Biomarkers, targeted and immunotherapies for breast cancer

This section covers the following topics:

• Tumor biomarker testing for treatment selection
• Genetic testing for inherited mutations for treatment selection
• Tumor biomarker testing for prognosis
• PARP inhibitors
• Immunotherapies
• Other targeted therapy

Biomarker testing for treatment selection

Biomarker tests look at samples of blood, tumor or other tissue for changes or abnormalities caused by cancer. These tests can give doctors clues about the cancer, including:

• how fast the cancer is growing
• which treatments are most likely to work
• whether or not the cancer is responding to treatment or growing
• whether or not the cancer has come back after remission

Biomarker tests may be used to select treatments, and help patients avoid side effects from treatments that will not work for them. Biomarker tests used to select a specific treatment are sometimes called "companion diagnostic tests." These tests may be done on tumor tissue or (in many cases) on blood. See our Biomarker Testing section for more information. 

HR (ER and PR) and HER2

After breast cancer tissue is removed by surgery or biopsy, all breast cancers should be tested for three common biomarkers:

• Hormone receptors (HR): These are also sometimes called estrogen and progesterone receptors (ER/PR).
  • Cancers that test positive for estrogen and progesterone receptors are known as HR-positive. They may also be called ER/PR-positive. These cancers are often treated with hormone therapies. 
  • Cancers that test negative for estrogen and progesterone receptors are known as ER/PR-negative or HR-negative. These cancers are not usually treated with hormone therapy. 
• HER2 is a protein that is found on all breast cancer cells. Tests measure the amount of HER2 protein in the tumor and provide a HER2 score from 0 to 3+.
  • Cancers with a score of 3+ are considered HER2-positive. These cancers are often treated with drugs called "anti-HER2 agents."
  • Cancers with a score of 1+ or 2+ are considered HER2-low. This is a relatively new label for breast cancer. In the past, these cancers would have been called HER2-negative or borderline. Advanced HER2-low breast cancers may be treated with the anti-HER2 agent Enhertu (T-DXd). 
  • Cancers with a score of 0 are called HER2-negative. These cancers are not treated with anti-HER2 agents.

Biomarkers for Advanced Breast Cancer

For people with advanced breast cancer, additional biomarker testing may be done to study the genes and proteins within the cancer to help doctors choose the best treatment. Some treatments will work best for people whose cancer cells have specific changes. These treatments are sometimes called targeted therapies. The biomarker test for a specific targeted therapy is sometimes called a companion diagnostic test. Some tests look for only one biomarker at a time. Examples of single biomarker tests for breast cancer include:

• ESR1 mutation: Testing for ESR1 can help find people who will benefit from treatment with the SERD, Oserdu (olacestrant). 
• PIK3CA: Testing for this gene in advanced ER-positive, Her2-negative breast cancer can help find people most likely to respond to the medication PIQRAY (alpelisib).  
• PD-L1: Testing for the PD-L1 protein can help find people with advanced triple-negative breast cancer (TNBC) who are most likely to respond to the immunotherapy drugs Tecentriq (atezolizumab) and Keytruda (pembrolizumab).
• HER2-low: Testing for HER2 is standard-of-care for all breast cancer. In the past, cancers were labeled HER2-positive or HER2-negative. New research shows that the drug Enhertu (trastuzumab-deruxtecan or T-DXd) can be used to treat advanced breast cancers that are HER2-low.

If you have advanced or metastatic breast cancer and were told your cancer is HER2-negative or triple-negative, it's important to find out more about your HER2 test scores. Cancers that were labeled as HER2-negative in the past may be HER2-low. Some people with advanced or metastatic HER2-low cancers may benefit from the drug Enhertu. 

Panel tests look for multiple markers, including FDA-approved treatments as well as those that have not yet been proven effective in breast cancer. Examples of multiple biomarker tumor tests for breast cancer include:

• FoundationOne
• MSK-IMPACT
• Tempus xT

Genetic tests for inherited mutations for treatment selection

Genetic testing for an inherited mutation may be used to guide treatment selection for people diagnosed with breast cancer.  

• People with advanced breast cancer who test positive for an inherited BRCA1 or BRCA2 mutation may benefit from treatments known as PARP inhibitors. Two PARP inhibitors—Lynparza and Talzenna—are approved as targeted therapy for treating advanced breast cancer in people with a BRCA1 or BRCA2 mutation.
• Lynparza may be used to as maintenance therapy after treatment for people with an inherited BRCA1 or BRCA2 mutation who have early-stage breast cancer this is high risk for recurrence. 
• People who test positive for other inherited gene mutations may qualify for clinical trials looking at targeted therapies to treat hereditary breast cancer. 

Tumor biomarker tests for prognosis in early-stage breast cancer

These tests are used for people with early-stage ER/PR-positive cancers to predict:

• if the cancer is likely to come back
• the benefit of adding chemotherapy to the treatment plan
• how long hormonal therapy should be used

Some examples of the most commonly used prognostic tests for breast cancer are listed below:

• Oncotype Dx™ 
• Breast Cancer Index™ 
• MammaPrint™ 
• Prosigna™ 

PARP inhibitors 

PARP inhibitors work by blocking a protein used by cells to repair damaged DNA. They were initially developed to treat cancers in people with an inherited gene mutation BRCA1 or BRCA2 mutation.

• For metastatic breast cancer, two PARP inhibitors have received FDA-approval as targeted therapy for treating people with an inherited BRCA mutation:
  • Lynparza (olaparib) 
  • Talzenna (talazoparib)  
• For people with early stage breast cancer at high risk for recurrence:
  • Lynparza may be used as maintenance therapy after chemotherapy in people with an inherited BRCA1 or BRCA2 mutation. Although the FDA has not yet approved Lynparza for this indication, doctors may still prescribe it off-label. Several expert guidelines now include recommendations for Lynparza for patients with high-risk, early stage breast cancer and a BRCA1 or BRCA2 mutation. 

Research is ongoing to learn if PARP inhibitors are affective for treating breast cancer in other situations, including:  

• people with an inherited mutation in a different gene that repairs DNA damage (for example: PALB2, ATM or CHEK2).
• people who do not have an inherited gene mutation, but their tumor tested positive for an acquired mutation in a gene that repairs DNA damage.

Immunotherapies 

Immunotherapies are cancer treatments that help the body’s immune system detect and attack cancer cells. Immune checkpoint inhibitors are a type of immunotherapy used to treat several types of cancer, including breast cancer. Some cancer cells produce proteins which can switch off immune cells and keep them from attacking. Immune checkpoint inhibitors are drugs that prevent cancer cells from switching off immune cells. This allows the immune system to find, unmask and destroy cancer cells. Immune checkpoint inhibitors are approved for treatment of the following types of breast cancer. 

• Keytruda (pembrolizumab) is approved in combination with chemotherapy for treatment of triple-negative breast cancer that is metastatic or locally recurrent and unresectable that tests positive for a biomarker called PD-L1.
• Keytruda is approved for the treatment of early-stage triple-negative breast cancer that is at high risk for recurrence. In this setting, Keytruda is used along with chemotherapy as neoadjuvant therapy before surgery. Following surgery, Keytruda is continued alone.

See our Immunotherapy section for more information. 

Other targeted therapies

Targeted therapies are treatments that act on certain molecules or targets within cancer cells to prevent the cancer cells from growing or spreading while sparing normal cells. Tumor biomarker testing can help doctors identify the patients most likely to benefit from a targeted therapy. Common targeted therapies used in breast cancer include:

• HER2-positive breast cancers are often treated with drugs that target the HER2 protein. Common anti-HER2 therapies include Herceptin (trastuzumab), Perjeta (pertuzumab) and Tukysa (tucatinib), Phesgo (pertuzumab, trastuzumab and hyaluronidase) and Enhertu (fam-trastuzumab-deruxtecan-nxki or T-DXd).
• HER2-low advanced or metastatic breast cancers may be treated with the anti-HER2 drug Enhertu. 
• People with ER/PR-positive advanced breast cancer are often treated with CDK4/6 inhibitors. CDK4/6 inhibitors target proteins found in some breast cancers called CDK inhibitors. The three CDK4/6 inhibitors approved for use in breast cancer are: Ibrance (palbociclib), Kisqali (ribociclib) and  Verzenio (abemaciclib).
• The drug Piqray (alpelisib) is FDA approved for people who have advanced, ER/PR-positive breast cancer who test positive for a tumor biomarker called PIK3CA. PIK3CA is an acquired gene mutation found in some ER-positive breast cancers. 

Table of targeted and immunotherapies for breast cancer