Mechanism of Action

HER2 is a transmembrane protein tyrosine kinase receptor that is important to the signal transduction pathways in normal and abnormal cells.2 Breast cancer cells with higher-than-normal levels of HER2 are called HER2-postive.4 Approximately 15% to 30% of human breast tumors express amplification of this protein, and as a biomarker, is an indicator of poor prognosis.2 This subtype of breast cancer has been recognized since the early 1980s when the link between HER2 and cancer cells’ ability to grow rapidly was discovered.3 The metabolic activity of HER2-positive cancer is high; these tumors tend to grow and spread faster than other breast cancer types.4

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HER2 receptors signal to the nucleus when bound to their ligand or heregulin, or simply through homodimerization (a chemical reaction that combines 2 identical proteins) or heterodimerization (a chemical reaction that combines 2 non-identical proteins) between HER2 and its partners, HER1, HER3, and HER4. This understanding of the activity of HER2 led to the discovery and development of trastuzumab, a monocolonal antibody that targets HER2 overamplification, meaning that there are too many copies of a normal-appearing gene and that there is an overabundance of the protein that the gene produces.3 Normal cells have two copies of the HER2 gene, but HER2-positive cancer cells have multiple copies.3 HER2-positive breast cancer is considered to be one of the most dangerous kinds of breast cancer as result of its uncontrolled and aggressive cellular growth.


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However, understanding the science behind HER2 mutations has made all the difference in developing therapies that have forever changed the natural history of this disease. HER2 proteins have been noted to be a driver mutation or proto-oncogene. This means that in cancers that are positive for HER2, the signal can be blocked, if the signal is blocked then the protein is not produced and cellular growth is stopped.3

This knowledge and mechanism of action for HER2 positive breast cancer has transformed a disease that was once characterized only with a poor prognosis to one that can be effectively treated if not cured with early diagnosis.3 Yet, we can still aim for prolonged survival benefit and quality of life even in cases of metastatic and advanced disease.

Diagnostic Tests

Validating the HER2 status of breast cancer is imperative to treatment outcomes. HER2 positivity is a crucial factor in determining therapies that treat primary disease vs metastatic disease. There are several methods for diagnosing HER2-positive disease.

Tests for HER2 status of stage I-III disease are performed on the biopsy specimen at the time of the initial surgery3; whereas HER2 status in stage IV or recurrent disease is confirmed at the site of metastasis when feasible. The FDA has approved 4 methods for HER2 testing: fluorescent in situ hybridization (FISH) assay, immunohistochemistry (IHC), in situ hybridization (ISH), and subtraction probe technology chromogenic in situ hydridization (SPoT-Light HER2 CISH) (Table 1).3,5

TABLE 1. FDA-Approved Tests for HER2 Positivity6

Test What Test Measures How Results Are Reported
FISH Number of HER2 gene copies inside each cell Positive
Negative
Indeterminate
IHC How much HER2 protein is present on cancer cell surface Negative: 0-1+
Borderline: 2+
Positive: 3+
ISH Number of HER2 gene copies in cancer cells Positive
Negative
SPoT-Light HER2 CISH Number of HER2 gene copies in cancer cells Positive
Negative
Indeterminate
Key: FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ISH, in situ hybridization; SPoT-Light HER2 CISH, subtraction probe technology chromogenic in situ hybridization.

HER2 status, as well as hormone status, should be tested at initial diagnosis and in the setting of recurrent or metastatic disease. The changes in diagnosis from these stages of disease can impact treatment decision planning.

Where We Are Today

Long-term survival for patients with HER2-positive breast cancer has forever been changed. Treatment options for all stages of disease have grown and expanded, which has proven to be the “good side” of HER2-positive disease.6 Current treatment algorithms for invasive HER2-positive disease has transformed the face of a disease with a death sentence to one with prolonged and overall survival benefit. Management of this disease has shifted from a one-size-fits-all approach to one in which patients are properly categorized by risk (ie, low risk to high risk). A greater understanding of patients’ treatment needs leads to meaningful and durable response to treatment with HER2 therapies.

From combination therapies to single-agent monoclonal therapies, the treatment arsenal for HER2-positive breast cancer continues to grow. Both combination therapies and single agents have altered the approach to HER2-positive treatment for clinicians and have been life changing for patients. The therapeutic options for HER2 positive disease are broad and variable (Table 2).

TABLE 2. Chemotherapeutic Regimens for HER2-Positive Breast Cancer5,6

Early Stage
ACTH (doxorubicin [Adriamycin], cyclophosphamide [Cytoxan], followed by a taxanea and trastuzumab [Herceptin])
TCH (docetaxel, carboplatin, trastuzumab)
Trastuzumab as single agent after other therapies
Neoadjuvant
Any early-stage regimen plus pertuzumab (Perjeta) and trastuzumab
Metastatic
Taxanea, trastuzumab, pertuzumab
Ado-trastuzumab (Kadcyla)
Extended Treatment
Neratinib (Nerlynx) for 1 year of treatment beyond adjuvant therapy in high-risk patients
aThe taxane in these regimens is paclitaxel (Taxol) or docetaxel (Taxotere).

With ongoing clinical trials and studies, the treatment paradigm for patients with HER2-positive breast cancer will continue to evolve. Advances to date have already greatly changed what HER2-positive disease was more than 30-years ago. New approaches to management will extend further to second- and third-line therapies and improved agents that can cross the blood-brain barrier.

As a discipline, the commitment to discovering agents for high-risk patients and metastatic disease must continue.6 The discovery of HER2-positive therapies have led to better outcomes and improved survival rates.4


Jiajoyce Conway is an advance practice oncology nurse with Cancer Care Associates of York, in York, Pennsylvania.  


References

1. Porter K, Quinn Rosenzweig M. Current and emerging therapies for HER2-positive women with metastatic breast cancer. J Adv Pract Oncol. 2017;8(2):164-168.

2. Bishop CS. Biomarkers in breast cancer. J Adv Pract Oncol. 2011;2(2):101-111.

3. Wilson C. Managing the care of patients with HER2 positive breast cancer: a collaborative practice model. J Adv Pract Oncol. 2016;7(suppl 2):5-20.

4. Breast Cancer HER2 Status. American Cancer Society website. https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed April 16, 2018.

5. De Santis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin. 2014;64(1):52-61.

6. Battaglia G. Optimizing HER2-targeted therapy. https://www.onclive.com/web-exclusives/optimizing-her2targeted-therapy. Accessed April 16, 2018.