The following article features coverage from the 2022 Oncology Nurse Advisor Summit. Click here to read more of Oncology Nurse Advisor‘s conference coverage.

Although HER2-positive metastatic breast cancer remains incurable, the development of HER2-targeted treatments have offered improved outcomes for patients. During a presentation at the 2022 Oncology Nurse Advisor Summit, Madelaine Kuiper, RN, MSN, of UCLA Santa Monica Parkside Cancer Care, discussed the use of guidelines and clinical data to evaluate new and emerging therapies for HER2-positive metastatic breast cancer and the management of adverse events in this patient population.1

The estimated incidence of new breast cancer in 2022 will be roughly 290,560 people across all stages and types of breast cancer. HER2 breast cancer accounts for 2% of all primary breast cancer diagnoses and 2% to 4% of metastatic breast cancer. More research is needed to better understand what percentage of nonmetastatic breast cancer diagnoses will ultimately be diagnosed as metastatic disease.

Kuiper stressed that HER2 testing is the most important process to get right, as it pertains to treatment selection for patients with metastatic disease. Patients who do not undergo HER2 testing or whose testing is incorrectly performed may not receive the appropriate HER2-targeting therapy, which can result in increased cost of care and potentially loss of life. HER2 retesting (or testing) should occur at metastatic presentation, progression, or when patients are not responding to therapy as expected. Kuiper highlighted the importance of using a validated lab and to retest at any time if there is any question.

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HER2 testing by validated IHC assay that results in an ICH of 0 or 1+ is negative whereas IHC 2+ is equivocal and should be reflex tested with ISH (or order a new test with IHC or dual probe ISH if a new specimen is available). IHC 3+ is a positive complete intense staining and is considered HER2-positive. Approximately 20% of current HER2 testing is inaccurate and not all testing is equivalent because testing is subjective to interpretation and pathologist experience, Kuiper explained. The American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) guidelines have been designed to eliminate sources of variation in HER2 testing, and these guidelines recommend in situ hybridization assays in patients with IHC 2+ and IHC 3+.2 With this, the pathologist looks at and physically counts the HER2 copy number on the chromosome 17 probe in a more objective process, producing a more accurate result. Kuiper highlighted the importance of knowing the copy number and, if there are ever any concerns, using a specialized lab to retest the sample.

Kuiper went on to review the timeline of HER2-directed therapy, which began with the US Food and Drug Administration (FDA) approval of trastuzumab (1998), followed by lapatinib (2008), pertuzumab (2012), trastuzumab emtansine (2013), trastuzumab biosimilar (2017), trastuzumab biosimilar SQ (2019), trastuzumab deruxtecan (2019), neratinib (2020), tucatinib (2020), biosimilar trastuzumab, trastuzumab + pertuzumab (2020), and margetuximab (2020).

There are 4 members of the HER2 receptor family (HER1, HER2, HER3, and HER4), and these are the targets of lapatinib, neratinib, pyrotinib, and tucatinib. The HER2 extracellular domain has no known ligand and is activated by the formation of homo- or heterodimers. These dimers lead to phosphorylation of tyrosine kinase residues in the cytoplasmic domain, which function as docking sites for proteins that activate the PI3K and MAPK signaling pathways downstream leading to cell cycle progression and proliferation.

Kuiper also highlighted the importance of fam-trastuzumab deruxtecan, an HER2 antibody drug conjugate; neratinib, a tyrosine kinase inhibitor; tucatinib, another tyrosine kinase inhibitor; and margetuximab, a monoclonal antibody, across a variety of settings.

Kuiper went on to review the NCCN guidelines for HER2-positive metastatic breast cancer, highlighting that category 1 indicates high level evidence there is uniform consensus that the intervention is appropriate and category 2a guidance is based upon lower-level evidence. Overall, there is uniform NCCN consensus that the intervention is appropriate. First-line therapies include pertuzumab + trastuzumab + docetaxel (category 1) and pertuzumab + trastuzumab + paclitaxel (category 2A). Second-line therapy includes fam-trastuzumab deruxtecan (category 1) and ado-trastuzumab emtansine (category 2A). There are a number of recommendations for third-line treatment (and beyond), including tucatinib + trastuzumab + capecitabine (category 1), trastuzumab + docetaxel or vinorelbine (category 2A), trastuzumab + paclitaxel with or without carboplatin (category 2A), capecitabine + trastuzumab or lapatinib (category 2A), trastuzumab + lapatinib without cytotoxic therapy (category 2A), trastuzumab + other agents (category 2A), neratinib + capecitabine (category 2A), and margetuximab + chemotherapy (category 2A).

Future directions in therapy, Kuiper highlighted, include HER2-targeting treatments in clinical trials, next generation sequencing, and targeting HER2 low expression. Researchers are also seeking to better understand treatment for hormone receptor-positive, HER2-positive disease.

When considering treatment-related adverse events, cardiomyopathy with left ventricular ejection fraction decline is the biggest concern in HER2-targeted therapy. This is mainly associated with trastuzumab emtansine, trastuzumab + pertuzumab, and margetuximab. Kuiper reminded the audience that it’s important to look for signs of cardiac failure, which include dyspnea, cough, and lower extremity edema. Kuiper also recommended that patients work with a cardiologist oncologist to maximize their left ventricular ejection fraction.

Interstitial lung disease/pneumonitis also is an important side effect to be aware of, particularly in patients who receive fam-trastuzumab deruxtecan, trastuzumab emtansine, margetuximab, and tyrosine kinase inhibitors. Patients should be alerted to look out for a dry cough, dyspnea, and fever and to call the office if these symptoms are present so that they may be evaluated.

Other toxicities of concern are elevated liver function, elevated creatinine, which can be identified by changes in skin or eye color, urine output, and mental status. Kuiper stated that an important element of managing these adverse events is patient education, monitoring lab work, and addressing CYP enzyme interactions. She also noted that gastrointestinal toxicities can also occur, including diarrhea, nausea and vomiting, and abdominal cramping. Patients must be educated about the possibility of these side effects and be aware of what actions to take should they occur to avoid the need to interrupt therapy.

“Shared decision making is incredibly important, at the metastatic diagnosis and any time [patients] change therapy because of progression of disease or because of quality of life changes, we need to [discuss] these with patients,” Kuiper concluded.

Read more of Oncology Nurse Advisor’s coverage of 2022 Oncology Nurse Advisor Summit by visiting the conference page.


  1. Kuiper M. HER2-positive metastatic breast cancer: new options, new hope. Oral presentation at: 2022 Oncology Nurse Advisor Summit; March 25-27, 2022.
  2. Wolff AC, Hammond EH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(20):2105-2122. doi:10.1200/JCO.2018.77.8738