HER2’s Genetic Link to Breast Cancer Spurs Development of New Treatments

When NCI-supported researchers discovered that the HER2 gene is important for breast cancer growth, this led to the development of the drug trastuzumab and other targeted treatments that have improved survival for women with HER2-positive breast cancer.

Exploring Why Some Cancers Grow and Spread and Others Don’t

For years, doctors and researchers have noted that not all cancers are alike. Some patients’ tumors grow quite slowly and never spread beyond the site where they first formed. But for other patients, their tumors grow rapidly and spread like wildfire.

In the early 1980s, after the discovery that a mutated gene called HER2 could stimulate excessive cell growth and division, many scientists wondered if certain genes might make cancers grow and spread rapidly. Researchers around the world began searching for genes that spur cancer growth.

Blocking HER2 Slows or Stops Some Types of Breast Cancer

NCI-funded researcher Dennis Slamon, M.D., was among the many scientists searching for genes that can lead to cancer. In 1987, he and his colleagues discovered that the growth factor receptor gene HER2, which produces HER2 proteins, might be a good candidate.

At the same time, a team of NCI researchers led by Stuart Aaronson, M.D., were among the first to show that the HER2 protein could cause normal cells to grow uncontrollably like aggressive cancer cells.

Dr. Slamon’s team found that the HER2 protein is present at high levels (HER2 positive) in about 30 percent of breast cancers. They also discovered that high levels of HER2 are linked to a greater likelihood of metastasis  and relapse and an overall decrease in patient survival. The group concluded that HER2 might play a role in the development and growth of breast cancer.

This led researchers to a groundbreaking hypothesis: If HER2 could be blocked, the growth of HER2-positive breast cancer might be slowed.

One way to block the action of a protein is to use laboratory-made monoclonal antibodies that attach to a specific protein and disrupt its function. With NCI support, Dr. Slamon and colleagues from the University of Texas Health Sciences Center had a breakthrough. They showed that an antibody specific to HER2 could slow the growth of metastatic breast cancer cells and other types of cancer in a laboratory dish.

A collaboration between Genentech and UCLA researchers subsequently showed that HER2-specific antibodies could suppress the growth of HER2-positive tumors in mice.

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Researchers at Genentech then modified and developed a HER2-specific antibody, called trastuzumab (Herceptin), for use in humans.

Trastuzumab Targets Breast Cancer in Clinical Trials

Researchers launched three clinical trials of trastuzumab in the mid-1990s for patients with HER2-positive metastatic breast cancer. By 1998, the results of the phase 3 clinical trials showed that breast cancer in patients treated with trastuzumab and chemotherapy grew at a slower rate than in patients treated with chemotherapy alone. Subsequent clinical trials also showed positive outcomes among women with early-stage HER2-positive breast cancer.

On November 16, 2006, the US Food and Drug Administration (FDA) granted approval to trastuzumab used with chemotherapy as an adjuvant treatment for women with HER2-positive breast cancer. The drug has improved survival rates for women with stage 1 to 3 HER2-positive breast cancer by more than 30 percent.

HER2 protein is expressed at high levels in several other cancers besides breast cancer, and in 2010, FDA approved the use of trastuzumab in combination with the chemotherapy drug cisplatin and a type of cancer drug called a fluoropyrimidine to treat some patients with HER2-positive gastric or gastroesophageal junction cancers.

Researchers Develop Additional HER2-Targeted Treatments

Despite these successes, many women with breast cancer don’t benefit from current HER2-targeted treatments, or they become resistant to the effects of these drugs after initial treatment.

Therefore, researchers continue to test new or modified drug combinations. For example, in  2012, FDA approved pertuzumab (Perjeta) as a treatment for women with HER2-positive metastatic breast cancer to be used in combination with trastuzumab and docetaxel (Taxotere), a chemotherapy drug. In 2017, pertuzumab received approval for use in combination with the same drugs as an adjuvant treatment for patients with HER2-positive early breast cancer at high risk of recurrence. Pertuzumab works by blocking HER2 from sending signals to other proteins that cause cells to grow and replicate.

Other drugs that have been approved for treatment of HER2-positive breast cancer include ado-trastuzumab emtansine (Kadcyla), lapatinib ditosylate (Tykerb), and neratinib maleate (Nerlynx).

NCI continues to support research on developing HER2-targeted treatments that can treat a wide range of cancers, while also reducing harmful side effects and improving survival and quality of life.

— Update: 15-02-2023 — cohaitungchi.com found an additional article Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer from the website www.ncbi.nlm.nih.gov for the keyword her2 mutation breast cancer.

1. Introduction

Breast cancer is the most common cancer type worldwide and is considered a heterogeneous genomic disease in terms of molecular markers, prognosis, and treatments [1, 2]. At the molecular level, at least five clinical subtypes have been defined: hormone receptor-positive (luminal A and luminal B), human epidermal growth factor receptor-2 (HER2-positive), basal-like, normal-like, and triple-negative breast cancer (TNBC) [2–4]. Based on this classification, the oncologist is able to prescribe the best endocrine therapy, chemotherapy (alone or combined), and/or HER2-targeted therapy. About 20–25% of all breast cancers overexpress human epidermal growth factor receptor-2 (HER2) and are referred to as HER2-positive. HER2 overexpression is linked to an aggressive phenotype resulting in reduced disease-free and overall survival compared with other breast cancer subtypes, and different strategies have been developed to try to block this receptor [5–9]. According to clinical data, HER2-targeted therapy significantly improves the survival of breast cancer patients showing HER2 overexpression. However, recent data suggest the presence of oncogenic mutations in HER2 affects clinical outcome in HER2-positive breast cancer patients [10].

Read more  Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

In 1983, the receptor tyrosine kinase 2 gene (ERBB2 or newly named HER2) was cloned [11]. This gene is located on the short arm of chromosome 17 and its product is the glycoprotein, HER2, which has several functional domains (Figure 1) that resemble those of other members of the tyrosine kinase family (HER1, HER3, and HER4): an extracellular domain (ECD, containing four subdomains), a transmembrane domain (TMD), an intracellular region that consists of a juxtamembrane domain (JMD), and a tyrosine kinase domain (TKD) [12]. HER2 is an atypical member of the ERBB family because it has no known ligand and its ECD constitutively adopts an open conformation [13]. This has led several authors to suggest a role of HER2 as coreceptor [14]. HER2 preferentially heterodimerizes with ligand bound untethered (open) HER3 or with HER4 and HER1, thereby affecting the downstream signaling of these receptors. In overexpressing cells, HER2 forms homodimers that are capable of signaling [13, 15, 16]. HER2 promotes oncogenic signaling by modulating the expression and activity of proteins controlling cell proliferation, differentiation, death, migration, and angiogenesis, activating specific PI3K/Akt (phosphatidylinositol 3-kinase/Akt, also known as PKB, protein kinase B) and MAPK (mitogen-activated protein kinase) pathways (Figure 2). Unlike other ERBB receptors, HER2 remains on the cell surface for prolonged periods after being activated to signal, which contributes to its ability to transform cells when overexpressed. New findings in breast cancer cells indicate that plasma membrane calcium ATPase2 (PMCA2) is vital for the localization of HER2 and its partners, EGFR and HER3, to activate membrane signaling domains contributing to HER2’s ability to transform cells when overexpressed and prevent HER2 internalization after receptor stimulation and it sustains downstream signal transduction. This means that targeting PMCA2-HER2 interactions could be a new therapeutic approach [17]. Recently, HER2 and the cannabinoid receptor CB2R have been described to physically interact. In effect, the expression of heteromers (HER2-CB2R) has been correlated with a poor prognosis, while their disruption promotes an antitumor response suggesting these heteromers could be used as therapeutic targets and prognostic tools in HER2-positive breast cancer [18].

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HER2 gene amplification, or protein overexpression, is still considered a major mechanism of HER2-driven tumorigenesis and is used as a main predictive biomarker to identify patients who might benefit from therapy with anti-HER2 agents. There are, thus, many different cancer drugs approved by the US Food and Drug Administration (FDA) that target the deregulation of HER2, including monoclonal antibodies, antibody-drug conjugates, and small-molecule TKIs (tyrosine kinase inhibitors), such as trastuzumab, pertuzumab, lapatinib, trastuzumab-emtansine (T-DM1), and neratinib [19–21], as well as others under investigation such as afatinib [7, 22–25] (Table 1). Molecular studies have shown that HER2-positive breast cancers are heterogeneous and that the different tumors may be classified as HER2-enriched or luminal molecular subtypes based on estrogen receptor expression (ER), with implications in their response to targeted therapies [26]. Furthermore, HER2 mutations are identified in 4% of breast cancer patients; these mutations are independently associated with HER2 amplification status, occurring in both hormone receptor (HR)-positive/HER2-negative and HER2-positive [21, 27–30]. Some authors suggest that the prevalence of HER2 mutations changes according to certain histological subtypes in breast cancer [21, 27, 31].

Recently, data from preclinical and clinical studies have attributed somatic mutations in HER2, a role in the constitutive expression [31–33] or differential regulation of HER2 that leads to resistance (primary or acquired) to anti-HER2 therapy and endocrine therapy [4, 6, 10, 34–36]. Such mutations therefore undermine the clinical benefits of HER2-targeted treatment in HER2-positive breast cancer patients. Besides, different mutations in HER2 have been found in several tumors although their role in tumorigenesis is not fully understood. To assess the possible clinical implications of HER2 mutations in HER2-positive breast cancer patients, we here review the spectrum of single nucleotide polymorphisms (SNPs) produced in the HER2 gene. Our working hypothesis was that recurrent mutations in specific HER2 domains in these patients could be good biomarkers of the efficacy of anti-HER2 therapy.


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