Immunotherapy for Breast Cancer

Immunotherapy drugs for breast cancer have until recently been relatively ineffective when compared to the sometimes dramatic responses to these drugs in cancers such as melanoma and lung cancer. This changed in March 2019 with the accelerated approval of the drug Tecentriq (atezolizumab) for women and men with metastatic (stage 4) or locally advanced and unresectable triple negative breast cancer. The approval comes along with a companion test to help select which people who might benefit from the treatment.

The drug Keytruda (pembrolizumab) may also be used for some people with metastatic breast cancer that has a particular molecular alteration.

Basics of Immunotherapy

Immunotherapy is a treatment that uses the immune system or products of the immune system to fight cancer. It is based on the knowledge that our bodies already know how to fight cancer, and it is this immune response that is thought to underlie the rare but well-documented spontaneous regression of cancer that occurs in some people.

Despite having immune cells in our bodies that seek out and destroy cancer cells, specifically T cells, cancers have unfortunately discovered ways to evade the immune system. They may do so by essentially putting on a mask so they can hide, or by secreting chemicals that suppress the immune response.

Immunotherapy for Breast Cancer

Despite improvements in survival rates with the use of immunotherapy drugs in challenging-to-treat cancers such as metastatic lung cancer and melanoma, it was thought that these drugs would be less effective for breast cancer. This makes sense when considering situations in which these drugs tend to work better or worse.

Checkpoint Inhibitors

The immunotherapy drugs that may currently be used (outside of a clinical trial) for breast cancer are referred to as checkpoint inhibitors. In the immune system, there are several checkpoints that ensure that the immune system isn't overactive. In fact, conditions known as autoimmune diseases are related to an immune system run amok that then attacks normal tissues in the body.

If you think of the immune system as a car, checkpoints are the brake pedals. In this analogy, checkpoint inhibitors are drugs that remove the foot from the brake pedal so that the immune system can speed up its job of eliminating foreign material and cells.

Checkpoint inhibitors tend to be more effective for tumors that have high levels of a protein called PD-L1 or a high mutational burden. Mutational burden refers to the number of mutations present in a tumor.

Since cells with more mutations should theoretically appear more abnormal, when the immune system is unleashed to attack it should recognize cells with more mutations better than cells containing fewer mutations. With lung cancer, people who have smoked tend to have tumors containing a significantly greater number of mutations than lung cancer tumors in people who have never smoked, and people who have smoked tend to respond more to these drugs than never smokers.

In general, breast cancer cells have significantly fewer mutations than some other types of cancer.

In addition, using immunotherapy drugs alone for breast cancer (single-drug therapies), rather than combining the drugs with chemotherapy, has resulted in little effect on breast tumors due to a low number of tumor-infiltrating lymphocytes (a type of white blood cell) in most breast cancers.

Tecentriq (Atezolizumab) for Triple Negative Breast Cancer

Tecentriq (atezolizumab) is approved for both women and men with breast cancer that is triple negative (breast cancers in which estrogen receptor, progesterone receptor, and HER2 status are negative). The drug is also approved for bladder cancer and stage 3 non-small cell lung cancer when surgery is not possible. While it is still too early to determine the overall survival benefit, findings thus far are encouraging.

Tecentriq is a PD-L1 antibody that works by blocking PD-L1. PD-L1 (programmed death ligand 1) is a protein that is found on the surface of some cancer cells that prevents the immune system from attacking the cell. Tecentriq blocks PD-L1, essentially taking the mask off of the cancer cell so that the immune system can recognize and then attack the cell.

Testing

Before Tecentriq can be used for people with triple negative breast cancer, a companion test must be done (the VENTANA PD-L1 Assay) to determine who may respond to the drug. Tecentriq is most effective in people who have high PD-L1 expression, or a large amount of the PD-L1 protein on the surface of the breast cancer cells. The test is considered positive when PD-L1 stained tumor-infiltrating immune cells cover one percent or more of the tumor area.

Effectiveness

When considering the option of using Tecentriq for breast cancer, it's helpful to look at its effectiveness in studies to date.

In a 2018 study known as the IMPassion 130 trial published in The New England Journal of Medicine, researchers compared the results of Tecentriq used along with Abraxane (nab-paclitaxel), to people treated with Abraxane plus a placebo. (Abraxane is a type of chemotherapy for metastatic breast cancer). The study included 902 people who had not previously received chemotherapy for metastatic disease.

The median progression-free survival (the amount of time at which half of the people had either died or were alive but their tumors had grown or spread, and half were alive without any worsening of their cancer) was 7.4 months in the immunotherapy group in contrast to 4.8 months in the group that received Abraxane alone. Objective response rates were seen in 53 percent of people in the immunotherapy group vs. only 33 percent in the group without immunotherapy.

In a different 2019 study published in JAMA Oncology, researchers looked at the safety and tolerability Tecentriq in combination with Abraxane in 33 patients with stage 4 or locally recurrent triple negative breast cancer who had received up to two lines of prior chemotherapy. These people were followed for a median of 24.4 months. Responses to treatment were noted even in people previously treated with chemotherapy and, despite side effects, most patients had a manageable safety profile.

How it is Given

In the studies, people received Tecentriq 840 mg (or a placebo) by intravenous infusion on days one and 15 of each 28-day cycle. Abraxane (100 mg/m2) was given intravenously on days one, eight, and 15 of each 28-day cycle. This was continued until cancer progressed or side effects led to discontinuing the treatment.

Side Effects

The most common side effects of treatment with the combination of Tecentriq and Abraxane (occurring in 20 percent or more of people) included:

• Hair loss
• Peripheral neuropathy
• Fatigue
• Nausea
• Diarrhea
• Anemia
• Constipation
• Cough
• Headache
• Neutropenia (a low level of the type of white blood cells called neutrophils)
• Vomiting
• Decreased appetite

Adverse Reactions/Complications

As with most cancer treatments, there are some risks associated with this combination of drugs. Less common but more serious side effects may include:

• Pneumonitis (inflammation of the lungs)
• Hepatitis (inflammation of the liver)
• Colitis (inflammation of the colon)
• Disorders of the endocrine system such as hypothyroidism or adrenal insufficiency
• Infections
• Allergic Reactions

Contraindications

The combination of Tecentriq and Abraxane should not be used in pregnancy as it could lead to birth defects. For women who are premenopausal, effective birth control (but not hormonal therapies such as the birth control pill) should be used.

Cost

Unfortunately, as with many new drugs approved for cancer in recent years, the cost of immunotherapy treatments currently approved is very high.

Keytruda (Pembrolizumab)

The drug Keytruda (pembrolizumab) is also a checkpoint inhibitor that is approved to treat metastatic or inoperable cancer that has either a molecular alteration called MSI-H (microsatellite instability-high) or dMMR (DNA mismatch repair deficiency).

In clinical trials, there is some evidence that Keytruda may also have a role in treating metastatic HER2 positive breast cancer (along with a HER2 targeted therapy such as Herceptin (trastuzumab) with high PD-L1 and high levels of tumor-infiltrating lymphocytes.

Other Types of Immunotherapy in Breast Cancer

While there are not currently any other immunotherapy drugs approved for breast cancer, a number of methods are being evaluated in clinical trials.

Myths surrounding clinical trials abound, and many people express anxiety about participating. It's important to keep in mind that every therapy we currently have approved was once studied in a clinical trial.

Combinations of Immunotherapy and Targeted Therapies

A potential therapy for breast cancer includes combining immunotherapy drugs (checkpoint inhibitors) with targeted therapies such as HER2 targeted therapies, CDK 4/6 inhibitors such is Ibrance (palbociclib), angiogenesis inhibitors such as Avastin (bevacizumab), poly (ADP-ribose) polymerase inhibitors (PARPs), other chemotherapy drugs, and radiation therapy.

Targeting Desmoplasia

Fibroblasts are a type of connective tissue cell that surrounds tumors. An overgrowth of this connective tissue around tumors, a condition referred to as desmoplasia, prevents immune cells from accessing the tumor and is thought to be one of the reasons why breast cancers respond poorly, in general, to checkpoint inhibitors.

A drug that is currently used for bone marrow transplants, Mozobil (plerixafor), targets desmoplasia and may allow checkpoint inhibitors to work more effectively. This concept involving looking at the tissues surrounding a tumor, or the tumor microenvironment, is currently a topic of great interest in the development of better cancer therapies.

Tumor-Infiltrating Lymphocytes (TILS)

Since tumors tend to be much more responsive to checkpoint inhibitors if they have a greater number of tumor-infiltrating lymphocytes, researchers are considering adding these cells to target tumor mutations.

Adoptive Cell Transfer (ACT)

In a clinical trial, one patient with breast cancer experienced a complete remission of metastatic breast cancer with a new form of adoptive cell transfer after failing to respond to any other treatments such as chemotherapy or hormonal therapy.

Therapeutic Vaccines

Clinical trials are currently in progress studying the potential effect of therapeutic vaccines on breast cancer.

Immunotherapy as Adjuvant or Neoadjuvant Therapy

While immunotherapy has been looked at most often as a treatment for metastatic breast cancer, researchers believe it may have a role in the earlier stages of breast cancer as well.

Studies are in place looking at the use of immunotherapy before breast cancer surgery (neoadjuvant immunotherapy) for people with triple negative breast cancer or HER2 positive breast cancer. There are also studies examining immunotherapy after surgery (adjuvant immunotherapy) using the checkpoint inhibitors duralumab and tremelimumab for people with estrogen receptor positive stage 2 or stage 3 breast cancer.

Other Treatments for Metastatic Breast Cancer

In addition to general options for metastatic breast cancer, it's important to note that physicians are increasingly using local treatments for breast cancer metastases. This includes the use of bone-modifying drugs for bone metastases from breast cancer, and sometimes surgery or stereotactic body radiotherapy (SBRT). SBRT is high dose radiation therapy given to a small, localized area of tissue with the intent to eradicate the metastasis.

These treatments are used to try to eliminate areas of spread to areas such as the lungs or brain when only a few metastases are present.

A Word From Verywell

In recent years, progress has been made that can often extend the lives of people with metastatic breast cancer. While the immunotherapy drugs known as checkpoint inhibitors have had sometimes dramatic effects on a few other types of cancer, until recently the role of these drugs in breast cancer treatment has been limited.

Fortunately, a better understanding of the immune system and how these drugs work raises hope that altering factors such as the tumor microenvironment may clear the path around breast tumors so that immunotherapy drugs can be active in breast cancer. Other types of immunotherapy offer hope as well, and many clinical trials are in progress or being planned at the current time.