Evolving Mutations in Metastatic Breast Cancer
At the 2018 American Association for Cancer Research Annual Meeting, Dr. Nayar presented research looking at how acquired HER2 mutations can make some metastatic hormone receptor-positive breast cancers resistant to hormonal therapy.
Listen to the podcast to hear Dr. Nayar explain:
the number of metastatic hormone receptor-positive breast cancers that become resistant to hormonal therapy
what whole exome sequencing is and why she and her colleagues used it in this study
the possibility that genetic sequencing of cancers could be an ongoing part of treatment at some point in the future
Dr. Utthara Nayar is a research fellow in medicine at the Dana-Farber Cancer Institute, the Harvard Medical School, and the Broad Institute of MIT and Harvard. A cancer biologist, her broad research focuses on the interface of basic biology, targeted medicines, and drug resistance.
— Last updated on May 3, 2022, 2:16 PM
This content made possible by Lilly Oncology.
This podcast is made possible by the generous support of Lilly Oncology.
Jamie DePolo: Hello, everyone. I’m Jamie DePolo, senior editor at Breastcancer.org. We’re podcasting on location at the 2018 American Association for Cancer Research Annual Meeting in Chicago. My guest is Dr. Utthara Nayar, a research fellow in medicine at the Dana-Farber Cancer Institute, Harvard Medical School, and the Broad Institute of MIT and Harvard. A cancer biologist, her broad research focuses on the interface of basic biology, targeted medicines, and drug resistance. She’s presented research looking at how acquired HER2 mutations can make some metastatic, hormone receptor-positive breast cancers resistant to hormonal therapy.
Dr. Nayar, welcome to the podcast.
Dr. Utthara Nayar: Thank you so much for having me, Jamie. It’s a pleasure to be here.
Jamie DePolo: So how common is it that hormone receptor-positive breast cancer becomes resistant to hormonal therapy?
Dr. Utthara Nayar: Patients with early-stage breast cancer that is hormone-receptor-positive are usually effectively treated with hormonal therapy. However, patients with metastatic, hormone-receptor-positive breast cancer, which is late-stage disease, who are still often effectively treated with anti-hormone therapies initially will go on to develop resistance to those therapies in virtually every case. In fact, the biggest cause of breast cancer mortality in the U.S. is currently due to resistance to hormonal therapy in patients with hormone-receptor-positive metastatic disease -- and that’s to the tune of more than 20,000 deaths per year. So, as you can imagine, it’s a very pressing issue to try to understand the causes of this resistance.
Jamie DePolo: And when that resistance happens, is it to all types of hormonal therapy -- tamoxifen, aromatase inhibitors, Faslodex -- is it everything?
Dr. Utthara Nayar: Actually, the type of resistance mechanism that develops seems to depend on the type of hormonal therapy that the patient received. So, for example, we know that patients who received aromatase inhibitors, which depletes circulating estrogen in the body, in at least about a quarter of cases become resistant by developing mutations in the estrogen receptor itself. (Just to note that if I say “ER,” I’m referring to estrogen receptor.) We think that this is because such mutations in the estrogen receptor allow the estrogen receptor to continue signaling in cells without depending on the presence of the hormone, which is estradiol, or estrogen.
So, those patients luckily still often respond to other types of anti-estrogen receptor -- that is anti-hormonal -- therapy such as Faslodex, because Faslodex, for example, acts by degrading the ER itself, so that effectively makes the presence or absence of an ER mutation effectively irrelevant. However, patients who develop resistance through methods that don’t involve the estrogen receptor may be cross-resistant to several different types of hormonal therapy. And in fact, in up to 75% of cases of resistance, we don’t currently know the mechanism.
Jamie DePolo: So how did the idea for your study come about?
Dr. Utthara Nayar: My principle investigator, Dr. Nikhil Wagle, leads a large clinical sequencing study in Dana-Farber Cancer Institute’s Center for Cancer Precision Medicine, which aims to do something pretty ambitious. Specifically, this is a multi-disciplinary team of clinicians and investigators that has invested a significant effort in developing a more systematic framework to characterize metastatic tumors from patients with metastatic breast cancer more intensively. So, as part of this endeavor, we attempted to study tumor evolution by performing whole exome sequencing.
Jamie DePolo: Okay. I’m going to stop you. I’m sorry. Can you explain to us what whole exome sequencing is? Because we talk a lot about genetic testing and genomic testing of tumor tissue, and this seems to be a new phrase that’s becoming more prevalent throughout the research.
Dr. Utthara Nayar: Yes. I’ll try. Whole exome sequencing will fall under the banner of genomic testing. It’s basically a technique in which we can characterize all of the 20,000 genes in the human genome within the tumor sample. Basically, what we end up doing is extracting DNA from tumor biopsies, and then we capture only the parts of the genome that code for proteins. And that’s what makes it whole exome sequencing, as opposed to whole genome sequencing. And then, once we sequence those, those are compared to the published human genome.
To analyze that, we have computational biologists in our group who use software to test the quality of the sequencing data. Afterwards, they will deploy other computational analysis tools to determine the actual genetic changes in the tumor, compared to normal cells from those patients. So, our study added another layer of complexity onto that, in that we compared sequencing results to those obtained from earlier stages of the disease -- that is before they had developed resistance. In that way, we were able to identify only those genetic changes that were acquired as the tumor has developed resistance.
Jamie DePolo: So, when you were looking for those mutations, did you have an idea that they were going to be HER2 mutations? Were you looking specifically for those, or were you just looking for any mutations?
Dr. Utthara Nayar: Well, I would say that the overall initiative is for the agnostic, so we were essentially looking for any kind of genetic change within the resistant tumor that may hypothetically be able to confer resistance to targeted therapy, So, for example, if a resistant tumor amplified a specific oncogene, which was not present in turn in the original tumor, in that case, we could conceivably imagine that that amplified oncogene could play a role in resistance. So, the reason we actually zoned in on the HER2 mutations in this study is that out of all of the genetic changes that we identified in resistant tumors, the acquisition of HER2 mutations was one of the top candidates statistically, and also, it never co-occurred in resistant tumors that had ER mutations.
So, I just want to clarify again and to try to break down what I mean by that: We know that ER mutations confer resistance, and also, we know that they occur in a fairly large number of resistant tumors -- a quarter is quite a large percentage. So, therefore, the fact that the tumors that we found to have HER2 mutations, once they were resistant, never appeared to have ER mutations in the same tumor, suggested that they develop the HER2 mutations as an independent mechanism of resistance, which is why we decided to follow up on them.
Jamie DePolo: If I understand correctly -- let me make sure I get this -- your results are suggesting that some metastatic breast cancers… they’re continuing to evolve these new mutations as they’re being treated because the cancers were not HER2-positive when the people were diagnosed?
Dr. Utthara Nayar: Yeah.
Jamie DePolo: Is this something that’s been considered, thought about a lot before, or is this something relatively new that is being studied?
Dr. Utthara Nayar: I wouldn’t want to take credit for the idea itself that tumors evolve, because there’s consensus within the scientific field and among clinicians that metastatic breast cancer can continue to evolve new mutations, especially as they’re being treated and acquiring resistance to therapies. But, for various reasons -- institutional limitations or other limitations -- patients’ tumors are not usually regularly sequenced as they’re being treated, and in many cases, they may not even be sequenced at all. So, in fact, breast cancer treatment is often tailored on the basis of the initial tumor characteristics only, even though the tumor may be actively evolving.
There’s one other point I wanted to dwell on, which you mentioned in your question, that these tumors were initially HER2-negative, so I wanted to note they actually do remain HER2 -- so, they were not HER2-positive when they were diagnosed, and in fact, even all the resistant tumors that we found with HER2 mutations would still be classified as HER2-negative by pathologists.
Jamie DePolo: Oh, really? Oh. Okay.
Dr. Utthara Nayar: Yeah, so in fact, the only way that you can detect these mutations is by performing sequencing.
Jamie DePolo: I see. So, it’s not something that if you did a regular tumor test or another path report on it, it still wouldn’t come back….
Dr. Utthara Nayar: Exactly. You would not have noticed. Yeah.
Jamie DePolo: I see. Oh, that’s very, very interesting as well. So, if the resistance to hormonal therapy is caused by these HER2 mutations, and your study found that you could overcome that though, which is a good thing, by a combination of Nerlynx and Faslodex…
Dr. Utthara Nayar: Yes.
Jamie DePolo: So how did you come up with that treatment combination to see if it would work? Did you try a bunch of them, and that one just happened to work, or how did that happen?
Dr. Utthara Nayar: We did. We did try a bunch of different inhibitors -- and actually, most of them did not work -- but there was a specific reason we focused on Nerlynx. Nerlynx, which is also known as neratinib, as you may know, is part of a class of HER2 inhibitors that directly inhibit the kinase domain of the HER2 molecule. Where Nerlynx differs from other HER2 kinase inhibitors, such as Tykerb, or lapatinib, is that it’s irreversible, which means that once the drug binds to the molecule, it’s permanently inhibited.
We selected this treatment combination because a couple of the mutations we had identified had previously been characterized in terms of their responsiveness to other anti-HER2 inhibitors, and at least one of them, we knew, did not respond to the other inhibitors, and that included Tykerb. On the other hand, all of the mutations that we identified had been previously found to be sensitive to Nerlynx. So, in terms of what you’re wondering about whether other HER2 therapies would work in these patients, it’s possible that another HER2 medicine such as Herceptin may work for some of these patients, depending on which specific HER2 mutation they had in their tumor. But, I would stress that at this point, we don’t have any laboratory evidence that these tumor cells, bearing these mutations, can be inhibited by those drugs.
At least currently we think Nerlynx, or something similar to Nerlynx, would be the most comprehensively effective inhibitors for these mutations. Now, in terms of how we came up with the combination of Faslodex plus Nerlynx -- this is a very complex question. Essentially, there’s a lot of evidence from cell lines that, in breast cancer cells, there may be extensive cross-talk between ER and HER2. For example, as you know, breast cancer type in general is determined on the basis of whether the tumor is ER- or HER2-positive, while there is a subset of cases that express both molecules. Additionally, in some ER-positive breast cancer cell lines, when you suppress ER over long periods of time, the cells upregulate HER2 and thus become dependent on HER2 signaling.
Similarly, we imagined that, in cases where the ER-positive tumors had developed activating HER2 mutations in response to ER suppression, if we inhibited only the HER2 mutation with Nerlynx, we would eventually provide an avenue for the tumor to revert back to ER dependence. That’s why, to achieve maximum tumor suppression, we hypothesized that we’d need to simultaneously inhibit both ER and HER2 with the Faslodex plus Nerlynx combination. And indeed, as you mentioned, this was the most effective -- and the only effective -- combination against ER-positive tumor cells with the HER2 mutations.
Jamie DePolo: That’s pretty fascinating. So, finally, to me, you know, your study was small. I get it. It’s early. It does suggest that these breast cancers, the metastatic breast cancers, are continuing to change genetically in response to treatment. So, to me, the question is then: Does it become feasible that cancers should be sequenced in an ongoing way as part of treatment to make sure that people are getting the best treatments?
Dr. Utthara Nayar: The short answer, especially from our group, is definitely "yes" because we do know that ER-positive metastatic breast cancer evolves, we know that the mutations that are acquired can be relevant for resistance and can direct enrollment on clinical trials. So, we just… we think that there’s really great value in performing genomic and molecular and pathological characterization of tumors as an ongoing part of treatment. Now, the reason this may not be widely adopted, so far, is that there may be a concern on the part of many physicians that repeated sequencing of a tumor may be more trouble than it’s worth.
I think that’s for a couple of major reasons. The first of which is that repeated biopsies are invasive and they’re painful for the patients. And secondly, since we may not know the significance yet of any genetic changes that we observe, or worse, we may not be able to use any information we discover to tailor treatment for the patients, there’s concern that -- will this kind of repeated sequencing actually achieve any sort of improvement in clinical outcomes?
In response to the first issue, there are newer technologies, such as liquid biopsies, in which we can sequence circulating tumor cells within a vial of blood from a patient instead of performing a traditional biopsy. And, currently, there are many scientific groups working on understanding how best we can use these to predict the evolution of the tumor. And there’s a lot of hope that we can soon reach a point where these can be used to tailor therapy. But specifically, where our study comes in is to provide evidence rebutting the second concern -- the issue of the usefulness of the re-sequencing.
In our study, not only were we able to identify oncogenic activating mutations that weren’t incidental and actually directly conferred resistance to the therapy that the patient was currently on, but these were actually mutations for which effective inhibitors were currently available -- that is Nerlynx, in this case. So, it demonstrates sort of the power and the validity of this approach, since these patients can now immediately be directed to new treatment strategies or clinical trials that test combinations that we think may be effective. And, actually, anecdotally, one of the patients in our study who developed one of the HER2 mutations that I’m talking about was actually directed to a clinical trial testing the combination of Nerlynx plus Faslodex, and she actually went on to respond to that combination for a good period of time.
Finally, this study also suggests that it may be worth treating patients with effective combinations upfront, which may -- we don’t have evidence yet -- but it may prevent these kinds of mutations from even emerging in the first place in the tumor. I just want to say, ultimately, that’s the entire purpose of this kind of study, which is to be able to deliver better precision medicine.
Jamie DePolo: Right. That’s fascinating and so interesting. Thank you so much. It sounds like this could have huge implications. It’s early, and people need to look at this and understand it, but it does sound like this could have a lot of implications for treatment.
Dr. Utthara Nayar: Absolutely. We hope so. We think so… yeah.
Jamie DePolo: Thank you so much.
Dr. Utthara Nayar: Thank you so much for having me, again.