Next to skin cancer, breast cancer is the most common cancer among women, and more than 300,000 new cases of breast cancer are expected in 2018 in the United States. However, men can also have breast cancer. Today, many people diagnosed with early-stage breast cancer can be successfully treated with drugs known as “targeted therapies,” which have been developed to attack a specific biologic marker (or “biomarker”) in the tumor or cancer cells.
Tumor biomarkers are specific molecular changes in the blood, bodily fluids, or tissue of a person with cancer. A tumor biomarker may have one or more tests (or “assays”) to determine its status in a patient. Testing for tumor biomarkers can be used to help guide cancer treatment decisions, as well as the likelihood of a successful treatment or disease recurrence (return).
Daniel F. Hayes, MD, FACP, FASCO
Moreover, biomarkers today offer opportunities to treat people in a way that’s more precise than ever, according to Daniel F. Hayes, MD, FACP, FASCO, Immediate Past President of the American Society of Clinical Oncology (ASCO) and the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Comprehensive Cancer Center.
“In the past, our approach toward all cancer has been one size 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. So, instead of treating all our cancer patients with chemotherapy, we now only treat the people who need it, and who we know for whom it will actually work,” Dr. Hayes told CONQUER in an interview.
Understanding the biology behind tumor biomarkers, researchers are now able to develop targeted drugs that can block only the growth and spread of cancer cells, unlike chemotherapy drugs, which attack all fast-growing cells, including healthy cells. Therefore, the treatment of a patient with breast cancer is often determined by the molecular characteristics of the tumor (or tumor biomarkers) that could be treated with a specific targeted therapy.
In breast cancer, “actionable biomarkers,” those that match an available therapy to a specific biomarker, include hormone receptor (HR) status, HER2 mutations, and the BRCA1 or BRCA2 genetic mutations.
Hormone Receptor Status
Some breast cancer cells only grow when they contain receptors for the female hormones, estrogen and/or progesterone. An HR test shows whether the breast cancer cells contain these receptors, that is, whether the breast cancer is “estrogen receptor” (ER)-positive or “progesterone receptor” (PR)-positive. In HR-positive breast cancer, the cancer cells use estrogen to promote cancer growth. So knowing the HR status of a patient helps to determine whether the cancer is likely to respond to anti-estrogen therapy, or “endocrine therapy.”
Most breast cancers (about 70%) are HR-positive, and the percentage is even higher among older women.1Testing for HR status is done with a tissue biopsy, which helps to determine the course of therapy.
“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.”
For patients with ER-positive early-stage breast cancer, additional tumor profiling (genetic or genomic testing) can be done to predict the risk that the cancer will metastasize (spread to other organs). If a test shows a high risk for metastasis, patients may want to consider a more aggressive treatment that includes hormone therapy and chemotherapy. New therapies have recently been approved for advanced or metastatic breast cancer.
“We have substantial evidence that chemotherapy reduces the chances of your cancer metastasizing by about one-third,” Dr. Hayes said. But if the chances of metastasis are low, the patient does not need to use chemotherapy. “These tests have reduced the use of adjuvant chemotherapy in women who don’t need it,” he added.
Many tumor-profiling tests that look for gene changes in a person with breast cancer are available today, but Oncotype DX is the most common test used in breast cancer in the United States. Oncotype DX tests the tumor for a group of 21 genes. Other tumor-profiling tests include the Breast Cancer Index test, EndoPredict test, Mamma Print test, Mammostrat test, and the Prosigna Breast Cancer Prognostic Gene Signature Assay.2 “Any of the available tests would be reasonable for a patient to use when deciding whether or not to receive adjuvant systemic therapy,” Dr. Hayes said. “However, ASCO urges patients and their doctors to choose one test and stick with it, as opposed to comparing results from various tumor-profiling tests. They may not give the same results, and we do not know which is ‘true’; therefore, having the results of two tests can be confusing.”
Drugs for HR-Positive Breast Cancer
Several drugs are approved today for patients with HR-positive breast cancer. Nolvadex (tamoxifen) is often prescribed to block estrogen from binding to the cancer cells. To decrease the amount of estrogen in postmenopausal women, drugs known as aromatase inhibitors, such as Arimidex (anastrozole), Aromasin (exemestane), or Femara (letrozole), may be used. Another drug often used in postmenopausal women whose cancer has spread (or metastasized) to other organs, such as bone, liver, or lung, is Faslodex (fulvestrant).
In recent years, new targeted drugs have been approved by the FDA that can be used alone or in combination with hormone therapy. In postmenopausal women, several drugs are approved for patients with HR-positive breast cancer, including Afinitor (everolimus), Ibrance (palbociclib), Kisqali (ribociclib), and the most recently approved drug, Verzenio (abemaciclib).
The HER2 Biomarker
The human epidermal receptor type 2 (or HER2) gene plays a critical role in the development of cancer in 20% of patients with breast cancer. Typically, the HER2 gene makes HER2 proteins that help to control how healthy cells grow, divide, and repair themselves. But when a cancer cell has too much of the HER2 proteins, which occurs most often when the cancer cell makes many more copies of the HER2 gene than normal, the cancer grows and spreads more rapidly than a breast cancer that does not have this abnormality. HER2-positive breast cancer can be HR-positive or HR-negative; therefore, anti-HER2 therapies and endocrine therapies may (or may not) be given to the same patient.
In a collaborative guideline, ASCO and the College of American Pathologists suggest that every woman diagnosed with breast cancer be tested for HER2 status to determine if the tumor has the HER2 biomarker. There are 2 types of tissue biopsies used to test this biomarker: “immunohistochemical stains” are used to test for HER2 protein and the “FISH” (fluorescence in situ hybridization) test is used to determine if there are too many copies of the HER2 gene.
“What we’ve done is taken a biomarker, HER2, and created really good tests for it related to the treatment. It helps to save people’s lives, and not treat people with medicine that won’t help them,” Dr. Hayes said. He noted that HER2 status in breast cancer can change over time, from positive to negative and vice versa, meaning that HER2-positive breast cancer could later become HER2-negative, which will require a change in treatment. For this reason, he always recommends repeat biopsies if the cancer comes back.
“There are many studies suggesting that there is about a 15% discordance rate between what the original cancer was, and what you may have later,” Dr. Hayes said. “That is most important if a cancer goes from being called ‘negative’ originally to being called ‘positive’ later, because now there are additional therapies that can be used.”
Drugs for HER2-Positive Breast Cancer
Before around 1990, patients with HER2-positive breast cancer had worse prognosis compared with those with HER2-negative cancer. However, over the past 3 decades, anti-HER2 therapies have resulted in remarkably improved outcomes, such as longer survival, in these patients.
The FDA has approved several targeted therapies for patients with HER2-positive breast cancer, including the antibodies Herceptin (trastuzumab) and Perjeta (pertuzumab), as well as small molecules that inhibit the HER2 action, Tykerb (lapatinib) and Nerlynx (neratinib). Moreover, Kadcyla (adotrastuzumab emtansine), which is a combination of a chemotherapeutic drug (emtansine) linked to Herceptin, works even after Herceptin stops working if the cancer is still producing HER2. In this case, Herceptin is acting as a “Trojan horse,” by delivering the chemotherapy directly to HER2-positive cancer cells.
Surprisingly, investigators have also found that 2% to 5% of breast cancers that make normal amounts of HER2, and therefore would be called “HER2-negative,” have mutations within the gene that result in an overactive HER2 protein. Furthermore, in laboratory studies, Nerlynx (but not other anti-HER2 drugs) appears to inhibit growth of cells that contain the HER2 mutation, and a small clinical study has suggested that this drug may also be active in patients with HER2-mutated cancers.
Understanding BRCA1 & BRCA2 Genetic Mutations
Unlike genomic mutations that are developed over time in our cells, the BRCA1 and BRCA2 mutations are inherited from a parent via either the sperm or the egg, which are labeled as “germ cells.” This term has nothing to do with “germs” but rather comes from gardening, in which seeds “germinate” to grow into a plant. These inherited genetic changes are therefore called “germline mutations.”
We all get 2 copies of every gene—1 from our mother and 1 from our father. When the 2 copies of these genes are normal, they help to fix mutations that occur in other genes within the cell, much as a spell-checker does in a word-processing program, and therefore they prevent the development of cancer. However, when the genes are mutated (changed) in a way that prevents their normal activity, the person is at a much greater risk of getting breast, ovarian, or a few other types of cancer than people who have normal copies of the gene.
Therefore, BRCA1 and BRCA2 are called “susceptibility” genes. Many such genes have been identified—some are relatively specific to certain types of cancers (such as BRCA1 or BRCA2) and some result in different types of cancer, such as the p53 gene. According to the National Cancer Institute, about 70% of women who inherit a BRCA mutation will have breast cancer by age 80.
“Knowing whether a person has a BRCA1 or BRCA2 mutation is important for two reasons,” Dr. Hayes said. “First, it means you are more susceptible to getting breast cancer than if you had normal copies of these genes. Second, in terms of treatment, if you have one of these mutations and you get a breast cancer, knowing the mutational status makes you more responsive to a particular therapy.”
First, because BRCA1 and BRCA2 are susceptibility genes, people with a family history of these mutations may need to have a blood test to look for these mutations. If an individual has inherited a mutated BRCA1 or BRCA2, she (or he!) may wish to pursue prophylactic (preventive) surgery, such as removal of apparently healthy breasts or ovaries. Making this decision can be traumatic, and people are strongly urged to seek professional consultation with highly trained genetic counselors.
In a woman who comes from a high-risk family known to harbor mutations in BRCA1 or BRCA2, but she did not inherit that mutated gene, her risk for breast or ovarian cancer is not greater than for any other woman and, therefore, she does not need to have preventive surgery.
In February 2018, the FDA approved the first direct-to-consumer test for 3 types of BRCA mutations, including BRCA1 and BRCA2 (see article on page 23 in this issue). This means that people can now order the test on their own, without a doctor, although experts strongly advise men and women to talk with their doctor before ordering the test.
The risk of carrying a BRCA1 or BRCA2 mutation in the average population is quite low. Therefore, not everyone should be tested. Rather, for a person diagnosed with breast cancer, several guideline bodies, including ASCO, recommend testing for BRCA1 and BRCA2 only in those younger than 40 who have a strong family history of cancer (a sister, mother, or grandmother with breast cancer, or a relative further removed with ovarian cancer), or if the person is male. In addition, women with triple-negative breast cancer (meaning ER-negative, PR-negative, and HER2-negative cancer) may also consider testing for the BRCA biomarker.
“Up to 20% of women with triple-negative breast cancer have an inherited mutation of BRCA1 or BRCA2,” Dr. Hayes said. “So, many physicians are recommending that those patients be tested for the gene mutation.” Because having this mutation increases the risk for getting a second cancer, Dr. Hayes strongly suggests that those just diagnosed with breast cancer who have one of the risk factors mentioned above get BRCA1 and BRCA2 testing, because if they do have the mutation they can take precautions against getting a new cancer down the road.
BRCA1 and BRCA2 are not the only susceptibility genes involved in breast and ovarian cancers. After the United States Supreme Court ruled that a company cannot patent a gene, several companies began offering genetic testing for a panel of germline genes, some of which we know are highly associated with the risk of these cancers, such as BRCA1 and BRCA2, as well as others about which we really are not sure.
Furthermore, all these genes occasionally harbor mutations that may not affect their normal function; these are called “variants of undetermined significance.” Identifying such a mutation in a known susceptibility gene or, worse, in a gene of unknown importance, can lead to confusion. Therefore, such testing is strongly recommended in the context of professional genetic counseling to help determine the meaning of the test results.
Role in Treatment
Second, BRCA mutations may drive the types of therapies a patient may receive. For example, certain kinds of chemotherapy called “platin salts” (for example, cisplatin, carboplatin), which are very active in other types of cancers, such as lung, ovarian, or testicular, are more active in breast cancers in patients with germline BRCA1 or BRCA2 mutations than in those with normal BRCA1 and BRCA2 genes.
In a very exciting series of clinical trials, drugs called “PARP inhibitors” that inhibit another gene that repairs DNA mistakes appeared to work in patients with BRCA1 or BRCA2 mutations. In January 2018, the PARP inhibitor Lynparza (olaparib) became the first drug ever to be approved by the FDA specifically for breast cancer associated with a BRCA1 or BRCA2 mutation. However, patients must have received chemotherapy before using Lynparza.
The Future of Biomarkers?
Understanding the potential of targeted drugs is an exciting frontier. As testing for biomarkers or gene changes increases, and new targeted therapies are developed, researchers are beginning to try using the same therapies for biomarkers across different tumor types, based on the biomarker rather than the type of cancer. For example, therapies that were initially approved for lung cancer based on a specific biomarker found in lung cancer are now used for the treatment of patients with colon cancer who have the same biomarker.
Dr. Hayes said that treating cancer based on the specific tumor type still has a role in cancer care. However, he notes that ongoing clinical research is suggesting that molecular information related to genes and genetic changes will provide opportunities for new treatments based on tumor biomarkers and the molecular profile.
“I also believe that we will continue to find opportunities to treat people based on their molecular findings that are different from what we ever imagined,” Dr. Hayes concluded.
1. Susan G. Komen. Tumor characteristics. Updated January 19, 2018. ww5.komen.org/BreastCancer/TumorCharacteristics.html.
2. Breastcancer.org. Tumor genomic assays. Updated January 26, 2017. www.breastcancer.org/symptoms/diagnosis/genomic_assays.
- In breast cancer, “actionable biomarkers” include HR status, HER2 mutations, and the BRCA1 or BRCA2 genetic mutations, so knowing this ensures you will receive the best therapy
- About 70% of women who inherit a BRCA mutation will have breast cancer by age 80
- Genomic mutations develop in our cells over time, but BRCA1 and BRCA2 mutations are inherited “genetic mutations”
- Up to 20% of patients with triple-negative breast cancer have an inherited BRCA1 or BRCA2 mutation
- Breast cancer often changes over time, so testing for biomarkers again is important to ensure appropriate treatment
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American Society of Clinical Oncology
National Cancer Institute
US Preventive Services Task Force