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Banu Arun, MD: Hello. I'm Banu Arun. Welcome to Medscape's InDiscussion series on advanced and metastatic breast cancer. Today we will build upon discussions we've had in previous episodes around access to new drugs and health disparities, with a particular focus on triple-negative breast cancer, underrepresentation of patient groups in clinical trials and how this impacts everything from drug design to efficacy. First, let me introduce my guest, Dr Stephanie Graff. Dr Graff is the director of breast oncology at Lifespan Cancer Institute and co-lead of the Breast Cancer Translational Disease Research Group at Legorreta Cancer Center at Brown University. She's also an assistant professor of medicine at the Warren Alpert Medical School of Brown University and a medical advisor for the Dr. Susan Love Foundation for Breast Cancer Research. Welcome to InDiscussion. I usually like to ask each of my guests what they believe is the most relevant issue in advanced and metastatic breast cancer today. Stephanie, do you want to give us your thoughts?
Stephanie Graff, MD: Yes. Obviously the most relevant issue is that we need more effective drugs to treat metastatic disease. We've had a flurry of new approvals, which is really exciting. One of the other key issues is how those puzzle pieces could best fit together. Today we're mostly talking about triple-negative disease, but there's been new approvals with oral selective estrogen receptor degraders (SERDs). Should SERDs be given in combination? How should we sequence them with the new antibody-drug conjugates (ADCs)? Could we sequence them after each other? Should we be using them earlier? There are a lot of great questions right now that I'm excited to be a part of helping to answer.
Arun: Wonderful. Thank you. In our past episodes, we have spoken about ADCs. Can you briefly tell us why and how these ADCs are changing the landscape of treatment for metastatic breast cancer patients?
Graff: I'm sure everyone listening knows that ADC is a targeted therapy bound to a chemotherapeutic with a linker, hence the antibody-drug conjugate. There are sacituzumab govitecan, trastuzumab deruxtecan, and T-DM1, so there are many ADCs now for use in the breast cancer space and across indications — breast cancer that is estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) positive, or HER2 low. They're exploding everywhere. What's great about these compounds is that we've seen they have a wide reach. Again, we're able to use them in a variety of different breast cancer indications. They've shown remarkable efficacy. We're seeing really deep separation of the curves when we're comparing them to treatment of the physician's choice. Because they have that antibody aspect, we seem to be getting slightly less broad toxicity than what we're seeing with traditional chemotherapeutics. Now, that's not to say they're innocent. They certainly come with some side effects. But those factors together really make them a revolution in drug development.
Arun: Wonderful. These are all very valuable studies that really change the landscape. We are learning so much. I want to ask you something important. What about the representation of non-White and non-Asian populations in these very important trials?
Graff: That's a big problem not just in breast cancer — what you and I are going to focus on — but in cancer research in general, and I imagine in research in general. Let's focus on ADCs in breast cancer specifically and look at the ASCENT trial, which looked at sacituzumab govitecan in metastatic triple-negative breast cancer. That trial accrued 529 patients, but only 12% of these patients were Black. Out of 529 patients, 63 were Black women. That is against a backdrop where Black women are more likely to be diagnosed with triple-negative breast cancer and particularly Black women under the age of 50. Black women are more likely to die of advanced disease, and Black women are more likely to be diagnosed with advanced disease. We are underrepresenting black women in drug development for triple-negative breast cancer, despite the fact that they are overrepresented in the population. Then, we move to a trial like DESTINY-Breast04, which was trastuzumab deruxtecan for HER2-low breast cancer. That included both hormone receptor–positive and triple-negative breast cancer patients. Again, 80% or more of the patients were hormone receptor–positive. A very small percentage of those patients were triple negative. In DESTINY-Breast04, there was a total of 557 patients, and only 10 patients were Black. There were some patients where race and ethnicity weren't reported because some countries don't allow reporting, which is a separate issue we need to better understand. Out of those 10 patients, nine of them were in the hormone receptor–positive cohort. That means only one Black patient was accrued into that triple-negative population. When we specifically considered trastuzumab deruxtecan for HER2-low breast cancer, we've got this really narrow population as we look at the available reported data. DESTINY-Breast03, which was the HER2-positive population with trastuzumab deruxtecan, accrued 524 patients with only 19 Black women. All these trials accrued around 500 patients. We have small numbers of patients eligible so that we have the randomized highest level of data. Obviously, real-world data will continue to become available, but that comes to a different scientific caliber. We need this information so we understand how things like response, toxicity, pharmacokinetic dosing, drug delivery, and drug clearance could be different in different populations. If our studies aren't conducted in a representative sample of the patients diagnosed with the disease, it's hard to then take that into practice and speak to the patient in front of you in clinic and know you're giving them a representative sample of what they're going to experience.
Arun: I want to expand on something you mentioned. We are so focused on the results and excited, but drug clearance and toxicity is really different in different populations. With these new targeted agents, not only the ADCs, we are learning every day how to manage new side effects we never had to deal with in traditional chemotherapeutic agents. I'm also talking about immunotherapy, which is not the topic today, but it makes it even more important that we understand the toxicity and drug clearance in different populations. What are your thoughts about that?
Graff: That is super relevant. I remember in Lung and the Journal of Thoracic Oncology, there was an analysis that looked at all of the immunotherapies that have been done in lung cancer and the number of women who were included, and it was shockingly low. I don't have the number in front of me, but the majority of lung cancer trials were done in a population of more men than women. The data on immunotherapy outcomes for women with lung cancer are low. I remember thinking about that when I sat at the American Society of Clinical Oncology (ASCO) annual meeting and looked at I-SPY 2 results and the toxicity of immunotherapy in women treated neoadjuvantly with immune checkpoint inhibitors. We were seeing our first results of what happens to women treated with neoadjuvant checkpoint inhibitors and saw slightly higher rates of things like hypothyroidism or panhypopituitarism than we had expected with immune checkpoint inhibitors from treatment in other disease types. I thought to myself that it kind of made sense. Women have higher rates of autoimmune diseases globally. We would expect them to have of a higher rate of autoimmune diseases as a result of an exposure to an immune checkpoint inhibitor. What is that going to look like as we expand immune checkpoint inhibitors into breast cancer, which is obviously a disease that predominantly affects women? That's an example of research bias. Gender is so easy to determine or report. Race and ethnicity are so much more complicated because they should be self-reported. They're not always self-reported. Often, we limit patients. There have been several groups that have done really nice work looking at categories like Asian or Asian and Pacific Islander and the limitations around that language. For example, what box does a patient check if they are from the subcontinent of India? Is somebody who is Hawaiian or Japanese or Chinese the same as somebody who is an Alaska Native? They might all check the same box, but genomically, drug clearance, diet habits, cultural habits, and drug exposures all might be very, very different. These are things we don't fully understand yet.
Arun: You also mention that Black women have a higher mortality rate than White women in the United States. But even if the mortality was the same, the representation in clinical trials should be equal. I know this question could be another whole 1-hour discussion, but what can we do? What is the lowest-hanging fruit that can be done to have equal representation? How can we as a research community use a stepwise approach and hopefully make improvements quickly? Because it cannot go on like this. Responsibility falls on many parties — not only academic centers and recruiting physicians and patients — but many agencies, companies, cooperative groups, and the National Cancer Institute.
Graff: Luckily, bunches of people are working on this. I'm proud to report and glad to say that, for example, the American Society of Clinical Oncology in partnership with the Association of Community Cancer Centers are working on a project called Increasing Racial and Ethnic Diversity in Cancer Clinical Trials. They have undertaken this broad review of the landscape and these different mechanisms by which we can start moving toward change by doing things like improving access to clinical research and improving equity in the design of the clinical trials. These are things as simple as the formula we use to define creatinine clearance. That should be a no-brainer. They review community partnerships, research partnerships, and patient advocacy partnerships to make sure they have diversity and equity embedded in them, promoting education and training programs to educate and train a more diverse workforce. They invest in equity, diversity, and inclusion resources broadly across the clinical trial landscape — not just in physicians but in clinical research coordinators, data scientists, and data managers — and then they are broadly sharing those data and strategies across the broader clinical trial ecosystem. They've already published a few of their results. They did two quick studies where they looked at clinical trials and site self-assessment where they had sites use an equity, diversity, and inclusion tool kit to identify what they could do to implement change. Eighty-two percent of the sites were able to identify opportunities for improvement, and 63% of sites were able to go ahead and start implementing specific strategies to help them become more equitable clinical trial research sites. In their second project, they had clinical research teams do the Implicit Association Test (IAT), which is an implicit bias training tool. They saw that sites that used this IAT instrument increased their knowledge around implicit bias and were able to maintain that increase in knowledge across time, which should help promote diverse accrual to clinical trials. The BECOME project was another interesting project that was published and showcased at ASCO in 2022 and presented by Stephanie Walker, who is a metastatic breast cancer patient advocate living with metastatic disease. I'm sure you remember that. Stephanie's work showed that across Black women living with metastatic breast cancer, when they were asked if they wanted to participate in clinical trials, the resounding answer was yes. But most of them had not been approached with the opportunity. Nobody had said, "Hey, do you want to do this trial?" When asked what would inspire trust in them and what would most help them accept a clinical trial if someone were to approach them with it, the number one factor was if they could talk with someone who was more like them. Interestingly, "like them" had a very broad definition. It could be someone who had a similar racial or ethnic identity as them. It would be amazing if we could employ more Black physicians, Black research nurses, Black nurse navigators, and Black lay navigators who could speak to patients about that experience. If we didn't have a Black patient who could approach the patient, Black women also felt more comfortable participating in a clinical trial if they could speak to any other person who had previously participated in a clinical trial who had been diagnosed with breast cancer or metastatic breast cancer. Building shared experiences for our patients helps inspire trust in the opportunities they're presented with. I thought that was really powerful as we think about how to optimally design our care teams.
Arun: Right. I think building shared experiences is really important, as well as understanding the barriers and then a stepwise approach. We discussed a little bit what we can do in the United States, but of course, it's a global issue. How do we improve on the real-world science that goes beyond what we do here in the United States? How can we bring teams together? Is it industry? To me, it sounds like it's easier for the industry because they open trials in different countries and facilitate local recruitment for these global trials. Any thoughts on that?
Graff: The best global care is local care. Culturally competent care is local. It's really important that we connect to the local leaders and ask what's going to work well for them and how we can modify this trial toolkit to work well for them. What makes the trial feel comfortable? How do we communicate about a trial? In Rhode Island vs Texas vs China vs Ukraine, these answers are going to be very different things. My patient might need babysitting. Your patient might need a gas card. Their patient might need a hotel room. Somebody else's patient might need a cell phone or elder care. All of us have different tools and resources. The beautiful thing is that until we ask the question and figure out what's missing, we're blind to it. It starts with connecting with what that local need and resource looks like and then figuring out strategies to help build it.
Arun: Thank you so much, Stephanie, for your wonderful thoughts. They have been enlightening and very motivating.
Graff: Thank you.
Arun: Today we talked with Dr Stefanie Graff about access to new drugs, clinical trials, and health disparities in advanced metastatic breast cancer. Thank you for tuning in. Take a moment to download the Medscape app to listen and subscribe to this podcast series on advanced and metastatic breast cancer. This is Banu Arun for InDiscussion.
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Cite this: Advanced and Metastatic Breast Cancer: Health Disparities and Underrepresentation of Black Women in Clinical Trials - Medscape - Aug 08, 2023.