What’ve hormones got to do with it?

Secondary HR+ Positive Breast Cancer

Two women holding hands

In the final blog of our series, we want to share with you reliable information surrounding advanced breast cancer and the available treatments. Nearly a third of people diagnosed with earlier stages of breast cancer will eventually develop advanced disease1,2. 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 through3,4. As part of our campaign this Breast Cancer Awareness Month, we are advocating to increase awareness of all types of breast cancer alongside the treatments available. In this blog, we will be sharing with you accessible treatments for advanced hormone receptor positive, HER2 negative breast cancer (if you are HER2 positive, head to our previous blog). 

What is hormone receptor positive HER2 negative advanced breast cancer?

Secondary breast cancer (also called advanced, metastatic or stage IV)  is a breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body. Hormone receptor positive (ER positive) HER2 negative metastatic breast cancer indicates that cancer cells grow in response to the hormones oestrogen and progesterone but not in response to the protein HER2. Although it is possible to be initially diagnosed with metastatic breast cancer (called “de novo metastasis”) it is more common to develop metastatic disease after having previously had surgery to treat a localised breast cancer. In fact, a study that looked back at 60,000 women with ER positive localised breast cancer after hormone therapy showed that even some patients with low risk breast cancer (<2 cm tumours, lymph node negative) develop metastatic cancer5. Women that finish hormone therapy five years after having surgery still have a risk of cancer coming back. Therefore, in order to reduce this probability and increase survival, understanding drug resistance, managing side effects so patients can continue treatment and have a great response to therapy is key. 

“Something to look forward to is what everyone does. You might have to scale it back from not looking forward to something that is in five years time, but if you can look forward to something that is in three weeks and something that is in three months, and dare to plan it and dare to believe you be able to enjoy it and you will, you will be able to”6 Diane, secondary breast cancer patient

Your treatment options 

We have pulled together all the different treatment options for ER positive, HER2 negative metastatic breast cancer that are available on the NHS. We have classified them into four types: hormone therapy, CDK4/6 inhibitors, PIK3/mTOR inhibitors and chemotherapy. In this blog, we are going to identify them all, explain how each work and whether or not they have been approved by the National Institute for Health and Care Excellence (NICE), or by its Scottish counterpart’s, the Scottish Medicines Consortium (SMC) and the Scottish Intercollegiate Guidelines Network (SIGN) which approve new drugs and create guidelines, respectively. If you have locally advanced breast cancer (stage III) where the cancer has spread to the surrounding skin, lymph nodes or chest wall, these treatments will also be available to you. 

Hormone therapy 

The goal of therapy in this type of cancer is to decrease oestrogen production and/or activity. Thus, all of the hormone therapies look to break the pathway by which oestrogen molecules are produced and interact with breast cancer cells In fact, these therapies can control secondary breast cancer for long periods of time and they are usually the treatment offered as first line therapy.

First line therapy refers to the first treatment given for a disease. If this doesn’t cure the disease or causes severe side effects, then second line therapy would be given, and so forth.
Ovarian suppression 

Ovarian suppression is a first line therapy for premenopausal women with secondary breast cancer. Decreasing or stopping ovarian oestrogen production with drugs, such as goserelin (Zoladex®) and Lupron®, or by a surgical removal of the ovaries improves survival7,8.

Aromatase Inhibitors 

Aromatase is a protein that converts androgens (created in the adrenal glands) into oestrogens in the fat, liver, muscle or brain cells. Aromatase inhibitors such as Letrozole (Femara®), Anastrozole (Arimidex®) or Exemestone (Aromasin®) inhibit this conversion, decreasing oestrogen levels in the body. These drugs are used in women who are postmenopausal as they improve progression-free survival compared to other therapies such as tamoxifen7,9. Diagram explaining aromatase inhibitors

Tamoxifen

Tamoxifen binds directly to the oestrogen receptor (ER) of breast cancer cells, reducing oestrogen activity. It is recommended by NICE along with ovarian suppression for men and premenopausal women10. To know more about tamoxifen and aromatase inhibitors, head to our previous blog. Diagram showing how tamoxifen works

Fulvestrant

Fulvestrant (Faslodex®) blocks the oestrogen pathway through a different method to tamoxifen. It binds to the oestrogen receptor (ER) and degrades/breaks this receptor. Therefore, if the oestrogen receptor is degraded, oestrogen cannot bind and drive cancer growth. Fulvestrant is normally offered alongside other therapeutics (find out more below), and is not recommended as an alternative to aromatase inhibitors11.

Why do some patients become resistant to hormone therapy?

Although many people with ER positive breast cancer respond well to hormone therapy, a percentage may become resistant to this treatment after a number of years. Recent studies have looked at the genetics of metastatic ER positive tumours and have found some ways by which cancer cells outsmart hormone therapy. In other words, cancer cells change over time and use alternative pathways to grow. This means that they may no longer be dependent on oestrogen (ER negative) and therefore hormone therapies are not effective.  One of the suggested mechanisms points to the oestrogen receptor itself. Mutations in the oestrogen receptor can cause resistance to aromatase inhibitors12,13. Therefore, in cases with ER mutations, some studies suggest that therapies that degrade the receptor can be more effective, such as fulvestrant,14. In fact, patients that become resistant to hormone therapy can benefit from the CDK4/6 inhibitor abemaciclib (described below) in combination with fulvestrant as a second line treatment15 Diagram showing drug resistance

CDK4/6 inhibitors 

CDK4/6 inhibitors are a class of oral drugs that inhibit proteins called CDK4 and CDK6. These proteins are important in cell division.  Cells have a cell cycle which consists of growing, making DNA (genetic material) and then dividing into more cells. This cell cycle is tightly controlled by many proteins, including CDK4 and CDK6. Therefore, if these proteins are blocked, the cell cycle is interrupted and growth and division are stopped16 Abemaciclib (Verzenio®), palbociclib (Ibrance®) or ribociclib (Kisqali® ) in combination with an aromatase inhibitor are recommended as a first line treatment by NICE for previously untreated metastatic breast cancer7. In fact, clinical trials have demonstrated that these treatments improve survival for around 10 months versus using an aromatase inhibitor alone17,18,19,20. However, currently there are no biomarkers to predict the response to these therapies17. Abemaciclib, palbociclib or ribociclib in combination with fulvestrant can also be prescribed for secondary patients treated previously with hormone therapy (second line therapy) under the Cancer Drug Fund, only if Everolimus combined with exemestane (described below) is the only possible alternative7

What is the Cancer Drug Fund? The Cancer Drugs Fund is part of the British organisation that reviews new and existing drugs, called NICE. It was made to fund new drugs and accelerate the process of drugs becoming available in England. If there are recently developed treatments that may be of benefit to you, your specialist will fill out an application on your behalf. To find out more about Cancer Drugs Fund, head to Cancer Research UK’s website.

 

“This is absolutely fantastic news and will now open the door for thousands of women who have received prior hormone therapy to benefit from innovative CDK 4/6 inhibitors, which until now had only been available to newly-diagnosed patients with locally-advanced or metastatic breast cancer.” Baroness Delyth Morgan, Chief Executive at Breast Cancer Care and Breast Cancer Now21.

iPhoneXS Trends - FatigueCDK4/6 inhibitors can cause a severe decrease in white blood cells (immune cells). Because of this, palbociclib and ribociclib are followed with a seven-day break to allow white blood cell levels to recover. Abemaciclib can be given continuously however fatigue and diarrhea are often experienced. Liver and heart function tests may also be carried out22. Do 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.  

Everolimus

Everolimus is a targeted therapy that blocks the protein mTOR. This protein affects how cells grow and divide. Everolimus with the aromatase inhibitor exemestane is recommended if other treatments such as hormone therapy are ineffective, due to its success in increasing progression-free survival. As with CDK4/6 inhibitors, there are no biomarkers that predict the response to everolimus, so it cannot be determined prior to treatment if it will be effective for your specific breast cancer23  Some of the most common side effects of this therapy are high blood sugar/diabetes, mouth sores, lung inflammation and fatigue. Interestingly, a study found that steroid mouth rinse improves mouth sores from everolimus24. Due to its severe side effects, CDK4/6 inhibitors alongside fulvestrant are the preferred treatment20

Did you know that Everolimus (Rapamycin) was discovered in Easter Island “Rapa Nui”?25.

 Chemotherapy

The most common chemotherapy regimen recommended by the NHS includes both a taxane:

  • Paclitaxel (Taxol®), nab-paclitaxel (Abraxane®) or docetaxel (Taxotere®)

And an anthracycline:

  • doxorubicin (Adriamycin®), epirubicin (Ellence®), doxorubicin (Doxil®), daunorubicin (Cerubidine®) or mitoxantrone (Novantrone®).

For patients who are not suitable for anthracyclines, docetaxel is offered as first-line treatment, followed by vinorelbine or capecitabine7Gemcitabine can be used when it is combined with paclitaxel, and after other chemotherapy medicines like anthracyclines have either not worked or were considered unsuitable7 During the COVID-19 pandemic,  chemotherapy regimens have slightly changed.  Some common   intravenous chemotherapy  drugs  (e.g   Taxol®)  are being  replaced  by oral chemotherapy   pills   such   as   Capecitabine   (Xeloda®), and Abraxane® might be prioritised over Taxol® due to its reduced toxicity (fewer side effects) (if you want to understand the difference between Taxol and Abraxane, head to this Instagram post)26.

After chemotherapy: Eribulin 

The chemotherapy drug eribulin is recommended after two or more chemotherapy regimens with anthracycline or taxane, and capecitabine. The most common side effects of this therapy are hair loss, nausea, low white cell counts, fatigue and numbness or tingling7.

Did you know that eribulin (aka Halaven®) was created using a sea sponge?

It’s modelled from halichondrin B, which was first discovered in 1986 in marine sponges. Due to its complexity and the lack of it naturally, a synthetic version was made. 

Metastases

Bone metastases

If your breast cancer has spread to your bones, there are an array of treatments that you could be offered for both preventing fractures and other bone-related problems, as well as pain management. 

Bisphosphonates and Denosumab

There are multiple bisphosphonates available, namely zoledronic acid (Zometa®) and ibandronate (Bondronat®), which can be offered either orally or through injections27. They act through targeting the cells that break down old bone. In bone metastases, where there is already a deficit of healthy bone cells, bisphosphonates stopping bone cell breakdown can make the bone denser and less likely to fracture28 Denosumab is a type of targeted therapy called a monoclonal antibody (find out how monoclonal antibodies work in our blog). These can be offered instead of bisphosphonates, even though their function is the same. Rather than being absorbed by the cells that break down bone, as bisphosphonates are, denosumab targets a protein that controls the cells.  A review of denosumab found that it was more clinically effective than bisphosphonates in terms of the length of time before skeletal-related events occurred. There were also less side effects in the kidneys. As denosumab is administered through an injection under the skin, it decreases the number of trips needed to the hospital27.

Brain metastases

Whole brain radiotherapy will be offered to people who have a single or small number of metastases in their brain that could be resectable and to those whom surgery is not appropriate29.

Pain relief 

There are accessible treatments that have been shown to effectively control pain during secondary breast cancer. You will initially be given mild pain relief which can then develop to moderate and then strong pain relief when necessary.  Morphine-based pain relief has been shown to be effective in controlling many types of pain. Morphine is taken through oral pills, patches or injections under the skin30. Some of the most common morphine side effects include sleepiness, constipation and nausea. It is also important to remember that it is illegal to drive when using morphine. Interestingly, this is not the case in Scotland31 Doctors often use several other types of drugs to help manage pain. These include:

  • Anti-inflammatory drugs, such as ibuprofen, diclofenac or naproxen steroids. 
  • Anti-depression and epilepsy drugs, which can also help relieve certain types of pain.

Future treatments 

Treatment for advanced ER positive breast cancer is constantly developing. With better understanding of the biology of cancer cells, new therapies can be created. Here we have listed the therapies that are currently being studied. 

Advanced Genomic Profiling

In breast cancer, treatment options are decided depending on the presence of oestrogen receptors or HER2 on breast cancer cells. This does not highlight the changes from tumour evolution, causing cases such as the hormone therapy resistance described earlier. To allow for more targeted therapies, advanced genomic profiling provides a more in-depth understanding of your breast cancer type. Through rigorously searching your DNA, changes in genes are identified that could make you eligible for different treatments or clinical trials.  Certain changes in genes can make you eligible for a specific treatment. An example of this is in the gene PIK3CA, which makes you eligible for alpelisib (see below). Other findings are not as direct as these, and it is the accruing of various factors that will help decide the best treatment option for you. If you are not responding to your current treatment, we suggest researching the potential of genomic profiling. Although unavailable on the NHS at present, there are multiple companies that provide the service which can be refundable through healthcare insurance. It is vital to note that you should discuss this with your oncologist. Together you can decide whether it could improve your treatment. 

Companies providing advanced genomic profiling:
Anti-TROP2

Initially created to target triple negative breast cancer, anti-TROP2 therapy may have potential in ER+, HER2- breast cancer. The therapy, sacituzumab govitecan, targets TROP-2, which is vital for cancer growth. A study in 2018 found that this could be a feasible treatment option with response rates comparable to those seen in CDK4/6 inhibitors32. Further trials are currently ongoing to compare its benefit compared to chemotherapy after 2-4 previous regimens33

Alpelisib (Piqray®) with fulvestrant

A study found that the addition of alpelisib alongside fulvestrant improved overall survival by 8 months34. Alpelisib is a type of targeted therapy that targets a certain protein variation present in some types of breast cancer. Normally the protein, called PI3K, helps all cells get the energy they need. If there is a change, then PI3K works a lot quicker than normal, allowing cancer cells to survive and grow35. The inclusion of alpelisib will depend on the presence of this mutation in your cancer cells. It is thought that 40% of HR+, HER2- breast cancer are positive for this mutation36. The possibility of alpelisib remains optimistic. However the treatment has currently not been accepted by NICE, due to insufficient evidence from the pharmaceutical company that created the drug, Novartis37.

PARP inhibitors 

Another form of treatment tailored to your genetic profile are PARP inhibitors. This treatment is offered to people who are BRCA positive. The most well known of these, olaparib, is currently under review for NHS patients with breast cancer, waiting for the manufacturer to submit new data. At this given time, PARP inhibitors are usually only available on the NHS as part of a clinical trial for people with secondary-breast cancer and an altered BRCA gene. 

Combined Immunotherapy 

Cancer immunotherapy, which includes monoclonal antibodies such as Herceptin, have been successful in improving survival, however its success have been limited to subsets of the population. MORPHEUS trial is currently studying the effect of combining immunotherapy with chemotherapy or targeted therapy. This is using the drug atezolizumab, a monoclonal antibody, used in triple negative breast cancer and HR+ breast cancer38

HDAC inhibitors 

A new method of targeting individuals specific breast cancer cells is through inhibiting histone deacetylase. The treatment (HDAC’s), including tucidinostat and entinostat,  block the function of histone deacetylase, a protein vital in the process of cell growth. Tucidinostat was found to significantly improve progression-free survival compared to having the aromatase inhibitor exemestane alone. This could pose as a new treatment options for postmenopausal women with advanced breast cancer who have not responded to hormone therapy. However, adverse side effects were noted in 50% of the patients given the drug, and therefore further research is necessary39.

And that’s all the treatments summed up for advanced hormone receptor-positive breast cancer.

We hope that you now better understand your treatment options and can feel confident in discussions with your care team. Our aim is to make sure you are kept informed so make sure to follow our Instagram and Twitter accounts for any updates.  If you found this article useful and would like to share it with anybody, head to the share icons at the bottom of this page.

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References

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