November 2016 Ask the Expert: Know Your Subtype
Breast cancer is often thought about as one disease. But in reality, different breast cancers grow for different reasons and need different treatments. There are three main subtypes of breast cancer: hormone receptor-positive, HER2-positive and triple-negative. Do you know your subtype?
Researchers have created therapies specific to certain subtypes to best treat each type of the disease. They’re always learning more about these subtypes, trying to find new subtypes, and working to create new treatments.
In November, Living Beyond Breast Cancer expert Debu Tripathy, MD answered your questions about breast cancer subtypes.
Remember: we cannot provide diagnoses, medical consultations or specific treatment recommendations. This service is designed for educational and informational purposes only. The information is general in nature. For specific healthcare questions or concerns, consult your healthcare provider because treatment varies with individual circumstances. The content is not intended in any way to substitute for professional counseling or medical advice.
This Ask the Expert residency was sponsored by AstraZeneca.
There are several factors that influence the risk of recurrence. The stage of the cancer, including the tumor size and whether and how many of the lymph nodes under the arm are affected, is important. The grade of the tumor also influences the risk of recurrence. HER2-positive and triple-negative breast cancers are associated with a higher risk of recurrence, although with the availability of HER2-targeted therapies, HER2-positive cancers aren’t considered as a high risk as they used to be.
There are newer tests, called gene profiles, that examine multiple genes at a time and can help categorize breast cancer risk more accurately. In certain breast cancer cases, this can help when making decisions about the need for chemotherapy.
Many advances in technology help find and measure mutations in several genes, which allows doctors to classify some breast cancers above and beyond the classical biomarkers of estrogen, progesterone and HER2 receptors. But the primary decisions are still made on the basis of these three receptors. Some decision-making though, especially about whether to add chemotherapy to hormonal therapy for people with hormone receptor-positive, HER2-negative breast cancer, is being made with commercially available gene profiling tests. Mutations are increasingly being used to match people to specific clinical trials, but research hasn’t yet shown this should be standard.
There is very little information about whether lifestyle changes affect how certain subtypes respond to treatment or how likely they are to recur. There is some evidence to suggest that obesity, particularly in postmenopausal women, raises the risk of hormone receptor-positive breast cancer. But doctors generally recommend that people with any subtype of breast cancer live a healthy lifestyle that includes maintaining an ideal body weight, exercising regularly, drinking alcohol in moderation or not at all, and avoiding tobacco.
Yes, there are associations between certain subtypes and some hereditary breast cancers. For example, in people who carry a mutation in the BRCA1 gene, 80 to 90 percent of breast cancers that develop are triple-negative. But in BRCA2 mutation carriers the different subtypes are distributed the same as in the general population. Due to the association of BRCA1 mutations with triple-negative breast cancer, it is now recommended that anyone with triple-negative breast cancer under the age of 60, regardless of family history, be referred for genetic counseling and testing.
There is very little known about the impact of birth control pills when used to prevent pregnancy in people who are diagnosed with hormone receptor-positive breast cancer. Because there is an association between estrogen and progesterone and the development of breast cancer, doctors generally advise women with a history of breast cancer to use non-oral or non-progesterone contraceptive methods, such as an intrauterine device (IUD).
There are certain subtypes of breast cancer that are more common in specific racial or age groups. For example, triple-negative breast cancer (negative for estrogen, progesterone and HER2 receptors) is more common in people of African or African-American descent for reasons not fully understood. It is also more frequent in younger people, in part because BRCA mutation-related breast cancers tend to appear at a younger age, and breast cancers associated with BRCA1 mutation are much more likely to be triple-negative.
On the other hand, breast cancers that appear in post-menopausal women are more likely to be hormone receptor-positive and less aggressive. In fact, post-menopausal women have a lower chance of dying of breast cancer compared to those diagnosed at a younger age.
Hormone-responsive breast cancers (those positive for estrogen receptors, progesterone receptors, or both) can recur or metastasize years and even decades after the initial diagnosis. For that reason, it was assumed that hormonal therapy should be given for several years. When the first medical hormonal therapy (it really should be termed “anti-hormonal” therapy), tamoxifen, was tested, studies compared taking the medicine for 1 versus 2 years, and then 2 versus 5 years. These studies found 5 years of treatment to be most effective in lowering the risk of recurrence.
But since recurrence still can occur even after that point, studies comparing 5 versus 10 years of treatment were started. These results have become available in recent years and do show a few percentage point reductions in recurrence with 10 compared to 5 years of tamoxifen or with the aromatase inhibitor letrozole (Femara). The differences are modest, and must be balanced against long-term side effects. In those at higher risk for recurrence, such as those with positive lymph nodes, we assume the differences are larger and may provide more motivation to recommend 10 years of hormonal therapy.
Yes, the androgen receptor (AR) is present in several tissues in both men and women, and is also expressed in some breast cancers. This is the case more often in hormone receptor-positive cases, but it’s also seen in cases that are otherwise considered triple-negative. The big question is whether blocking AR can treat breast cancer, as is the case with prostate cancers which almost always express AR. AR-blocking medicines like bicalutamide (Casodex) and enzalutamide (Xtandi) have been tested in breast cancer and responses have been seen in a small percentage of AR-positive cases. These trials are small pilot studies, and efforts are underway to do large-scale testing and also to combine AR blockers with standard breast cancer medicines.
Different metastatic breast cancer cases can take very different courses. One of the important variables that predict (although not fully) how long people may respond to different therapies and how long they may live is the presence of hormone (estrogen and progesterone) receptors (HR) and HER2 receptors. HR-positive metastatic cases tend to respond for longer periods of time (although not forever) to therapy, and less toxic hormonal therapies are usually tried first. HER2-positive breast cancer used to be very aggressive with shorter life spans, but that has changed with the advent of several HER2-targeted medicines. Now people with this subtype can usually experience longer remissions. Triple-negative breast cancers only respond to chemotherapy and tend to have shorter responses (although some can have durable, long responses), so in general this subtype is considered the most aggressive. Much research is focused on defining new “targets” against which effective biological medicines can be developed.
Yes, breast cancer that is both HER2-positive and hormone receptor-positive is a distinct subset. With some of the newer classifications based on the expression levels of several genes, this subset is sometimes referred to as Luminal B. This subset of breast cancer is treated with both HER2-targeting medicines and hormonal therapy.
For early-stage disease, the treatment is typically chemotherapy with trastuzumab (Herceptin) and sometimes pertuzumab (Perjeta). Both of those medicines are anti-HER2 antibodies. When the chemotherapy portion is completed, the anti-HER2 treatment is continued for a total time of 1 year. Hormonal therapy is also started when chemotherapy is completed and typically continued for 5 to 10 years.
For advanced breast cancer, chemotherapy and anti-HER2 medicines are also used. After a response is seen, the chemotherapy part is discontinued and replaced with hormonal therapy, but the anti-HER2 medicines are continued.
There has been one large clinical trial that tested trastuzumab (Herceptin) for a longer time period than the usual 1 year. This trial compared 1 year to 2 years of treatment and found no difference. But the low risk of heart problems was increased when people took the medicine longer. So the standard total treatment time with trastuzumab remains 1 year.
The breast cancer subtype can change from the primary cancer to the time of metastasis. It can change in either direction, from being positive for hormone receptors or too many HER2 proteins to being negative, or from being negative to being hormone receptor-positive or HER2-positive. In about 5 to 10 percent of cases, breast cancer that was once called estrogen receptor-positive is deemed estrogen receptor-negative after a metastatic recurrence. HER2 status can also change about 5 to 10 percent of the time.
It is difficult to know if the there was a difference in how the test was run or if the biology really changed. But our treatment recommendations are guided by the markers seen on the metastasis. So when possible, it is recommended a biopsy be done when a metastasis is seen, not only to confirm that it is truly a recurrence of cancer, but to determine estrogen, progesterone and HER2 receptor status for treatment decisions.