COMMENTARY

Crowdsourcing: A New Era in Breast Cancer Research

Kathy D. Miller, MD; Nikhil Wagle, MD

Disclosures

February 13, 2017

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Kathy D. Miller, MD: Hi. I'm Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis, Indiana. Welcome to Medscape Oncology Insights, coming to you from the 2016 San Antonio Breast Cancer Symposium. Genomics are increasingly driving cancer research and informing clinical decisions in the care of our breast cancer patients. Here to update us on this emerging field is my guest, Dr Nikhil Wagle, assistant professor at Harvard Medical School and deputy director of the Center for Cancer Precision Medicine at the Dana-Farber Cancer Institute in Boston, Massachusetts. Welcome, Nick.

Nikhil Wagle, MD: Thank you.

Dr Miller: Genomics means many different things to many different people. When you talk about genomics, what are you talking about?

Dr Wagle: That is a great question. When I talk about genomics, I am thinking about the underlying structure of the DNA and RNA in tumor cells and how we can use that information to both understand the behavior of the tumor and exploit that information to make better treatment decisions.

Dr Miller: There are some genomic-based assays available in the commercial space. Which of those do you really use in your own practice?

Dr Wagle: There are a couple of genomic and precision medicine tests that are a part of standard of care. The simplest one in breast cancer is understanding what subtype the breast cancer is. It's not strictly a genomic test, but even things like understanding receptor status—estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status—help us distinguish between the types of cancer and what treatments to use. Beyond that, the most commonly used genomic test that is part of standard of care is the Oncotype DX test or the MammaPrint test, which helps you think about the need for chemotherapy in the early-stage setting.

Dr Miller: You just made this topic less frightening for many people. I don't think we had reflected that when we were assessing for ER and HER2, we were doing a rudimentary form of genomic testing.

Dr Wagle: I often use genomics and precision medicine together. When we think about precision medicine, what we are trying to do is figure out the molecular, genomic, pathologic, and clinical characteristics that help us make the right decision for the patient. Knowing whether something is ER-positive is very important because it changes what types of drugs we are going to use. Genomics just adds more layers of information on top of that.

Dr Miller: More layers of information often means a whole lot more layers of complexity. How are we ever going to sort through this huge volume of data and make it information instead of chaos?

 
Our technology right now is far ahead of our ability to interpret it and act on it clinically.
 

Dr Wagle: That is the biggest challenge. Our technology right now is far ahead of our ability to interpret it and act on it clinically. One of the areas where we run into trouble is when we conflate the things we are doing in the research setting and the things that are ready for use in clinical medicine. In the research setting, it's an incredibly exciting time. We have technologies that allow us to look at the whole genome or all of the proteins in the cell and try to understand how they affect response to treatment or resistance. In the clinic, to be able to use something and make a decision, these things need to be rigorously tested. They need to be part of clinical trials. We need to prove to ourselves that when you see a particular genomic alteration and that makes you choose a particular drug, it has a positive impact on the patient. It is that translation between the research world and the clinical world where a lot of work is being done. But we need more information.

Dr Miller: You have a fascinating project that has really captured the imagination of our patients: the Metastatic Breast Cancer (MBC) Project.[1] Why are my patients asking me to send tumor samples to Boston?

Dr Wagle: The MBC Project was born out of the idea that we can learn a lot about breast cancer. We can learn a lot about how to better treat breast cancer if we can study as many tumor samples and medical records and saliva samples from patients as possible. A part of the problem is that, historically, the samples that have been studied have been from patients who were cared for at large academic cancer centers. By some estimates, only about 15% of adult cancer patients in the United States go to these large academic medical centers. That means that for the vast majority of patients, their tumors have never been studied for research, largely because no one has ever asked them if they would be willing to donate their tissue for research.

 
Your patients are asking to send their tissue to Boston so that it can go into a big database that anyone around the world can use to study.
 

The MBC Project seeks to engage patients around the country and partner with them in order to try to accelerate metastatic breast cancer research. What it means is that patients can sign up online on our website, MBCProject.org. They can say, "I have metastatic breast cancer. I am potentially willing to contribute information, maybe samples, and I would like to be a part of the research team." When they do that, they become a part of this project. They send a saliva sample, we get their medical records, and we get a portion of their tumor tissue. We analyze the genomics of that tumor tissue, which will then go into a large database that will be freely accessible to all researchers. Your patients are asking to send their tissue to Boston so that it can go into a big database that anyone around the world can use to study.

Dr Miller: It is a hugely successful project. What have you learned from this so far? Perhaps the first thing is that if you ask, patients will come.

Dr Wagle: That is exactly right. That is the first lesson. We launched this a year ago. In the first year, 3000 women and men with metastatic breast cancer around the United States have signed up. We have people from all 50 states, people who live near academic centers, people who live nowhere near academic medical centers. You are right—the first lesson is, if you ask patients to participate and you make it easy for them, they are more than happy to say, "Count me in; I want to be a part of this." The second thing we have learned is that you can get a lot of information simply by asking patients to tell you about themselves. We are getting medical records and abstracting medical records, and we will have full medical information from every participant. In the meantime, patients are telling us what kind of cancer they have and when they were diagnosed. That information alone is incredibly valuable.

We have now sequenced the first 100 tumors or so from the patients who have participated. I am excited that everything seems to be feasible. We are getting 10-year-old tumor tissues that are being mailed to us from across the country. Those have been successfully sequenced in our lab. We are hopeful that as we grow this project, we will be able to generate an incredibly large database of clinical data and tumor samples.

Dr Miller: This is going to be a gold mine for research for decades to come. Will the patients who participate get anything from this?

Dr Wagle: That is a great question and one that we get asked all the time. This goes back to what I said before about research versus clinical use of genomic medicine. The MBC Project is a research project. Patients are donating their tissue and donating their information in order to create this big research database for us to make advances in developing new treatments and treatment strategies. What we share with patients are discoveries, our progress, and the aggregate data that we generate, just like we share with the researchers. In large part because of regulatory and logistical reasons, we do not have the ability to sequence someone's tumor and return their individual result to them for clinical purposes. There are companies and many private institutions that can do something like that. This is largely to generate a research database. Patients are certainly informed of what we are doing every step of the way and are kept as partners throughout.

Dr Miller: When we think about sequencing patients' tumors, there are a lot of other questions that come up that I think might not have been given the attention that they deserve. One is that while you are sequencing the patient's tumor, any germline mutations that came with that patient are likely to be reflected in the tumor. That might not always be. If there are large chromosomal losses, you might lose that information. But how do you handle the situation when you have talked to a patient about sequencing her tumor in your own clinic with the goal of using it for clinical decision-making, and then you stumble on a germline abnormality? That is usually not part of the discussion when we are talking about sequencing a patient's tumor. Should it be?

Dr Wagle: You raise an important complexity in the era of genomic medicine, which is secondary findings, sometimes called incidental findings. You are looking to be able to answer one question, and then you inadvertently stumble on a result that answers a different question, but you don't know if the patient wants to know that information.

Dr Miller: It has implications for other people, those who are not the patient.

Dr Wagle: That's right. This is a big area of study. At our institution, we have been working on a study with the National Human Genome Research Institute (NHGRI), which helps us try to answer these questions. In that study, we consent patients to do whole exome sequencing of their tumor as well as their germline. We ask patients about incidental findings and whether they would like to be informed about incidental findings in the germline that may affect them or their family members. If they do want to find out about them and we find them, we involve genetic counselors. That is part of a big research study. The question is, how do we translate that information and what we learn to routine clinical practice? I don't think there is an answer in the field yet.

People struggle with the idea of testing the germline. When we test the germline, it actually makes interpreting the tumor much easier, but along with that comes the complexities of how we deal with the information. The most important thing is to make sure that patients are informed about what they are getting and to have resources such as genetic counselors to help patients with any decisions they might need to make.

Dr Miller: What is your next hope for the MBC Project? You have proven that it is feasible. Patients will come. You can get the information and get the material to do the sequencing. What is the first thing you hope to use this resource to understand?

 
Every so often, patients will have a dramatic response to a therapy...We can potentially learn from those patients.
 

Dr Wagle: There are so many pressing questions that we want to answer. I will tell you a few that we are excited about. We can use this database to find rare groups of patients who may have been understudied. One example of a rare group is patients who have had extraordinary responses to some therapies. Every so often, patients will have a dramatic response to a therapy or will be on a therapy for many more years than anyone expected. We can potentially learn from those patients. Was there something different about their tumor that made them respond so well to that particular therapy? Can we use that information to either design therapies for other patients or find other patients who might also respond to that therapy? We have identified hundreds of patients who have had extraordinary responses to specific chemotherapies and targeted therapies. We are excited to see if we can understand why those patients responded so well.

We have also started studying patients who present with metastatic disease, de novo metastatic breast cancer. They are a relatively small group of patients compared with those who present with early-stage breast cancer, but their tumors might help us understand the metastatic process and how metastasis happens to begin with. We have talked to many other researchers around the country who have their own important questions. We hope to generate a number of demonstration projects that other researchers will see and say, "This is the question that I want to answer. I want to use the MBC Project data for that." I imagine that many of these projects will start to get described over the next year or so.

Dr Miller: Thank you for joining us, Nick. This is going to be an era that we will be talking about for years to come, with so much for us to learn.

Dr Wagle: Thanks for having me.

Dr Miller: This is Dr Kathy Miller, reporting from the San Antonio Breast Cancer Symposium in 2016. Thank you for joining us.

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