May 2015 Ask the Expert: Tests For Making Treatment Decisions and Monitoring Your Health
Deciding whether or not to have chemotherapy for early-stage breast cancer, finding out if your cancer is HER2-positive and monitoring stage IV disease over time are all examples of occasions when medical tests may be helpful. Simple blood and saliva tests can give you and your healthcare team a wealth of information about the type of breast cancer you have, including what treatments may work best for you, what your next steps are, how likely it is for the cancer to come back, and whether your genes may play a role in how well a medicine works. They can also help monitor metastatic breast cancer so that you and your doctors can plan ahead.
In May, Living Beyond Breast Cancer experts Timothy J. Pluard, MD, and Baljit Singh, MD, answered your questions about tests.
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.
Dr. Singh: There are many commercially available tests for mutations in panels of genes. Most of these mutations lack evidence for specific treatments that target them. These tests may occasionally find a genetic link that may explain a hereditary trait or syndrome. To access these tests, it is best to enroll in a clinical trial which incorporates one of these tests.
Dr. Pluard: We know that all triple-negative breast cancers are not genetically the same. Chemotherapy remains the most effective treatment available. There are tests being performed on the tumor to try and identify mutations or abnormalities within that tumor that might respond to specific drugs targeting that abnormality. These tests are available and are usually done as part of a clinical trial.
Mutations in BRCA 1/2, associated with hereditary breast and ovarian cancer, are an example of this approach. Research has identified the cellular abnormalities in cancers caused by BRCA mutations, and a new class of drugs called PARP inhibitors has been developed to exploit this weakness. In women with breast cancer and a BRCA mutation, clinical studies are testing the addition of PARP inhibitors to chemotherapy both in early-stage and advanced cancer.
Your doctor should be able to tell you if there is a clinical trial that would be appropriate for you. Not all oncologists have access to clinical trials within their practice but they can help direct you to a center that does. You can also search for clinical trials on cancer.gov.
Dr. Singh: The biomarker profile of the recurrence may be different from the primary breast cancer. The HER2 status of the recurrence will determine therapy now. The testing methods have improved considerably in the last decade. It is possible to run the test again on the primary tumor if the tissue is still archived in the pathology laboratory, but that will not help in decision-making now.
Dr. Pluard: If the original tumor from 10 years ago is still available, it is possible to still test for HER2 if that was not done previously. As it was standard to test HER2 at that time, I suspect it was done at initial diagnosis. Knowing the HER2 status of the original tumor may help establish the relationship between the original and current tumor, if they happen to be in the same breast. However, the HER2 status of the previous tumor would not impact treatment recommendations for the current cancer.
Dr. Singh: The American Society of Clinical Oncology recently published guidelines for endocrine therapy, and you should discuss these with your doctor. In 5 years the recommendations may change based on new evidence.
Dr. Pluard: Letrozole is an anti-estrogen pill used in postmenopausal women to minimize the risk of recurrence following surgery for breast cancer. Taking letrozole for 5 years is currently the standard recommendation. We know that in women treated with tamoxifen, which is an anti-estrogen pill that works differently than letrozole, 10 years of treatment lowers the risk of recurrence more than 5 years of treatment. While studies have been completed comparing 10 versus 5 years of treatment with letrozole, we are still awaiting these results.
There are currently no tests than can help us predict on an individual basis which woman might benefit from continuing letrozole beyond 5 years. The decision right now is based on an individual’s risk of recurrence, balanced against side effects and other health issues.
Dr. Singh: Circulating tumor cells (CTCs) can be tested to follow tumor burden. However, their routine use is not recommended by current guidelines. This is an active area of research, and you should ask your doctors how they intend to use the information.
Dr. Pluard: When treating metastatic breast cancer, it is important to monitor the effectiveness of the current treatment on a regular interval. The most common means of doing this is with imaging (X-ray, CT scans, MRI ) to see if the cancer is shrinking, growing or remaining stable.
Blood tests can also be used to measure proteins made by the cancer. These are called tumor markers (CA 15-3, CA-27-29, CEA) and provide a barometer of the treatment effectiveness. If the tumor is shrinking, the level of these markers will generally decline in the blood. As not all cancers make these proteins, they are not useful in all women.
Blood tests can also detect CTCs (circulating tumor cells) in about half of women with metastatic disease. Rapid decline in CTCs after starting chemotherapy is generally an indicator of treatment effectiveness. These tests are continually evolving and may be useful in the future to look at the mutational profile of the cancer.
Dr. Singh: Review by a pathologist of material taken during a biopsy determines the stage of breast cancer and is the basic “test” for breast cancer. The pathology report also determines the grade of the tumor and other characteristics of the tumor that are useful in determining treatment. You may want to get a second opinion to ensure the staging was done correctly.
Every invasive breast cancer is tested for estrogen and progesterone receptors and HER2/neu overexpression. If ER and/or PR are overexpressed then the patient is a candidate for anti-estrogen therapy. If HER2 is overexpressed then anti-HER2 therapy is given along with chemotherapy, in most cases. For ER/PR-positive stage 1 cases there are genomic tests (Oncotype DX, Prosignia, MammaPrint) which are useful to determine which patients may or may not benefit from chemotherapy in addition to anti-estrogen therapy. Oncotype DX usage has decreased chemotherapy use in 20 to 30 percent of such patients in the last decade.
Dr. Pluard: The tumors are routinely tested for the presence of estrogen receptors, progesterone receptors and the HER2 protein. Patients who have none of these three have triple-negative cancer and are treated with chemotherapy. Those patients that have overexpression of HER2 should receive chemotherapy and trastuzumab (Herceptin) after surgery unless the tumor is extremely small.
Those patients who are ER- or PR-positive should receive anti-estrogen therapy (tamoxifen or an aromatase inhibitor) orally for at least 5 years. In some situations, additional tests (Oncotype DX, Prosignia, MammaPrint) analyzing the genetic makeup of your specific tumor are done to find out if there is a benefit to using chemotherapy in addition to anti-estrogen therapy.
Dr. Singh: Triple-negative breast cancer (breast cancer that does not overexpress ER, PR or HER2) is a heterogeneous group and the subject of intense research currently. One clinical trial has shown the benefits of anti-androgen therapy in metastatic breast cancer that overexpresses the androgen receptor. More than 20 ongoing clinical trials are targeting this pathway. Similarly, there are numerous other pathways which are being targeted in early clinical trials. It would be useful to find out which TNBC trials are offered where you are being treated.
FoundationOne genomic testing is not currently recommended under any professional guidelines for breast cancer but may provide some insight into which pathways are active in a tumor.
Dr. Pluard: As our understanding of triple-negative breast cancer (TNBC) evolves we are beginning to recognize various different subtypes. Some TNBC actually express the androgen (testosterone) receptor and early studies have shown some benefit for enzalutamide, a pill used to treat men with prostate cancer. The tumor can be stained for the presence of the androgen receptor to see if this might present a treatment option.
Another potential new avenue in treatment of TNBC is a kind of medicine called immune checkpoint inhibitors. We know that some cancers evade the body’s immune response to the cancer cells. They do this by producing a protein, PD-L1 which silences parts of the immune system that would normally destroy the cancer cells. Drugs that disrupt this silencing and restore the immune response are effective and approved for use in melanoma and lung cancer. Early studies have also shown activity in TNBC where the cancer cells produce the PD-L1 protein. These drugs are still in clinical trials in TNBC.
FoundationOne is an excellent test which looks for genetic abnormalities in the tumor that might identify potential treatment targets. One of the limitations of all genomic tests is that the cancer may change or mutate over time in response to treatment. Newer technologies offered by several companies, including Foundation Medicine, are able to isolate DNA from the tumor that is circulating in the blood. This allows repeat testing over time (called “liquid biopsies”) to assess the real-time status of the cancer. This is new technology and how this will impact treatment choices in advanced breast cancer is unclear.
Dr. Singh: Our genes produce proteins that regulate all the functions of the human body. A problem in this process may lead to many different kinds of diseases, including cancer. Mutations in certain genes lead to certain diseases. For example, BRCA mutations make a person more likely to get breast cancer. A test for a particular mutation in a particular gene is a genetic test. These mutations may be inherited, so these tests are used extensively by genetic counselors.
A test that uses information from many genes is a genomic test. This may include multiple genes and also genetic material between genes. A genomic test can be used to answer a clinical question, such as “Should a certain patient with breast cancer be treated with chemotherapy?” Other genomic tests, such as FoundationOne, look at a wide swath of genes to see which pathways are active.
Recent advances in testing methods have made genomic tests quick and affordable. Both genetic and genomic tests are an active area of research with discovery of new genetic mutations and pathways that help us understand the cause of diseases and create new prevention and treatment strategies.
Dr. Pluard: Humans have 23 chromosomes, which contain the thousands of genes that make up our unique genetic program. There are two copies of every gene, one from the mother and one from the father. Every cell in the body carries the same genetic signature that we have inherited from our parents and that define our genetic traits. When we are doing genetic testing we are looking at these genes that we have inherited. Variations in some of these genes, BRCA1/2 for example, may increase the risk of developing cancer.
The development of cancer involves mutations of one or more normal genes within a specific cell. This ultimately leads to uncontrolled growth of a cancer clone. When we do genomic testing we are looking at the DNA in the cancer cells and comparing it to normal cells in the body to find the mutations unique to the cancer cells. These unique abnormalities may identify treatment targets.
Dr. Singh: The American Society of Clinical Oncologists (ASCO) and the College of American Pathologists (CAP) have published guidelines for estrogen and progesterone receptors and HER2 testing based on published literature. As per these guidelines, if more than 1 percent of cancer cells overexpress the estrogen or progesterone receptor, then they are categorized as ER/PR-positive and are candidates for anti-estrogen therapy. The higher the expression of ER/PR, the better the response to anti-ER therapy. But the cutoff recommendation was based on the evidence that cancers with low level expression of ER and/or PR also respond to anti-estrogen therapy. Currently, we use immunohistochemistry tests to assess ER and PR expression. ASCO/CAP guidelines have gone a long way in standardizing testing of breast biomarkers in the US. The breast biomarker results are best tested in a CAP-accredited laboratory that adheres to stringent quality assurance guidelines.
Dr. Pluard: This is a tricky question, as different labs may have different cutoffs. Breast cancer is routinely tested by staining the biopsy tissue to see if the estrogen receptor is present in the cancer cells. Some studies have suggested that just 1 percent of cells having the estrogen receptor present predicts for some benefit form anti-estrogen based therapy. The Allred scoring system gives an ER score of 0-8. On this scale, 3 or higher is considered positive and studies have shown that the higher the Allred score the higher the chance of the person responding to anti-estrogen therapy.