertuzumab] weekly as paclitaxel with trastuzumab or pertuzumab or to receive paclitaxel with margetuximab and pertuzumab. It is looking to see if substituting margetuximab for trastuzumab in the preoperative setting could potentially lead to improvements in pCR. Of note, the trial is restricted to patients who have the CD16A-F allele, given some of the data we’ve seen from the SOPHIA trial, which we’ll discuss later on. We’ll have to see if that’s the case.

We will also soon be opening the COMPASS trial. This trial is looking at de-escalating therapy based on response to therapy. It is administering THP [paclitaxel, trastuzumab, pertuzumab] with either docetaxel or paclitaxel with trastuzumab and pertuzumab prior to surgery, and if a patient achieves pCR, that patient can go on to continue trastuzumab-pertuzumab. The idea being that this may spare patients more intensive chemotherapy and allow us to de-escalate now that we have dual HER2 therapy available. There are many other trials ongoing in this space, including 1 that’s even looking at an escalation strategy adding immunotherapy to preoperative treatment. We’ll see more options in the future, but it is nice to see that there are some de-escalation studies ongoing.

For this particular patient, the COMPASS trial specifically would be an attractive option as well, especially if she achieved pathologic complete response to her up-front therapy with a THP [paclitaxel, trastuzumab, pertuzumab]–based approach if that’s what she began with. That way, we can offer her that therapy without having to escalate with additional systemic agents. If she had residual disease, the COMPASS study also allows a further randomization for patients with residual disease, so they could get either T-DM1 [trastuzumab emtansine] or T-DM1 [trastuzumab emtansine] with tucatinib. We can escalate where it’s needed and de-escalate for others. This is the way we’re trying to do right for our patients, so we can personalize their treatments and offer them the optimal therapy that a tumor can have good outcomes with.

Case 1: Choosing Therapy for Early Stage HER2+ Breast Cancer 

This patient went on to get preoperative therapy. She had a tumor of 2 cm and had nodal involvement, so we wanted to give preoperative treatment. She got 6 cycles of TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] therapy and proceeded to breast surgery, where she had a mastectomy. It was found that she had residual disease. There was a 2-cm residual intermediate-grade DCIS [ductal carcinoma in situ], but there was also 0.9-cm residual invasive disease that was ER [estrogen receptor]–negative, HER2/3 [human epidermal growth factor receptor 2/3]–positive, and FISH [fluorescence in situ hybridization] amplified. She had no lymph nodes that were involved at the time of surgery, so her pathologic staging at the time of surgery was T1N0.

Let’s talk about retesting receptors on residual disease. Dr Sadimin, as a pathologist, is this standard of care? Can you comment on what your institution does?

In our institution [Rutgers Cancer Institute of New Jersey], we routinely do testing on residual disease on excision and on post-treatment excision. In most cases, the results are going to be the same, but there are some cases in which it is different. Usually, when we see the difference, there is more difference in the receptor status. As reported in the literature, it’s usually 15% to 30% in difference in ER/PR [progesterone receptor], and for many patients, there is more difference in PR than in ER. The 

 is usually similar, but we sometimes see a difference in about 10% to 15% of cases. I don’t have the numbers for our in-house cases, but it’s about the same as has been reported in the literature. Do remember that, in the resection, we have a larger area, so it may be a difference of different areas or just different expression in different areas. We need only about 10% to call something positive. If we happen to have the most negative area in the biopsies, and in the resection, we have the remaining area that is positive, then it would be different. In this case, the IHC [immunohistochemistry] was equivocal 2+ on the initial and 3+ on the excision, and the 

 expression level at the baseline or the 

 status on the surgical specimen with the residual disease as our factor in decision-making? Dr Tolaney, how would you answer that question?

 expression at baseline to guide my treatment recommendation with the idea being that, if the patient is 

-positive, then we want to be giving HER2-directed therapy. If they lose 

 expression at the time of surgery, which we see in about 15% to 30% of cases, then it is interesting that there are some prognostic data suggesting that loss of HER2 is associated with worse outcomes from a few retrospective series that have been done. Interestingly, more recent data from the KATHERINE trial found that, in those patients who had discordance where they lost HER2 at time of surgery, it appeared that those patients still derived benefit from T-DM1 [trastuzumab emtansine]. It seems that regardless of the loss of 

, we still would administer adjuvant T-DM1 [trastuzumab emtansine] to that patient. It’s the baseline 

Great. Dr Jhaveri, would you order any additional work-up for this patient at this point, knowing that she has residual disease?

At this point, there’s no rule for any additional work-up. When we think about systemic staging, we do that up front. Because we also look at the expression levels from baseline as we do for neoadjuvant chemotherapy patients, if there’s a need for systemic staging, we do that up front, and the residual disease doesn’t change our systemic staging work-up or necessitate any additional imaging to do something more. It is more about how we approach and adapt given the KATHERINE data in this setting where patients have residual disease.

What would be your next step for this patient?

Based on the compelling data from the KATHERINE trial, where patients with residual disease were treated with either T-DM1 [trastuzumab emtansine] or trastuzumab, there was a statistically significant improvement in the invasive disease-free survival and an absolute improvement of 11% from 77% to 88% favoring T-DM1 [trastuzumab emtansine], so I would offer T-DM1 [trastuzumab emtansine] to this patient at this point.

Case 1: Adjuvant Treatment for Residual Disease in Early Stage HER2+ Breast Cancer 

Let’s talk about a similar patient who originally had node-positive disease, but this patient achieves a pathologic complete response [pCR] after neoadjuvant treatment. She could get the same neoadjuvant treatment that we talked about already. What would you do in this case in terms of adjuvant therapy decision-making?

We know that, for a patient who has residual disease, we should give T-DM1 [trastuzumab emtansine] based on the KATHERINE study. In someone who achieves a pCR, we do not have any data to suggest that we need to escalate therapy. In fact, the recommendation would be to continue HER2 [human epidermal growth factor receptor 2]–directed therapy in the adjuvant setting. The area of controversy that comes up is about if you give trastuzumab and pertuzumab to someone who achieves a pCR to dual HER2-based therapy, or should you give trastuzumab alone? The challenge is that we don’t have a trial that has adequately addressed this question, so we don’t have a study that randomized patients with a pCR to HP [trastuzumab, pertuzumab] or H [trastuzumab] after preoperative HP [trastuzumab, pertuzumab]–based treatment.

Our data come with long-term outcomes from the APHINITY trial, which was an adjuvant study, so it wasn’t adapted based on preoperative therapy, in which we have long-term outcomes for patients who had gotten a year of HP [trastuzumab, pertuzumab]. That data look compelling and suggest that there’s good benefit from HP [trastuzumab, pertuzumab] treatment. However, there was no benefit in the node-negative population from HP [trastuzumab, pertuzumab]. If you had a node-negative patient, this is where the controversy comes up even more. One would argue about whether you need to give the pertuzumab. It becomes complicated because you didn’t know if the patient was node-negative prior to your preoperative treatment. You could have had treatment effect in that node.

My personal preference has been regardless of nodal status. For anyone who is getting preoperative therapy, I have given HP [trastuzumab, pertuzumab]–based therapy. We know it improves pCR, and it could potentially have an impact on local therapy options. It can have long-term treatment benefit in those patients, particularly with node-positive disease. I then continue the HP [trastuzumab, pertuzumab] out back if they got a pCR. I understand that we may be overtreating some patients, particularly those node-negative patients who are likely not deriving long-term benefit from pertuzumab, but it is challenging to tease out which patients you could omit pertuzumab from. One could also argue that the patient developed a pCR to the pertuzumab-based therapy and were likely deriving benefit, so I end up continuing it out back. We don’t have the answer for whom we could omit pertuzumab from in someone who achieves pCR.

I follow along exactly as you said. For patients who achieve a pCR, I also give HP [trastuzumab, pertuzumab] to finish the year for the same reasons you just stated. What about you, Dr Jhaveri?

I completely concur. Rarely, we’ll have a patient who might struggle with toxicity based on their nodal status. As Dr Tolaney was pointing out, if she was node-negative and knowing what we know from the APHINITY data, then perhaps that’s the patient population that did not derive a disease-free survival benefit. We discussed getting rid of the pertuzumab and completing the trastuzumab-based option, but those are rare patients. Most patients tolerate HP [trastuzumab, pertuzumab]–based chemotherapy out back very well and complete the year, so I do the same, acknowledging that we might be overtreating.

Case 1: Adjuvant Therapy After pCR in Early Stage HER2+ Breast Cancer  

Let’s talk about other agents in this adjuvant setting. What about the use of neratinib? Can you comment on the EXTENET trial data and how we should put that into context given that we’re now treating patients in the neoadjuvant setting? Dr Tolaney, do you want to start?

The EXTENET trial was a randomized phase 3 trial that looked at taking patients who had completed their year of adjuvant trastuzumab-based therapy and then randomize them to get extended adjuvant treatment with a year of neratinib or placebo. This trial demonstrated that there was an improvement in disease-free survival from adding that year of neratinib. In the overall trial, the difference was only about 2.5%, but what was quite interesting was that, if you looked at the hormone receptor–positive subgroup, that’s the group where all the benefit was seen. It was almost a 5% difference in that hormone receptor–positive group in the overall trial, whereas there was no absolute difference between the 2 arms in the hormone receptor–negative group. They did a separate subgroup analysis looking at the highest-risk patients with hormone receptor–positive disease, so those patients had residual disease after preoperative therapy that was hormone receptor–positive where they saw a little over 7% absolute difference. These data suggest that neratinib has benefit in an extended adjuvant setting, particularly in hormone receptor–positive high-risk patients.

The challenge is 2-fold. One is that it causes toxicity. It was associated with a 40% rate of grade 3/4 diarrhea, without antidiarrheal prophylaxis in this trial, however. The second is that the trial was conducted when we weren’t giving pertuzumab or T-DM1 [trastuzumab emtansine], so we don’t know what the efficacy of neratinib is in patients who have had prior pertuzumab or T-DM1 [trastuzumab emtansine].

In the current era, I take these data to say high-risk, hormone receptor–positive patients probably benefit from neratinib. I don’t know what the benefit is going to be in my patient who got pertuzumab and T-DM1 [trastuzumab emtansine], but I would use it only in those patients who really had residual disease that was node-positive, hormone receptor–positive disease after preoperative therapy, understanding it is a bit data-free. I would probably offer it to them in that situation, and I would use it with antidiarrheal prophylaxis.

Thank you. Dr Jhaveri, any comments on neratinib in addition to what Dr Tolaney just said?

No. The challenge has always been what that right patient population would be, because we are now further escalating therapy for our patients. We start out with neoadjuvant-based therapy as we made a case for most patients with stage II/III disease where we justify dual anti-HER2 [human epidermal growth factor receptor 2]–blockade with pertuzumab and trastuzumab regardless of the hormone receptor status. We have great data; we have this option for our patients, and what we struggle with is that we don’t have data specifically in the current context where we’re utilizing pertuzumab-based therapy for neoadjuvant patients, and we’re utilizing T-DM1 [trastuzumab emtansine] if there is residual disease. Yes, for your high-risk patient population, we have data from the EXTENET study for neratinib, which obviously did not account for the pertuzumab and T-DM1 [trastuzumab emtansine].

Right. We’re faced with the data that we have and have to make the best decisions we can from them. Thank you both for summarizing that nicely.

Let’s get back to the KATHERINE trial for a moment. Can you discuss the recent data that we saw at ASCO [American Society of Clinical Oncology Annual Meeting] 2020 regarding this use of biomarkers for early stage 

The KATHERINE trial was a study that looked at giving T-DM1 [trastuzumab emtansine] vs trastuzumab in the adjuvant setting, and the data we saw at ASCO looked at several biomarkers that were predominantly off the residual-disease tissue. About 80% of the analysis was done from tissue obtained at the time of surgery. They looked at outcomes based on several of these biomarkers. One of them was looking at 

 mutation status, and they found that T-DM1 [trastuzumab emtansine] had benefit independent of mutation status. Regardless of whether there was a mutation, T-DM1 [trastuzumab emtansine] was beneficial. They also looked at several other biomarkers, including 

 expression. They found that patients with high 

 expression had worse outcomes in the trastuzumab arm, but there is no difference in outcome in the T-DM1 [trastuzumab emtansine] arm. They looked at many immune biomarkers, including PD-L1 expression, and they found that patients who had low PD-L1 expression seemed to have worse outcomes in the trastuzumab arm but not in the T-DM1 [trastuzumab emtansine] arm.

They suggested that there was no biomarker that could be identified to predict a lack of benefit to T-DM1 [trastuzumab emtansine], whereas there were a couple of factors that may influence benefit to trastuzumab, such as low 

Excellent. Thank you for that nice summary.

Case 1: Adjuvant Trials for HER2+ Breast Cancer

 Let’s move on to a different topic in the adjuvant setting. Let’s talk about deescalation of therapy. We’ve talked in the neoadjuvant setting about escalation of therapy, especially for patients who do not achieve a pathologic complete response. Let’s touch on the deescalation of adjuvant anti-HER2 [human epidermal growth factor receptor 2] therapy, which you had started to allude to for the patients with smaller node-negative tumors. Dr Tolaney, do you want to summarize the data we know so far?

For small node-negative tumors, the data that we have for de-escalation predominantly comes from the APT [adjuvant paclitaxel-trastuzumab] trial and the ATEMPT trial. APT looked at a year of paclitaxel and trastuzumab in patients who have node-negative, 

-positive tumors that were less than or equal to 3 cm, and it demonstrated with 7 years of follow-up that the recurrence-free interval was 97.5%. Rare distant recurrences were seen in this trial, so TH [taxane, trastuzumab] has become an option for many of our stage I patients.

Our group [at Dana-Farber Cancer Institute] in particular was interested in seeing if we could get away with something, and we even thought it had potential to be less toxic than TH [taxane, trastuzumab], utilizing T-DM1 [trastuzumab emtansine]. We knew in the metastatic setting that T-DM1 [trastuzumab emtansine] seemed to be at least equally efficacious compared with TH [taxane, trastuzumab] did in the ATEMPT trial, which looked at a year of T-DM1 [trastuzumab emtansine] and compared it with TH [taxane, trastuzumab]. But it is important to note that the comparison was only for toxicity and that the study was designed to evaluate efficacy for a year of T-DM1 [trastuzumab emtansine] and then to compare the 2 arms for toxicity. It found few recurrences in the T-DM1 [trastuzumab emtansine] arm. Of the 375 patients who got T-DM1 [trastuzumab emtansine], there were only 2 distant recurrences, so the 3-year disease-free survival was almost 98%: an excellent efficacy with T-DM1 [trastuzumab emtansine].

When we compared clinically relevant toxicities, which was an end point we defined, there was no difference between the 2 arms. The percentages of clinically relevant toxicities was identical between the arms, but there were different toxicity profiles. We know T-DM1 [trastuzumab emtansine] was associated with more thrombocytopenia and more LFT [liver function test] issues, whereas TH [taxane, trastuzumab] was associated with more neurotoxicity, alopecia, and infusion reactions. They have different toxicity profiles, but what we learned was that, when we looked at patient-reported outcomes like quality of life, quality of life was actually better in the T-DM1 [trastuzumab emtansine] arm. We also saw that there was less impairment of work productivity, and we saw there was less amenorrhea with T-DM1 [trastuzumab emtansine] for our premenopausal patients on the trial.

Given the totality of the data, I felt comfortable thinking about T-DM1 [trastuzumab emtansine]. One challenge was that there was a high rate of treatment discontinuation in that arm: almost 20%. It has made us wonder about how, if there’s such good efficacy yet people need to discontinue early for toxicity, we could get away with an even shorter duration of T-DM1 [trastuzumab emtansine]. We have a trial planned to look at 6 cycles of T-DM1 [trastuzumab emtansine] in the adjuvant setting for stage I patients, and we’ll learn more. For now, it’s a nice space to de-escalate our lower-risk stage I patients.

 Dr Jhaveri, can you comment on whether listening to the T-DM1 [trastuzumab emtansine] data changes your practice for these smaller node-negative patients?

It was definitely an option that came up more in a timely way given the COVID-19 [coronavirus disease 2019] era that we’re dealing with. It became more important to think about that data for our patients because we’re bringing these patients in every 3 weeks vs weekly infusions, perhaps with immunosuppression. As Dr Tolaney was pointing out, the discontinuation rates were high, and it didn’t seem superior, so it did not necessarily change my practice. I offer TH [taxane, trastuzumab], but it was a reasonable option, and it certainly was a reasonable consideration in March and April when we were dealing with COVID-19 in New York, and the pandemic was a significant issue at that time. It is something we could have thought about for our small-tumor patients who needed to initiate therapy.

 That’s an excellent point, thinking about the amount of time patients have to come in for the treatment and how that would serve their purposes better given the current situation.

The 6 cycles of T-DM1 [trastuzumab emtansine] would be an interesting attempt to look at whether we can get away with a shorter duration with T-DM1 [trastuzumab emtansine], avoid the discontinuations, and be able to maintain the efficacy for these small-tumor patients. That would be an important attempt.

Case 1: De-Escalation of Adjuvant Anti-HER2 Therapy for Breast Cancer 

 In the context of COVID-19 [coronavirus disease 2019], let’s talk about the subcutaneous therapeutic options and the potential benefits we’ve seen with using the subcutaneous formulations of pertuzumab and trastuzumab.

 I’ve been excited about subcutaneous HP [trastuzumab, pertuzumab], particularly during the time of COVID-19, when it could potentially get patients in and out of infusion quite quickly. We have initially seen data from the FeDeriCa trial, which looked at the efficacy of subcutaneous trastuzumab-pertuzumab compared with IV [intravenous] HP [trastuzumab, pertuzumab]. It looked at patients getting up-front anthracycline-based therapy followed by a taxane with either subcutaneous or IV HP [trastuzumab, pertuzumab], and it found identical pCR [pathologic complete response] rates between the 2 arms, suggesting that the efficacy is the same. They have also looked at drug levels, which were the same.

We’ve seen data now from the PHranceSCa study, which looked at patient preferences. This study had a clever design because patients could get IV HP [trastuzumab, pertuzumab] or subcutaneous HP [trastuzumab, pertuzumab] and then switch over to what they didn’t get. The patients then looked at which they preferred and could then choose to continue on whichever formulation they liked more. It was clear from this data that patients preferred getting the subcutaneous HP [trastuzumab, pertuzumab] over getting IV HP. When you look at the toxicity profiles,what we see is that there can be some injection-site reactions to the subcutaneous HP [trastuzumab, pertuzumab], but outside that, there were no worse toxicities compared with IV HP [trastuzumab, pertuzumab]. We’re excited about the option of being able to administer a fixed-dose infusion quite quickly; it doesn’t take calculation by the pharmacist for dosing. It’s a quick 10-minute subcutaneous injection.

There is a lot of work ongoing to see if this is something that could be administered at home by home-infusion nurses because there is a huge movement toward doing this with COVID-19 and trying to keep patients out of the infusion center. There’s an ongoing trial looking at the feasibility of using home nursing to give subcutaneous HP [trastuzumab, pertuzumab]. Hopefully, it would be a movement with further work that we could get toward because it would be great for patients, particularly in the adjuvant setting, when they’re on just HP [trastuzumab, pertuzumab] maintenance, not to have to come into infusion every 3 weeks.

 Right. Dr Jhaveri, has your group [at Memorial Sloan Kettering Cancer Center] transitioned to using the subcutaneous formulation?

Yes. We definitely have options including biosimilars for trastuzumab and subcutaneous options for our patients with trastuzumab already. We’re also going to be participating in the clinical trial that Dr Tolaney was talking about. We’re going to try to do subcutaneous injections for both trastuzumab and pertuzumab in patients’ homes. This is a clever study design, and this is the wave of the future given what we’ve learned about how to deal with COVID-19. It was enlightening to me that this was already happening in certain European countries. In the United Kingdom, it was a standard practice for nurses to go to homes and administer even fulvestrant to the patients. This is something that, in the United States, we’ve not seen. But given the situation we’re in, this is timely, and it’s something that our patients will be able to benefit from in terms of convenience and exposure.

 I want to thank all 3 of you very much for a robust discussion on the treatment of early stage 

 [human epidermal growth factor receptor 2]–positive breast cancer. With that, we’re going to move to our next case, Dr Jhaveri’s case: a patient with relapsed/refractory hormone receptor-negative, 

Case 1: Subcutaneous Trastuzumab-Pertuzumab for HER2+ Breast Cancer 

This patient is a young, 39-year-old woman who presented with a 4½-cm mass in her left breast, and at the time of presentation, she was also found to have 3 palpable axillary lymph nodes. A core biopsy that was performed from the left breast mass confirmed to be invasive ductal carcinoma that was ER/PR [estrogen receptor/progesterone receptor] negative and 

 [human epidermal growth factor receptor 2/3] positive by immunohistochemical staining. Systemic staging that was performed revealed 3 liver lesions, the largest of which measured 3 cm.

 What are your next steps in taking care of this patient? Particularly, would you biopsy the liver?

Yes. Our practice [at Memorial Sloan Kettering Cancer Center] has been to biopsy the first metastatic site, especially when there is a suspicion based on systemic imaging. For a majority of our patients, we do that to confirm the receptor status, and it remains the same in the primary and the metastatic sites. For 14% to 15% of our patients, we have seen discordance in the receptor status. These are some of the main reasons: First, to confirm that this is metastatic disease and that we’re treating the patient appropriately for that, and second, to confirm that we’re treating them for the right disease that we thought we were dealing with.

 Thank you. Dr Sadimin, do you want to comment on concordance between the primary site and the metastatic site with hormone receptors as well as 

Yes. We do generally test the initial site if we have them and in the metastatic sites. In a majority of cases it would be the same. But as mentioned, some cases would be different. It’s a team approach in terms of how to treat the patient.

 Dr Jhaveri, would you consider ordering a baseline brain MRI for this patient in doing your initial work-up?

That is an interesting question, and it is even more relevant given the approvals that we’ve had for our patients in the metastatic setting with newer agents in 2020. The current guidelines and the track that we follow for these patients is that we don’t reflexively order screening-brain MRIs. We do systemic staging, but we order brain MRIs only if there’s a suspicion for brain involvement with some neurological deficit or some other symptom that the patient presents with. This is an active area of research for which there are ongoing trials trying to address the question of what the incidence would be and how we can prevent neurological deficits by catching brain lesions earlier for patients, specifically those with 

-positive and triple-negative breast cancer. It is something we might see evolve and change in the near future, but in 2020, I am not ordering screening-brain MRIs for my patients.

 Thank you. Dr Tolaney, what about you? It’s off-trial, but would you order a baseline brain MRI?

I have started discussing it with patients more recently. I was a hard no on that; it wasn’t in the guidelines. We were supposed to do it only with symptomatic neurologic symptoms to get MRIs, but the incidence is so high in 

-positive disease: 50% of people end up with brain metastases. We now have approval, as Dr Jhaveri was alluding to, for using tucatinib that can result in a survival benefit for patients with brain metastases. As Dr Jhaveri noted, we don’t have any robust data to suggest that screening itself would improve survival or prevent neurological symptoms, but there are trials that are ongoing trying to address this.

At our institution [Dana-Farber Cancer Institute], for example, we have a trial in which we are screening patients up front, and with each subsequent restaging with an abbreviated brain MRI, we are seeing if that will prevent onset of neurological symptoms sooner than someone who wasn’t getting screening MRIs. As Dr Jhaveri alluded to, there’s going to be more to come with this, and we’ll get more data. Our threshold has changed dramatically because we now have agents available that can improve survival for patients with brain metastases.

It’s something to discuss with patients. A lot of patients have trouble getting brain MRIs, so it’s not the easiest thing if you’re claustrophobic and so forth. I mention it to patients, and I have offered it. It obviously also depends on whether insurance will pay for it because they will sometimes deny it if the patient is asymptomatic.

Case 2: Relapsed/Refractory HR-/HER2+ Breast Cancer 

Dr Jhaveri, back to your patient, what treatment regimens are you thinking about when you first meet this patient, and which would you most likely recommend?

When we think about patients who have to be treated in the first-line metastatic setting with 

 [human epidermal growth factor receptor 2]–positive disease, we have compelling data from the phase 3 CLEOPATRA study that supports the use of the taxane with trastuzumab and pertuzumab, where we saw significant progression-free and overall survival benefits that changed our treatment paradigm. We were using trastuzumab with a chemotherapy with paclitaxel until a decade ago, but these data have been practice changing, and that’s what we’ve been utilizing.

We had multiple attempts with other agents. For example, we tried to see if T-DM1 [trastuzumab emtansine], which is approved in the second-and-beyond setting based on the EMILIA trial and in the third-line-and-beyond setting based on the TH3RESA trial. There was an attempt made in the MARIANNE trial to see if we could utilize T-DM1 [trastuzumab emtansine] alone or T-DM1 [trastuzumab emtansine] in combination with pertuzumab in the first-line setting. However, we did not see any superiority when we compared it with TH [taxane, trastuzumab]; it was similar. The control arm there, TH [taxane, trastuzumab], was our old standard, so it was surprising to see that even T-DM1 [trastuzumab emtansine] plus P [pertuzumab] was not superior to TH [taxane, trastuzumab]. Short of a patient who is not a candidate for a taxane-based chemotherapy because of preexisting disease or preexisting diabetic neuropathy, somebody who is unwilling to accept the adverse effects of chemotherapy, patients who have progressed within 6 months of their adjuvant therapy with a taxane and Herceptin [trastuzumab]—because that was a small subgroup of patients in the phase 3 EMILIA trial where T-DM1 [trastuzumab emtansine] could be offered—I am utilizing the CLEOPATRA-based regimen of a taxane with trastuzumab and pertuzumab. In fact, at our center, Chao Dang had led a phase 2 trial looking at weekly paclitaxel with trastuzumab and pertuzumab. In the CLEOPATRA study, we’d seen about a 14% febrile neutropenia rate with docetaxel and HP [trastuzumab, pertuzumab]. We had seen a 0% febrile neutropenia rate with the weekly Taxol [paclitaxel]–based regimen, so that has been endorsed by NCCN [the National Comprehensive Cancer Network] and ASCO [the American Society of Clinical Oncology]. My preference for this patient would be weekly paclitaxel with HP [trastuzumab, pertuzumab].

Dr Tolaney, any additional thoughts or comments when thinking about first-line treatment for this patient?

I would completely agree. My preference has also been to use a weekly paclitaxel regimen instead of using docetaxel with trastuzumab and pertuzumab. Given the impressive survival data from the CLEOPATRA trial, using pertuzumab-based therapy has been my standard in the first-line setting too.

Case 2: Previously Treated HER2+ Breast Cancer

Let’s get back to your case, Dr Jhaveri.

This patient received THP [taxane, trastuzumab, pertuzumab] for 6 cycles followed by maintenance. This was something that we had done in the CLEOPATRA trial where patients would get their chemotherapy initially, and once they have maximum response or 6 to 8 cycles, we could drop off the chemotherapy backbone and continue their maintenance HP [trastuzumab, pertuzumab]. She had a great partial response in the breast and had complete response in her liver lesions. However, 18 months later, systemic staging done to look at response showed 3 new liver lesions, and the largest this time measured 1.5 cm.

At this point, what are your next steps for this patient?

In the second-line setting, we have approval for T-DM1 [trastuzumab emtansine] based on the phase 3 EMILIA trial that we were talking about. That was compared with our standard at the time, which was lapatinib plus capecitabine, and these were not patients who had seen prior pertuzumab. They don’t necessarily fall into this patient population particularly, but that’s what we deal with in clinic, and that’s what we’ve been doing in clinic with patients who have progressed on a THP [taxane, trastuzumab, pertuzumab]–based regimen. We offer them second-line T-DM1 [trastuzumab emtansine]–based therapy based on the progression-free survival [PFS] and overall survival benefit seen with T-DM1 [trastuzumab emtansine]–in the second-line setting. This is what I would offer the patient at this point.

This patient received standard-of-care T-DM1 [trastuzumab emtansine]. I want to make a plug for 1 of the clinical trials that is available. We are looking at 2 clinical trials in the second-line space, so the treatment landscape continues to evolve. It’s an embarrassment of riches. We’ve had 3 new approvals this year alone for anti-HER2 [human epidermal growth factor receptor 2]–based therapies, and we’re now trying to see how we can further optimize outcomes for our patients. There are 2 attempts. The first is looking at T-DM1 [trastuzumab emtansine] compared with trastuzumab deruxtecan, and we’ll talk about those agents in the second-line setting. Second, we’re also looking at the combination of tucatinib with T-DM1 [trastuzumab emtansine] compared with T-DM1 [trastuzumab emtansine] alone in the second-line setting. We did not have that trial opened at the time, otherwise that would be a good option to offer these patients.

This patient received the standard of care T-DM1 [trastuzumab emtansine] and achieved partial response in both her breast mass and her liver lesions, and she stayed on this therapy for about a year, after which there was progression in her liver. She was also found to have 2 brain metastases at that time; the largest brain lesion was about 2.1 cm in the frontal lobe. She then underwent stereotactic radiation surgery for both these brain lesions.

At this point, you have a patient who has progression systemically in her liver as well as the new development of brain metastases, which has been treated locally. At this point, what therapeutic options are you going to consider? As you mentioned, the newly approved regimen in the HER2-positive metastatic breast cancer setting, can you talk about how you think about these new data, including what was presented at ASCO [the American Society of Clinical Oncology Annual Meeting] 2020 in terms of individualizing the treatment selection and the sequencing of our available therapies.

We definitely have a good problem with trying to think about the best way of treating patients and what therapy to best apply to this patient. The short answer is that we have a few good options, and the 2 good ones that come to mind directly are, No. 1, a regimen with trastuzumab deruxtecan. This was based on a phase 2 trial with this novel antibody-drug conjugate. The payload is rather distinct from what we have with T-DM1 [trastuzumab emtansine], which is an antimicrotubular agent, and trastuzumab deruxtecan, we have a TOP1 inhibitor payload. We have a cleavable linker, and the drug-to-antibody ratio that we see is almost double of what we see with T-DM1 [trastuzumab emtansine].

We’ve been able to see exciting results with this agent in this phase 2 trial; patients who had a median of 6 prior lines of therapy had a 16-month progression-free survival. The median progression-free survival was 16 months, and the median duration of response if the patient stayed on this therapy was also about 15 months. The disease control rate was about 98%. It has exciting efficacy data across all the efficacy end points that were evaluated on this trial.

The 1 thing we did see with this study was a 14% rate of interstitial lung disease [ILD] and pneumonitis, and that was even fatal in certain patients. This is something we have now become very cognizant about with multiple therapies. We had initially seen that with everolimus in hormone receptor–positive disease. We then quickly learned about management of pneumonitis and many other 

-like presentations when we had checkpoint inhibitors that were approved in triple-negative breast cancer and other cancers. We have seen that more with antibody-drug conjugates, specifically with trastuzumab deruxtecan. That’s 1 option with those important adverse effects that we have to keep in mind. Patients also get some alopecia, neutropenia, and nausea with this agent as well. That’s 1 option we can think about given the exciting efficacy and bearing these toxicities in mind.

The second option that one could think about would be a combination of tucatinib with trastuzumab and capecitabine based on the exciting data from the HER2CLIMB clinical trial. The initial results were already presented and showed that this triplet met the primary end point of progression-free survival, and we have also heard about exciting data presented at ASCO this year by Nancy Lin. She presented the data on patients with brain metastases who were enrolled on this study. This study had a requirement that all patients undergo a baseline MRI at the time of screening and for eligibility reasons. With the brain MRI done, patients who were already treated for brain metastases were labeled as stable brain metastases patients. Eligible patients who were untreated were either newly diagnosed based on their brain MRI but did not warrant immediate local therapy requirements, or they were patients who had prior radiation but had progressing brain lesions that did not require any local intervention right away. There was a huge effort in that regard on this study, which was commendable and good for our patients.

In that trial with this specific subgroup, we saw a significant improvement in progression-free survival; both intracranial progression-free survival and the overall survival end points were also met. This is exciting for our patients not just with stable brain metastases but also those with active brain metastases or progressing brain metastases.

The overall population had a PFS of about 7.8 months. It was something that we’ve seen in the third-line-and-beyond setting. We’ve seen that with T-DM1 [trastuzumab emtansine] in the TH3RESA trial with a median PFS of about 6 months, and we’ve seen that with the phase 3 SOPHIA trial with margetuximab. We’ve seen a PFS of about 6 to 8 months in the third-line setting. That’s where trastuzumab deruxtecan stands out in terms of PFS, at least in this straight phase 2 open-label trial, and we await the registration of phase 3 randomized data. What we don’t have from the trastuzumab deruxtecan data are the overall survival mature data, and we eagerly await that to make a compelling case for that. There were some data on the stable brain metastases patients that was presented at ESMO [European Society for Medical Oncology Congress] from the study with trastuzumab deruxtecan, where we did see some activity. Those patients continue to benefit systematically with stable brain metastases. It is not a robust cohort or as big a cohort as in the HER2CLIMB study, and it was not a randomized trial, but there was some hint of activity there, which is something we can discuss.

At this point with this patient, it would be important to discuss both of these options, to review the data with her, and to consider either option. An oral-based therapy during COVID-19 [coronavirus disease 2020] makes it easier. It has a good toxicity profile, and not having to worry about ILD and pneumonitis makes a compelling case during COVID-19. It’s something we need to discuss with our patients. Both are reasonable options, and both can be discussed well with our patients.

Case 2: Later-Line Treatment of HER2+ Breast Cancer

Dr Tolaney, what are your thoughts on these options, and does the presence or absence of brain metastases in a patient influence what your next treatment selection would be?

As Dr Jhaveri alluded to, it’s a problem with having multiple effective treatment options, which is a nice situation to be in. In this third-line, post–T-DM1 [trastuzumab emtansine] setting, the presence or absence of brain metastases influences my decision-making for now. We have impressive data from the HER2CLIMB study suggesting a survival benefit in patients with brain metastases. That is not something we have with another agent at this time. We have to be careful, though, with what we mean by 

 because this particular patient had radiation, so she has what we would consider a stable treated brain metastases. This patient would have been eligible for the trastuzumab deruxtecan trial with an appropriate washout with stable treated brain metastases, and there were 24 patients in the trastuzumab deruxtecan single-arm, phase 2 trial that had stable treated brain metastases. Their PFS [progression free survival] was 18 months. This is similar to what we saw in the overall population, which is reassuring.

In my mind, both options are appropriate in a stable-treated brain metastases patient. However, if a patient had active brain metastases, progressive brain metastases, postradiation or de novo untreated brain metastases, we see people who sometimes have multiple brain metastases where they’re not a candidate for SRS [stereotactic radiosurgery] and would otherwise need whole-brain radiation. That’s a patient for whom I would turn to the HER2CLIMB trial regimen because I’d want to spare them whole-brain radiation, or they have progressive brain metastases postradiation. We know that there is a hazard ratio of about 0.5 after survival in patients with active brain metastases, so it’s important to think about tucatinib in that situation. In that situation, the preference would be to use the HER2CLIMB study.

I want to add a couple of points as I’m hearing Dr Tolaney talk about this. There are 1 or 2 things we need to acknowledge and understand as a community when we’re thinking about these patients. We’re excited about these data, and we’re excited about being able to offer tucatinib to patients with active brain metastases. This is a huge leap in the way we think about these patients; we can offer therapies that are effective, and we definitely need more of that. However, it is important to recognize that the way they define active brain metastases is something that you’ll be able to see on your MRI, but it does not require immediate local intervention, meaning these patients are not necessarily symptomatic. Today, if you see a 4-cm brain lesion because the patient presented with blurry vision, a headache, or a focal neurological deficit, we’re not thinking about applying those data to those patients. We still have to resort to local interventions immediately for those patients. That’s 1.

The other thing we need to think about is what is happening to their systemic disease. The guidelines are there, and I’m sure we’ll be revisiting these guidelines as we get more data. Is the systemic disease decently controlled? What is the systemic disease burden? If there is extensive systemic disease that is also progressing at the time this patient is supposedly found to have progressing brain metastases that is not symptomatic but active with the systemic disease exploding, I’m still going to think about trastuzumab deruxtecan because it’s not a bad option given that the PFS and the responses that we’ve seen with that are significant. When we look at the subgroup analyses from the HER2CLIMB trial for the stable metastases patients, we did not see a big difference in the overall survival for that subgroup. There were small numbers; slicing the data down even further, one would wonder whether that lack of difference in the overall survival in that subgroup is driven by exploding systemic disease, meaning your brain was stable but your body disease was growing quickly, and that may be why there was not a big difference with the addition of tucatinib. This is something we have to keep in mind for the given patient we see in clinic.

Lastly, we definitely have our standard options of trastuzumab plus chemotherapy in the third-line-and-beyond setting. Those options are here to stay, and we can still utilize them eventually. These 2 exciting new options will certainly be our third-line choices for a given patient in front of us.

Case 2: Impact of Brain Metastases in HER2+ Breast Cancer

Let’s talk in general about brain metastases. What are some of the known risk factors for brain metastases in patients with breast cancer?

What we have learned is that the risk of brain metastases is high. It’s higher for our patients with a triple-negative breast cancer, and Dr Tolaney had mentioned that the risk is about 50% for our patients with 

 [human epidermal growth factor receptor 2]– positive disease, and 50% will have it. It remains an unmet need for these patient populations. We’re thinking about this with more lines of therapy and heavily pretreated patients in the ER [emergency department], and we’re thinking about it sooner because there is a higher prevalence of brain metastases in patients with 

-positive and triple-negative breast cancer.

Can you comment on whether, in your institution [Memorial Sloan Kettering Cancer Center], you use a multidisciplinary team to manage these patients with brain metastases?

Yes, we do. It depends on exactly how the patient has presented. Was this an incidental finding from an MRI [magnetic resonance imaging] that was done for a particular symptom? We’ll start seeing that more patients are going to get MRIs done based on the current data. Are these patients who presented with a symptom and were found to have a mass affecting an isolated lesion or fewer than 3 lesions of no more than 3 cm in size? We’re thinking about how we get involved and get our neurosurgeons involved. Is this patient appropriate for up-front surgery? Is this a patient who has multiple brain metastases and would benefit from whole-brain radiation therapy? Are there no more than 3 of no more than 3 cm in size? Can we do stereotactic radiosurgery [SRS] for these lesions? Are there active lesions ongoing? Can we offer SRS for more than 3 lesions? That’s an active area of research. Yes, a multidisciplinary way of treating patients is the way to go here because we want to engage the right folks and the right team, if not all of them, when we have a patient diagnosed with brain metastases.

Dr Tolaney, we’d love to hear from you about a multidisciplinary team and about how you continue current systemic therapy vs switching in a patient who has progression in the brain.

Like Dr Jhaveri, we are all interested in making sure that we get a multidisciplinary consult when someone has brain metastases. We [at Dana-Farber Cancer Institute] have a multiclinic that involves neuro-radiation oncology as well as neurosurgery. They would be seeing us in addition to the medical oncologist. It is extraordinarily helpful. I’m constantly emailing our neuro-radiation oncologists for help along the way. It is critical to work as a team to make decisions because it’s hard for me to know, for example, for a patient who has had prior SRS, can they get more SRS for their progression in an area that’s near that? I can’t make those decisions without consulting them and getting their thoughts. It is critical in managing our brain metastases patients, to work very carefully with this team.

Then to your other questions about what to do if someone has controlled systemic disease vs progression at this time in the brain and what to do. The guidelines have said that if someone has systemically controlled disease but progresses in the brain, then one should consider local therapy to the brain and return to the systemic drug that the patient was on. It wouldn’t be an indication to change systemic therapy. If someone has progression both systemically and in the brain, then we think about whether they’re a candidate for local therapy and switching systemic treatment.

It brings up a question: Should there be a shift in our guidelines now that we have tucatinib available? There is survival benefit for patients with brain metastases, so do we need to change to tucatinib in someone who has brain metastases but has otherwise systemically controlled disease? We don’t have sufficient data to know that. For now, I would generally continue my practice. If someone had a focal area in their brain that could be treated with SRS, but the patient was systemically stable, then I wouldradiate and continue their current therapy.

Case 2: Risk Factors for Brain Metastases in HER2+ Breast Cancer

Dr Jhaveri, you touched on the safety data for these new regimens. Can you share some personal experience you may have had with either or both of the regimens as well as some practical management and tips for treatment-related toxicities from either of these regimens?

As we were talking about trastuzumab deruxtecan, the common adverse effect that we have encountered in treating our patients either on trials or now as standard of care has been nausea. We’ve been looking at myelosuppression and neutropenia, making sure that their ANC [absolute neutrophil count] levels are OK. Do they require any growth factor support if they’re becoming neutropenic? Alopecia is something we’re discussing with our patients up front. Another thing we keep a close eye on has been the risk for pneumonitis and interstitial lung disease. Patients who have had a prior history of pneumonitis or interstitial lung disease are not candidates for this therapy. We want to make sure that not only we physicians but also our frontline nurses who are dealing with phone calls with patients when they call in with symptoms are aware of what to expect, whether it’s cough, shortness of breath, extreme fatigue, or fevers. We want to keep a close eye on it.

Another thing we have started looking into is about how we can quickly intervene if we have any suspicion. If it’s a radiologically detected suspicion, we call that grade 1. This is your asymptomatic patient where we, on imaging, are suspecting some ground-glass opacities that make us worried about pneumonitis or interstitial lung disease. We want to hold their therapy; we want to start steroids quickly. We usually offer 0.5 mg/kg of prednisolone for management for these patients, and we send them to our pulmonologist for further evaluation including pulmonary function tests and high-resolution CT [computerized tomography] scans, so we can closely monitor them.

On the other hand, when we encounter a patient who presents with symptomatic disease and is having fevers, cough, shortness of breath, or a desaturation, and imaging confirms pneumonitis, this is when we discontinue therapy. This is not when we’re thinking about rechallenging the patient. We take this seriously, and we should be treating them with a higher-dose steroid, including 1 mg/kg of prednisolone with a prolonged taper over a few weeks, and we ensure close proximity and monitoring for them. That’s something that we want to keep in mind for our patients who will be treated with trastuzumab deruxtecan.

When it comes to tucatinib, it’s fortunately a well-tolerated drug. It’s a reversible 

 [human epidermal growth factor receptor 2] small molecule inhibitor. We see some diarrhea, which is easily manageable. This is unlike what we were talking about with neratinib. Without prophylaxis, the grade 3 diarrhea event rates can be 40%, and we need to think about prophylaxis with multiple measures, including Imodium [loperamide] and Lomotil [diphenoxylate and atropine] as well as budesonide and colestipol. With tucatinib, it’s predominantly grade 1/2, which can be easily managed with Imodium [loperamide]. We have seen some hand-foot syndrome–like features with tucatinib but not severe grades. We’ve seen some LFT [liver function test] changes, which is something that is not severe and is easily manageable.

It’s a rather well-tolerated agent overall. Those are the kinds of adverse effects we want to keep in mind.

Case 2: Adverse Effects of Treatments for HER2+ Breast Cancer

Now that we’ve talked about, as you described it, our embarrassment of riches that we have to treat patients beyond first line in the 

 [human epidermal growth factor receptor 2]– positive metastatic breast cancer setting, let’s touch on whether there are any key factors that drive treatment selection and sequencing, particularly when you think about exposure to certain treatments that the patient may have had in the 

-positive early breast cancer setting. How does this influence your decision-making for the patients’ metastatic disease?

That’s an important situation that we’re facing. Not only do we have multiple agents to think about in the metastatic setting that are currently approved, but we also need to understand the implication of the data that was preceding what we have right now. We don’t know if patients have already been exposed to pertuzumab in the early stage setting or with T-DM1 [trastuzumab emtansine] in the early stage setting with the KATHERINE trial. How do that data apply for them in the metastatic setting?

Let’s break this down. Let’s think about a scenario for which we’re thinking about purely metastatic disease, and we’re not thinking about these exposures. Right now, we’re doing THP [taxane, trastuzamab, pertuzumab] in the first-line setting, we’re doing T-DM1 [trastuzumab emtansine] in the second line setting, and in the third line setting, as we discussed, we’re thinking about multiple options, including trastuzumab deruxtecan and tucatinib, especially if they have active brain metastases. We’re dealing with that more with tucatinib-capecitabine-trastuzumab. We then have options such as neratinib and capecitabine based on the NALA trial, and we have trastuzumab with chemotherapy-based options.

As we were saying, even T-DM1 [trastuzumab emtansine] in the second line setting was based on the EMILIA study for which patients were not treated after being exposed to pertuzumab. We do that in clinic right now because we don’t have any other data there, and that might be evolving as we’re trying to study both tucatinib in the second-line setting with T-DM1 [trastuzumab emtansine], and we’re comparing head-to-head T-DM1 [trastuzumab emtansine] with trastuzumab deruxtecan in the second-line setting. That space can be evolving based on that data.

We are also utilizing pertuzumab in the first-line setting, 1 of the early-stage settings based on neoadjuvant approaches in adjuvant therapies and then based on KATHERINE, T-DM1 [trastuzumab emtansine] in the postresidual disease patients in the adjuvant setting. The way I’m thinking about the patients is that I’m still thinking about disease-free interval, which is what we did with T-DM1 [trastuzumab emtansine] as well. If we have patients in the early stage setting, who have progressed after 6 months of completion of adjuvant therapy, I’m still offering them THP [taxane, trastuzamab, pertuzumab]–based therapy as first-line treatment. If I have a patient who is progressing in less than 6 months and had not seen T-DM1 [trastuzumab emtansine] in the early stage setting, then think T-DM1 [trastuzumab emtansine] can be offered as an option in the first-line setting based on the EMILIA study and based on some data that we got for noninferiority from the MARIANNE trial. That could be 1 option.

We don’t have concrete data, but if I have a scenario where patients, based on the KATHERINE trial, got in the postresidual disease setting T-DM1 [trastuzumab emtansine] and then progressed within 6 months, we can still get away with giving them THP [taxane, trastuzamab, pertuzumab] at that point first. If we have a clinical trial option that we can offer, we could offer that as well. I doubt that that proportion of patients who have gotten taxane-HP [trastuzamab, pertuzumab]–based therapies, who had residual disease, and who then got T-DM1 [trastuzumab emtansine] is going to be high. We’re not seeing many such patients progressing quickly and becoming metastatic so soon. That is not a scenario that is common in the clinic, but if that were to exist theoretically, based on the disease-free interval, we can offer these, and the changing treatment landscape based on the ongoing trials will further change our management strategies.

Case 2: Sequencing Treatments for HER2+ Breast Cancer

Dr Tolaney, can you comment on any other novel agents that are being investigated in late-stage clinical trials for our 

 [human epidermal growth factor receptor 2]–positive metastatic breast cancer patients, including anything presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2020?

We’ve touched upon several approvals that we’ve seen this year for 

-positive metastatic disease, including trastuzumab deruxtecan as well as the HER2CLIMB trial regimen, and we also have approval for capecitabine-neratinib. In terms of other novel HER2-directed therapies, there is an agent called margetuximab, which is a novel monoclonal antibody against 

 that has an engineered Fc receptor, so it increases binding to CD16A to increase antibody-dependent cellular cytotoxicity. This agent was studied in the SOPHIA trial. This was a randomized phase 3 study for patients who had progressed on 2 prior anti-HER2 therapies, including pertuzumab, and patients were randomized to receive chemotherapy with margetuximab or chemotherapy with trastuzumab. Initially, we had seen data in which there was a modest improvement in progression-free survival [PFS], and the updated PFS data suggest only a 1.3-month difference between the 2 arms, favoring margetuximab. We then saw the second interim analysis for overall survival [OS] at San Antonio [Breast Cancer Symposium] in 2019, which did not find a statistically significant improvement in OS but rather a little under a 2-month difference in survival between the 2 arms.

What was interesting about this agent is that the survival benefit seemed to be dependent on the genotype status. If a patient had a CD16A-F allele, they had about a 4-month improvement in overall survival with margetuximab, although it was not statistically significant. If you looked at those patients who had the V allele, which is a small population with only about 14% of patients, the trend was reversed. Trastuzumab seemed to perform better than margetuximab in the V allele population. This agent is under FDA review, so we’ll have to see if it leads to an approval for margetuximab as an alternative to trastuzumab with chemotherapy in the third-line setting and beyond and whether that approval could be genotype specific. We don’t know that at this point, but it certainly appears to be a promising agent, so hopefully there will be more to come with it.

In terms of other agents in this space, there is a lot of interest in thinking about immunotherapy for 

-positive disease. We’ve seen some data from the KATE2 trial for T-DM1 [trastuzumab emtansine] plus or minus atezolizumab, suggesting a trend toward survival benefit in the PD-L1–positive subgroup of this study for the combination. There is a registration study in the first-line metastatic 

-positive setting for THP [taxane-trastuzumab-pertuzumab], plus or minus atezolizumab, being run through the NRG [National Research Group]. That study is unselected for PD-L1 but will have a subgroup analysis looking at outcomes by PD-L1 status. Immunotherapy may have a role in this space in the future.

There are other novel agents that are being explored, including agents like novel 

 TKIs [tyrosine kinase inhibitors], as well as other ADCs [antibody-drug conjugates] and bispecific antibodies. There is so much going on in the HER2 space, and hopefully all these agents will lead to further improvements in outcomes for our patients.

Case 2: Novel Agents in Late-Stage Clinical Trials for HER2+ MBC

 We’ll move on to our third case, which is a case of triple-positive metastatic breast cancer. This patient is a 49-year-old premenopausal woman of Middle East descent who is diagnosed with a grade 3 invasive ductal carcinoma. It’s ER [estrogen receptor] positive, PR [progesterone receptor] positive, and 

 [human epidermal growth factor receptor 2] positive. Her 

 mutation testing shows that she’s wild type. She is treated initially with neoadjuvant TCHP [taxane, carboplatin, trastuzumab, pertuzumab] and has a good clinical response but some residual disease. She’s a residual T2N0. She’s treated with adjuvant radiation therapy as well as adjuvant T-DM1 [trastuzumab emtansine]. Let’s ask Dr Sadimin to comment on this subtype of patient with triple-positive disease or ER-positive, PR-positive, and 

We look at the different subtypes of breast cancer based on their hormone receptor status and the 

 expression, and we divide them into 4 subgroups: luminal A, luminal B, 

 expressers, and triple negative. In this case, with ER positive/PR positive and 

 positive, it would be categorized as luminal B, which accounts for about 10% to 12% of the patient population. A majority of patients have luminal A–type cancer, which is ER positive, PR positive with 

 expressers are the negative hormone receptor status with a positive 

. For the patients with triple-negative breast cancer, everything is negative.

 Thank you. Dr Tolaney, do you have any comments on the typical natural history or outcomes for patients with triple-positive diseases as compared with the ER-negative, PR-negative, 

We treat these patients similarly to our ER-negative patients. In fact, outcomes are fairly similar. We do see that the hormone receptor–positive, 

-positive patients seem to have less brain metastases compared with the ER-negative, 

Case 3: Triple-Positive Metastatic Breast Cancer

Clinical Cases in HER2+ Breast Cancer

Experts in breast oncology review 3 clinical cases of HER2+ breast cancer and discuss individualized treatment approaches for each patient.

Clinical Cases in HER2+ Breast Cancer | Expert Perspective Tumor Board

EP 1: Case 1: Early Stage HER2+ Breast Cancer

EP 2: Case 1: Molecular Testing for HER2+ Breast Cancer

EP 3: Case 1: Neoadjuvant Therapy for Early-Stage HER2+ Breast Cancer

EP 4: Case 1: Choosing Therapy for Early Stage HER2+ Breast Cancer

EP 5: Case 1: Adjuvant Treatment for Residual Disease in Early Stage HER2+ Breast Cancer

EP 6: Case 1: Adjuvant Therapy After pCR in Early Stage HER2+ Breast Cancer

EP 7: Case 1: Adjuvant Trials for HER2+ Breast Cancer

EP 8: Case 1: De-Escalation of Adjuvant Anti-HER2 Therapy for Breast Cancer

EP 9: Case 1: Subcutaneous Trastuzumab-Pertuzumab for HER2+ Breast Cancer

EP 10: Case 2: Relapsed/Refractory HR-/HER2+ Breast Cancer

EP 11: Case 2: Previously Treated HER2+ Breast Cancer

EP 12: Case 2: Later-Line Treatment of HER2+ Breast Cancer

EP 13: Case 2: Impact of Brain Metastases in HER2+ Breast Cancer

EP 14: Case 2: Risk Factors for Brain Metastases in HER2+ Breast Cancer

EP 15: Case 2: Adverse Effects of Treatments for HER2+ Breast Cancer

EP 16: Case 2: Sequencing Treatments for HER2+ Breast Cancer

EP 17: Case 2: Novel Agents in Late-Stage Clinical Trials for HER2+ MBC

EP 18: Case 3: Triple-Positive Metastatic Breast Cancer

EP 19: Case 3: Distant Metastases in Triple-Positive Breast Cancer