Ask the expert: Metastatic breast cancer

In this program, Tufia C. Haddad, MD answers questions about treatment options, recent drug approvals, clinical trials, symptoms and side effects, and other questions related to metastatic breast cancer.

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Catherine Ormerod, MSS, MLSP:

Let's start with biomarkers. In the short bio I just read about you, you receive funding for biomarker research. If you would, start at the beginning and tell us what biomarkers are and how they impact people with metastatic breast cancer, and, very importantly, should all people with MBC be offered biomarker testing?

Dr. Haddad:

That's such a great question, and a great place to start. I think about the original breast cancer biomarker being the estrogen receptor. We've known well before we even knew what the estrogen receptor was that anti-estrogen treatment approaches could help treat and manage breast cancer. When scientists then subsequently identified the gene for the estrogen receptor, and the protein within breast cancer cells – that estrogen receptor -- what we found, is that women and men whose tumors expressed the estrogen receptor were more likely to derive benefit from anti-estrogen treatment approaches, as opposed to patients whose cancer did not have that estrogen receptor protein. So that was the original breast cancer biomarker.

We knew it was important to test all tumors for the estrogen receptor because if it was present, we could then offer anti-estrogen therapies with the hope that they would be effective and work. And, we could prevent giving those treatment options and the side effects that come with them to patients whose tumors did not have the estrogen receptor, because it wasn't going to work based on the research.

With that, the field of biomarkers grew. We were able to identify other important genes in proteins like HER2, so a biomarker and routine testing for HER2 is now important as well, because we have anti-HER2 therapies to offer for patients whose tumors overexpress HER2, a protein, or have amplification of the HER2 gene in the cancer cell nucleus as well. At a really high level, hopefully those examples explain why biomarker testing is so important. We use it to help drive treatment decisions.

As biomarker research has evolved, we're now becoming a lot more sophisticated. Rather than testing one or two proteins or genes, we're doing larger panel testing, and we're looking at the cancer genome, all the genes within a tumor –usually it's not all, but more like a panel of genes that have been well defined in oncology – and we're looking to see, are those genes present? Are there extra copies? Are mutations in those genes that code abnormal proteins that can make the cancer cell behave badly, so to speak. As we do this larger panel testing now, we're starting to identify more mutations, more alterations.

That's also driving drug discovery and the development of new drugs, some of which now, for metastatic breast cancer, are FDA approved. So, I think, yes, it is important, especially because we now have therapeutic options available. I think it is important that patients are requesting biomarker or even genome testing of their tumors, because it might help drive treatment decisions with drugs that are already FDA approved today. It might also uncover a possible drug therapy combination with an emerging mutation where that drug is available through a clinical trial, for example. That's how we're going to continue to develop new, hopefully better, targeted therapies.

Hopefully that provides some explanation to the importance of biomarkers. When I was asked this question about 3 years ago, I said, “all patients might not benefit yet,” but that's how quickly things have changed and evolved with new therapies becoming available, either as standard care or through clinical trials. At this juncture, it really should be a standard and an expectation for all patients. And thankfully we're seeing the insurance companies and payers, including Medicare, covering these tests now as well for breast cancer.

Catherine Ormerod, MSS, MLSP:

Great. Well, thank you. And people should ask their oncologists about biomarker testing, and make sure they get it. I really appreciate the timeframe. You're so right. Things have changed so much in a short amount of time, which is for the good. Another question came out about San Antonio, and asked about the EMERALD trial, which is related to another one of your areas of research, drug resistance. Can you explain the EMERALD trial, and what it its key findings are?

Dr. Haddad:

Yeah. In this study they were evaluating, based on prior smaller studies with encouraging results, a new class of drugs for estrogen receptor-positive breast cancer. This was looking specifically at elacestrant, a name I will yet get down, to see how this drug, which is an oral pill, compares against a current standard for this class of drugs, which is an injection given once a month. That standard therapy that has been FDA approved for many years, called Fulvestrant, is what we call a SERD, a selective estrogen receptor degrader. That's what that acronym stands for. It's a little bit different than aromatase inhibitors, which are really pure anti-estrogens, they lower estrogen levels. In this case, the SERDs, whether it's the investigational agent that was studied in the EMERALD study, or the fulvestrant, the standard of care injectable SERD, what they are doing, is literally what it sounds like, they are degrading the estrogen receptor.

In order for breast cancer cells to grow in this estrogen receptor-positive type of tumor, you need estrogen to bind into the estrogen receptor. If that interaction occurs, that's what sends the signal to grow. So you can either block estrogen, or you can block or degrade the receptor. That's what this class of drugs is looking at, the SERDs. The standard of care, fulvestrant, was the injectable. The new oral agents are thought to not only be perhaps preferred, because it's a pill rather than an injection, two shots actually into the buttocks. So, it's not only the convenience of having an oral pill, but also the emerging research is that this may even be more effective than the fulvestrant. That's what this phase III study was looking to see if the new oral agent would be superior to the standard of care.

It was a positive study. Indeed, the oral formulation, the oral SERD, was better than the standard fulvestrant injectable. That's something that we are certainly excited about. We have a new drug that has shown great promise in a large phase III clinical trial.

The reason why enthusiasm was tempered in this study, is that how long this drug worked, or how long this drug was effective, was measured in a few months. The enthusiasm is dampened when we are seeing a close to 3 month benefit from the oral agent versus just slightly less than 2 months of average effectiveness for these drugs in the two groups of patients.

The challenge that we're facing, that we're up against, is that these drugs may not be as effective in the setting that they were studied. That setting in which they were studied was not upfront at the time of a brand new diagnosis. All of these patients had previously received an anti-estrogen with a CDK4/6 inhibitor. One of the big take homes from that study, was that perhaps just single agent, just anti-estrogen or estrogen degrader therapies alone might not be effective enough in this specific setting. I think it gives us reason for excitement, again, not only to have an oral drug, but one that might be better. And perhaps if we just study it in a different setting, we can find the right home for it. Because I really do think there will be a home and a place for this drug in the future.

Catherine Ormerod, MSS, MLSP:

Great. Thank you for that. And so are SERDs, then, another area of promise and hope, is that what you're saying to us?

Dr. Haddad:

Yeah. And I think the part that's really exciting about this class of drugs as a whole, and even more so with the oral SERDs again, is in the setting of the development of what we call ESR1 mutations. ESR1 is actually the name of the gene that makes the estrogen receptor protein. If we think about suppressing the ovaries from making estrogen, in the setting of long-term estrogen deprivation, one of the ways by which breast cancer cells can escape, is by acquiring a mutation in that gene. When you have a mutant estrogen receptor gene, you're going to make a mutant protein, a mutant estrogen receptor.

And what that mutant estrogen receptor does, is it constantly fires. In that case, if I remove estrogen, that receptor's going to keep firing. It doesn't care whether estrogen is present or not, it's going to keep firing. The way to overcome that is to degrade it. That's where these oral SERDs seem to show more promise: compared to the fulvestrant, in overcoming that ESR1 mutation. So the thought is, if we move this drug more upstream, we can maybe help prevent the development of those ESR1 mutations, possibly using these drugs instead of anti-estrogens. That's where I think the research could be moving.

Editor’s note: On January 30, 2023, elacestrant (Orserdu) was FDA-approved to treat hormone receptor-positive, HER2-negative advanced or metastatic breast cancer that has tested positive for an ESR1 mutation with disease progression following treatment with at least one hormonal therapy. Read more about elacestrant.

Catherine Ormerod, MSS, MLSP:

Great. Thank you. There are a number of questions about oligometastases and some research that was presented. Please define what that is, and tell us about that research?

Dr. Haddad:

Oh boy, this is such a great question. Oligometastatic breast cancer, there really isn't a uniform, accepted definition, if I’m really candid. But generally speaking, we think of it as the presence of a very limited number of metastases, in the range of 1 to 5, generally speaking, confined to one organ. But sometimes people will accept if there is perhaps one spot in the liver, one spot in the bone, two different organs, but two total areas of tumor metastasis would be potentially classified as oligometastatic disease. So that's the what it is. The “how to manage it,” this webinar is not long enough to discuss all the possibilities, or all the controversies.

One of the big things that did occur at San Antonio was not quite the pros and cons, but the controversies, addressing the controversies about how to best manage a disease in this setting.

Some of the big controversies that arise, especially with women who have perhaps a newly diagnosed breast cancer with tumor in the breast, possibly local lymph nodes, and one or two distant metastases elsewhere in the body, the question is how aggressively to treat. Typically with stage IV disease, we think about our goals of care as treating this as a chronic condition. Using medical therapies to control the disease for as long as possible, while offering the best possible quality of life. But the question is, if there are one or two metastases that could also be potentially removed by surgery, ablated by radiation therapy, and if we are to move the primary tumor in the lymph nodes, is there the possibility for a cure? We hesitate to use the word, "cure,” but can we really improve long-term survival in potentially a gap without needing to be on systemic therapy indefinitely, if we were to take a different treatment approach.

The research that's out there right now suggests that removing the primary tumor in the setting of metastasis does not improve survival. That was a very large randomized study that was previously performed. That's why for many surgeons, or radiation oncologists who manage breast and lymph node disease, there's a lot of reluctance in this setting to remove the primary tumor in the setting of oligometastatic disease, based on that prior study.

However, a tiny minority of patients in that study had oligometastatic disease. For more of the participants, it was more widespread disease. So, I'm not sure that study really answers the question about the value of removing the primary tumor in lymph nodes in that setting. I will say at Mayo Clinic, we have had three to four large, meetings our surgeons, radiation oncologists, pathologists, medical oncologists, around the table to try and outline a standard approach, and how to manage oligometastatic disease.

At the end of four meetings, we have some very general guidelines, but what it really comes down to is that we do evaluate on a case-by-case basis, because there are so many nuances and what-if's, different tumor types, et cetera. We have a long ways to go in terms of understanding the best treatment approach. But I do think that there is a unique biology, in that it is very reasonable to potentially treat more aggressively if you will, in this setting, based on the existing research we do have today.

Catherine Ormerod, MSS, MLSP:

Great. Well, thank you. I mean, that's an update on the research. So, thank you. With the biomarker testing, there've been a few questions. Just to clarify, could you name some of the tests that people may hear, next generation sequencing? What would be a little more familiar to biomarker testing?

Dr. Haddad:

You bet, you bet. Often you'll hear the phrase, "platforms used.” These different platforms, are really just different methods, and potentially different gene panels used by the different companies that offer these tests. Different institutions, different individual oncologists, might have preferences for one over the other. Generally speaking, for advanced breast cancer, I don't know that one is necessarily better than the other. But some of the names are FoundationOne, Tempus. Those are probably two of the more commonly used, just a few examples.

There are also individual institutions, sometimes larger academic medical centers, that might have their own in-house testing that they've developed as well. In addition to testing on the actual tumor specimen, there are also some tests on blood looking for these different mutations in the blood, when there are either tumor cells, or even cell-free –

just tumor DNA available in the blood. For patients who have tough-to-access metastasis for a biopsy to get a tumor sample for testing, bone metastasis are notoriously difficult for NextGen sequencing, it's tough to get adequate tumor tissue on bone biopsies. So sometimes these blood-based tests is another thing to ask of your doctor.

Catherine Ormerod, MSS, MLSP:

Great. Well, thank you. That's really helpful. And there've been a number of questions about testing in here. We could do an entire program on testing.

Dr. Haddad:

Agreed.

Catherine Ormerod, MSS, MLSP:

People are asking what the threshold for change after a progression is. And I will throw that to you.

Dr. Haddad:

That is such a great question. It really is. And for me, this is just really a heart-to-heart conversation with each individual patient. Some people will, if they know that the cancer is progressing, it's very simple, we need to change treatment, and mentally, that's how they're processing things, "I need to change treatments. I can't live, I can't function knowing that the cancer is growing." For other patients, and I would say increasingly, as I build trust with my patients and get to know them, when we think about those overarching goals of care, if we do see a consistent trend that it's clear that the cancer is progressing, first and foremost, is it causing symptoms?

If it's not causing symptoms, and it's not in a location where even millimeters of growth would be a concern. Those are some of the things that I'm thinking about when I lay out the options of whether or not to change now, versus stay the course and do really close follow up, close observation. If I have a patient who does not have symptoms of progression, I can afford, based on where the tumor is, in vital organs, in particular, I can afford a little more growth, I'm confident about the tempo of the disease progression not being really fast, but smoldering. Then equally importantly, that the current therapy they're on is tolerable.

I have to hit at least those four things, and then importantly, the patient telling me, "Yes, I will be fine staying on this current treatment regimen, knowing that the cancer is slowly progressing." In that setting, we know with most, all of our treatment regimens, we only get one shot with them. Sometimes even 2 more months or 3 or 4 more months with a drug that's giving them a good quality of life, despite showing that it's starting to lose its effectiveness, is absolutely worth it. Those are the kinds of things that I think about, and I have candid conversations with my patients about, when we think about when to make the switch.

Catherine Ormerod, MSS, MLSP:

Okay, great. At San Antonio, was there any new news, or news of note at any rate, for triple-negative breast cancer in the metastatic setting?

Dr. Haddad:

Yeah, it's a great question. One of the things that we were excited to see was the longer-term follow up from the first line study, the Keynote-355, that was looking at the effectiveness of immunotherapy with pembrolizumab in combination with chemotherapy. The reason that the long-term follow-up was so important, was because it was about a year ago, we had accelerated FDA approval based on early results from the clinical trial that were showing a lot of promise that the combination of pembrolizumab, or immunotherapy with chemotherapy, was more effective than chemotherapy alone. The long-term follow-up and final analysis, if you will, was presented this year, and it did confirm a very substantial improvement that was significant in both overall survival, as well as what we call progression-free survival, living longer without progression of the cancer.

We're excited it about that long-term follow-up. It validates it. We expect the FDA, we anticipate, this will now mean a full approval. The reason this is important, is that the very first immunotherapy drug that was approved for triple-negative breast cancer, was atezolizumab. Actually earlier this year, the FDA withdrew that accelerated approval, because a subsequent study actually did not show the benefit in terms of overall survival and progression-free survival. So that was a big setback. I think it gave us all pause about utilizing immunotherapy, but we're very grateful to see that durable long-term benefit from pembrolizumab, and that I anticipate now will be here to stay.

The other thing I might just quickly add, because there was such great discussion about the importance of NextGen sequencing and biomarker testing. One of the other studies that that was shared, was called the Nimbus study. That was also looking at immunotherapy, at different checkpoint inhibitors. This one called nivolumab, in combination with a different form of immunotherapy, called ipilimumab. But this is important across all tumor types. This particular study was looking at, regardless of estrogen receptor status, HER2 receptor status. What it was looking at on the NextGen sequencing report, is what is the tumor mutation burden. And for patients whose tumors have a high tumor mutation burden, we have actually, pembrolizumab has received FDA approval for all cancers, all solid tumors, even beyond breast cancer if that tumor has a high mutation burden. Now the issue was that clinical trial that led to this approval, there were five patients with breast cancer in that large study. It was less than 2 precent of all patients.

So we really weren't sure how effective immunotherapy for high mutation burden metastatic breast cancer was. What we saw in this particular study, and it was only a phase II trial looking at the combination therapy, is, again, we do see that, it was roughly 16 precent of patients that had a response, meaning their tumors shrunk in response to the immunotherapy. And again, these were all high tumor mutation burden, but it really confirmed that, "Yes, we do see responses with this drug in this population of patients with metastatic breast cancer." What's really interesting is that when patients have a response, they get a lot of mileage. The median progression-free survival again, in this case, was estimated around 12 months. That's the median.

There were some patients who were already in their second year. So if you get a response, it's a small percentage of patients, but man, if you're that one in 10, 1 in 5 or so, you get a lot of mileage. So this is yet another reason to be really advocating for that NextGen sequencing, because in addition to looking for specific tumor mutations, they'll measure the overall tumor mutation burden. And opens the door to immunotherapy across all subtypes of breast cancer.

Catherine Ormerod, MSS, MLSP:

Great. Thank you. That's very helpful. Here's a question about people who have been heavily pre-treated, and she's wondering if there are any emerging treatments or clinical trials for heavily pre-treated people, and ER-positive. And there's a number of questions about this HER2-low, which is starting to be discussed at San Antonio and elsewhere.

Dr. Haddad:

Those are a couple of great questions. I always encourage patients to be talking to their oncologists, or asking for referrals if needed, or even self-advocating and self-referring for clinical trial opportunities in the setting of this heavy pretreatment. Often in that setting, most people have, I wouldn't say exhausted, but many of our top-line, frontline anti-estrogen treatments, or anti HER2-treatments, or even our top three or four chemotherapy drugs as well, in that setting of it having resistance to those standard of care agents, that's when we really need to show the tumor something novel, something new, something different than what it's seen before, these traditional therapies. And really getting access to those new and emerging treatment approaches, whether it's a new targeted agent, whether it's more of a novel immunotherapy approach. Most of those are going to be offered through phase I, sometimes phase II, but more early-phase clinical trials, which are often honed at larger academic medical centers.

That's what I encourage. That's where also having that genomic sequencing, or NextGen sequencing testing of the tumor, where there might be a drug available through a clinical trial that targets that specific mutation. That's usually what I advocate for in that setting.

So, HER2-low is really interesting to see where the research is moving here. Being HER2-positive is not a single score that tells us positive or negative. Really what we're looking for, with HER2-positive disease, is overexpression. Lots of copies of the HER2-protein on the outside of the cancer cell, or lots of copies of the HER2-gene in the nucleus of the cancer cell. And there are different, very specific ways in which we grade how much is present, and how much crosses that threshold that we call it HER2-positive.

For those tumors where HER2 is present, so it's positive, but not at that cut point for overexpression, which we call HER2-positive, it gets the name HER2-low. And they're starting to look at different treatment approaches with different HER2-directed therapies, to see if any might be effective in this setting for HER2-low. The reason HER2-positive, that cut point was selected, was going back to the very original drugs, the very original clinical trial with trastuzumab, or Herceptin.

Because that was the cut point where we saw the most effectiveness, it didn't mean, per se, that there weren't some patients with HER2-low who didn't benefit. So that's where we're really trying to move the needle now to see. We now have eight drugs, FDA-approved, for HER2-directed therapy for metastatic disease. So maybe if we take a different drug, and we can better identify the patients with HER2-low who may benefit from these strategies, that's where a lot of the clinical trials are starting to emerge now, as well as looking at HER2-based immunotherapies, or vaccines, as another example.

Catherine Ormerod, MSS, MLSP:

Great. There are a number of questions about CDK4/6 inhibitors. There are three currently on the market, and people are wondering: if you progress on one, can you go to another? This has been a question that continues to come up, and it's an important one.

Dr. Haddad:

It is an important one. What I can say is that with where we are with the clinical trials and research today, we don't have a specific clinical trial or research study that says, "Yes, if you start with X and you switch to Y, it will work, or, there's a 20% response rate that it would work." We don't have those clinical trial data yet. What I can say is that they don't appear to all be equal. When you look at the individual drugs, the different dosing, the different side effects, and you look at the different trials in which they were evaluated, we don't yet have a head-to-head comparison of these drugs in a clinical trial. But we commonly see palbociclib and ribociclib, they are a bit more similar. They're very comparable in terms of effectiveness, in terms of side effect profile, and again, taking it for 3 weeks on and 1 week off.

Abemaciclib is different. It has a very different side effect profile. It's dosed continuously, every day. And when you look across the clinical trials, the response rate for that drug tends to be higher. And again, the response, meaning shrinking metastatic tumors, seems to be higher than the other two drugs, but it comes with more side effects. It definitely has more gastrointestinal [side effects], especially diarrhea, and it can be terrible diarrhea. So when we think about which of these drugs we should use, we're a little more likely to use palbociclib or ribociclib up front, because they’re a little bit better tolerated in terms of side effects. But if we need a response, we need quick results, if we have a very symptomatic patient, we might lean for the abemaciclib first. Those are some of the things that go through our minds when we think about which one do we use up front.

But what I will say, is that since most all of our patients are commonly, but not always, started on the palbociclib or ribociclib, I will say many of us have tried to use abemaciclib later in the overall cancer journey, in the disease course. Have I seen patients respond in that setting? I have. Have I seen patients not respond? I have. So we really can't project what the response rate is without actually conducting a clinical trial to answer this question. I think many of us in the field feel it's very reasonable to consider utilizing abemaciclib in later lines, when one of the other two agents has been used up front.

Catherine Ormerod, MSS, MLSP:

Great, thank you. There are some questions about neutropenia, specifically related abemaciclib. And there are also other questions about the use of palliative care. Could you maybe merge those two questions in an answer? How you approach palliative care?

Dr. Haddad:

Yeah, so, palliative care, it's a phrase that can be polarizing. I think many of us will define it in different ways. My definition of palliative care, is really supportive care. It could be supportive in terms of the measures that we take to help control symptoms of the cancer, to control side effects of therapy. Often what we use to help manage those, many of them are medications, but we're also learning a lot more about non-pharmacologic ways to help manage some of these side effects, or symptoms of the cancer as well. But supportive care goes beyond symptom management. I mean, it's whole-body, whole-self, it's mind, it's spiritual, it's everything. And that's why having a dedicated palliative care team, not even an individual provider, but a palliative care team, is so complementary to what the more treatment-focused cancer, oncology care teams can offer. I am a huge advocate for early integration of palliative care into the metastatic breast cancer journey.

We might not need all that symptom control and symptom management collaboration with those specialists up front, but it's all those other services that come with it that I think are so important. So that we are addressing more than the physical, and really thinking about the person more holistically. That's where this team has such a unique skillset, and is so complementary.

This hasn't been studied in breast cancer specifically, but there's a beautiful study in patients with advanced lung cancer that very clearly demonstrated that upfront enrollment in palliative care, concurrent with a diagnosis and treatment, as opposed to standard care, when patients are referred often much later in the disease course, actually improves survival – that's how powerful it can be. So I think it's good to be talking to your oncologist about it, talking with your family members about it. Don't equate palliative care with hospice. That is just one facet of palliative care overall. I think earlier engagement, the better, certainly if people have access to such resources.

Catherine Ormerod, MSS, MLSP:

Yes, the earlier, the better, that is true. There's a question here: Is there a review of San Antonio for patients to read? There are many reviews. LBBC covered it in our News & Opinion section. You can find it there on some of the major findings that were announced. We also had a program, our CEO, Jean Sachs, interviewed Dr. Virginia Kaklamani, and that is also on lbbc.org. So there's more San Antonio news there.

People are asking about testing: We're going back to testing again, and it's both genetic and genomic testing with progressions. What is the cadence? What is your recommendation to your patients when people progress? Should they get additional testing?

People are reflecting that sometimes subtypes are changing, and that they're finding that surprising. It’s hard to learn all about metastatic breast cancer and subtypes, et cetera. And then sometimes they change. What do you tell your patients?

Dr. Haddad:

So, a couple comments. One is I'd be remiss if I didn't address: we talk a lot about tumor genetic testing, but there's also the bloodline, what or what we call germline testing, that I strongly advocate for every patient with metastatic breast cancer to have, it's blood tests. This is actually looking at your genetics, the genes that we inherit, the genes we pass on. We know that identification, especially of the BRCA1 and 2 gene mutations, has treatment implications. We have FDA approved drugs. Sometimes these drugs are incredibly effective for patients who have these germline gene mutations. So I just have to put a plug in there, because sometimes still, out in smaller practices, we don't see the patients being referred, especially if they might be older, or they might not have a family history of breast cancer. But every patient with metastatic disease should absolutely have genetic testing. So I just had to put that plug in really quick.

But thinking about should we be doing additional testing at progression? That's a really great question. I say it's –mandatory is a strong word --but it would be strongly encouraged, if we see discordant results on a progression scan. And I will tell you, this is not uncommon. What that means is the cancer perhaps is stable in one site, in the bones and maybe even still responding. But now there's a new spot in the liver, or if there already were metastases in the liver, they're progressing, very clearly progressing there. So why is one spot behaving, and one spot not, to the same therapeutic regimen? That usually is telling us there's something different about those tumor cells.

So, in that setting I very frequently, if it has the potential to change treatment strategies, I will recommend a biopsy at a minimum to retest the estrogen receptor and the HER2-receptor.

One example, we were talking about different ways that estrogen receptor-positive breast cancer cells can become resistant to anti-estrogen therapies, one more common pathway is actually to up-regulate HER2, that it's actually a mechanism of resistance, a new way to grow despite anti-estrogen treatment. We know that can happen in about 10 to 15 percent of patients, where the tumor was initially HER2-negative, but after a long duration of different anti-estrogen or estrogen receptor degrader treatments, those tumor cells are now overexpressing HER2. That potentially opens the door to all the HER2 directed therapies is as well.

That's the importance of repeat biopsies, repeat biomarker testing with certain progressions. The only reason to do it though, is if there is the potential for a change in treatment strategy, like the scenario I just described there. Whether or not to do NextGen sequencing over and over at multiple progressions, I think that is an area where we still have much to learn. More often than not there isn't a whole lot of change in the genomic alterations. Over time, at least with the panels that we're using today, but I don't know that we know the true value to that. We have to be cautious about whether or not there would be [insurance] coverage as well. That would be something where I'd want to make sure we have authorization, prior authorization and coverage for repeat NextGen sequencing. So that's just something else to keep in mind. But the value of repeat NextGen sequencing is to be determined yet.

Catherine Ormerod, MSS, MLSP:

Thank you. There's a couple follow-up questions about genetic testing, and are there are different kinds of genetic testing, is the question. And what is the cost? Should that be covered for metastatic patients or is ...

Dr. Haddad:

…their insurance was denied, that makes me like physically ill. I feel grateful, I haven't seen a denial for a referral for genetic testing and actually conducting. I will say, for hereditary germline genetic testing, now that we have a therapeutic option, if you get a denial, get whoever you can to help write letters, get your oncologist to show the research, show the drugs that you could potentially benefit from should you be found to have a genetic mutation. It goes without saying the potential implications that would have for other family members as well, a positive finding. Even beyond BRCA1 and 2, there are more mutations now, where new clinical trials are testing agents in other types of mutations. So PALB2, RAD51C and 51D, those are just a few, where some more targeted therapies are being investigated in clinical trials. So, appeal [denials], get your oncologist to help appeal those denials, and look for clinical trial opportunities.

Catherine Ormerod, MSS, MLSP:

Yeah, and I do want to give a plug to one of our advocacy partners, Triage Cancer. I would urge people who are denied to go to their website. They have webinars, they also have other services.

Dr. Haddad:

Thank you for putting that plug in, that's an important one.

Catherine Ormerod, MSS, MLSP:

We have time for one more question, I think. It’s hard, this hour has gone by very quickly.

There have been a number of questions about denosumab (Xgeva), treatments for bone. Can you explain the use for it, when people are offered it and when they’re not?

Dr. Haddad:

Great question. Bone supportive care is so important, in two cases in particular. One, most certainly, in the presence of bone metastasis. We want to keep those bones as strong as possible, prevent fractures. The other setting is in patients who are on long-term anti-estrogen therapy that really accelerates normal age-related loss of bone mineral density. Those are two settings where we are often incorporating bone supportive care more broadly as part of the overall treatment regimen. It's not cancer directed-therapy, but more supportive care. Very critical, important, supportive care.

Now the drug Xgeva, or denosumab is the generic name for that, is one option. Also Zometa or zoledronate, is another option. And actually the latter has been around for decades, and we've been using that for a longer period. The drugs have been compared head-to-head in a clinical trial for bone metastasis in particular. Indeed the denosumab is a little more effective than the zoledronate. It's an injection monthly. The zoledronate is an infusion once every 3 months, in this setting. Generally speaking, they're both pretty well tolerated.

There is a reason we sometimes pick one over the other, but for some people, the convenience of just an infusion once every 3 months is preferred to shots once a month. Those are things to keep in mind. There also are cost considerations that we also counsel patients about as well. But that's really the value of these drugs, helping to prevent fractures, helping to keep the bones strong, whether it's the presence of bone metastasis or long-term anti-estrogens.

Catherine Ormerod, MSS, MLSP:

Well, my goodness, we are really out of time. Dr. Haddad, thank you so much for answering a wide range of questions.

I want to thank everybody on the webinar tonight for joining us. It's been great to be with you. I do want to just do a shout out again to our sponsors, AstraZeneca, Genentech, Lilly Oncology, MacroGenics, and Seagen.

Keep following us on our social media channels and look at lbbc.org for our coverage of San Antonio Breast Cancer Symposium, it's under the News & Opinion section, and watch the interview with Dr. Kaklamani.

We have lots of rich information, and we are here also to help you cope with all of the medical, emotional, and practical challenges of living with a metastatic breast cancer diagnosis. We have a Helpline, and we have leadership volunteers who are ready to support you, and closed Facebook communities as well. Check us out, and thank you again for spending your time with us tonight. Peace and joy in the holiday season. And thank you again, Dr. Haddad.

Dr. Haddad:

Thank you everyone.