May 2015 Ask the Expert: Tests For Making Treatment Decisions and Monitoring Your Health

May 1, 2015

Deciding whether or not to have chemotherapyinfo-icon for early-stage breast cancerinfo-icon, finding out if your cancer is HER2-positive and monitoring stageinfo-icon 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 medicineinfo-icon works. They can also help monitor metastaticinfo-icon 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 providerinfo-icon because treatment varies with individual circumstances. The content is not intended in any way to substitute for professional counselinginfo-icon or medical advice.

Question: I have stage III triple-negative breast cancer and am about to start chemotherapy. I read online about some tests that would tell me if I have mutations that might allow me to try experimental therapies. Are these tests available now? Would my doctor know about them?

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 geneticinfo-icon link that may explain a hereditaryinfo-icon trait or syndrome. To access these tests, it is best to enroll in a clinical trialinfo-icon which incorporates one of these tests.

Dr. Pluard: We know that all triple-negative breast cancers are not genetically the same. Chemotherapyinfo-icon remains the most effective treatment available. There are tests being performed on the tumorinfo-icon 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 cancerinfo-icon, 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 PARPinfo-icon inhibitors has been developed to exploit this weakness. In women with breast cancer and a BRCA mutationinfo-icon, clinicalinfo-icon studies are testing the addition of PARP inhibitors to chemotherapy both in early-stageinfo-icon 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

Question: I had breast cancer 10 years ago and had a lumpectomy, chemotherapy and radiation. Now I’ve been diagnosed again but the doctor says it’s HER2-positive. How can I be sure the last one wasn’t also HER2-positive? Can I find out now or is it too late? Does it even matter?

Dr. Singh: The biomarker profile of the recurrenceinfo-icon may be different from the primary breast cancer. The HER2 status of the recurrence will determine therapyinfo-icon now. The testing methods have improved considerably in the last decade. It is possible to run the test again on the primary tumorinfo-icon if the tissueinfo-icon is still archived in the pathology laboratory, but that will not help in decision-making now.

Dr. Pluard: If the original tumorinfo-icon 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 diagnosisinfo-icon. 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.

Question: I have an estrogen/progesterone-positive breast cancer, but no cancer in the lymph nodes. My doctor says I should take 5 years of letrozole (Femara) but we may also consider 10 years. What tests is she using to make her recommendation? Should I ask for any others? What are the differences between them?

Dr. Singh: The American Society of Clinicalinfo-icon Oncologyinfo-icon 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: Letrozoleinfo-icon is an anti-estrogeninfo-icon pill used in postmenopausalinfo-icon women to minimize the risk of recurrenceinfo-icon following surgeryinfo-icon for breast cancer. Taking letrozole for 5 years is currently the standard recommendation. We know that in women treated with tamoxifeninfo-icon, 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.

Question: I have metastatic breast cancer and I don’t understand all the tests being used. My doctor said he wants to use CTCs, but I’m unclear how he will use them. What are the differences among these tests?

Dr. Singh: Circulating tumorinfo-icon cells (CTCs) can be tested to follow tumor burdeninfo-icon. 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 metastaticinfo-icon 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 imaginginfo-icon (X-ray, CT scans, MRIinfo-icon ) 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 chemotherapyinfo-icon 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.

Question: What tests are helpful in determining treatment for stage I breast cancer?

Dr. Singh: Review by a pathologistinfo-icon of material taken during a biopsyinfo-icon determines the stageinfo-icon of breast cancer and is the basic “test” for breast cancer. The pathology reportinfo-icon also determines the gradeinfo-icon of the tumorinfo-icon and other characteristics of the tumor that are useful in determining treatment. You may want to get a second opinion to ensure the staginginfo-icon was done correctly.

Every invasive breast cancerinfo-icon is tested for estrogeninfo-icon and progesteroneinfo-icon receptors and HER2/neuinfo-icon overexpression. If ERinfo-icon and/or PRinfo-icon are overexpressed then the patient is a candidate for anti-estrogen therapyinfo-icon. If HER2 is overexpressed then anti-HER2 therapy is given along with chemotherapyinfo-icon, in most cases. For ER/PR-info-iconpositive 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 proteininfo-icon. 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 trastuzumabinfo-icon (Herceptininfo-icon) after surgeryinfo-icon unless the tumor is extremely small.

Those patients who are ER- or PR-positive should receive anti-estrogen therapy (tamoxifeninfo-icon or an aromatase inhibitorinfo-icon) orally for at least 5 years. In some situations, additional tests (Oncotype DX, Prosignia, MammaPrint) analyzing the geneticinfo-icon makeup of your specific tumor are done to find out if there is a benefit to using chemotherapy in addition to anti-estrogen therapy.

Question: I was diagnosed with triple-negative breast cancer in May 2009. In May 2014 the cancer returned with mets to my liver, brain and lungs. I had FoundationOne genomic testing in 2014 to aid in treatment decision-making. Are there new or better tests available that can identify targets for my specific tumor type?

Dr. Singh: Triple-negative breast cancerinfo-icon (breast cancer that does not overexpressinfo-icon ERinfo-icon, PRinfo-icon or HER2) is a heterogeneous group and the subject of intense research currently. One clinical trialinfo-icon has shown the benefits of anti-androgen therapyinfo-icon in metastaticinfo-icon breast cancer that overexpresses the androgen receptorinfo-icon. More than 20 ongoing clinical trials are targeting this pathway. Similarly, there are numerous other pathways which are being targeted in early clinicalinfo-icon 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 tumorinfo-icon.

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 medicineinfo-icon called immune checkpoint inhibitors. We know that some cancers evade the body’s immune responseinfo-icon to the cancer cells. They do this by producing a proteininfo-icon, PD-L1 which silences parts of the immune systeminfo-icon 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 geneticinfo-icon 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.

Question: What is the difference between genetic and genomic tests?

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 mutationinfo-icon in a particular geneinfo-icon is a geneticinfo-icon test. These mutations may be inheritedinfo-icon, so these tests are used extensively by genetic counselors.

A test that uses information from many genes is a genomic testinfo-icon. This may include multiple genes and also genetic material between genes. A genomic test can be used to answer a clinicalinfo-icon question, such as “Should a certain patient with breast cancer be treated with chemotherapyinfo-icon?” 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 preventioninfo-icon 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 cellinfo-icon 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 testinginfo-icon we are looking at these genes that we have inherited. Variations in some of these genes, BRCA1info-icon/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.

Question: What is the cutoff for deciding whether a cancer is estrogen-sensitive?

Dr. Singh: The American Society of Clinicalinfo-icon Oncologists (ASCO) and the College of American Pathologists (CAP) have published guidelines for estrogeninfo-icon and progesteroneinfo-icon receptors and HER2 testing based on published literature. As per these guidelines, if more than 1 percent of cancer cells overexpressinfo-icon the estrogen or progesterone receptorinfo-icon, then they are categorized as ERinfo-icon/PR-info-iconpositive and are candidates for anti-estrogen therapyinfo-icon. The higher the expression of ER/PRinfo-icon, 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 immunohistochemistryinfo-icon 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 assuranceinfo-icon guidelines.

Dr. Pluard: This is a tricky question, as different labs may have different cutoffs. Breast cancer is routinely tested by staining the biopsyinfo-icon tissueinfo-icon to see if the estrogen receptorinfo-icon 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.

May's program was funded by NanoString, the makers of Prosigna.

NanoString 2015
Prosigna 2015