The treatment paradigm for HER2-positive breast cancer has undergone rapid evolution in recent years—and that pace continues today. In early-stage HER2-positive disease, the use of targeted agents as neoadjuvant and adjuvant therapy has markedly improved survival, and in the metastatic setting, newer regimens have extended median overall survival (OS) to nearly 5 years. In addition, trastuzumab deruxtecan (T-DXd), tucatinib, margetuximab, and neratinib/capecitabine are now all approved for patients with previously treated HER2-positive disease. However, oncologists, nurses, and pharmacists all must grapple with selecting and optimally sequencing therapy for individual patients, as well as developing reliable disease- and treatment-related symptom management plans. Lastly, shared decision-making with the patient and the multidisciplinary team improves the patient’s experience and facilitates adherence to medication and management of adverse events (AEs).

Managing Patients With Stage I-III, HER2-Positive Early Breast Cancer

Sara Hurvitz, MD, FACP:
Patients with HER2-positive early breast cancer who present with node-negative small tumors (<1 cm) can proceed directly to surgery. Results from the pathology report can guide which systemic adjuvant therapy to use. Often this is trastuzumab plus paclitaxel. Traditional treatment with docetaxel, carboplatin, and trastuzumab (TCH) or TCH plus pertuzumab (TCHP) also is useful for patients with an unexpectedly large disease burden (eg, lymph node metastasis discovered during surgery).

For patients with a larger tumor (1-1.5 cm) that is node negative, it is appropriate to proceed directly to surgery but in some situations can start with neoadjuvant therapy to test the responsiveness of their disease to systemic therapy. There also is not a consensus on whether neoadjuvant therapy is beneficial for tumors 1.5-2 cm in size, but we do occasionally use this approach in our clinic. One benefit of neoadjuvant treatment is the ability to reassess adjuvant therapy plans if, say, residual disease is found during surgery.

Patients who have node-positive disease or a tumor that is T2 (2-5 cm) or greater should receive neoadjuvant therapy with a taxane-containing regimen with HER2-targeted therapy, such as TCHP. My preference is to avoid an anthracycline-based regimen, given multiple studies that have failed to demonstrate that an anthracycline adds benefit to a taxane-based regimen. Following 6 cycles and surgery, those with a pathologic complete response (pCR) can complete the full year of trastuzumab (and potentially pertuzumab, particularly for patients who had node-positive disease).

Patients with residual invasive cancer in the breast or lymph nodes after neoadjuvant therapy should receive adjuvant trastuzumab emtansine (T-DM1) per results from the phase III KATHERINE trial, which showed a 50% decreased risk of recurrence vs trastuzumab alone. Neratinib also may be considered as extended adjuvant treatment for patients with residual disease, per results from the ExteNET study, but is controversial when used following pertuzumab or T-DM1. Neratinib was approved in 2017 as adjuvant therapy following trastuzumab, and the benefit appears limited to those with hormone receptor (HR) coexpression, particularly with node-positive disease or residual disease after neoadjuvant treatment. In our clinic, we use it mostly for very high–risk patients with multiple involved lymph nodes.

Dr Bardia, can you explain how you choose which systemic chemotherapy to give patients in this setting?

Aditya Bardia, MD, MPH:
I do not use anthracycline-based therapy in my clinical practice for the current management of HER2-positive early breast cancer. The use of a nonanthracycline-based regimen such as TCHP is standard for patients who have either lymph node–positive disease or lymph node–negative disease. Results from the TRAIN-2 study showed similar rates of pCR in patients who received an anthracycline vs nonanthracycline regimen, but the AEs, particularly cardiac effects, were higher in patients who received anthracyclines. The decision point for me is whether to recommend docetaxel, trastuzumab, and pertuzumab (THP) or TCHP, and this decision is based on each patient’s age, ability to tolerate therapy, and lymph node positivity, as well as whether the tumor is estrogen receptor (ER) positive or ER negative.

What can you tell us about using biosimilar agents for HER2-targeted therapy in clinical practice?

Danielle Roman, PharmD, BCOP:
Using biosimilar agents does require some healthcare provider and patient education. Initially, there was a lot of concern with those changes, especially from a healthcare professional talking to a patient about potentially changing their therapy and what to expect from that change.

In addition, the multiple available biosimilar agents for trastuzumab can be confusing to healthcare professionals and patients with regards to which agent to choose. Now, much of the decision-making is based on formulary decision at an institution level and insurance coverage. It can be very institution specific—and payer specific—on which biosimilar to use. Therefore, it is important to be light on our feet and able to adjust to various payer requirements for patient care.

Thankfully, we have not seen many situations where patients need to switch mid therapy, although that can be reasonable to consider. However, for patients starting new therapy, considering a biosimilar therapy is certainly an option. 

Kristi Kay Orbaugh, MSN, NP, AOCNP:
I would like to add that using SC formulations for trastuzumab and pertuzumab (HP) can be convenient for patients, particularly in the adjuvant setting, when a patient is receiving HP. Frequently, patients appreciate having the SC option. This allows them to spend less time the clinic and more time living their lives. In addition, opening up chairs in the infusion room can be beneficial to the clinic as well.

Danielle Roman, PharmD, BCOP:
I agree, but it becomes a bit more challenging for home administration of SC formulations, in terms of needing to use a patient’s prescription drug coverage vs their medical benefits for insurance purposes. We should consider the overall cost to a patient and the logistics of working through that process. However, some of these issues can be avoided using administration in a clinic setting.

Case: A 38-year-old patient presents with high-risk, HR-positive/HER2-positive early breast cancer that is small (cT2) and node negative. She received neoadjuvant TCHP, but at the time of surgery pathology revealed a residual 1.5-cm tumor with 3 of 7 lymph nodes positive (macrometastases up to 5 mm). What next?

Aditya Bardia, MD, MPH:
Given her residual disease following neoadjuvant therapy, I would consider adjuvant T-DM1. If she is able to tolerate therapy with 1 year of T-DM1, I also would consider additional treatment with neratinib following T-DM1, but not all patients have the bandwidth for more treatment. Furthermore, neratinib has not been studied in this setting in patients with prior T-DM1.

Sara Hurvitz, MD, FACP:
Long-term analyses (>10 years) suggest that patients who have ER-positive/HER2-positive disease with multiple involved lymph nodes remain at a fairly high risk for recurrence. A treatment like neratinib—which inhibits “cross talk” between HER receptors and HR signaling—may be a reasonable choice for these tumors with luminal biology.

Dr Bardia, how does the patient’s HR status impact therapy selection for HER2-positive disease?

Aditya Bardia, MD, MPH:
Whether a patient with HER2-positive disease also has ER-positive disease matters. As long as the anti-HER2 regimen is not compromised, a patient with ER-positive disease can receive T-DM1—maybe even neratinib—followed by an aromatase inhibitor with ovarian suppression. For patients who have difficulty with ovarian suppression, I feel comfortable switching to tamoxifen. Whether endocrine therapy is started with concurrent adjuvant HER2-targeted therapy or after HER2-targeted therapy is complete depends on the patient’s risk profile, age, and ability to tolerate treatment. Older, higher-risk patients should receive endocrine therapy following T-DM1, whereas younger patients at high risk of recurrence can start T-DM1 and then endocrine therapy shortly thereafter.

How would your management approach change for a patient who is ER positive and strongly HER2 positive at diagnosis but has residual disease with low expression of HER2 after neoadjuvant TCHP?

Aditya Bardia, MD, MPH:
In clinical practice, we sometimes see HER2-positive tumors become HER2 negative by the time of surgery. In fact, this was a subset evaluated in the KATHERINE trial, and data showed a benefit with T-DM1 in patients with HER2-low or HER2-negative disease. For a patient like this, I would consider T-DM1 despite their low HER2 expression. This paradigm may change if results from DESTINY-Breast05 show that T-DXd is superior to T-DM1 in this setting. For a strongly ER-positive tumor with low HER2 expression, I would consider endocrine therapy, as well.

Sara Hurvitz, MD, FACP:
Adjuvant T-DM1 should definitely be used in this setting, and I agree that T-DXd is very exciting. Phase III clinical trials are continuing to clarify optimal adjuvant treatment of patients with high-risk, HER2-positive breast cancer. These include the ASTEFANIA study of T-DM1 with or without atezolizumab, the DESTINY-Breast05 study of T-DXd vs T-DM1 that Dr Bardia mentioned, and the CompassHER2 RD study evaluating the addition of tucatinib to T-DM1. Another consideration when we are deciding whether to use adjuvant neratinib is the potential benefits in the central nervous system, as neratinib does cross the blood–brain barrier and has been shown to reduce recurrences and delay time to progression in the central nervous system in the metastatic setting.

Neratinib has shown benefit for HER2-positive breast cancer, but AEs can be difficult. What strategies can help minimize neratinib-associated diarrhea?

Kristi Kay Orbaugh, MSN, NP, AOCNP:
The ExteNET trial showed us that diarrhea was a major toxicity for neratinib, but data from the subsequent CONTROL trial showed us effective ways to help mitigate this AE. Neratinib dose escalation at the beginning of therapy can help dramatically decrease the incidence and severity of diarrhea. Loperamide also can be added as needed or used early with budesonide or colestipol. If diarrhea still occurs, there are dose modifications to help manage it.

Education is essential to help patients and caregivers understand when to take oral antiemetic and antidiarrheal medications at home. Patients need to increase fluids if they are having diarrhea. They also need to understand the importance of calling the clinic to report toxicities that are not controlled with their home medications. If AEs are not controlled, the patient may need to come into the clinic for further evaluation and management.

Sara Hurvitz, MD, FACP:
I was impressed to see the diarrhea managed well with escalating doses of neratinib. In my clinic, we use dose escalation but take approximately 2 weeks at each dose level, especially for patients who are more fragile or who have comorbidities. In fact, dose escalation of neratinib has become a standard-of-care strategy that has decreased rates of grade 3 diarrhea to approximately 15%, which is far lower than the 40% rate seen in the clinical trials.

Danielle Roman, PharmD, BCOP:
In my practice, we have found the dose-escalation strategy to be effective, as well. In fact, the packaging for neratinib now has the information on dose escalation included, which is helpful for patients. We still instruct patients to have loperamide on hand in case they experience diarrhea but there has been a dramatic decrease in the incidence with the use of neratinib dose escalation.

Case: A 61-year-old female presented with metastatic HR-negative/HER2-positive invasive ductal carcinoma with dermal lymphatic involvement. She completed 8 cycles of TCHP with very good partial response, then continued on maintenance HP. She initiated therapy with T-DM1 after progressive disease with development of liver metastases, which were biopsied and consistent with original pathology. She continued T-DM1 for 13 months until further progression of liver metastases.

Sara Hurvitz, MD, FACP:
Today, THP is the recommended first-line option for HER2-positive metastatic breast cancer based on results from the CLEOPATRA study, which showed that the addition of pertuzumab to trastuzumab and docetaxel improved both progression-free survival (PFS) and OS. Median OS with this regimen is nearly 5 years. I am optimistic that this can be extended with T-DXd, and multiple clinical trials are currently evaluating this possibility.

Previously, T-DM1 was the standard second-line therapy based on the EMILIA study, which compared it with lapatinib and capecitabine. At the 2021 European Society of Medical Oncology Congress, results presented from the DESTINY-Breast03 study showed much longer PFS with T-DXd than with T-DM1 (hazard ratio: 0.28). OS data are not yet mature, but this has prompted us to consider T-DXd for second-line therapy and shifted T-DM1 to a later-line setting for many healthcare professionals, with the caveat that it is unknown whether it is effective following progression on T-DXd.

In the third-line setting, numerous treatment options are available, including tucatinib plus trastuzumab and capecitabine, trastuzumab plus docetaxel, trastuzumab plus paclitaxel with or without carboplatin, trastuzumab or lapatinib plus capecitabine, trastuzumab plus lapatinib, neratinib plus capecitabine, or margetuximab plus chemotherapy. Many patients with HER2-positive breast cancer develop brain metastases, and results from the HER2CLIMB study—in which nearly one half of patients had brain metastases—showed an OS benefit with the addition of tucatinib to trastuzumab and capecitabine. Subsequently, the FDA approved this regimen for patients with HER2-positive metastatic breast cancer, including patients with brain metastases, who have received ≥1 previous regimen with HER2-targeted therapy for metastatic breast cancer. The data for the subset of patients with stable brain metastases who enrolled on the T-DXd study are promising as well, but we do not yet have phase III evidence in this particular setting, nor do we have mature OS data. 

What treatment options exist for patients with metastatic HER2-positive breast cancer, and what options exist following progression on HER2-targeted therapy such as TCHP, T-DM1, or neratinib in the adjuvant setting?

Aditya Bardia, MD, MPH:
For patients with de novo metastatic HER2-positive disease, I would use THP based on the CLEOPATRA study. After 6 cycles, if the patient is doing well, I drop the chemotherapy and continue with just HP. If a patient is both ER positive and HER2 positive, I also add endocrine therapy.

For patients with recurrent, metastatic disease, it is important to assess their disease-free interval between completing adjuvant therapy and the development of metastatic disease. If it has been <12 months, second-line therapy is appropriate. If it has been >12 months, I would feel comfortable with a first-line regimen such as THP. For many years, the second-line standard of care has been T-DM1, but the results of DESTINY-Breast03—which Dr Hurvitz mentioned—are practice changing, and I now consider T-DXd as optimal second-line therapy, including for patients with recurrence within 12 months. I do also consider tucatinib plus trastuzumab and capecitabine in patients who have progressive brain metastases based on the HER2CLIMB data.

Sara Hurvitz, MD, FACP:
T-DXd will likely become the standard first-line approach to HER2-positive metastatic breast cancer if the comparison to THP in the ongoing DESTINY-Breast09 trial is positive. However, T-DXd has substantial associated gastrointestinal toxicity (nausea, diarrhea, vomiting) and generally has more toxicity than T-DM1 due to off-target effects. Of importance, T-DXd also carries the risk of interstitial lung disease (ILD).

Kristi Kay Orbaugh, MSN, NP, AOCNP:
Because of the risk of ILD, it is important to understand at baseline whether patients have preexisting conditions that may predispose them to ILD, including emphysema or previous chest radiation, as well as their tobacco smoking history. Physicians also should be alert to unusual fatigue or shortness of breath. Of note, CT scans are better for assessing ILD than chest x-rays. That said, in my practice, none of my patients on T-DXd has developed ILD.

Danielle Roman, PharmD, BCOP
The pharmacy team also can play an important role here, including developing standard treatment plans and helping to educate patients on ILD, which can help with early identification and management. If ILD does develop in a patient receiving T-DXd, treatment should be held at once, even if the patient is asymptomatic, and corticosteroid treatment can be considered. If grade 1 (asymptomatic) ILD resolves within 28 days from onset, T-DXd can be resumed at the current dose, and if it resolves ≥28 days from onset, T-DXd should be resumed at 1 dose level lower. For symptomatic ILD, T-DXd should be permanently discontinued, and corticosteroid treatment should be initiated. It also is reassuring that, in DESTINY-Breast03, no grade 4 or grade 5 ILD was associated with T-DXd.

Shared Decision-making in Real-world Clinical Practice

Sara Hurvitz, MD, FACP:
What tools or approaches do you use to help patients understand their treatment options and truly participate in shared decision-making?

Danielle Roman, PharmD, BCOP:
The role of clinical pharmacists in the ambulatory oncology environment has become more significant over the years. Each member of the patient’s care team—pharmacists, nurses, and providers—need one another to make the best treatment decisions. Also, patient preferences are very important, particularly when discussing which toxicities they might be able to tolerate.

Kristi Kay Orbaugh, MSN, NP, AOCNP:
Before patients start a new regimen, we sit down and discuss the risks and benefits, and we provide the same information, with online resources, on a handout they can take home. We know patients will research their disease and treatment online, and we want to make sure they are accessing reliable, accurate information.

Aditya Bardia, MD, MPH:
In our practice, we also work with both advanced practice providers and pharmacists to develop the treatment plan. We educate patients on which toxicities to expect, whom to call, and how to manage those toxicities. If a patient also is receiving chemotherapy, they receive education on it from either the pharmacist or nurse practitioner. Of importance, the best tool for meaningfully involving a patient in shared decision-making is listening to them and trying to understand their goals of care.

Your Thoughts?
What has recently challenged you in treating breast cancer? Share your experience in the comments below.