Mary Ann Holoska, 64, of Venice, Fla., was diagnosed with stage III triple-negative breast cancer (TNBC) in 2010. Like many women, she was proactive in seeking the best medical care. She consulted with a local doctor and then chose to get a second opinion, finding herself at MD Anderson Cancer Center in Houston, Texas, over 1,000 miles from her hometown.
MD Anderson’s expertise in treating cancer drew her there, but Mary Ann also notes their willingness to offer clinical trials designed to help better treat TNBC. Clinical trials, research studies with human participants, often test new treatment methods or medicines after the FDA confirms they are reasonably safe to use in humans, following several years of data review from studies conducted in animals.
For Mary Ann, participating in a trial was a way to access more than the standard treatment regimen for TNBC—surgery followed by chemotherapy and, in some cases, radiation—which, at present, is the most effective therapy for this aggressive type of breast cancer.
Some breast cancers respond to certain treatments better than others. Triple-negative breast cancer does not need estrogen, progesterone or HER2 to grow, the way that other types of breast cancer do. Because of that, TNBC doesn’t respond well to anti-HER2 medicines like Herceptin, given to women with HER2-positive disease, or to hormonal therapies like tamoxifen, given to women with hormone receptor-positive cancer.
“There’s no pill I can take [after chemotherapy] to give me the assurance that I’m lowering my risk of recurrence,” says Mary Ann. “Each cancer is different. Clinical trials were my best option.”
Changing the Way We Think About Breast Cancer
Only a few decades ago, doctors treated breast cancer as a single disease, giving almost all women a standard regimen of surgery and chemotherapy, and sometimes radiation therapy. Women like Mary Ann would have received some of the same medicines as women with estrogen receptor-positive breast cancer, which needs estrogen to grow, or HER2-positive breast cancer, in which extra copies of the HER2 gene leads to uncontrolled growth of cancer cells.
Today, these terms have become part of the common language of breast cancer, and researchers have learned that certain medicines work better for certain types of tumors. Even chemotherapy, still a standard therapy for most breast cancers, is more effective at treating some cancers than others. Matthew P. Goetz, MD, associate professor of oncology at the Mayo Clinic in Rochester, Minn., and a lead researcher on the Breast Cancer Genome Guided Therapy Study (BEAUTY Project), says one of the key questions in current research is why treatments work in some women, but not in others.
“BEAUTY is designed to identify and characterize the genetic factors that are inherited (host) as well as those within the tumor (somatic), which affect whether or not a woman’s tumor will respond to [common chemotherapies like] Taxol or AC (Adriamycin plus Cytoxan),” Dr. Goetz says. “Can we identify why some tumors literally melt away with chemotherapy; why others do not respond well, or at all?”
Many years ago, breast cancer research began to focus on tumor biology, the genetic makeup of a tumor at the cellular level, and tumor response, the way tumor cells react to cancer treatments. Yet researchers have only recently confirmed that breast cancer isn’t just one disease, but a family of diseases that are all genetically different.
Researchers used to divide breast cancers into groups based on the expression, or activity, of the estrogen receptor, progesterone receptor and HER2 proteins. Recently, the use of more sophisticated gene expression tests, which allow thousands of genes to be measured at one time, confirmed the importance of each of these proteins and led to the identification of four main molecular subtypes of breast cancer: luminal A, luminal B, HER2-positive and basal-like.
Tests such as the PAM50 can be used in the research setting to identify these breast cancer subtypes. Luminal A tumors are HER2-negative and hormone receptor-positive; Luminal B tumors are also HER2-negative and hormone receptor-positive, but are more aggressive. HER2-positive breast cancers can be subdivided into those that are HER2-positive and hormone receptor-negative, and those that are HER2-positive and hormone receptor-positive. Finally, triple-negative tumors are estrogen receptor-negative, progesterone receptor-negative and HER2-negative. TNBC accounts for about 15 percent of all breast cancers and can be divided into at least seven subgroups, one of which is the basal-like subtype. Each of these subtypes responds differently to cancer medicines.
Where Molecular Subtyping is Leading Us
Molecular subtyping can provide insight into why cancer cells grow, as well as what keeps tumors from spreading. Researchers are studying how molecular subtyping may become useful in developing medicines that target abnormalities driving the growth of cancer.
Beyond that, molecular subtyping may also help doctors offer individual women treatments that will benefit them the most, with the fewest side effects, based on the genetics of the tumor and the genetics of the woman herself. The goal of BEAUTY is precisely that—to take the framework of molecular subtyping a step further by using genomic information to guide the development of new treatments and choose the best medicines for that tumor in that person.
“In oncology it’s very important to compare the genotype of the tumor to that of the patient,” says Judy C. Boughey, MD, associate professor of surgery at the Mayo Clinic and a lead researcher on the BEAUTY Project. “Once we compare that information, we can make a decision about what targeted agents we may be able to study further.”
This kind of genomic research could lead to more effective targeted therapies for women with triple-negative breast cancer, like Mary Ann, in the future.
Shannon Lee, 65, of Pelham, N.Y., feels this shift in research has increased our understanding of the disease. A retired special education teacher and writing coach diagnosed with stage I, estrogen receptor-positive, HER2-positive breast cancer in October 2011, Shannon keeps herself informed by reading about new research as it is published.
“There’s a lot of funding, a lot of brainpower and a lot of science going into genomic research right now,” Shannon says. “So much has been done since my treatment 2 years ago. It does seem to be moving very quickly.”
Analyzing the billions of data points collected during genomic research requires a team of professionals dedicated to the project’s bioinformatics, Dr. Goetz says. Bioinformatics combines computer science, engineering and biology to create software systems that can correctly identify gene mutations, analyze them, and compare data. Funding the “brainpower” to carry out this process is the most expensive and time-consuming part.
“The price of this genetic sequencing is going down, but one of the most critical aspects of this work is the team who interprets the data,” Dr. Boughey says.“Still, only a short time ago this kind of research would have cost millions.”
Treatment in the Future
Participants in the BEAUTY Project are candidates for neoadjuvant chemotherapy, or treating the cancer with chemotherapy before taking it out surgically, which is usually a standard of care for higher-risk breast cancers. A biopsy and breast imaging are done when the participant joins the study, and then 12 weeks after starting the 20 week course of chemotherapy. The researchers then compare how the tumor changes once chemotherapy is used.
“We’re able to ask, ‘What has happened?’ and ‘Why is this tumor still growing?’” Dr. Boughey explains. “Through the imaging and biopsy we can see what’s going on in the tumor in the middle of chemotherapy treatment and use that information to identify what pathway drives the tumor’s growth. We hope that this is going to change the way women are cared for in the next 3 – 5 years.”
Beyond capturing how tumors respond to neoadjuvant chemotherapy, biopsy samples of tumors taken from study participants are inserted into mice, where they are preserved as living tumor samples. This way, the tumor itself is always available for testing, whether for new medicines or to see how tumor activity changes throughout treatment.
“This is a piece of breast cancer research that’s missing in most clinical trials today,” says Dr. Goetz. “While hundreds of clinical trials are ongoing to study new drugs for many different cancers, we often don’t understand why certain tumors do not respond to drugs that are predicted to work. In BEAUTY, we immortalize the tumor so that we can test new medicines without risking negative impact on women themselves.”
Drs. Goetz and Boughey believe that, eventually, it could become standard practice for a woman to have a biopsy and genetic tumor analysis, and then have her treatment directed by the genetic information in the tumor.
As the study moves forward, researchers expect to determine how different molecular subtypes of breast cancers act biologically. They also hope to identify new subtypes as the research evolves.
“There’s incredible genomic diversity in breast cancer, and we already know that there is great diversity even within the known molecular subtypes,” says Dr. Goetz. “We don’t expect to find a blueprint, but that we’ll be able to identify subsets of patients most likely to benefit from each treatment.”
Women diagnosed with breast cancers like triple-negative disease stand to gain the most from genomic research because, at present, no targeted therapies for TNBC exist. While TNBC can respond exceptionally well to chemotherapy, the knowledge gained from genomic research may help doctors determine which forms of triple-negative disease respond best to which chemotherapy medicines.
Researchers are digging deeper into the molecular breast cancer subtypes and looking for genetic diversity in each of them. One such study has already explored the differences in basal-like and triple-negative tumors, though many oncologists consider them to be the same, clinically.
For Shannon, the benefit of these advances is knowing what she’s up against. “It’s really reassuring to know the enemy a little bit [better],” she says.
Mary Ann feels the same. With scientists working toward improving and individualizing breast cancer treatment, she believes genomic research is going in the right direction. She hopes that one day, this kind of research may make it possible to not only treat cancer, but also to prevent it through a concrete understanding of the genomics of tumor cells and individual people.
“If one day doctors would be able to work with you to use a genetic map to take preventive action, wow,” she says. “It would be great if they could look into all of these genes.”
Beyond Breast Cancer: Genomic Research and the U.S. Supreme Court
In June, the U.S. Supreme Court ruled that human genes cannot be patented by any company or individual, in the landmark case Association for Molecular Pathology v. Myriad Genetics. The decision, agreed on by all of the court’s justices, took away the right of Myriad Genetics, a lab based in Utah, to hold patents on the BRCA1 and BRCA2 genes. Healthcare professionals believe that over time removal of the patents will lower the cost of, and increase access to, BRCA testing.
Research professor Robert Cook-Deegan, MD, of the Duke Institute for Genome Ethics, Law & Policy, says this case may have an impact on genomic research as it moves forward, whether in breast or other cancers.
“Cancer-related genes are among those most likely to have been patented as they were discovered, so the patent landscape is complex,” he says. “It can be hard to figure out which tests can be developed without fear of getting sued.”
Still, the introduction of new labs, whole-genome testing, multi-gene testing and molecular subtyping of cancers is moving cancer genomics in a new direction—one that very well could mean lower costs and greater access to testing.
“The full promise of genomic technologies can only be captured if the fantastic reduction of cost in DNA sequencing that has been realized over the past decade can be used for patient benefit, by making DNA sequence information more widely available,” Dr. Cook-Deegan says. “At its core, this was a patent case that was really about who controls medical decisions pathways. Patent rights trumped everything else for over a decade. The question now is whether that will change.”