Dr. Laura van ’t Veer is focused on advancing personalized medicine by applying knowledge of the genetic makeup of both the tumor and the patient to improve patient care and breast cancer outcomes. Her work has been instrumental in the development of molecular diagnostics based on genomics technology in breast cancer risk assessment, including the MammaPrint assay, a diagnostic test used to assess the risk that a breast tumor will metastasize to other parts of the body. Her work includes studying how environmental factors may influence the risk of metastasis and understanding which subtype of tumors will likely respond to what therapy.
BCRF recently spoke with Dr. van ‘t Veer about her work.
BCRF: What was your inspiration to pursue a breast cancer research career?
Dr. van‘t Veer: My interest in biology started in high school. My high school biology teacher was studying for his master’s degree, so we benefited by essentially learning what he was learning in his graduate studies. As a result, I became very interested in genes and DNA and developmental biology – the processes that occur during embryonic development. Later, as an undergraduate, I worked at the Netherlands Cancer Institute (NCI) where I began to study these processes in relation to cancer.
I’ve always been interested in translational research – even before we had a name for it. After completing my postdoctoral training at Harvard Medical School, I returned to the Netherlands and was later selected to start a department in molecular pathology at NCI. This gave me a wealth of experience in learning how to build bridges between the clinic and other disciplines, which was crucial in conducting the studies that laid the groundwork for MammaPrint.
BCRF: How did the MammaPrint assay come about?
Dr. van ‘t Veer: As part of my research at NCI, I was tasked with designing a diagnostic program for all cancer types, although my focus ultimately became estrogen-dependent breast cancer growth. This led to my collaborations with Rene Bernards and with Stephen Friend, who was a pioneer in the development of gene expression studies. Together we developed a risk prediction assay called MammaPrint that is based on the level of expression of 70 genes that are frequently altered in breast cancers that will recur.
Our goal was to design a precise test to predict risk of recurrence with a low chance of a false negative test (meaning a test that failed to identify a breast cancer that was likely to metastasize). This required coordinating the efforts of many specialists, including engineers, statisticians, physicists, bioinformaticians, clinicians and molecular biologists.
Our publications resulting from the initial MammaPrint studies, published in 2002 in the journals Nature and New England Journal of Medicine, demonstrated for the first time that tumor gene expression can be used to predict breast cancer recurrence.
We continued to refine our test with newer patient cohorts including a Dutch trial called RASTER, where the MammaPrint test result was added to the clinical information to assess the risk of recurrence. Based on the MammaPrint results, two-thirds of the patients decided to forego chemotherapy. So far, after five years of follow-up, these patients have done equally well without chemotherapy as those who elected to receive it.
Another thing we noticed in the later cohort was many more low-risk patients than we had in our original research series of patients– women who had been diagnosed approximately 15 years earlier. Based on these findings, we are now working on identifying other prognostic categories, such as an ultra-low risk group.
BCRF: Your BCRF project supports work that you’re doing on the I-SPY 2 trial. Tell us more about that.
Dr. van ‘t Veer: I-SPY 2 is an adaptive trial design where multiple new drugs are tested with existing chemotherapies and patients are monitored at short time points to see if the experimental drug is working. It’s called “adaptive” because the patient treatment is adapted (or adjusted) to the patient’s response to the drug. Drugs that work are “graduated” to a phase III (final) trial for further testing.
Patients in I-SPY2 are treated before surgery (this is called neoadjuvant therapy) to test responsiveness and ideally to shrink the tumor. Biopsies are obtained at the start of treatment and again after treatment. The tumor biopsies are used to identify genetic and biological biomarkers to assess response to treatment.
For our BCRF research, we are using the pre-treatment biopsy along with additional biopsies after treatment and at surgery to compare the tumor biology before and after chemotherapy and then use this information to assess how each patient is responding. Our goal is to identify chemotherapy-induced changes in genes and proteins that can serve as biomarkers to predict who will and who will not respond to a particular therapy. We are also comparing changes in the tumor biology with tumor MRI to see if imaging can detect those changes earlier. Having early predictors of non-response could radically change the standard of care for breast cancer by providing insight early on about how to treat an individual patient and would allow changes in type of therapy if needed.
While this study is looking at the neoadjuvant setting, the concept also would be suitable to study metastatic breast cancer. In fact, we’re seeing more of this type of adaptive trial design not only in cancer, but in other diseases as well. This design allows researchers to use the same clinical trial infrastructure essentially to conduct multiple trials of drugs at the same time, as opposed to conducting individual trials for single drugs against a standard therapy. It’s an enormous cost-savings in addition to accelerating the approval of new drugs, which can never happen fast enough for patients.
BCRF: How will what we’ve learned about tumor biology and genetics change prevention strategies?
Dr. van ‘t Veer: Breast cancer susceptibility is another major interest of mine. While I was in Amsterdam, we established a cohort of 5,000 breast cancer patients to look at breast cancer susceptibility and to identify other susceptibility gene variants in addition to BRCA1 and BRCA2. My work at UCSF is adding information on genetic factors with other risk factors including breast density and lifestyle to create a risk model that we then use to classify young healthy women as very high, average or below average risk of developing breast cancer. In that way we hope to identify women who do not need regular screening because their risk of getting breast cancer is very low, versus women who may have a very high risk and should receive more frequent cancer screening or who would benefit from chemo-prevention with anti-estrogen therapies, such as tamoxifen or anastrozole.
BCRF: What are the major challenges facing breast cancer research and treatment?
Dr. van ‘t Veer I think one of the challenges is in understanding what risk actually means and how we respond to it. For instance, we know that in low-risk women between the ages of 40 and 50, approximately two women in 100,000 will get breast cancer. So the question is, can you forgo 10 years of screening for such a low-risk group of women, risking that two breast cancers will go undetected? Whichever option you choose, there is an associated cost not only on the healthcare system, but on society and the individual. It’s a perplexing question and highlights the need for more advanced screening technology that includes genetic biomarkers so that we can better assess actual risk.
We face similar challenges at the other end of the spectrum in metastatic breast cancer. How do we best assess risk of metastasis to prevent it and how do we know how best to treat it? This is where the BCRF’s Evelyn H. Lauder Founder’s Fund and the accompanying AURORA US and AURORA EU tumor sequencing studies will be very important. If we find that there are gene mutations in metastatic breast cancers that are also found in other types of cancer, we can then test drugs that are approved for other types of cancer in metastatic breast cancer – what is known as off-label drug use.
The Founder’s Fund studies are very important for two reasons: 1) Without this information, the health insurance companies may not pay for the drug for treatment of metastatic breast cancer (even though it’s approved for another use); 2) Telling a patient that his/her tumor has a specific mutation is not helpful if you can’t give that patient a drug that is likely to be effective against that mutation.
I think it is important that each patient be given a choice to try other potential therapies when one isn’t working. In order to do that we have to monitor the patient frequently to be sure she or he is responding, and if not, be able to try something else. Most likely a metastatic tumor will have multiple gene alterations and we don’t necessarily know which therapy will be best.
BCRF: What does the future of breast cancer look like to you?
Dr. van ‘t Veer: I think, as many others do, that in addition to prognosis prediction, the work of Chuck Perou in identifying the major subtypes of breast cancer has led to a better understanding of the molecular networks at play, even within a particular breast cancer subtype, and opened the door to new opportunities to determine the best therapeutic options. One of the reasons I left Amsterdam to join Laura Esserman in her efforts on the I-SPY trials is that we will be able to target very specific pathways, and also because I hope that we will be able to change how we test new therapies in clinical trials.
We’ve learned from genomics that each patient tumor is unique and we can no longer compare one group of patients to another as is done in the traditional clinical trial structure of Phase I, Phase II and Phase III trials. We need to monitor response in the individual patient, and the I-SPY2 trial is an excellent example of how we can efficiently do that. I’d like to see us complement this strategy with tumor imaging and perhaps blood-based assays to detect circulating biomarkers to monitor in-patient responses and prevent overtreatment, as well. The MammaPrint assay helps us to identify patients at high-risk for recurrence, who need more aggressive therapy, but even after that, we should carefully assess patient response so that the type of drug they are exposed to is appropriate.
BCRF: What do you think it the biggest impact of BCRF on advances in breast cancer?
Dr. van‘t Veer: BCRF’s unique model really allows researchers to work on the next out-of-the-box idea. It creates a melting pot of new discoveries and with BCRF’s large grantee group often stimulates new collaborations to address complex issues. The flexibility of BCRF’s process is very stimulating and I’m very enthusiastic to be a part of it.
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