Navigating the Antibody– Drug Conjugate Treatment Landscape for Patients With HER2-Positive or HER2-Low Metastatic Breast Cancer

December 2023 Vol 14, No 12 —December 18, 2023


Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women.1 Most cases are diagnosed in an early stage, with advanced, or metastatic, breast cancer (MBC) remaining incurable, but treatable.1 Breast cancer is heterogeneous with varying molecular drivers and clinical behaviors, which make individual treatment management necessary.1 Each breast cancer case can be classified according to hormone receptor expression and human epidermal growth factor receptor 2 (HER2) gene amplification/gene overexpression, which are used to guide treatment decisions and to determine patient prognosis.1 HER2-positive breast cancer is diagnosed when HER2 expression is scored 3+ by immunohistochemistry (IHC) or if it has an IHC score of 2+ with HER2 gene amplification tested by in situ hybridization (ISH).1,2 Patients with HER2-positive breast cancer are eligible for treatment with agents targeting HER2.2 These include the monoclonal antibodies margetuximab, pertuzumab, and trastuzumab; antibody–drug conjugates (ADCs) ado-trastuzumab emtansine and fam-trastuzumab deruxtecan-nxki (T-DXd); and tyrosine kinase inhibitors lapatinib, neratinib, or tucatinib.2

The phase 3 DESTINY-Breast04 clinical trial demonstrated that T-DXd significantly improved survival in patients with advanced HER2-low breast cancer when compared with chemotherapy.

Recently, a change in HER2 breast cancer scoring defined a new category: HER2-low.2 HER2-low is defined as breast cancer with an IHC score of 1+ or 2+/ISH-negative.2 Recent clinical trials had success with treatment of HER2-low breast cancer with ADCs.2 The phase 3 DESTINY-Breast04 clinical trial demonstrated that T-DXd significantly improved survival in patients with advanced HER2-low breast cancer when compared with chemotherapy.2 This led to FDA approval of T-DXd for treatment in patients with metastatic or unresectable HER2-low breast cancer in August 2022.2

The breast cancer treatment landscape continues to evolve at a rapid pace. The development of new, innovative therapeutic agents, frequently updated treatment protocols, and changes in healthcare delivery have had a positive impact on patient survival and quality of life. Due to continuous treatment updates, it is imperative that advanced practice providers have comprehensive current and emerging disease-specific treatment knowledge, use best practices for adverse event management, have shared decision-making discussions with their patients, have confidence in ADC therapy, and the necessary tools to maximize patient adherence. With the new classification of HER2-low MBC, patients may have questions and confusion as to the pathology, prognosis, and treatment of this type of MBC. A recent roundtable discussion with key opinion leaders elicited important aspects of the role that navigators play in the treatment journey of patients with MBC.

Nurse navigators play an important role as liaisons between care team members and the patient. An additional important role is to encourage patients to discuss treatment options and to encourage patients and their family members to actively participate in shared decision-making. This can be accomplished by asking patients to think about their goals, preferences, and values they would like to incorporate into the treatment plan prior to visits with their oncology team. If the patient has had prior treatment, discussing the outcomes of this treatment along with side effects can help patient find a treatment regimen they can adhere to and tolerate. Ample time, which will vary from patient to patient, for each navigator visit should be allotted to answer patient questions, explain medical terminology, and discuss pathology results.

To reinforce these conversations, the SHARE approach promoted by the Agency for Healthcare Research and Quality can be used. SHARE is based on patient outcomes and takes into consideration evidence that supports treatment options; the expertise, knowledge, and experience of the physician; and, most importantly, patient values and preferences. As the oncology treatment landscape has changed so drastically in the past few years, sharing and discussing updated National Comprehensive Cancer Network guidelines with the patient and their family members may also help with treatment understanding. A lack of health literacy and knowledge deficits can be a barrier to healthcare. Resources like Chemocare, drug manufacturer websites, major cancer center websites, institutional educational materials, and package inserts are helpful with patient education on treatment and prognosis.

Patients with MBC typically have numerous questions and concerns when receiving their diagnosis. Disease prognosis and survival time are at the forefront of their minds. Treatment concerns, including therapeutic options, treatment length, and second and subsequent lines of treatment, are also important. Patients will also ask about the risks/benefits of treatment, what they can expect from treatment, and how to know if their treatment is working. Patients may also inquire about clinical trial availability, biomarker testing, and current MBC research. Second opinions may also be sought by patients. When discussing ADC therapy for HER2-positive or HER2-low, patients should be encouraged to discuss their biomarker status with their oncologist, and, in cases of prior treatment, any changes in biomarker status should be explained to avoid confusion about treatment options or changes to treatment plans. Biomarker status changes may lead to treatment re-evaluation, dose modifications, and new patient concerns.

Side effects are always of concern to patients. Navigators can assist patients in managing side effects and treatment adherence by providing information on potential side effects prior to treatment utilizing Chemocare, drug manufacturer websites, internal institution documents, treatment order sets, side effect monitoring tools, and package inserts on what side effects can be expected. ADC use can lead to nausea, hair loss, fatigue, and neutropenia, which may cause the patient to consider abandoning treatment.3,4 Toxicity concerns include cardiac toxicity, pneumonitis, interstitial lung disease, and hepatotoxicity.3,4 Patients need to be prompted to quickly communicate these issues with the healthcare team, and routine monitoring for toxicity needs to be discussed. Navigators should ensure patients know how and when to report side effects. As these medications can cause life-threatening cardiac and pulmonary adverse effects, the patient should know the importance of reporting side effects early and to visit the emergency department or call 911 if necessary.

Preparing the patient for these potential side effects by using treatment calendars, symptom diaries, and side effect diaries to map out treatment days and when side effects can be anticipated to emerge can help patients manage these side effects. However, the most effective tool is provider–patient communication. Dose delays or reductions are other avenues to control side effects and minimize the emergence of grade 3 or grade 4 side effects. Having medication on hand to control nausea, dietary management, and daily management to incorporate adequate rest and household help can also minimize side effect impacts. Working with the rest of the healthcare team, navigators can help tailor side effect treatments and follow-up with the patient.

Patients with metastatic breast cancer typically have numerous questions and concerns when receiving their diagnosis. Disease prognosis and survival time are at the forefront of their minds.

Motivational interviews with patients will help navigators determine their patients’ life goals while managing MBC and what motivates them to continue treatment. Important life or family events, employment, a productive life, and a good quality of life have all been cited as important motivators for patients with MBC. For some patients, contributing to scientific advancements and helping fellow patients with MBC are also significant motivators. ADC therapy has been found to improve patients’ overall survival compared with chemotherapy.3,4 These therapies have also been found to be well tolerated in patients with HER2-positive3,4 and HER2-low MBC3 while providing a good durability of response and good progression-free survival, and reducing overall chemotherapy toxicity.3,4 One of the ADC therapies available to patients with MBC also provides a new treatment option for patients with HER2-low MBC that was not previously available. It has been found that some patients assume ADC therapy is not chemotherapy, so patients need to be reminded that these agents still have chemotherapy effects. To mitigate confusion, navigators should discuss with patients immunotherapy versus chemotherapy, combination therapy, the mechanism of action of ADCs, and therapy delivery methods.

Despite the availability of new treatments, patients with MBC often encounter barriers to care. Healthcare accessibility may be a problem due to lack of finances, the high cost of medications, the patient’s employment status, insurance coverage or authorization issues, and transportation vulnerability. Other barriers may include delays in accessing care, including early palliative care, lack of available tissue for testing or in testing completion, prior lines of treatment, prior reactions/side effects, and limited access to clinical trials due to strict eligibility criteria. The use of triage lines or patient portals can help those patients experiencing side effects and living a distance from treatment centers determine if their symptoms can be managed at a local emergency department or if they need to travel to the treatment center. During patient conversations, navigators should ask about any barriers to healthcare and refer to social workers or financial workers, if necessary.

Navigators are in a unique position to help patients with MBC with all aspects of their cancer journey. By keeping communication open, listening to patients’ concerns, involving patients in shared decision-making, providing thorough resources, and asking appropriate questions, treatment adherence and quality of life may be maximized for patients with MBC.


  1. Antonarelli G, Corti C, Tarantino P, et al. Management of patients with HER2-positive metastatic breast cancer after trastuzumab deruxtecan failure. ESMO Open. 2023;8:101608.
  2. Zhang H, Peng Y. Current biological, pathological and clinical landscape of HER2-low breast cancer. Cancers (Basel). 2022;15:126.
  3. Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc. Published August 2022. Accessed November 7, 2023.
  4. Kadcyla [package insert]. San Francisco, CA: Genentech, Inc. Published 2022. Accessed November 7, 2023.

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Last modified: December 19, 2023

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