Clear Search

Meet the Researcher: Dr. Funmi Olopade, Part One

By BCRF | March 3, 2015

Dr. Olopade Talks Triple-Negative Breast Cancer

In this two-part series presented in conjunction with Triple-Negative Breast Cancer Day (March 3, 2015) we are sharing a conversation with BCRF grantee, Dr. Funmi Olopade, on what we’ve learned about the causes of triple-negative breast cancer (TNBC), how we treat it today and prospects for new therapies in the future.

Dr. Olopade is a geneticist and medical oncologist based at the University of Chicago whose work focuses on the genetic causes of breast cancer, with an emphasis on identifying women at risk and making sure they have access to appropriate screening, prevention and treatment.  The ultimate goal of Dr. Olopade’s BCRF-supported research is to reduce global disparities in breast cancer outcomes by developing and applying new approaches to prevention, diagnosis and treatment. The program involves a multidisciplinary approach including cancer genomics, statistical genetics, experimental therapeutics, epidemiology, behavioral science, anthropology and bioinformatics, and includes collaborations across the globe.

First, some backgroud about forms of breast cancer. When a person is diagnosed with breast cancer, one of the first things to address is what “type” of breast cancer her/his disease is. Terms like “hormone receptor”, “HER2” or “triple-negative” quickly become a part of the patient’s lexicon.  She or he will be told their cancer is “hormone receptor (HR)-positive/HER2 –negative(HR+/HER2-)” or vice versa (HR-/HER2+), or both (HR+/HER2+), referring to whether the tumor cells have or do not have signs of proteins called receptors for the hormones estrogen and/or progesterone or another type of receptor called HER2. They may learn they have DCIS (ductal carcinoma in situ) – which some doctors don’t think should be called cancer at all, put a pre-cancer because these non-invasive lesions don’t always progress to invasive breast cancer.

These “markers” help doctors decide what type of treatment will be most effective for a particular tumor. Drugs that are effective against HR+ breast cancers called anti-estrogens (tamoxifen and aromatase inhibitors are examples) are widely used to treat and often to prevent these breast cancers. Another class of drugs that targets the HER2 receptor (Herceptin®, lapatinib, pertuzumab and TDM1 are examples) have been very effective in treating HER2+ breast cancer. The anti-estrogen and the anti-HER2 drugs are called targeted therapies because they work by “targeting” and shutting down a specific protein on the tumor cell that is helping the tumor to grow.

About 20 percent of breast cancers, however, do not have any of these proteins. These are called “triple-negative” because they lack estrogen, progesterone, or HER2 receptors and, so far, targeted therapies.

TNBC remains a huge challenge in clinical practice. It disproportionately affects young women and women of African ancestry and therefore contributes to health disparities. It tends to be more aggressive and faster growing than other types of breast cancer, and scientists are discovering that TNBC is not just one type of breast cancer but includes other sub-types with unique genetic, molecular and biological characteristics.

Note: In 2014, BCRF awarded over $12.5 million to support projects studying TNBC in the US, Africa, Europe and the Middle East.

The complexity of this disease presents enormous challenges in its treatment and prevention, but progress is being made. Scientists around the world are working tirelessly to better understand the causes of TNBC, oncologists are learning how to optimize chemotherapies to treat it, new therapies that target unique characteristics of TNBC are be being tested in clinical trials, and the expansion of genetic testing may have a huge impact on identifying women at risk before cancer occurs.

Part I. The Genetics of TNBC

BCRF: Dr. Olopade, first tell us how you became interested in breast cancer research and how TNBC became a part of that.

FO: I was originally interested in lymphoma and did my medical fellowship with the medical geneticist Janet Rowley at the University of Chicago. For more than a decade Dr. Rowley had been trying to convince oncologists and hematologists about the importance of chromosomal change in lymphoma and leukemia.  While working in her laboratory, I discovered abnormalities on Chromosome 9 in melanoma and became interested in looking for similar characteristics in solid tumors, which was very hard to do at that time.  I soon met Mary-Claire King, who had been mapping Chromosome 17 and had just identified the BRCA 1 gene. It was at that meeting that I first realized that this previously unidentified gene was going to be very important in understanding breast cancers that occur in families, what we now call hereditary breast cancer.

Nearly half of the patients I was seeing in my oncology practice on the South Side of Chicago were African American women and were known to have a high risk of early onset breast cancer. After Dr. King’s discovery, I began thinking if there could be a genetic link to their cancers as well and so I started a cancer risk clinic to find families who were at a risk of cancer that may be caused by a gene mutation. In the first year of our cancer risk clinic, about 90 percent of the patients who came had family histories of breast cancer.  I noticed that whenever Dr. King or Dr. Francis Collins, then director of the National Human Genome Research Institute at the NIH, spoke publicly about the hunt for the BRCA1 gene, high-risk women called our clinic.   We began to collect information on these families who may be carriers of the BRCA1 gene mutation.

With the advent of gene expression profiling, we began to see a trend in the tumors from women with BRCA1 mutations. These tumors had unique characteristics called basal-like, meaning they didn’t look or act like breast epithelial cells. They were faster growing and able to invade surrounding tissue. It soon became clear that BRCA1-associated breast cancers were also more likely to be triple-negative, meaning they do not depend on hormone signaling (estrogen or progesterone) or the HER2 receptor to grow.  As a clinician and scientist I had both medical and scientific curiosity in understanding what was causing the high rate of cancer in these families, and with the link between BRCA1 and TNBC, my work naturally became more focused on both the genetic and environmental factors of its causes.

BCRF: What have we learned about the genetic basis of TNBC?

FO: When a disease affects a younger population as is the case with most TNBC, it is more likely to have a genetic component. My work in Africa illustrates this perfectly. There is not a lot of breast cancer in Africa, but what we see is that the breast cancers that do occur are in young women and are triple-negative.  We know this is not due to lifestyle factors, which take many more years to cause cancer. In fact we found that almost 15 percent of the women we tested had BRCA mutations and if we expand the testing to include other genes, as many as 25 percent of patients have some kind of mutation.

When we consider all TNBC, we find that about 25 percent occur in women with BRCA1 mutations. From analyses in our high risk population, we know that there are about seven other genes associated with breast cancer, but not necessarily with TNBC. The BRCA2 mutation, for instance, usually results in ER+ breast cancer, though it does cause TNBC less frequently. So we’ve become interested in other mechanisms of TNBC that do not depend on mutations in BRCA1 gene.

That is why we are working so hard to characterize the gene mutations found in other populations around the world and why collaborations are so important. BCRF support has been a driving force in making this work possible by helping us to broaden our international network.

Another way to affect gene expression is by a process called methylation or epigenetic change which can result from environmental causes or lifestyle factors.  This happens when DNA is chemically modified in a way that alters gene expression that can result in cancer.  Unlike inherited DNA mutations, epigenetic changes to the DNA can be reversed.  There’s a lot of interest in understanding how epigenetic events may cause TNBC so that we can learn to prevent it and more effectively treat it.

How can genetic testing help to identify women at risk of TNBC?

Over the last two decades, we’ve relied on family history for risk assessment, but research by Mary-Claire King and her colleagues Ephrat Levy-Lahad and Moien Kanaan in Israel and Palestine, along with my team in Africa, has shown that BRCA1 mutations, the most common cause of TNBC, are present in every population. One of the things we have found is that most people who have been identified to have a BRCA mutation don’t have a strong family history, so if we only use family history as the basis of genetic testing, we’re going to miss a lot of people who are at risk.

The debate is whether it is cost effective to have everyone tested for BRCA mutations as Dr. King has proposed based on her studies in the Ashkenazi Jewish population.  We and others are making the argument that especially in Jewish families, where family structure is limited, for instance where the family is predominantly men and therefore we don’t have information on familial breast cancer, population-wide genetic testing will have a significant impact on identifying women at risk of TNBC. If we have the tools to offer the testing and can interpret the data to properly counsel women on the results – and BCRF investigators are learning to interpret multi-panel genetic tests–we have huge opportunities for early detection in women at risk of TNBC.  

Twenty years ago, the only option a woman had was to have her breasts removed, but now women have a choice that is guided by genetic testing.  In the process of genetic testing we can learn about other environmental or lifestyle factors that may help modify risk so we can learn how to prevent TNBC in all women.

Click here to read Dr. Olopade’s Q&A, Part Two