It’s All About HER2

Woman holding a magnifying glass

We’re kicking off our in-depth explorations of breast cancer subtypes with HER2-positive breast cancer. 20-25% of breast cancers have high levels of HER2 protein1, which can influence outlook and treatment. Here we are going to explain exactly what HER2 is and how it can affect your treatment plan.

So, what is HER2?

Human Epidermal Growth Factor Receptor 2, commonly known as HER2, is a protein on the surface of cells and acts as a receptor, responding to signals from its environment. Normally responsible for the healthy growth and development of cells, in up to 20-25% of breast cancer patients the genetic code containing the HER2 gene is altered, resulting in much more HER2 protein expression on the breast cancer cells. This leads to abnormal cell division and growth. 

How do I know if I’m HER2-positive or negative? 

The analysis of your tissue sample from a biopsy or surgery indicates if your tumour over expresses the HER2 protein. The expression of this protein is analysed by a staining technique called immunohistochemistry (IHC). If the IHC result is 0 or 1+, your sample is considered HER2-negative. If it is 3+ it is HER2-positive and if it is 2+ the result is inconclusive 2. You can review this in your pathology report. To find out more about the contents of your pathology report, head to our previous blog.   

Are there treatments specific for HER2-positive breast cancer? 

The significance of HER2 in the growth of breast cancer cells drove research for treatments that targeted the protein. This was first achieved by the organisation Genentech, who in the 1990’s developed Trastuzumab, commercially known as Herceptin®. Herceptin® is now the standard treatment for early and advanced HER2-positive breast cancer. However, the further discovery for treatments continued. Particularly in the last decade, we have seen a rise in the number of HER2 targeted therapies coming to the market. 

Did you know?

The future of Herceptin® was almost halted by the disbanding of cancer drug development in Genentech. However in the late 1980’s, the mother of a senior Genentech vice president was diagnosed with breast cancer. “Just like that, one man flipped the switch on HER2.” He convinced his colleagues that Herceptin® was worth Genentech’s investment. 

Robert Bazell, The Making of Herceptin®, a Revolutionary Treatment for Breast Cancer

Whilst this is invaluable for people to get the best care possible, with all the different terminology and decisions to be made, it can be easy to feel overwhelmed. So we have pulled together all the different HER2 treatment options you could have on the NHS. These are classified into three types: Monoclonal antibodies, antibody-drug conjugates and kinase inhibitors. In this blog, we are going to identify them all and explain how they work.

NICE is the British organisation that reviews new and existing drugs. In Scotland, NICE guidelines are not applied. They have the Scottish Medicines Consortium (SMC) and Scottish Intercollegiate Guidelines Network (SIGN) which approve new drugs and create guidelines, respectively. Therefore, the drugs available in NHS Scotland may differ to those in England 3.

1. Monoclonal antibodies

Monoclonal antibodies are drugs that block the HER2 receptor, blocking the pathway of HER2 and reducing the cell growth. To find out more on Monoclonal Antibodies, head to our previous blog. Trastuzumab and Pertuzumab are the most common monoclonal antibody therapies, which we will explore further here. 

1.1 Trastuzumab (Herceptin®)

This first targeted therapy for HER2 is given intravenously for both early and advanced breast cancer, often alongside chemotherapeutic agents such as paclitaxel.  During Covid-19, you are more likely to be given oral capecitabine (Xeloda®) to reduce likelihood of adverse side effects4. Herceptin® can also be given to you separately if you have already received two chemotherapy regimens for secondary breast cancer5.

Herceptin® was the original brand name for the drug, however several similar versions (called biosimilars) are now available. Biosimilars for Herceptin® include Ogivri®, Herzuma®, Ontruzant®, Trazimera®, and Kanjinti®. They are clinically identical, with no changes in effectiveness. However, having multiple options on the drug market allows for the driving down of costs. Although practically identical in their treatment against cancer, they should not be used interchangeably and therefore you are commonly prescribed the brand name rather than the generic name6.

Did you know?

Herceptin® was a breakthrough for HER2-positive breast cancer subtypes. Clinical trials showed that the introduction of Herceptin® halved cancer recurrence and reduced mortality by 30%7,8,9. To find out more about the history of Herceptin®, check out our blog

1.2 Trastuzumab-hyaluronidase injection

Trastuzumab has also been approved to be delivered subcutaneously, meaning with an injection that goes under the skin rather than through the blood. This has been approved for people with HER2-positive early and advanced breast cancer. There has found to be no difference in the effectiveness of trastuzumab with either method of administration10

The decision for each individual for whether intravenous or subcutaneous administration would be suitable depends on the ability to receive treatments at home, the local support that is available and whether other intravenous treatments are included in their treatment plan. If receiving other intravenous treatments, having HER2 at home would not save a significant time in hospital, one of the main benefits of the subcutaneous injection11

1.3 Pertuzumab (Perjeta®)
Diagram explaining monoclonal antibodies

Pertuzumab, another HER2-specific monoclonal antibody, can be used for both primary and secondary breast cancer. It is included in standard care for neoadjuvant (before surgery) treatment in early breast cancer, alongside trastuzumab and chemotherapy. This is offered to people with locally advanced, inflammatory or early-stage breast cancer at high risk of recurrence12

In the study that supported NICE’s decision to give pertuzumab as adjuvant therapy for early breast cancer, it was found that adding pertuzumab to standard trastuzumab and chemotherapy increased disease-free survival13. This means that after treatment, there was a decreased likelihood of breast cancer spreading to other parts of the body. This did not include the appearance of other types of cancer. This is offered to people with lymph node positive early breast cancer (N1 and higher in TNM staging), as the cancer is more likely to recur in this group.

Pertuzumab is also offered alongside trastuzumab and docetaxel for secondary or locally recurrent breast cancer in adults who have not had previous anti-HER2 therapy or chemotherapy and are unable to have surgery to remove the cancer. This was after a review in 2018 that found pertuzumab significantly improved progression-free and overall survival14. During Covid-19, chemotherapy will not be included alongside pertuzumab and trastuzumab in early and advanced neoadjuvant and adjuvant therapy to reduce side effects4.

In Scotland, Perjeta® has been approved to be used in secondary breast cancer and as neoadjuvant therapy in early breast cancer, but was rejected in 2019 for adjuvant therapy in primary breast cancer 15

2. Antibody drug conjugates

An antibody-drug conjugate (ADC) is a monoclonal antibody linked to a chemotherapy drug. The monoclonal antibody targets and binds to the cell. The chemotherapeutic agent then becomes active when it enters the cell. This means that HER2-positive breast cancer cells can be targeted, and the cytotoxic effects of chemotherapy concentrated to the cancer cells. 

Diagram explaining antibody conjugates

2.1 Ado-trastuzumab emtansine (Kadcyla® or TDM-1)

Kadcyla® is an intravenous drug made up of trastuzumab and the chemotherapy drug emtansine. From May this year, Kadcyla® is approved by NICE to be given for early breast cancer in the NHS. Clinical trial evidence showed that the use of Kadcyla increases the time people remain free of disease compared to trastuzumab alone16.

“Additional treatment options that can increase the amount of time in which people remain free of disease after surgery, and perhaps stop it from coming back altogether, are particularly welcome.  We are therefore pleased to be able to recommend that trastuzumab emtansine is made available routinely for people with HER2-positive early breast cancer after surgery.”

Meindert Boysen, deputy chief executive and director of the Centre for Health Technology Evaluation at NICE

Kadcyla® is recommended for people who have locally advanced or secondary breast cancer who have previously been treated with trastuzumab and a taxane (another chemotherapeutic drug) after having surgery. If during or after treatment with trastuzumab and taxane the cancer comes back, Kadcyla® will be offered17

2.2 Future treatment possibilites: trastuzumab deruxtecan (Enhertu®)

At the moment, if the second line of therapy (taxane chemotherapy regimen and trastuzumab emtansine) is unsuccessful, there are no future HER2-targeted treatments that are suggested. Currently the NICE guidelines state that non-targeted chemotherapy, such as eribulin, should be used18

Trastuzumab deruxtecan, brand name Enhertu®, is trastuzumab joined with the chemotherapy agent deruxtecan, administered intravenously. In the United States it has been approved for people who have had two previous regimens of targeted therapy that have been unsuccessful. Its use in the UK is currently being reviewed by NICE, who are expecting to come to a decision by mid-202119.

3. Kinase inhibitors

HER2 is a type of protein known as a kinase. Kinases are proteins in cells that receive signals to prompt the cell to grow, divide or die. Therapies that block kinases are called kinase inhibitors. Whilst monoclonal antibodies block the HER2 receptor by binding to it outside the cell, kinase inhibitors block the pathway within the cell. This means that if they receive a signal that the cell should divide or grow, the protein cannot carry it out.

Diagram explaining kinase inhibitors

3.1  Lapatinib

Lapatinib (Tykerb®) was the first kinase inhibitor available and may be used as an oral drug for secondary breast cancer for people who have previously been treated with trastuzumab. Considering the results of further studies, lapatinib is no longer recommended by NICE and is not suggested to be used alongside aromatase inhibitors for first-line treatment in menopausal women20. This is due to the additional adverse effects caused through the combined therapy that outweighed potential benefits. Instead, chemotherapy and trastuzumab are suggested as standard treatment of care.

3.2 Neratinib

Neratinib (Nerlynx®) are oral pills used in early-stage breast cancer. They will be given it if they still have cancer cells after neoadjuvant (before surgery) chemotherapy and have completed having trastuzumab less than a year ago21

It could also be given along with the chemo drug capecitabine to treat people with secondary disease, typically after at least two other anti-HER2 targeted drugs have been tried. This is still under review and should be decided by the end of 2021 by NICE22

3.3 Tucatinib

Tucatinib (Tukysa®) are oral pills used to treat advanced breast cancer, after at least one other anti-HER2 targeted drug has been tried. It is typically given along with trastuzumab and the oral chemo drug capecitabine. Some kinase inhibitors have multiple targets, but tucatinib appears to predominantly bind to HER2, meaning there is less risk of side effects. 

There are current studies being carried out to test the effectiveness of tucatinib vs a placebo with capecitabine and trastuzumab in advanced HER2-positive breast cancer23,24. The results are so far promising, and an application has been sent to the FDA (the American drug committee) for its approval. The lead investigator, Dr Murthy, believes the combination of these drugs may become the new standard of care24.

What side effects will I be at risk of?

There are some common side effects for all HER2 therapies, however each drug varies in specific side effects that you may be at high risk of. There are some excellent resources online that give you a breakdown of the top side effects, such as Cancer Research UK’s A-Z list of cancer drugs.

It is well known that cardiac toxicity (heart dysfunction) is one of the most common adverse effects among patients receiving chemotherapy and HER2-directed therapy such as trastuzumab, pertuzumab or TDM-1. Therefore people receiving trastuzumab typically undergo cardiac monitoring, and treatment should be stopped if a heart measure called left ventricular ejection fraction (LEVF) drops by 10% from baseline and to below 50%25. However, what is less clear are the long-term cardiac complications for breast cancer survivors who received such therapy in the past26.  Recent studies have suggested that exercise training such as high intensity training could help prevent cardiac toxicity after cancer treatment27

Other common side effects you may experience are28:

  • Sleep problems
  • Muscle/joint pain
  • Redness at the IV site
  • Diarrhoea
  • Nausea
  • Tiredness
  • Headache
  • Mouth sores
  • Loss of appetite
  • Cold symptoms
  • Rash

Lapatinib, neratinib, tucatinib, and the combination of pertuzumab with trastuzumab can cause severe diarrhoea, so it is crucial to let your health team know any changes in bowel habits as they happen. 

Some kinase inhibitors, including lapatinib, neratinib and tucatinib can cause liver problems. Regular blood tests will be taken to check your liver function, but watch out for itchy or yellowing of the skin, dark urine or pain in the right upper belly area29

Device showing trends graphs screenshot of the OWise appDo you know that you can track your side effects with OWise? With over 30 side effects and symptoms to choose from, you can track any changes and share these with your care team and loved ones. Better communication with your care team can make sure you receive the best care possible. 

And that’s HER2-positive treatment summed up

We hope that you now better understand your treatment options and can feel confident in discussions with your care team. Whilst we have included HER2-positive treatment currently available on the NHS, there are current clinical trials being run and new treatments may become available in the near future. We want to make sure you are kept informed so make sure to follow our Instagram and Twitter for any updates. 

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References

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  2. Cancer.org. 2020. Breast Cancer HER2 Status | HER2-positive Breast Cancer. [online] Available at: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html [Accessed 7 October 2020].
  3. Cancerresearchuk.org. 2019. Scotish Medicine Consortium (SMC). [online] Available at: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/access-to-treatment/scottish-medicines-consortium-smc [Accessed 7 October 2020].
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  5. Nice.org.uk. 2020. Overview | Guidance On The Use Of Trastuzumab For The Treatment Of Advanced Breast Cancer | Guidance | NICE. [online] Available at: https://www.nice.org.uk/guidance/TA34 [Accessed 6 October 2020].
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