“I want to be defined by what I am, not by what I am not” – Dr Steven Isakoff (Breast Oncologist) on Triple Negative Breast Cancer

It’s time to focus on Triple Negative Breast Cancer (TNBC). As summed up by Dr Isakoff, TNBC has been defined by not what it is, but what it isn’t. So what is it not? TNBC means the growth of the cancer does not involve estrogen, progesterone (hormones often associated with breast cancer) receptors and HER2 receptors. Most recent treatments have been developed for breast cancer with these receptors. This has meant TNBC has had limited treatment options, namely surgery and chemotherapy. However, recent developments in research have allowed for a better understanding of TNBC and opened doors for new treatment options.   

“From my perspective, this means there is a huge amount of hope. We are clearly improving the treatments in early TNBC. And it clearly seems to me we are improving outcomes and cure rates.” – Dr Peter Schmid, Chair in cancer medicine at Barts Cancer Institute, Queen Mary University of London.

Here we are going to explain the characteristics of triple negative disease, the treatments that are commonly used, as well as newly approved treatments and potential therapies currently undergoing clinical trials.

How common is TNBC?

TNBC represents approximately 10-15% of all diagnosed breast cancers^1,2, with over 30,000 cases diagnosed every year in the US³. This type of breast cancer seems to be more common in African^4,5 and Latina women⁶, as well as in women under 40^7,8. The incidence of TNBC differs per state economic area (SEA). The adjusted TNBC incidence rate for the overall population of the US between 2011 and 2013 was 13.7 cases per 100,000 women per year. The map below shows the incidence rate per SEA³⁵.

For more information about familiar risk and breast cancer genetic mutations, head to our previous blog on BRCA.

What can your pathology report tell you about TNBC?

The analysis of your tissue sample from a biopsy or surgery will indicate that your tumor does not express estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor 2 (HER2). In your pathology results, you may read about the percentage of cells being positive for estrogen and progesterone. If this percentage is less than 1%, the cancer is considered to be hormone receptor-negative. For the HER2 protein, the result would be rated as 0, 1+, 2+ to be considered HER2-negative¹².

Triple negative cancer cells tend to look very different from normal breast cancer cells, which means that the cancer is classified as high grade (e.g. grade 3). Cells that behave in this way tend to have high levels of markers that indicate cell proliferation such as Ki67, p53+ and p63+. This means that the cells grow and divide quickly¹³.

Figure 1. This is an example of stained breast tissue. The brown color indicated the presence of estrogen (ER), progesterone (PR), and HER2 receptors. Tumor 1 is TNBC and tumor 2 is positive for ER, PR, and HER2. Image modified from Adisa et al, 2012³⁴

Testing of the protein PD-L1 (anti-programmed cell death-ligand 1) is approved for TNBC patients. This protein is located on the surface of some cancer cells. PD-L1 protein is recognized by a receptor (PD-1) on the surface of a type of immune cell (T-cell). The immune system is the defense system of the body that protects us against pathogens and disease. Recent research has shown that if PD-L1 is blocked, these immune cells will recognize cancer cells as foreign and would attack them¹⁵. Triple negative patients that are PD-L1 positive may benefit from newly developed therapies (see section below).

To better understand your pathology results, head to our previous pathology report blog.

Treatment plan

We have pulled together all the different treatment options for triple negative breast cancer that are available in the United States. We have classified them into three types: chemotherapy, PARP inhibitors and immunotherapy. In this blog, we are going to identify them all, explain how each work and whether or not they have been approved by the US Food and Drug Administration

The Food and Drug Administration (FDA) is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices; and by ensuring the safety of our nation’s food supply, cosmetics, and products that emit radiation.¹⁶

Chemotherapy

Chemotherapy is a treatment that uses anti-cancer drugs to target and kills fast-dividing cells in the body. It works by interfering with the cancer cells’ ability to divide and grow. It can be provided before surgery (neoadjuvant) or after surgery (adjuvant).

Chemotherapy before surgery

Neoadjuvant chemotherapy can either be anthracycline- or taxane-based chemotherapy. In addition to either of these, platinum chemotherapy is usually added to the regimen³⁶. 

• Platinum chemotherapy drugs include cisplatin, carboplatin and oxaliplatin.
• Taxane chemotherapy drugs include paclitaxel (Taxol®) and docetaxel (Taxotere®).
• Anthracyclines chemotherapy drugs include doxorubicin (Adriamycin®), epirubicin (Ellence®), doxorubicin (Doxil®), daunorubicin (Cerubidine®), mitoxantrone (Novantrone®).

This therapy can reduce the size of cancer and improve the chances of cancer disappearing in both the breast and lymph nodes in the armpit. However, platinum-based chemotherapy can produce severe side effects. This includes anemia which means you have a low number of red blood cells and neutropenia which indicates that you have a low number of neutrophils (immune cells that defend you from viruses and bacteria). It is possible that patients with additional medical conditions receive adjuvant chemotherapy (after surgery) as there is a lower risk of developing these side effects since other chemotherapy drugs are used¹¹. 

Chemotherapy after surgery

The adjuvant chemotherapy regimen recommended by the NHS includes both a taxane and an anthracycline drug¹¹. Taxane chemotherapy drugs include paclitaxel (Taxol®), nab-paclitaxel (Abraxane®) and docetaxel (Taxotere®).

PARP inhibitors

PARP (poly (ADP-ribose) polymerase) is a protein that helps both healthy and cancer cells repair DNA damage, allowing cells to survive and continue to function. PARP inhibitors work by blocking PARP proteins in cancer cells. This prevents them from repairing DNA damage, and often leads to cell death¹⁸. 

PARP inhibitors are a therapy for those with BRCA genetic mutations, which are common among TNBC patients. This is because PARP inhibitors are able to cause the death of cells carrying these genetic mutations. Two of the main PARP inhibitors are Olaparib (Lynparza®) and Talazoparib (Talzenna®). In the US both have been licensed for both early-stage and metastatic BRCA-positive disease²⁰. 

Immunotherapy

Immunotherapy uses the immune system to fight cancer. Therefore, it works by helping the immune system recognize and attack cancer cells. Some types of immunotherapy are also called targeted treatments or biological therapies.

The PD-1 protein is a receptor on the surface of a type of immune cell, called a T-cell (see figure 2 below). Cells in the body have the PD-L1 protein on their surface, this binds to the PD-1 receptor on immune cells and prevents immune cells from attacking human cells. In some cases, cancer cells can have the PD-L1 protein on their surface. The PD-L1 protein on cancer cells can bind PD-1 receptors on immune cells, enabling them to trick the body into thinking that they are normal cells and preventing the immune system from attacking them. Current immunotherapy treatments for TNBC can either block the PD-L1 protein on cancer cells or the PD-1 receptor on immune cells to stop the two from binding.

Pembrolizumab (Keytruda®)

Pembrolizumab blocks the action of the PD-1 protein on immune cells, enabling the immune system to recognize and kill cancer cells. Pembrolizumab is approved to treat early TNBC patients at a high risk of recurrence. High risk means either the tumor size is 1-2cm in diameter with positive lymph nodes or the tumor size is over 2cm in diameter with or without positive lymph nodes. The KEYNOTE-522 study compared treatment before and after surgery with pembrolizumab and chemotherapy or chemotherapy alone. Results showed that the cancer did to come back or spread in 84.5% of patients on pembrolizumab and chemotherapy, compared to 76.8% on chemotherapy alone²⁶.

To be eligible for treatment the tumor needs to have enough of the PD-L1 protein on its surface. In this case, the tumor must have a combined positive score > 10. Pembrolizumab can be given as neoadjuvant treatment (before surgery) with chemotherapy and then as adjuvant treatment (after surgery) alone²⁷.

Atezolizumab (Tecentriq®) with nab-paclitaxel (Abraxane®)

Atezolizumab blocks the PD-L1 protein on cancer cells, preventing it from binding to the PD-1 receptor on immune cells. This enables the immune system to recognize and kill cancer cells. It is approved in combination with the chemotherapy drug nab-paclitaxel (Abraxane®) to treat TNBC that is locally advanced (stage 3), cannot be operated on or is metastatic. This therapy can increase overall survival by around 9.5 months of metastatic or locally inoperable TNBC patients that are PD-L1-positive¹⁵. Immune cell staining must be done to determine if the tumor has enough of the PD-L1 protein on its surface. To be eligible for treatment immune cell staining needs to be > 1%.

Antibody-drug conjugate (ADC)

Sacituzumab govitecan (Trodelvy®) is a promising type of drug called an antibody-drug conjugate (ADC), which means it is made up of a monoclonal antibody linked to a chemotherapy drug. In this case, it is made up of the sacituzumab monoclonal antibody, linked to the chemotherapy drug SN-38. Sacituzumab targets the TROP-2 protein, which is a new protein found in abundance in this type of cancer²⁹. When sacituzumab targets and binds to the cell the chemotherapeutic becomes active, killing the cell. This therapy has now been approved for use as a third line treatment option for TNBC that is locally advanced (stage 3), cannot be operated on, or is metastatic.

Research and new treatments

Research has shown that TNBC is not a single subtype. Recent studies are showing that triple-negative breast cancer can be divided into different groups depending on the molecules/proteins cells express. In fact, triple negative breast cancers are very heterogeneous and have diverse characteristics. For example, using gene analyses, some research groups have identified six different TNBC subtypes: two basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype ²⁸ . These types of classifications are key for finding new therapeutic routes. 

Durvalumab (Imfinzi®) is currently approved to treat non-small cell lung cancer and is being trailed for use in breast cancer. This drug is a type of immunotherapy that blocks the PD-L1 protein on cancer cells. The GeparNuevo clinical trial studied this through treating early TNBC patients with durvalumab combined with chemotherapy or chemotherapy alone. Results showed that after 3 years, 92.5% of patients on durvalumab and chemotherapy were alive, compared to 83.5% on chemotherapy alone ³⁵. This highlights a potential treatment option for early TNBC patients that may become available in the future.

Common side effects

Chemotherapy targets all fast-dividing cells in your body. As cancer cells are fast dividing, it is particularly these cells that are targeted and destroyed. But other fast-dividing cells are also affected, including hair follicles, the lining of the mouth, skin, nails and intestines. That’s why hair loss, brittle nails and diarrhea are very common side-effects. Other very common side effects are sickness and vomiting.

Platinum-based chemotherapy may have severe side effects such as the risk of infection due to a drop in white blood cells (neutropenia), breathlessness and looking pale due to a drop in red blood cells (anemia) and bruising (due to a drop of platelets in your blood). Other platinum side effects include fatigue, feeling sick, loss of appetite, diarrhea, kidney damage, changes to your hearing and to the levels of minerals in your blood ³⁰.

Anthracyclines’ side effects include vomiting, nausea and alopecia. However, it can also cause heart function problems. This is why you might have heart tests to check the health of your heart before and during chemotherapy³¹.

Some common side effects of Atezolizumab (Tecentriq®) are loss of appetite, difficulty breathing, fatigue, diarrhea, feeling sick, skin changes, joint or back pain and urinary tract infections³². Lastly, the main side effects of PARP inhibitors are increased risk of infection, diarrhea, feeling sick, indigestion, headaches and changes to how your kidney and/or liver works³³.

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.

And that’s all of the TNBC treatments summed up

We hope that you now better understand TNBC, the treatment options and that you can feel confident in discussions with your care team. Our aim is to keep you informed with personalized information. You can access this by following our Instagram, Facebook, or downloading OWise.

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References

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