Breast and Ovarian Cancers Moon Shot update

MD Anderson Cancer Center
Date: 05-27-2014

Lisa Garvin: Welcome to Cancer Newsline, a podcast series from the University of Texas MD Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment, and prevention, providing the latest information on reducing your family's cancer risk. I'm your host, Lisa Garvin, and today we've got two guests in our studio, Dr. Shannon Westin, who is an assistant professor of gynecologic oncology, and Dr. Jennifer Litton, who is an associate professor in our breast medical oncology department. We are talking about two cancers that have become part of MD Anderson's Cancer Moon Shots Program, which is an ambitious research initiative to quickly translate discoveries in the lab to the clinical setting. The two cancers that we're talking about today are high-grade serous ovarian cancer and triple negative breast cancer. First of all, Dr. Litton, talk to us about triple negative breast cancer. What is that?

Dr. Jennifer Litton: So triple negative breast cancer is a subset of breast cancer where it's a bit of a catchall phrase for cancers that otherwise don't have targets such as tumors that aren't fed by estrogen or progesterone and don't over express the HER 2 protein. Within that group of triple negative breast cancers, which accounts for about 15 to 20 percent of all the breast cancers, that in and of itself is a very diverse group of breast cancers. For some, they can be very well treated and are very susceptible to chemotherapy and our current treatments, and there's a group that is very resistant and for which the Moon Shot is really targeting to improve outcomes and survival.

Lisa Garvin: Is this more of a young woman's disease like some types of breast cancer, or is this more a middle age -

Dr. Jennifer Litton: Well, they can certainly happen at any age, but it tends to be more in younger women, pre-menopausal, and African American women.

Lisa Garvin: And, Dr. Westin, what is high-grade serous ovarian cancer?

Dr. Shannon Westin: So when you look at ovarian cancer, the most common histology type are the epithelial histology types. They account for about 80 to 85 percent of all ovarian cancer, and high-grade serous is one of those epithelial histology types. It's the most common epithelial histology type and probably accounts for about 50 to 60 percent of all epithelial ovarian cancers -

Lisa Garvin: Why does it have that fancy name? What is it that's different, that it's high grade and serous

Dr. Shannon Westin: Sure. The serous part is just what the cells look like under the microscope. Basically tells you where they came from. The high grade means that those cells look more aggressive. So they have what we call more cellular activity. They look like they're dividing quickly, and they tend to be actually more chemo responsive in the beginning.

Lisa Garvin: Now, are these cancers, I don't want to lump them together, but do these cancers have a different prognosis than, and I hate to say run of the mill, but your typical breast or ovarian cancer diagnosis?

Dr. Jennifer Litton: So for breast cancer, I think there's a group of women who do very well with triple negative breast cancer when they receive standard therapies. That their tumor cells are very responsive, or in other words get killed off by the cancer. There's also a group whose tumors do not respond to the chemotherapy, and the tumors tend to grow quickly and have a different pattern of occurrence where the cells go and how quickly they do. And right now for those women, we are actively looking, and part of the Moon Shot is to find different therapies to find treatments that are really effective in this case.

Dr. Shannon Westin: For high-grade serous, it is, like I said, the most common, and so these tumors, when, in the upfront setting, tend to be very responsive to chemotherapy, and really survival and prognosis is directly related to the stage of the cancer or how far it's spread outside of the ovary. Unfortunately, although we can generally get a good response to chemotherapy, in about 80 percent of women with high-grade serous ovarian cancer, it is very common that these tumors relapse, mean come back. So, and on an average about a year and a half after completion of therapy, these women will have a recurrence, and so part of our emphasis in the Moon Shot is to determine what can we do in the upfront setting to maximize that time before recurrence, and then also what can we do to prevent that recurrence.

Lisa Garvin: Why were these diseases, a., chosen as Moon Shots, and, b., lumped together in one Moon Shot?

Dr. Shannon Westin: I think the diseases were, I would, I'll start with the second question first. Were lumped together in that our recent evaluation, there's something called the cancer genome atlas, which really molecularly characterized what these tumors looked like the cellular level, and actually when you look at high-grade serous ovarian cancer and triple negative breast, they're quite similar. So they have a lot of the same abnormalities in their cancer cells, and that, so that kind of made sense to put them together as part of one Moon Shot. And then further I think they're both areas where they're common enough that they cause quite a bit of mortality, and so the impact on patient survival and patient lives, which is what the Moon Shot's all about, would seem to be great -

Lisa Garvin: Do they share genetic mutations or biomarkers, known biomarkers at this point -

Dr. Jennifer Litton: Well, I think there's two different ways to look at that. The first is that when we look at people who have heredity cancers, I'm specifically thinking about BRCA1 mutations here. In breast cancer, the vast majority of women who carry a mistake in their BRCA1 gene do tend to get triple negative breast cancers, and on the flip side of that, they also have a significantly higher risk of developing a high-grade serous ovarian cancer. Not the other subtypes of ovarian cancer but really high-grade serous. So it makes sense also to look at and to take advantage of understanding that genetic pathway of the BRCA1 mutation and how it links these two cancers together. On the actual molecular side, and I'll defer to Shannon, but we also find one of the most significant mutations in the tumor besides being that same BRCA1 pathway is the P53 pathway that tends to be in triple negative breast cancer 80 to 90 percent of the time mutated, which is very different than our other subtypes, and this is not a P53 mutation in, that's inherited from someone's mother or father. I'm talking about a P53 mutation that happens in the tumor cells themselves -

Lisa Garvin: And that's also known as the tumor suppressor gene, is it not, P53 -

Dr. Shannon Westin: It is one of the tumor suppressor genes, and to carry from what Dr. Litton was saying, you know, approximately 95 percent of patients with high-grade serous are tumors with, high-grade serous tumors will have a P53 mutation as well. And so really molecularly they, they're quite similar, and when they drill down on additional abnormalities they saw very similar pathways. You know, the triple negative breast and the high-grade serous looked more similar to each other than other ovarian cancers or other breast cancers, and so it made some sense that potentially, they would have similar targets that we could use to direct therapeutics -

Lisa Garvin:  As part of the Moon Shot, I believe one of the goals for this Moon Shot is to identify new genetic mutations or new biomarkers, is that correct?

Dr. Jennifer Litton: Yes, that's certainly correct. Part of it is really getting a group of people together not only in a room but in research in general. To get the clinicians with the basic scientists, with the pathologists, with the radiologists, and that has been a huge push in what I would say a success of getting people to collaborate in ways that we hadn't previously thought of. So not only just doing just clinical trials but meaningful clinical trials that bring a lot of data as well as helping us to identify how to select patients for trials in the future. So we don't just do a trial and try a drug. We do a trial. We find out who responds. We find out the molecular underlying biology of that tumor to try to figure out is there a way to figure out who would respond before we even give them the drug. In addition, very exciting, we are making mouse models with actual human tumors instead of just using cells or cell lines where we're going to be able to study drugs in a much faster way before they ever get to humans, and by building this whole infrastructure, it's not one study or one project. It's going to continue to drive the research for years to come.

Dr. Shannon Westin: And with each clinical trial, not only looking at those patients that respond, but also evaluating which patients respond and then ultimately don't respond or that tumor starts to grow, or those patients that are from the beginning very resistant and looking at what additional ways their tumor might be finding to get around that agent. So, you know, maybe you're treating a tumor that you would expect to respond but it doesn't. So what does it have, what is it using to get around that agent, and so can you use two different agents or three different agents by identifying those pathways of resistance, then we can inform future trial development. And so that gets exactly what Dr. Litton was saying of, you know, not just one trial, but then informing the next trial and the next and continuing to grow that information so we can actually make a larger impact -

Lisa Garvin:  And I think that's the less glamorous part of Moon Shot. It's kind of hidden. A lot of what's driving this is the ability to crunch huge amounts of data to kind of help you inform new therapies. How is the platform going? Do you have a platform for that, or how is that going?

Dr. Shannon Westin: Well, I think there are several different platforms that get out that, there's a bioinformatics platforms, which is really where they're working on. How do you take in all of this data, and how do you, like you said, crunch those numbers and generate something that we can actually clinically work with. And then there are platforms that are helping to develop the models that Dr. Litton was talking about, and also inform, you know, doing basically what we call co-clinical trials. So doing the clinical trial in the patient, but then also doing it in mice. And so getting information real time as you're developing those trials. So I think it's been very exciting. We're, you know, everything has been, it's been how long now that we've been doing this Moon Shot, about a year. And so really things are kind of, at least on our end, getting off the ground for our clinical trials are coming through the companies now where we're getting patients on trial, and so stay tuned.

Lisa Garvin: And I know another part of the Moon Shot is universal genetic testing because typically genetic testing is either offered inconsistently or patients don't often like to know what their genes are doing. How important is universal genetic testing in fighting these diseases?

Dr. Jennifer Litton: Well, you know, at this point, a lot of times when we offer genetic testing, we look at some standard guidelines such as the National Cancer Conference of Cancer Network guidelines, and it's important that we continue to constantly re-evaluate the data and re-evaluate our guidelines. So, for an example, from the group of patients that we've been following at MD Anderson since 2003 under the leadership of Dr. Banu Arun and Dr. Karen Lu, we've been able to show that women with triple negative breast cancer, biology alone because previous to the, that it was just family history, age. From data that we've generated here showing that that alone is enough of a risk factor. One of the modeling showed to test everyone at age 50. The guidelines said, well, let's start, let's put the guidelines at 60 to make sure we're more inclusive, and we're taking it a step forward and saying let's test on biology. So everyone with triple negative breast cancer. And we're seeing more and more people come in and be referred since the NCCNA guidelines changed just a few years back, and if we catch more people before they're diagnosed or before a second unrelated breast cancer, and we can affect their families, then that is true disease-free benefit.

Dr. Shannon Westin: Yeah, and for high-grade serous, and similarly we have been expanding our catchment. Who do we test, and over the last few years, we've been basically testing universally all patients that have high-grade serous ovarian cancer, and because of that, we've seen higher proportions that, than what were previously reported in the literature. In, historically, the RCA was reported to be found in about 10 percent of all patients with ovarian cancer, but when we expanded our criteria and started basically testing everyone, it's increased to maybe 18 to 20 percent. So that's a huge impact on patients, and, in fact, recently, our society, there's Society for Gynecologic Oncology, actually changed their recommendations, and have recommended testing all patients with high-grade serous for BRCA. So already we've started moving the needle and changing kind of the practice -

Dr. Jennifer Litton: And this is a very coordinated effort between gynecologic oncology and breast oncology. We keep our hereditary cancer, clinical cancer genetics clinics on the same day. We're testing, we're moving patients, you know, effectively between the two departments previous to the Moon Shot, but it's certainly enhanced -

Dr. Shannon Westin: It's certainly enhancing -

Lisa Garvin:  Because it's interesting how even though we're a big comprehensive cancer center, there are still these silos, clinical silos, research silos. So they're all starting to come together now -

Dr. Shannon Westin: They are. Clinical cancer genetics is a very large program that is actually centralized, but we have several different genetic counselors, and they are embedded in the different clinics, but they are centralized by our steering committee -

Lisa Garvin: So what does 2014 look like for this Moon Shot? What sort of things are you expecting to happen in the next year?

Dr. Jennifer Litton: So I think you are going to see that we've been building, building, building these platforms that we've been talking about. You're going to see the clinical trials now rolling out and getting to patients. In fact, just as Shannon and I were walking over, as we've collaborated on quite a bit, we've got two or three clinical trials going to our IRB as early as next week, and not only building it for patients but also all of the other science that's going to go with these trials to build and build and build in the future.

Lisa Garvin: Are these new agents coming on line, or?

Dr. Shannon Westin: New agents and combinations. And so, you know, the heart of our initial kind of therapeutic platform for the Moon Shot is based on parp, because parp is something that we know we can use to target, and for everyone out there, that's basically an agent that acts on patients that have a BRCA mutation or an abnormality in their tumor that makes repair of DNA damage difficult. And so what we've learned is these agents are not only great for patients that have a BRCA mutation, but they're also great for another proportion of patients that have some type of abnormality in their tumor that, you know, that puts them at risk from this agent. And what we're looking at is not only doing single-agent parp, but a lot of our platform is going to be combination trials or putting parp earlier. For example, Jennifer has a trial with neoadjuvant which means before surgery. Getting parp inhibitors in the neoadjuvant setting to see how much impact they have. We have something called a window of opportunity trial where we're treating patients right before surgery with parp. And so we're doing lots of different things that'll be both, have therapeutic benefit, but also give us a lot of information molecularly to understand what changes happen in the tumors when we treat patients with these agents.

Lisa Garvin: And in closing, we'll start with you, Dr. Westin, how excited are you?

Dr. Shannon Westin: Well, I think we're very excited. This has been a long time coming, and over the last year we've really been doing a lot of the ground work, building the foundation for this Moon Shot, and now, you know, as Jennifer mentioned, you know, the trials are rolling out. We're starting to see the patient samples. We're testing the patients, impact on their families, and so it is a rush because finally I feel like we're actually seeing some of the benefits, and, you know, the real tangible things that we were hoping for when we've been developing this over the last two years.

Lisa Garvin: And, Dr. Litton, do you think we'll be moving the needle on morbidity, mortality and early diagnosis?

Dr. Jennifer Litton: I certainly hope so. If we identify more people with BRCA mutations earlier, when our interventions are less invasive, as far as systematic chemotherapy, and if we can improve response to our therapies, that will translate to better survival.

Lisa Garvin:  Great. Thank you, ladies, for being with us today.

Dr. Shannon Westin: Thanks for having us.

Dr. Jennifer Litton: Thank you.

Lisa Garvin: If you have questions about anything you've heard today on "Cancer Newsline", contact ask MD Anderson at 1-877-MDA-6789 or online at MD Anderson.org /ask. Thank you for listening to this episode of "Cancer Newsline". Tune in for the next podcast in our series.