Breast cancer is the most frequently diagnosed cancer worldwide and the leading cause of cancer death in women. In Singapore, breast cancer is the most commonly diagnosed cancer for more than 40 years and it is the leading cause of death in cancers affecting women. There are more than 7000 new cases a year (from 2006-2010) and it has been a rising incidence trend. The incidence rises sharply after 30 years old to peak in the 60s. Of the ethnic groups in Singapore, the age-standardised incidence rate is higher for Chinese than for the other ethnic groups.

Do all breast cancers behave the same way? This has been asked because doctors have noticed that some patients may have been having a breast lump for a long time, sometimes several years while others seem to appear in months even when the patient has had a negative recent mammogram. For patients with recurrent breast cancers, there are some who seem to do well for many years while others progress in a short time.

With the advancement of molecular techniques (such as immunohistochemistry, microarray, next generation sequencing), researchers began to try and profile breast cancers based on the genes that are expressed in the cancer. Understanding the molecular profile of breast cancer has changed our understanding and management of patients.

HER2 - Positive Breast Cancer

There is a subgroup of breast cancers that amplify or overexpress human epidermal growth factor receptor 2 (HER2, previously called HER2/neu, or ERBB-2).  This comprises 18 to 20% of human breast cancers. The HER2  gene is responsible for making HER2 proteins. The HER2 oncogene encodes for receptors on the cell membrane. Under normal circumstances, HER2 receptors help control how a breast cell grows, divides, and repairs itself. In some breast cancers, the HER2 gene can become abnormal and make too many copies of itself (amplification of the HER2 gene). Amplified HER2 genes command breast cells to make too many receptors (overexpression of the HER2 protein). It becomes more sensitive to growth signals and is predictive of several other consequences.

• When this happens, the overexpressed HER2 receptors shout at (rather than talk to) the breast cells to grow and divide in an uncontrolled way. This can lead to the development of breast cancer. Breast cancers that have amplified HER2 genes or that overexpress the HER2 protein are described in the pathology report as being HER2-positive. HER2-positive breast cancers tend to grow faster and are more likely to spread and come back (recur) when compared with HER2 -negative breast cancers. But HER2 -positive breast cancers can respond to targeted treatments that are designed to work against HER2 -positive cancer cells

• The drug, trastuzumab (Herceptin) is very effective in treating women who have high levels of HER2 expressing breast cancer. It is used as a single agent or together with cytotoxic chemotherapy in HER2 -positive metastatic disease. In addition, several international trials have shown that it improves survival significantly in the adjuvant treatment of HER2 -positive breast cancer.

• HER2 -positive breast cancers appear to be more resistant (in the absence of HER2 targeted therapy) to conventional chemotherapy often used to treat breast cancer such as anthracyclines (Adriamycin, Epirubicin) and taxanes (Paclitaxel, Docetaxel etc).

• HER2 overexpressing breast cancer is often more resistant to endocrine or hormonal therapy for breast cancer. Some studies using tamoxifen (SERM) or aromatase inhibitors show that blocking both hormone and HER2 signalling is important in cancer control.

• It has been noted that brain metastases is more common in HER2 overexpressing breast cancers. Brain metastases can occur in 30 to 40 percent of women living with HER2-positive breast cancer.

Diagnosis of HER2 Overexpression

Testing for HER2 expression has improved since the discovery of the gene and the advancement in the clinical utility of the information for clinical decision making and treatment.  There are many ways to measure HER2 oncogene expression.

• HER2  gene amplification by in situ hybridization (ISH) – Fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), silver-enhanced in situ hybridization (SISH), or differential polymerase chain reaction (PCR).

• Overexpression of the HER2 protein product – Western blotting, enzyme-linked immunosorbent assay (ELISA), or immunohistochemistry (IHC).

• Overexpression of HER2 RNA – Northern blotting or reverse transcription PCR (RT-PCR).

Several pathology and clinical oncology societies have recommended best practices for testing HER2  expression. This impacts patient treatment because the selection of therapy is so different. In addition, patients should not be deprived of the large benefit seen in the adjuvant Herceptin trials because of specimen or testing issue. Of course, in different parts of the world, cost and testing availability, quality and consistency of tests may be different. We are fortunate to work with reputable, approved laboratories in Singapore offering HER2 gene testing.

Once HER2 overexpression is established, HER2 directed therapy is used. In the setting of neoadjuvant, adjuvant or advanced cancer treatment, it may involve chemotherapy with drugs such as trastuzumab (Herceptin), lapatinib (Tykerb), pertuzumab (Perjeta), trastuzumab emtasine (T-DM1 or Kadcyla) or neratinib.

“Expert knowledge means better care for cancer”

Written by:

Dr Peter Ang
MBBS (Singapore)
MMed (Int Med)
MRCP (UK)
FAMS (Medical Oncology)