US Pharm. 2022;47(10):34-39.

ABSTRACT: Breast cancer is one of the most commonly diagnosed cancers in women as well as the second leading cause of cancer-related death in women in the United States. One in eight U.S. women will be diagnosed with breast cancer in her lifetime, and an estimated 6% of those initially diagnosed with cancer have metastatic breast cancer (MBC). Human epidermal growth factor receptor 2–positive (HER2+) breast cancer tends to be more aggressive than other types. HER2+ breast cancer accounts for 15% to 20% of all breast cancers. Although HER2+ MBC remains incurable, the development of a variety of targeted therapies has had a significant impact on patient care by slowing disease progression, improving clinical outcomes, and prolonging overall survival.

The American Cancer Society (ACS) notes that with the exception of skin cancers, breast cancer is the most commonly diagnosed cancer in women in the United States, accounting for an estimated 30% of all new female cancers annually.1 Moreover, the average risk of a woman developing breast cancer in her lifetime is 13%, representing one in eight women.1 Breast cancer is the second leading cause of death (following lung cancer) in U.S. women; however, thanks to advances in research, early detection, diagnosis, and clinical intervention, survival rates are increasing.1 In the U.S., an estimated 6% of women initially diagnosed with cancer have metastatic breast cancer (MBC).2 The 5-year survival rate for women with MBC is 29%; the rate in men is 22%.2 (Breast cancer in males accounts for 1% of total cases.1) The ACS estimated that in 2022 about 287,850 new cases of invasive breast cancer would be diagnosed in women; nearly 51,400 new cases of ductal carcinoma in situ would be diagnosed; and approximately 43,250 women would die from breast cancer.1

Breast cancer may be divided into three biological subtypes: 1) cancer cells expressing estrogen receptor (ER); 2) cancer cells expressing human epidermal growth factor receptor 2 (HER2), with or without ER expression; and 3) cancer cells not expressing ER, progesterone receptor (PR), or HER2 (i.e., triple-negative). Each of these subtypes has a direct impact on treatment selection.3,4

This article will focus on HER2-positive (HER2+) MBC and the evolving role of targeted therapies in its treatment and management.

Overview of HER2+ MBC

The transmembrane glycoprotein HER2, a member of the epidermal growth factor family of tyrosine kinase receptors, is expressed on the surface of many forms of tumors, including breast, gastric, lung, and colorectal cancers.5,6 There are two diagnostic tests to ascertain whether breast cancer is HER2+. The first technique, immunohistochemistry (IHC), measures receptors. If the IHC score is 3+, the cancer is HER2+; if the score is 0 or 1, the cancer is considered HER2-negative; if the score is 2+, further evaluation and testing are warranted.7 The second technique, in situ hybridization, measures the number of copies of the HER2 gene. This test is performed primarily when the IHC score is unclear.7

HER2 is overexpressed and/or augmented in an estimated 15% to 20% of breast cancers presenting with aggressive tumor behavior.3,8,9 Although HER2+ breast cancer historically has been correlated with an aggressive disease course and heightened risk of developing systemic and brain metastases, is incurable, and has a poor prognosis, the promising nature of HER2-targeting therapies has significantly transformed treatment and fundamentally enhanced clinical outcomes in many patients with HER2+ MBC.10,11 HER2 positivity is an established risk factor for the development of brain metastasis.12 Breast cancer metastasis commonly affects the lungs, liver, bone, and brain.13

Advances in research have led to a greater understanding of the role of HER2 biology in the development of targeted therapies to treat and manage HER2+ MBC. Although there is no cure, targeted anti-HER2 therapies have led to enhanced disease control and overall survival in patients with HER2+ MBC.14 In general, the primary goals of HER2+ MBC treatment include minimizing adverse effects from therapy, boosting life expectancy by slowing disease progression, and improving symptoms and overall health-related quality of life (HRQoL). The treatment plan should be tailored to patient need.

HER2-Targeted Therapies

Significant therapeutic advances for HER2+ MBC have been made, and HER2-targeted therapies are the standard treatment.15 It has been noted that the development of HER2-targeted therapies has changed the natural course of HER2+ early breast cancer and MBC by considerably reducing rates of relapse in patients treated with curative intent and by extending survival in patients with metastatic disease.15,16 HER2-targeted antagonist therapies (sometimes referred to as anti-HER2+ therapies) include HER2 antibodies, HER2 inhibitors, HER2 conjugates, and antibody drug conjugates. Over the past two decades, the pillar of treatment for both early-stage breast cancer and MBC has been the targeting of HER2 receptors with the humanized monoclonal antibody (mAb) trastuzumab, with or without adjuvant endocrine therapy, in combination with chemotherapy.17

The FDA has approved a number of HER2-targeted therapies for HER2+ MBC (trastuzumab/trastuzumab biosimilars, pertuzumab, lapatinib, neratinib, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, margetuximab-cmkb, tucatinib), and some agents are being investigated in clinical trials.5 HER2-targeted therapy is often administered with chemotherapy; however, it may be used alone or in combination with endocrine therapy. See TABLE 1.18-26

Recently Approved Fixed-Dose Combinations

In February 2019, the FDA approved a fixed-dose combination (FDC) of trastuzumab and hyaluronidase-oysk.27 This novel agent, which is available in a ready-to-use single-dose formulation, is administered SC and has different dosing than IV trastuzumab products. It is approved for the treatment of selected patients with HER2+ early breast cancer (node-positive or node-negative [ER/PR-negative or with one high-risk feature]) in combination with chemotherapy and patients with HER2+ MBC in combination with paclitaxel or alone in those who have received one or more chemotherapy regimens for metastatic disease.27 The recommended dosage is trastuzumab 600 mg and hyaluronidase 10,000 units SC over 2 to 5 minutes once every 3 weeks. It is important to note that this agent is not interchangeable with IV trastuzumab products.27 The most common adverse drug reactions (ADRs) in patients with MBC include fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash.27

In June 2020, the FDA approved an FDC of SC pertuzumab and trastuzumab with hyaluronidase for use in combination with IV chemotherapy for the treatment of early breast cancer and HER2+ MBC.28 This approval marks the first time that two mAbs have been combined for administration as a single SC injection. Administration is in the thigh only. For MBC, this novel agent should be administered in combination with an IV infusion of docetaxel every 3 weeks. In MBC patients, the most common adverse reactions (>30%) with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, nausea, alopecia, neutropenia, fatigue, rash, and peripheral neuropathy.28

Clinical Practice Guidelines

In order to make appropriate clinical recommendations tailored to patient need, it is imperative that pharmacists keep abreast of the most up-to-date guideline recommendations for HER2+ MBC.

According to the American Society of Clinical Oncology (ACSO), HER2-targeted therapy is recommended for patients with HER2+ MBC, excluding those with clinical congestive heart failure or considerably reduced left ventricular ejection fraction; these patients should be assessed by a clinician to ascertain appropriateness of therapy.29

In May 2022, the ASCO issued updates to its clinical practice guidelines for management of patients with HER2+ MBC who also have brain metastases.12 The expert panel recommends that patients with brain metastases receive appropriate local therapy and systemic therapy, if warranted. With regard to drug therapy, the guidelines note the following12:
• If systemic disease is not progressive at the time of diagnosis of brain metastasis, systemic therapy should not be shifted from the patient’s current HER2-targeted therapy regimen.
• If systemic disease is progressive at the time of diagnosis of brain metastasis, HER2-targeted therapy should be offered according to the algorithms for treatment of HER2+ MBC.
• The HER2CLIMB regimen of tucatinib plus capecitabine plus trastuzumab may be offered to patients with HER2+ MBC who have brain metastases without symptomatic mass effect and whose disease has progressed on one or more HER2-directed therapies for metastatic disease. If these agents are used, local therapy may be postponed until clinical confirmation of intracranial progression.
• The HER2CLIMB regimen of tucatinib plus capecitabine plus trastuzumab may be offered to patients with stable brain metastases after local therapy or intracranial disease progression, in addition to the option in the updated systemic-therapy guideline’s recommendation of trastuzumab deruxtecan as second-line therapy.

The ASCO also updated guideline recommendations for managing HER2+ MBC that has metastasized to parts of the body other than the brain. The patient and the clinician should engage in shared decision making, discussing the pros and cons as well as differences in treatment schedule, route, duration of therapy, toxicities, and so on, during this process.29

A summary of the updated recommendations includes the following29:
• Trastuzumab, pertuzumab, and a taxane should be employed for first-line therapy unless a contraindication is present.
• The optimal chemotherapy time frame is at least 4 to 6 months or until maximum response, contingent on toxicity and the absence of progression. HER2-targeted therapy can continue until development of progression or unacceptable toxicity.
• If a patient’s HER2+ advanced breast cancer progresses during or after first-line HER2-targeted therapy and the patient has not received trastuzumab deruxtecan (T-Dxd), T-Dxd should be recommended as second-line therapy.
• If a patient’s HER2+ advanced breast cancer has advanced during or after 2nd-line or higher HER2-targeted therapy and the patient has already received pertuzumab and T-Dxd, the clinician should recommend 3rd-line or higher HER2-targeted therapy. (If the patient has not already received pertuzumab, the clinician may recommend it.)
• The ASCO states that, owing to a lack of head-to-head trials, inadequate clinical evidence exists to support endorsing one regimen over another. For patients who have already received trastuzumab emtansine and pertuzumab, recommendations for 3rd-line therapy and higher include tucatinib with capecitabine and trastuzumab, T-Dxd (if not previously received), neratinib with capecitabine, lapatinib with capecitabine or trastuzumab, other combinations of chemotherapy with trastuzumab, and hormonal therapy when no contraindications are present.29

For more information on the updated ASCO  guidelines, refer to

Recently, the National Comprehensive Cancer Network (NCCN) updated its clinical practice guidelines for breast cancer according to cancer type.30 Several different chemotherapy regimens are recommended; all modalities should include trastuzumab with or without pertuzumab in order to target the HER2+ tumor cells. Refer to the NCCN’s current breast cancer guidelines for more information.30

Emerging Therapies

In July 2022, the FDA accepted for review a Biologics License Application (BLA) for [vic-]trastuzumab duocarmazine (SYD985) for the treatment of patients with HER2+ unresectable locally advanced breast cancer or MBC. The manufacturer has received a Prescription Drug User Fee Act action date of May 12, 2023. In January 2018, the FDA granted this agent fast-track designation based on promising results from phase I data involving heavily pretreated last-line HER2+ MBC patients (clinical trial NCT02277717). Acceptance of the BLA was based on data from the phase III TULIP multicenter, open-label, randomized clinical trial (NCT03262935), in which [vic-]trastuzumab duocarmazine demonstrated a statistically significant improvement in progression-free survival (PFS)—2.1 months—over physician’s choice of therapy.31

At the 2022 ASCO Annual Meeting, researchers announced that the ongoing phase III HER2CLIMB-05 trial (NCT05132582) will investigate the administration of tucatinib plus first-line standard-of-care maintenance therapy with trastuzumab and pertuzumab to determine tucatinib’s ability to lengthen PFS and preserve HRQoL in patients with HER2+ MBC.32


Even with advances in understanding the role of HER2-targeted therapies in the treatment of HER2+ MBC, early detection remains crucial so that clinical intervention has a better chance of slowing the disease progression and prolonging survival rates. Pharmacists can be instrumental in counseling patients about treatment expectations, potential ADRs and recommended management strategies for these ADRs, and when to contact their physician; they can also review monitoring parameters during therapy and provide supportive-care initiatives to improve patients’ HRQoL.

Across all practice settings, there are several ways in which pharmacists can be a fundamental educational resource for women with or at risk for HER2+ MBC, including encouraging routine mammography screenings and monthly breast self-examination; helping patients understand modifiable versus unmodifiable risk factors; and encouraging them to discuss these factors with their healthcare provider. Pharmacists can also give patients information about the various patient-support services and cost-savings programs for eligible patients provided by the manufacturers of many of the HER2-targeted therapies, as well as direct them to patient-education resources available from organizations dedicated to cancer awareness. The NCCN website contains a valuable patient resource on MBC.7 All of these resources will be invaluable to patients who have or are at risk for HER2+ MBC.


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