Breast cancer is the second most common cancer among women, but it is important to remember that men can also have breast cancer. Recent advances in therapy have led to the discovery of specific biologic markers (biomarkers) in cancer cells, which has further led to the development of drugs known as targeted therapies. These drugs target a specific biomarker that is involved in the growth and progress of cancer cells, blocking (or inhibiting) its activity and thus stopping the progression of the cancer, or its recurrence (coming back).
Unlike chemotherapy drugs, which attack all fast-growing cells, including healthy cells, targeted therapies target the biomarker and block only the growth and spread of cancer cells, sparing healthy cells.
“In the past, our approach toward all cancer has been onesize- fits-all, and everyone with the same cancer type basically got the same treatment. But now, biomarkers can be used to make our therapies more efficient,” Daniel F. Hayes, MD, FACP, FASCO, Professor of Breast Cancer Research at the University of Michigan Comprehensive Cancer Center, and former president of the American Society of Clinical Oncology, said in an interview with CONQUER magazine.
“Actionable biomarkers,” Dr. Hayes said, are biomarkers that match a specific therapy to a specific biomarker. The main actionable biomarkers in breast cancer today include the presence or absence of the hormone receptor (HR), HER2 gene amplification, and a BRCA1 or BRCA2 genetic mutation (abnormal changes), an inherited type of mutation.
Hormone Biomarkers: HR, ER, PR
Some breast cancer cells develop and grow when they contain 1 of the 2 types of the HR— the 2 female hormones, estrogen and progesterone. An HR test can determine if the breast cancer cells contain the estrogen receptor (ER) or the progesterone receptor (PR). HR-positive breast cancer means that the cancer cells use estrogen (called ER-positive breast cancer) to promote the growth of the tumor. Therefore, knowing the HR status of a patient helps to determine if the cancer is likely to respond to anti-estrogen (or endocrine) therapy.
The majority of breast cancers are HR-positive (or ER-positive); this type of breast cancer is particularly common among older women. Testing for HR status is done with a tissue biopsy, which helps to determine the best approach to treatment.
For patients with ER-positive early-stage breast cancer, additional genomic (tumor-specific biomarker) testing can be done to predict the risk that the cancer will metastasize (spread). The test results will help to determine whether the use of chemotherapy plus targeted therapy is needed for those at risk for metastatic disease, or if targeted therapy alone is appropriate.
This is one way in which the use of biomarker testing has helped to reduce the use of chemotherapy in women whose breast cancer is not likely to spread, according to Dr. Hayes.
For patients with HR-positive breast cancer, treatment usually begins with endocrine therapy. Endocrine (or hormone) therapy is now often used in combination with targeted therapies, which have been approved by the FDA in the past few years, including Ibrance (palbociclib), Kisqali (ribociclib), or Verzenio (abemaciclib); these targeted therapies specifically target biomarkers known as CDK4 or CDK6. In addition, Afinitor (everolimus), an mTOR inhibitor, blocks the activity of another biomarker, the mTOR protein.
The HER2 Biomarker
The other important biomarker in breast cancer is the HER2 gene amplification, which plays a critical role in cancer development in about 20% of patients with breast cancer. Normally, the HER2 gene makes HER2 proteins that help to control how healthy cells grow, divide, and repair themselves. But when cancer cells have too much of HER2 proteins, the growth of cancer cells is accelerated.
“We recommend that every biopsy of a breast cancer be tested for estrogen receptor, progesterone receptor, and HER2,” Dr. Hayes said. “And we recommend repeating those tests on every biopsy taken, because they drive therapies so accurately.”
HER2-positive breast cancer can be HR-positive or HR-negative; therefore, anti-HER2 therapies and endocrine therapies may be given to the same patient. A biomarker test to determine the HER2 status of breast cancer is therefore necessary to determine the best therapy. In the past 3 decades, anti-HER2 therapies have improved outcomes, including longer survival, in these patients.
Increasing numbers of FDA-approved targeted therapies are available today for patients with HER2-positive breast cancer, including Herceptin (trastuzumab), Herceptin Hylecta (trastuzumab and hyaluronidase injection), Perjeta (pertuzumab), Tykerb (lapatinib), Nerlynx (neratinib), and the most recently approved, Tukysa (tucatinib). Tukysa was approved in April 2020 for those with advanced-stage HER2-positive breast cancer or with cancer that cannot be removed by surgery.
In addition, several newer drugs have been developed as biosimilar to Herceptin and have recently been approved by the FDA for HER2-positive breast cancer, including Ogivri, Herzuma, Ontruzant, Trazimera, and Kanjinti.
Another Herceptin-based therapy, Kadcyla (ado-trastuzumab emtansine) can be used in early- stage or late-stage breast cancer after Herceptin stops working when the cancer is still producing HER2. One more type of Herceptin-based drug recently approved by the FDA is Enhertu (fam-trastuzumab deruxtecan).
BRCA1 & BRCA2s: Inherited Mutations
Unlike (tumor-specific or somatic) mutations that develop over time in the body and are not inherited from a family member, BRCA1 and BRCA2 mutations are inherited from a parent and are known as hereditary (or “germline”) mutations. Having this type of gene mutation increases the risk of breast cancer— in women as well as in men.
According to the National Cancer Institute, about 70% of those who inherit a BRCA mutation will have breast cancer by age 80. Therefore, when someone in the family has been diagnosed with breast cancer linked to the BRCA1 or BRCA2 mutation, it is recommended that other family members be tested for this mutation as well.
“Knowing whether a person has a BRCA1 or BRCA2 mutation is important,” Dr. Hayes said. That is because having that mutation increases the risk of breast cancer; in addition, if a person who has this mutation is diagnosed with breast cancer, knowing this will help the doctor to choose the best treatment available today for those with the BRCA mutation.
Because BRCA1 and BRCA2 mutations are inherited from the father or the mother, anyone who has a family member who is known to have that mutation is considered to have a high-risk family for the BRCA mutation and should have genetic testing to check for the presence of that mutation. The risk of carrying a BRCA1 or BRCA2 mutation in the average population is rather low and, therefore, not everyone should be tested, but those who come from a high-risk family for this mutation should be tested.
Certain populations, such as Jewish families from an Eastern European background, are at increased risk for that mutation, regardless of gender. Another population at risk for this genetic mutation are patients with triple- negative breast cancer (TNBC), meaning cancer that does not have the ER, PR, or HER2 biomarkers (ER-, PR-, and HER2-negative cancer).
Patients with TNBC may also benefit from having a test for the BRCA biomarker. According to Dr. Hayes, as many as 20% of women with TNBC have an inherited BRCA1 or BRCA2 mutation. “So, many physicians are recommending that those patients be tested for the gene mutation,” he said.
Having a BRCA mutation increases the risk for getting a second cancer; therefore, people with breast cancer and have a known risk for BRCA mutation should have a genetic test for BRCA1 and BRCA2. This will enable them to take precautions to prevent a new (second) cancer down the road, Dr. Hayes recommends.
Recently, a class of drugs known as PARP inhibitors, which block another gene that repairs DNA mistakes (mutations), has shown to improve outcomes for patients with BRCA1 or BRCA2 mutation. Currently, the FDA approved the PARP inhibitors Lynparza ( olaparib) and Talzenna (talazoparib) for the treatment of patients with BRCA-positive breast cancer.
So overall, testing for non-hereditary biomarkers as well as hereditary mutations in patients with breast cancer can help to ensure they receive the best available treatments. New targeted therapies are constantly being developed for breast cancer. All patients with breast cancer should ask their doctors about testing for the different breast cancer biomarkers, and what test is best for them.