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Dr. Lee: Good afternoon, everyone. Welcome to the show. I'm your host, Dr. Vivian Lee. I'm the Senior Vice President of the University of Utah Health Sciences. Today, we're going to talk about breast cancer. About one in eight women will develop breast cancer in her lifetime, and it is the second leading cause of cancer death in women.
One of the misunderstandings about breast cancer that we're just starting to understand now better is the fact that breast cancer is not just one disease, but it's actually many different diseases. That's a really important point to understand. Because breast cancer is different diseases, it means we have to have different treatments for women with breast cancer.
My guest today is Dr. Alana Welm, who's a researcher at the University of Utah's Huntsman Cancer Institute. Dr. Welm and her colleagues are making news all over the world because they have found a way to grow pieces of a woman's breast cancer in mice, and that's really going to transform the way we think about breast cancer treatment.
Now, I have read that your research means that we're going to treat women in a very different way where in the past we might try a treatment and it may work or it may not work. The women almost feel like they might be guinea pigs because we don't know how to treat them. Instead, your approach with these mice is almost like making a guinea pig for every patient. Is that a fair description of your work and its implication?

Dr. Welm: That's right. It's a science that's telling us now that breast cancer is probably more, like, ten different diseases. Currently, in the clinic, it's treated as though it were, really, three types of breast cancer. What we're doing is trying to personalize the therapy so that we can grow an individual person's tumor in a mouse and actually use that mouse or that tumor line as a way to determine what are the best therapies for that particular women are.

Dr. Lee: Well, if there are really ten different types and we only know about three, then what does it mean if a woman comes in now? If a woman comes into our clinic at the Huntsman Cancer Institute, how do we treat them now?

Dr. Welm: Currently, breast cancer is heavily over treated, believe it or not. So, we really are treating ten women for the benefit of three. We know that about 30% of breast cancer patients will go on to develop a relapse or a metastasis, and metastasis is what kills patients with breast cancer. Because we cannot determine which three women out of the ten will go onto develop metastatic disease, they are almost all getting treated with really toxic chemotherapies. So one of the goals of our study is to be able to use these tumors grown in mice to determine which ones are the most aggressive ones and then modify treatments according to that particular tumor.

Dr. Lee: One of the most interesting aspects of your work was that when you took these pieces of a woman's breast cancer and you put them into mice, the behavior of those tumors actually was just like when they're in people, right? They not only grew like breast cancers, but they also metastasized. What was it about how you did it that was different from what everyone else had previously tried to do and failed?

Dr. Welm: What we did was expand on an idea that we don't want to culture the tumors before we put them in the mice. So we don't want to put them in the lab on a petri dish like everybody had done before. Instead, we put them directly into the mouse breast tissue or the mouse mammary gland. This environment is so much like the human breast that it allowed these tumors to not only grow, but also to behave very similar to how tumors behave in patients.

Dr. Lee: One of the questions that came to my mind when I first read about this research was, won't it be easier to just take a piece of the breast cancer tissue, look at the DNA of it, and then figure out which of those ten types it is just from that?

Dr. Welm: We are doing that. We're examining the mutations in individual tumors. However, we believe that you have to combine some functional analysis of the biology of that tumor together with the genetic information. So just knowing that there's a mutation in a gene doesn't necessarily tell us about how that tumor will behave in terms of metastasis or in terms of response to therapy. Our idea is to really combine that genetics analysis with a functional assay of tumor biology and tumor behavior in order to make the best treatment decisions.

Dr. Lee: It's sort of, like, that old line that it's not just the genes but the genes and the environment? Just putting some of those breast cancer cells somewhere in the mice, but that didn't work but putting it in the breast tissue itself worked. So there's something about the genes and environment relationship that's important.

Dr. Welm: That's exactly right. The other advantage to using this type of an approach is being able to modify the genetics of a mouse in concert with asking about tumor biology gives us a chance to actually examine the interaction between the genetics, the tumor biology, and the host response to the tumor.

Dr. Lee: We have some questions from some listeners online. Laurie, in the West Valley asks this question. "The women in my family have breast cancer. My mother had it. Two of my aunts had it, and now my sister has it. What does that mean for me, and what does this research mean for people like the women in my family?"

Dr. Welm: We know that cancer is a genetic disease, meaning it can be hereditary. As you probably know, we made the original discovery of the BRCA mutations.

Dr. Lee: The breast cancer genes.

Dr. Welm: The breast cancer genes that are carried through certain families and contribute to a small proportion of breast cancer, but those patients who carry those genes have very, very high risk of breast cancer. That type of inheritance is what seems to be manifested in this family. Partly as a result of these kinds of discoveries in Utah, we have a fantastic high-risk breast cancer clinic that's directed by Dr. Saundra Buys at the University of Utah and Huntsman Cancer Institute. They can test people for these genes. They can provide genetic counseling as to how they might want to modify either their lifestyle or even take surgical precautions for breast and ovarian cancer in the case of BRCA mutation. They actually follow these patients. So rather than that just being the end of, you know, "Okay, here's mutation, and this is what it means for you," we actually want to be able to follow them with high screening.

Dr. Lee: Here's another question from Sandra in Murray. Sandra asks about men. "Can men get breast cancer?"

Dr. Welm: Men do get breast cancer. It's relatively rare. It's only about one percent of breast cancer that happens in men, but it is a problem, and it's not very well recognized.

Dr. Lee: Does it run in families the same way as women? We don't know?

Dr. Welm: We don't know. Yeah.

Dr. Lee: Since it's so rare, we just haven't done enough research in that. Well, Dr. Welm, thank you so much for being my guest today.

Dr. Welm: My pleasure.

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Interviewer: Researcher Alana Welm, a professor at the Huntsman Cancer Institute investigates the worst cases of breast cancer and has discovered a new way of thinking about how tumors in these patients progress and spread. Her work may lead to new type of cancer screening and new treatments. Dr. Welm, this work focuses on the most aggressive forms of breast cancer. Can you explain?

Dr. Welm: Yes, most patients with breast cancer who die from that disease, die because their disease spreads to other organs and that's called metastasis. So, we are trying to understand the most aggressive forms of breast cancer that are not cured by local therapy, like surgery and radiation but actually have the chance of spreading to other organs.

Interviewer: You were able to gain new insights into metastasis by looking at tumors from real patients.

Dr. Welm: Yeah, for example, we have one particular who presented with metastasis breast cancer. So, in this particular patient, it's a really interesting case in which the therapy was changed to a new combination of therapy and she had a very good response to this therapy and had stable disease for almost an entire year. Unfortunately, her disease eventually became resistant to that therapy and progressed. So what were able to do is, take her cells both before and after that therapy, put it in the model system and then test those exact therapies. What we found was, in fact in the model system, we could show that the first batch of tumors cells was sensitive to that therapy but then eventually became resistant and that matches the batch of tumor cells that have progressed after the treatment. So what this just tells us is that our model system is, at least in this case, faithfully recapitulating the progression of the disease and potentially will be able to predict whether or not a therapy would work for a given patient with cancer.

Interviewer: And this is a new way of researching tumors?

Dr. Welm: It's new in the sense that we are able to do this straight from patients instead of using well established cancer cell lines that have been grown in tissue culture, on plastic dishes for decades.

Interviewer: Either way, so you can use your model system to come up with personalized treatment plans?

Dr. Welm: Yes, we are in the process of designing a clinical trial in which we could grow individual breast cancer patients' tumors in our model system, in order to test the variety of therapies that are available to patients with metastasis breast cancer, and then determine which of those is the most effective in the model system, and then use that if necessary, if in the case of a metastasis relapse in that patient.

This would be initially just limited to people who have very aggressive form of the disease because it's pretty labor intensive and would be expensive, but we think it's a more accurate model of how an individual tumor behaves and so, it should also be more accurate model of how that tumor responds to therapy.

The reason why that's important is because it's very unlikely, given the complexity of cancer, that targeting a single gene, two genes or three genes or some combination of more genes is ever going to lead to a cure for cancer because it's so very complex, and every time you block a single gene function, the cancer finds a way to compensate by [inaudible 00:04:50] another gene. So the reason why we are so excited about this is because we found a single protein that can, by itself, work to activate more than a hundred genes, and we have an inhibitor to block this and we were able to show complete blockade of metastasis in our model system with cells from two different patients.

Interviewer: That's pretty remarkable.

Dr. Welm: It was very remarkable. There are not many things that can cause complete blockade of metastasis, it's a high hurdle. We know that this pathway isn't the only one that drives metastasis, so there is still a lot of work to be done. But one of the things that we have been able to get from this is, in [inaudible 00:05:31] fingerprint of a tumor that will tell us whether or not the pathway is on, and for those patients with pathway on and their tumor cells, they may be good candidates for this new inhibitor that is currently being developed. Interviewer: Do you have any idea of how common this mechanism works in cancer patients?

Dr. Welm: We found that this pathway is activated in approximately 25 percent of all breast cancers that we examined and we looked at around 2000 patients.

The other important thing to note is that, the signature is on more often in the so called triple negative subset of breast cancers. Those that are negative for the estrogen receptor, progesterone receptor and the [inaudible 00:06:13] gene, and this the subset of breast cancers for which we currently have no targeted therapy. The only current therapy there is chemotherapy and radiation, and so, if we can inhibit Ron, we will have potentially the first targeted therapy for triple negative breast cancer. It's also the most aggressive form of breast cancer.

Interviewer: And might this pathway be involved in other types of cancer?

Dr. Welm: The Ron pathway is actually [inaudible 00:06:38] in most solid tumors of epithelial origin. So pancreatic cancer, lung cancer, colon cancer, etcetera, and it has been shown to [inaudible 00:06:50] with poor prognosis. We haven't done the mechanistic work yet to determine whether this exact pathway is driving metastasis in those cancers. It's certainly worth to look at because it again goes with poor prognosis and bad outcome.

Interviewer: So how do you think you can use this new information to help patients?

Dr. Welm: Well, we hope that we can use this information to identify patients who might be at high risk of metastatic relapse because we can identify that their tumors have this pathway active. For me, the most important next step is getting this into clinical trials. So, the inhibitor that we have decided to work with is currently in phase I trials, which are simply to determine safety and dosing regiments for this drug and that trial is being conducted right now in Australia. So, we are working with the company who developed the drug to get a trial going in the U.S., like a phase II setting, so we could try and determine the ability to either shrink existing metastasis or block the growth of new ones.

Interviewer: Do you think finding this mechanism will prompt other scientists to look for epigenetic pathways being involved in cancer or cancer progression?

Dr. Welm: It's already being looked at in many settings. So, I think that's really the new frontier in cancer biology as we are learning that mutations do drive cancer. There are certain mutations for which you can use a targeted therapy and have some success but resistance is always a problem, so with any single mutation that you are targeting, you also will select four resistance populations. So, combinatorial therapy or therapies given in combination are really what's happening now at the forefront of clinical cancer care, but the problem becomes toxicity. If you can identify a pathway like we have, where hundreds of genes are regulated by a single targetable protein, you might have more impact to that disease than hitting a single mediator within a hundred genes.

Of course, I still think resistance will be a problem with Ron inhibitors, if history holds up. That's why our lab is also working separately on understanding all of the signaling pathways downstream the Ron, so that we can anticipate what might be the resistance pathways and preemptively think about combination therapies.