In the third blog of our partnership with Make2ndsCount, we want to share reliable information surrounding the science behind HER2 positive secondary breast cancer, as well as current and future treatments available. Nearly a third of people diagnosed with earlier stages of breast cancer will develop advanced disease^1,2. Even though many people are living with secondary breast cancer, it can often feel that it is excluded from breast cancer campaigns. Research has shown that women with advanced breast cancer often feel isolated and 67% of them feel like no one understands what they are going through^3,4. In this blog, we will be sharing with you accessible treatments for advanced HER2 positive breast cancer. 

“Every year, an estimated 55,000 people are diagnosed with breast cancer in the UK, of which up to one in five are estimated to have HER2 positive tumours.”

– Dr Alicia Okines, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, UK.

What is HER2 Positive Secondary Breast Cancer?

Secondary breast cancer, also referred to as advanced, metastatic or stage IV, is cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body. Breast cancer is usually categorised according to whether the cancer cells grow in response to different hormones or proteins. In HER2-positive cancer, cells over-express the protein HER2 on their cell surface. 

What is HER2?

HER2, short for Human Epidermal growth factor Receptor 2, is a protein on the surface of cells that acts as a receptor. Normally HER2 is responsible for the healthy growth and development of cells. However, when the HER2 protein is present in high amounts (overexpressed) on the cell surface of breast cancer cells this leads to abnormal cell division and growth. 

How do I know if  have HER2 positive Breast Cancer?

A pathologist will test the tissue sample taken from a biopsy to see if there is an over expression of HER2 proteins. Tissue samples are tested for HER2 using a technique called in-situ hybridisation (to find out the details of how this works check out our previous post on how HER2 is measured here). You should be able to find these results in your pathology report. The HER2 results are usually reported in the form of a score: 

• 0 score of cells is considered HER2 negative
• 1+ is considered HER2-low
• 2+ (with a negative FISH test) is considered HER2-low
• 2+ (with a positive FISH test) is considered HER2 positive
• 3+ score is considered HER2 positive

To learn more about HER2-low breast cancer check out the blog ‘What is HER2-low Breast Cancer?‘.

Current Treatment Options for Secondary HER2 Positive Breast Cancer

We have compiled the treatments available through the NHS for HER2 secondary breast cancer. Current treatments aim to extend survival, maintain good quality of life and relieve symptoms. The treatment chosen depends on the extent of spread and on the previous treatment you’ve received. 

We will outline and explain each of these treatment options and note whether or not they have been approved by NICE (National Institute for Health and Care Excellence) or by SIGN (Scottish intercollegiate guidelines network). 

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 England⁵.

Chemotherapy for Secondary HER2 Positive Breast Cancer

The common NHS chemotherapy regimen includes a taxane and an anthracycline. This is known as combination chemotherapy: 

• Taxanes include paclitaxel (Taxol®), nab-paclitaxel (Abraxane®) or docetaxel (Taxotere®)
• Anthracyclines include doxorubicin (Adriamycin®), epirubicin (Ellence®), doxorubicin (Doxil®), daunorubicin (Cerubidine®) or mitoxantrone (Novantrone®). 

Anthracyclines can be cardiotoxic, meaning they can have a damaging effect on the heart. Therefore, if people are not suitable for anthracyclines (because of previous treatment or the toxicity to the heart) the treatments offered are:

• Docetaxel (Taxotere®) followed by vinorelbine (Navelbine®) or capecitabine (Xeloda®) after docetaxel. 

Another treatment option is:

• Gemcitabine (Gemzar®) in combination with paclitaxel Taxol®) if docetaxel alone or docetaxel and capecitabine are also options⁶

Capecitabine and gemcitabine are antimetabolite drugs. Antimetabolites interfere with DNA and RNA (genetic material) by acting as a substitute for the normal building blocks of RNA and DNA. When this happens, the DNA cannot make copies of itself, and a cell cannot reproduce⁷.

After two or more chemotherapy regimes, with an anthracycline or taxane and capecitabine, the drug eribulin (Halaven®) is recommended as a third line treatment⁸. Please note that eribulin can increase your risk of infection as it lowers your overall white blood cell count, also called neutropenia. It is important to be aware of any potential symptoms of infection such as a fever, a sore throat, cough or diarrhoea. It can also cause increased bruising and bleeding⁹.

Do you know that you can track your side effects with OWise including neutropenia? With more than 30 side effects and symptoms to choose from, you can track any changes and share these with your care team and loved ones via a secure hyperlink. Having a better communication with your care team can make sure you receive the best care possible.

Targeted HER2 Therapy for Secondary HER2 Positive Breast Cancer

Treatments that specifically target HER2 are common options for both early and advanced HER2 positive cancer. These therapies specifically target and block the HER2 receptors on cells, reducing cell growth. They are called “monoclonal antibodies”. 

Antibodies are a natural part of your immune system and play a role in detecting when foreign particles, such as viruses or bacteria, are in your body. Antibodies have very specific shapes and bind to antigens (receptors) on cell surfaces which is how they recognise whether a cell is yours or foreign. Monoclonal antibodies are antibodies that are made in a lab that bind to specific antigens (such as the HER2 receptor protein). To find out more details on monoclonal antibodies, have a look at our previous blog. 

Did you know: If a treatment ends in the letters “Mab” you know it’s a monoclonal body. Mab stands for monoclonal antibody.

Trastuzumab (Herceptin ®) and pertuzumab (Perjeta®) are monoclonal antibodies used in treating both early and advanced HER2 breast cancer.

Trastuzumab-pertuzumab-hyaluronidase (PHESGO®) injection

In April 2021, an injection called PHESGO^®️ was offered by the NHS for people with HER2 positive breast cancer. PHESGO^®️ contains both pertuzumab with trastuzumab which were previously given as separate IV infusions. It also includes hyaluronidase protein which helps metabolise these targeted drugs so they can be administered together in one 5 min injection under the skin on your thigh. This significantly cuts treatment time.

Combination of Chemotherapy and Monoclonal Antibodies

Pertuzumab (Perjeta®) in combination with trastuzumab (Herceptin ®) and docetaxel is recommended as first line treatment for HER2 positive secondary breast cancer. It is recommended for secondary HER2 positive patients or patients who have had a recurrence after 1 year of completing an anti-HER2 treatment or chemotherapy after surgery.

More HER2 Monoclonal Antibodies for Secondary HER2 Positive Breast Cancer

Margetuximab versus Trastuzumab

Margetuximab is a monoclonal antibody which targets HER2 proteins. In an ongoing phase III clinical trial called SOPHIA, margetuximab in combination with chemotherapy is being compared to trastuzumab in combination with chemotherapy as treatments for secondary HER2 breast cancer in patients who have previously undergone at least two or more targeted HER2 therapies. Results have found that margetuximab and chemotherapy reduces the risk of cancer progression by 24% compared to trastuzumab and chemotherapy³⁵. This resulted in a statistically significant improvement in progression free survival in people who received margetuximab compared to trastuzumab ³⁶.

Based on the results of the SOPHIA trial, the FDA approved the use of margetuximab for secondary HER2 breast cancer in December 2020 ³⁷.

Antibody-Drug Conjugates (ADCs)

An antibody drug conjugate (ADC) is a monoclonal antibody (such as trastuzumab) linked to a chemotherapy drug. It helps the chemotherapy drug target the cancer cells more specifically, as the monoclonal antibody targets and binds to the cell and the chemotherapy drug becomes active as it enters the cell. This allows chemotherapy to be more targeted and lessens its effect on non cancer cells.

• Trastuzumab emtansine (TDM-1, Kadcyla®)

Currently, trastuzumab emtansine (T-DM1 or Kadycla®) is approved by NICE as a second line treatment for people with secondary HER2 positive breast cancer who have previously been treated with trastuzumab and a chemotherapy¹².

• Trastuzumab deruxtecan (TDX-d, Enhertu®)

Following a highly positive trial, secondary HER2 positive patients can now also access with a new ADC called trastuzumab deruxtecan (Enhertu®) after one or more previous anti HER2-treatments^31,38,39. 

This treatment option was approved by the FDA US in 2019³² and NICE UK in 2021³⁸, and has been investigated in clinical trials called DESTINY-Breast-01 and-03^{31 33,39}. The trial found that treatment reduced tumour size in this group of people and that Enhertu increased the period of being disease free to 25 months instead of 7 months on Kadcyla (T-DM1) ³³. However, there were significant side effects recorded particularly a lung related effect called interstitial lung disease (ILD). This prompted the FDA’s approval to include a clinician warning to carefully monitor patients receiving this treatment for lung disease²¹. 

Kinase Inhibitors for Secondary HER2 Positive Breast Cancer

Kinase proteins receive signals for cells to grow and divide or die, HER2 is a type of protein kinase. Kinase inhibitors are therapies that block these pathways. Kinase inhibitors differ from monoclonal antibodies because whilst monoclonal antibodies block the HER2 receptors, kinase inhibitors block the pathway within the cell. Therefore, even if a cell receives a signal to grow this will not be carried out because the pathway is blocked.

• Tucatinib (Tukysa®)

Tucatinib is a tyrosine kinase inhibitor and binds to a different part of the HER2 protein than existing drugs²¹. It is the only HER2-targeted kinase inhibitor to demonstrate overall survival benefit in patients with secondary HER2 breast cancer, and it is particularly noteworthy that the trial found positive results in people with brain metastases which are a particularly difficult subset of patients to treat^{16, 21, 23}. The HER2CLIMB trial found that the risk of central nervous system progression (such as brain metastases) or death was reduced by 68% compared to women who were treated only with trastuzumab (Herceptin®) and capecitabine^16,24.

Tucatinib (Tukysa®) is approved in combination with trastuzumab (Herceptin®) and capecitabine to treat HER2 positive, secondary breast cancer for people with or without brain metastases and who have previously had at least two targeted anti-HER2 treatments^21,25 . This approval is following the results of a phase II clinical trial called HER2CLIMB 2020²². To watch a video of a researcher discussing the trial click here. 

• Neratinib (Nerlynx®)

Neratinib is another kinase inhibitor which is currently approved for the treatment of early stage HER2 breast cancer in the UK by NICE ²⁶. It is being researched as a potential third line treatment for people with secondary HER2 cancer. In a Phase III NALA clinical trial, neratinib with capecitabine was compared to lapatinib (another kinase inhibitor which targets HER2 pathways) with capecitabine as a treatment for people with secondary HER2 breast cancer in which the cancer had spread to the central nervous system ²⁷. This trial found a 24% reduction in progression or death when treated with neratinib and capecitabine compared with people on lapatinib and capecitabine ²⁸.

Following the results of this Phase III NALA trial, neratinib with capecitabine has been approved by the FDA as a third line treatment for secondary HER2 breast cancer ²³. Neratinib is not currently approved by NICE to treat secondary HER2-positive breast cancer.  It has been noted that the utility of neratinib may be limited in comparison to tucatinib for secondary HER2 patients given the overall survival benefit and lower toxicity found with tucatinib, however it may be useful for people with a heart disease called cardiomyopathy ²³.

Common Secondary HER2 Positive Breast Cancer Treatment Side Effects

What are the common side effects of Chemotherapy?

Chemotherapy is cytotoxic, meaning it kills cells. Chemotherapy drugs target cells that are dividing, making it more likely to affect cancer cells as they usually divide much more frequently than healthy cells. However, this means that chemotherapy is likely to affect any fast dividing cells whether they are cancerous or not. Hair, digestive linings and skin cells all divide frequently and are therefore more likely to be affected by chemotherapy. This can lead to the following common side effects: 

• Hair loss
• Nausea, for more information on chemotherapy and nausea check out our previous post 
• Aneamia 
• Vomiting
• Skin and nail changes
• Fatigue: chemotherapy related fatigue is different to regular tiredness
• Effects on memory and cognitive function: for more information on chemobrain and how to manage it’s effects refer to our previous blog

For more information, Cancer Research UK has a thorough and helpful online breakdown of the most common side effects of cancer drugs which you can find here.

What are common side effects of HER2 Targeted drugs?

Due to their specificity, HER2 treatments affect non-cancer cells less than chemotherapy drugs and have less general side effects. However, there are some common side effects for all HER2 therapies, and specific effects may vary depending on the drug. 

It is well known that cardio toxicity (heart problems) is a common potential side effect of people receiving both chemotherapy and targeted HER2 therapy such as pertuzumab, trastuzumab or T-DM1. Because of this people undergoing HER2 targeted treatments typically have heart monitoring. Treatment should be stopped if left ventricular ejection fraction (LVEF, which is a measure of heart activity) drops by 10% below baseline¹³.

There are other common side effects to targeted HER2 therapies such as:

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

For further details on these side effects and advice on how to manage them, check out Cancer Research UK’s page on HER2 therapies.

What are potential side effects of kinase inhibitors?

An important note on potential side effects: some kinase inhibitors, including neratinib and tucatinib can cause liver problems. Regular blood tests will check your liver function, but it is important to check for itchy or yellowing of the skin, dark urine or pain in the right upper belly area³⁰.

Secondary HER2 Positive Breast Cancer and Metastases

Metastases is the spread of cancer cells to other parts of your body. Common types of metastases in HER2 secondary breast cancer are bone and brain: 

Bone Metastases

If the cancer has spread to your bones, there are treatments that help prevent fractures and other bone related issues, as well as pain management.

• Bisphosphonates

Bisphosphonates are therapies that help prevent bone breakdown by making healthy bone denser and less likely to fracture¹⁴.There are multiple bisphosphonates available, namely zoledronic acid (Zometa®) and ibandronate (Bondronat®), which can be offered either orally or through injections ¹⁵.

• Denosumab

A type of monoclonal antibody, which can be offered instead of bisphosphonates. Denosumab’s function is the same but it targets a protein that controls cell breakdown in bones. This is in comparison to bisphosphonates which prevent bone breakdown by making the bone denser, causing fractures to be more difficult.

Brain Metastases

As therapies have improved and prolonged survival, brain metastases may develop in up to half of patients with HER2 positive secondary breast cancer¹⁶. Please note that this is a higher rate than other subtypes of breast cancer¹⁷.  Typically, whole brain radiation and/or surgery is the course of treatment if HER2 positive cancer has spread to the brain.

For those who are receiving targeted HER2 therapy, trastuzumab, treatment should be discontinued if disease progresses and metastases outside of the central nervous system. If the metastases are solely within the central nervous system, trastuzumab treatment does not need to be discontinued¹⁸.

And that’s HER2-positive secondary breast cancers treatments summed up

We hope that you now better understand your treatment options and can feel confident in discussions with your care team. At OWise, we want to make sure you are kept informed so make sure to follow our Instagram and Facebook for any updates. Any questions? Get in touch!

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References

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