Bone mets with Carmen Bergom, MD, PhD and Katherine N. Weilbaecher, MD

Living Beyond Breast Cancer’s 17th annual Conference on Metastatic Breast Cancer was held April 28-30, 2023 as a hybrid conference in Philadelphia, PA in-person and virtually via our online conference platform. In this session, Carmen Bergom, MD, PhD and Katherine N. Weilbaecher, MD discuss the most common place for breast cancer to spread: the bones.

Watch the video or read the transcript below to learn about treatment options, and get strategies to limit side effects, manage bone pain, and maintain bone strength. They also discuss how to understand screening tests and share updates on clinical trials studying new treatments and quality of life.

Transcript

Katherine N. Weilbaecher, MD (00:01):
Hello. Thank you so much, and I’m truly honored to be here to talk about a topic that is near and dear to my heart. I’ve been studying this for the past 25 years, both in the lab and in the clinic. And I’m pleased to say within my lifetime we’ve made so many advances and people are living longer and better, and we’ve got to even do more and do better. But thank you for letting me have this opportunity to speak with you.

First, I’d like to say that a good deal about what I’ve learned about bone metastasis is from my patients and my patients are my teachers, more my patients are my teachers about how to live, but also they’ve taught me about what’s important and I just feel truly blessed to be a doctor.

What I’m hoping what we can do in the next 20 or so minutes is I want to review how common are bone metastases and what are they, and then how do the tumor cells change and alter the normal bone cells in a bone microenvironment to cause the problems. And then what are the benefits of strengthening the bones, not only to have strong bones, but to actually combat cancer.

As many of you may know, and I’m a breast cancer medical oncologist, I didn’t bring that up. Breast cancer when it, thankfully most of the time, breast cancer, we can treat locally, but breast cancer can spread outside the breast. And the most common site, if the breast cancer is going to metastasize, is to the bone. It’s by far the most common.

As you all know, breast cancer comes in many different subtypes, but in general terms, the more common “ER” or estrogen receptor-positive breast cancer is the most likely, if it’s going to metastasize, will metastasize, spread, to the bones. About 72 percent of patients with metastatic breast cancer would have bone metastasis, if they’re ER-positive. The HER2-amplified were about 50/50. And the triple negative, the ER-, PR-, HER2-negative, close to 50 percent, but a little bit less common.

And what we think about with bone metastasis is the tumors would start in the breast and then they can get into the bloodstream. And then if the tumor cells land in the bone, have the right makeup — we’re still trying to understand that — they can begin growing in, they come into the bone marrow and then they can grow in that bone marrow. But what a bone metastasis is, is it starts in the bone marrow, but it actually can invade into that hard bone surface.

And when we think about bone metastasis, this is a bone scan, which is a type of x-ray scan, a nuclear medicine scan, that looks at wherever there are areas of increased bone activity. That’s what you’ll see. And in the case of bone metastases, often we see many spots. It doesn’t mean that it’s necessarily really bad, it’s just that the bone marrow, all of our bones and the bone marrow are all connected. So often we do see more than one spot on a bone scan.

But what I’m going to try to show you is the tumor cells themselves can’t invade and grow into that bone. They actually recruit the normal bone cells to do their dirty work. And that’s what we’re going to try to block. And that can cause weakness of the bone. And if you look at this x-ray of the femur, in this case you might see an area where the femur is broken. And there’s that kind of the white is the calcium and then that faded area in the middle, that’s where the tumor has induced destruction of the bone, which weakens it and can cause fracture.

What we want to try to prevent and when a tumor gets into the bone, we can have what we call skeletal complication. The first most common thing is it can hurt. Or the bone can get weakened to cause a fracture. Sometimes there’s so much calcium release that you get high blood levels of calcium. And in, thankfully less commonly, but it can occur, the tumors near the spine bones can press on the spinal cord. And one of the things we know is that if we give bone strengthening agents that stop this bone destruction, we can decrease these complications by up to half, or a third to a half of the normal incidents. This is why I’m really going to be pushing our bone strengthening agents.

You’re all going to become little mini experts on bone biology. But essentially the green cells on the left are osteoblasts. Those are the bone forming cells and they’re laying on top of bone. And that weird cell that has that kind of jagged edge, those are the osteoclasts. Those are macrophage like cells that sit on the bone and secrete acid and collagenases to destroy the bone. As we, in normal life, you have a little microfracture or a little damage bone, the osteoclast resorb it, and then the green osteoblasts come in and fill in the hole. Every 10 years, our bones are completely turned over. This is a normal process. You get rid of old bone, put in new bone.

Well, what happens when breast cancer gets in there? Breast cancer cells can secrete factors that basically hijack this system and stimulate osteoclasts to start destroying the bone. And inside of the bone are these growth factors that can actually make cancers grow. And so it gets this sort of vicious circle. And what you’re going to see and what we’re going to talk about, and many of you are hopefully on these medicines, we have medicines that can block the osteoclast function so that we, we stop this destruction of the bone and block this cycle.

So basically when breast cancer cells get in the bone, they grow in the bone, that can induce a bone destruction and that destruction can release factors that can worsen the growth in the bone of the breast cancer. So we all want to stop the breast cancer growth. We want to give anti-breast cancer therapies. New ones are coming out every few months. It’s amazing. You’re going to hear from Dr. Bergom who’s an amazing radiation oncologist and researcher, that sometimes we need radiation to just stop it in its tracks. But the other thing we can do is we need to strengthen the bone, not only to build it back, but to stop that vicious cycle of growth.

We talked about our anti-cancer therapies. We can block estrogen, we can [give] Herceptin, we can give chemotherapy, we can give radiation therapy to locally block, or in the cases of strontium or samarium block it more globally. And we can give these bone strengthening agents. And I’m going to talk to you guys about mechanical loading and weightbearing exercise: Walking! It’s really good for the skeleton. And then what we can do in our diets as well, with calcium and vitamin D to give the bones what they need to grow back.
I’m going to be focusing on the bone-targeted therapies we have. You’re going to hear zoledronic acid, Zometa, which many of you all are on denosumab, or Xgeva or Prolia. That’s going to be the main focus for what we’re going to talk about.

So bisphosphonates. You might see over on the right hand side, you might have heard of Fosamax [alendronate] for osteoporosis, Boniva [ibandronate] for osteoporosis, Zometa, which can be given for osteoporosis, but that’s the drug we mainly use for breast cancer bone metastasis.

On the left hand side, this is a picture of a bone marrow with a little piece of a bone spicule. You know how inside the bones that kind of look spongy, calcified, spongy. What you can see is, all of the cells around that central piece are the bone marrow cells. And this is, if you see that little black line that lines the entire bone, that’s radiolabeled bisphosphonate, a single dose will line the whole bone, and the osteoclast, when they sit on that and try to resorb, they can’t. So the skeletal half-life is, these drugs can be there for quite a while, whereas in the serum, after you give it, it’s gone in a couple of hours.

And what we noticed was that — and there’d been proof in animal models — but then in our first studies in women with breast cancer, we found that — if you look on the left-hand side — skeletal complications, fracture, severe pain, need for radiation, cord compression, and that if you looked at women who were given placebo versus pamidronate, which is a weak bisphosphonate that we give for osteoporosis, that we significantly decreased the number of skeletal complications in the patients that received pamidronate.

The thing that surprised everyone was the pain, the impact on pain. That line, that vertical line of zero, that was considered the baseline. And when patients were given pamidronate, their pain scores went way down. And so that’s also been a huge benefit of these drugs.
Then there was a new drug that’s come around called denosumab or Xgeva. This is an antibody that blocks the key growth hormone for osteoclast, called rank ligand. If you don’t have rank ligand, the osteoclast don’t develop and so you can’t destroy the bone.

Both of these drugs can prevent skeletal complications, decrease bone pain, prevent fracture, and there’s data that they might even be able to prevent new bone metastases. Zometa, which many of you are probably on, it’s given intravenously — four milligrams IV every three to four weeks if you have bone metastases. And then after about three to 12 months of getting it every month, if the cancer is stable, we can back down to maybe every three months and even more. People are living so much longer with bone metastasis, thankfully.
Xgeva, it’s 120 milligrams, but we give this subcutaneously, you don’t need an IV. Again, it could be given every month, and then if things stabilize, you can back down. But you cannot go — it’s three to six months max, you can’t lengthen it more than that, and I’ll describe why.

If we were in a live audience, and the thing that I always tell people is that first dose of Zometa can be a doozy. About 70 percent of patients will get flu-like symptoms for their first dose and they freak out and they’re like, “I don’t want to ever get that again.” If you can take some Claritin and Tylenol, it’s helpful. And generally after the first dose, people are fine, so please stay with it.

For denosumab, Xgeva, consideration is this rebound bone loss. What happens is for denosumab, if you stop that drug suddenly, the body overcompensates by making more of that rank ligand that we had been suppressing. And as the drug wears off, you can get worse bone loss and high calciums. So we can’t just stop it cold turkey. If I have a patient that sometimes they want to come every six months, sometimes they want to come longer, I would be very hesitant because even after a month when you were due, you want to be really on time with this drug, beacuse we don’t want that rebound.

The other side effects of these drugs — and again, it’s always risk benefit, we don’t have a perfect drug — but there’s some more rare side effects. One that people read about is osteonecrosis of the jaw, which is rare, and I’ll tell you about. And then these atypical chalk stick fractures, which I’m going to talk about in a little bit. And people get low calcium because we’re always drawing blood and measuring. Usually it’s asymptomatic. But if you think about it, in order to rebuild the bone, you need calcium. So if people just supplement with calcium and vitamin D as they should, usually it’s not a problem.

Osteonecrosis of the jaw, what is it? It’s exposed visible bone along the jaw or the palate. And it’s believed, because you have a lot of like little micro infections and problems, the bone is very close to the gum line, and when you don’t have the osteoclast to eat up the old bone, you’re a little more susceptible to this. It’s about two in a hundred patients with bone metastasis who are on these drugs — both of the drugs can cause it — can get it.

Generally it’s very mild. But you try to do everything you can to prevent it. You want to make sure that you have very good dental hygiene. You try not to pull teeth or you try to avoid doing things that cause injury into the bone, like doing a dental implant. Fillings are OK, crowns, root canals, that’s OK. Our treatment is usually conservative. We try to avoid surgeries. We try antibiotics or antiseptics. Sometimes they’ll do just a little shaving off of the bone if it’s irritating someone. But generally people can live with this OK.

The atypical fractures. I was asked to discuss this. What is that? It’s when people who have been on these drugs for over two years sometimes, and we don’t understand well the mechanism, you can get a spontaneous or low trauma fracture, especially in the femur. It’s like a chalk stick. It just breaks straight across and it’s maybe one in a thousand patients could be at risk for this. I’ve personally have not seen it in my practice, but I know it can happen. So we usually stop the bisphosphate denosumab. We now have new drugs that build up bone that we could consider and sometimes they just have to pin and let it heal.

So what can we do in the last few minutes? What else can weaken our bones besides what the tumor is doing in secreting the factors? Well, it may not surprise you, estrogen builds bone. So before menopause estrogen causes those osteoblasts to make more bone and it actually suppresses the clast from destroying bone. Well, a lot of our therapy for ER-positive breast cancer is to lower estrogen levels, which can make this process worse. It can stimulate the osteoclast, and that’s where the denosumab and the bisphosphonates really come in.

But the other thing that we can do is weight bearing. Weight bearing can stimulate the osteoblast to grow new bone. Astronauts, the strongest men and women, they go into space for a couple of weeks, they get terrible osteoporosis because they’re not weight bearing. And what do I mean by that? Well, I’ll tell you in a minute.

Basically our bones have mechanoreceptors. The cells, they feel the pressure and the osteoblasts say, lay new bone. So what about this calcium and vitamin D? Calcium is key to the mineral of bones, and you need to have available calcium. If you’re going to strengthen the bone, you’ve got to make sure you have calcium. It’s like if you’re iron deficient, we need to give you iron to build your blood cells. Well, we need calcium to build our bone.

Vitamin D, what everyone should be on. Vitamin D actually helps you put calcium into the bone. It helps you absorb calcium from the GI tract as well as from the urine — you don’t secrete it out. And the lower calcium and vitamin D are, the more bone osteoclastic activity and destruction you have. So that’s why we want to replace that.

Weight-bearing exercises. Those bone cells will deposit calcium if there’s pressure on them, like walking, and those osteoblasts have these mechanoreceptors, they sense pressure, and that is what gives them the stimulus to grow.

What can you all do to strengthen your bones, is what I would love and I beg my patients and I write prescriptions and we talk about it, 20 minutes, four to five times a week of something. That’s what we build up to.

Walking is fantastic. Yoga, dancing, anything that could be fun. You don’t even have to break into a sweat. I will have patience. I said, “Can you walk from the chair to the kitchen and back? Let’s start with that.” Anything helps. But we want to do that.

In summary, how do we strengthen our bones? A) We want to strengthen our bones so we don’t fracture and we have less pain, but also it hurts the cancer cells. Cancer likes weak bones. We got to strengthen ours. So we can give the drugs, the bisphosphonates or denosumab. Weight bearing of some kind, it doesn’t have to be rocket science, it could be getting in and out of a chair but we’d like to build to be doing this. It’s good for the immune system too. We’d like you to try to do that almost every day, move your body somehow, even if it’s a little bit. And then of course for calcium, I usually say 1,000 to 1,500 milligrams, and then the vitamin D 800 to 2,000 milligrams a day, or you can get sunlight — cover your face, you don’t want wrinkle. You can get sunlight.

I think I should be almost done. What’s ahead? We have amazing new drugs ahead. We have, they’re using bisphosphonates, which go to bone, to bring drugs to the bone to kill the cancer cells. We’re doing all this work on the bone marrow where the immune system comes from to try to strengthen our immune system to help make that work better. We have so many new anti-tumor therapies coming, and you’re going to hear more from Dr. Bergom about radiation.

And so, to overly simplify: Breast cancer grows in bone, that decreases our bone strength. If we can increase our bone strength, breast cancer doesn’t like it so much and it doesn’t grow as much in bone.

I want to thank you. I want to thank all of our patients, their families for all participating in all the trials that have got us to that. And thank you.

Carmen Bergom, MD, PhD (21:44):
Thank you so much. I’m Carmen Bergom and I’m going to be talking to you about radiation and bone metastasis in breast cancer. I’m a radiation oncologist and a physician scientist, and in the lab we also study breast cancer and how to improve treatments and decrease side effects. And I have the pleasure of working with Dr. Weilbaecher in practice and seeing some of the same patients. So it’s wonderful to be able to be in this session with her today.

I don’t have to give much background because this stage was set so well for this session. But I’ll give a little bit of background about bone metastasis with respect to how radiation has a role in its treatment, and then talk about different courses of radiation, some of the responses that could be affected, side effects. And then talk about some new data, about potential roles for radiation in what we call oligometastatic disease or patients who have just a few sites of metastasis or in asymptomatic sites of bony metastasis.

As we just heard, advances in cancer treatments have led to increased survival and prolonged time with metastatic cancer and better quality of life and better outcomes. And with that, we have seen increases in metastatic bone disease in breast cancer. And as mentioned, there are a number of side effects that can be associated with bony metastasis such as pain, hypercalcemia, these pathologic fractures, or occasionally spinal cord or nerve root compression, if it’s in a site near the nerves or spinal cord. And early diagnosis and proactive management is key in having the best quality of life and outcomes.

This is just showing a number of different cancer types and the incidence of bony metastasis over time. And what we do see is there is an increase over time in the incidence of breast cancer. And sometimes it can be quite prolonged when we we’ll see bony metastasis, what’s important to follow patients for a very long time.

And the way in which bony metastasis can present, it often is asymptomatic, but pain is one of the side effects that we talk about and it’s really multifactorial the reasons for pain. I’m not going to go through all of these, but the interesting thing is that radiation is very effective at treating pain from bony metastasis in breast cancer and in many other cancers. And so radiation somehow can alter a number of these pathways and lead to, in some cases, very quick relief of pain when it’s used appropriately.

In treating bony metastasis, as mentioned earlier, there are two main type of types of treatments that I like to think about or I like to group them into systemic treatments, which are go throughout the whole body, and then local treatments that treat only specific targeted sites. And that’s what radiation is, it’s one of the types of local treatments. And depending on the extent and location of bony metastases as well as symptoms, one or both of these treatment strategies may be used. So a number of patients I see who I treat for bony metastasis are already on and maximized while on their systemic treatments, but there’s a lesion or different sites that are causing symptoms, that’s typically when I would see a patient.

Radiation leads to reduction of inflammatory cells in the region of the metastasis and inhibits release of a number of chemical pain mediators. It’s thought that that’s how it leads to reduction in pain. And occasionally we see patients that can see pain reduction even within 24 hours. Now that doesn’t always happen, but it can. However, it can take up to six to eight weeks to get the full effect of radiation with respect to pain reduction. But we do know that the goal that in about 70 to 80 percent of patients have some sort of symptomatic relief in pain. It doesn’t mean the pain completely goes away, but the patient may need to have less pain medication or occasionally it goes away. And then this leads to improvements in quality of life. And the goal of radiation is what we call symptom palliation, which means just improvement in symptoms, improvement in quality of life.

If any of you have had radiation before and if you, especially if you’ve had more than one course of radiation, perhaps at different sites, you may have noticed that you don’t always get the same number of treatments. And I wanted to just highlight the fact that there are many different ways to effectively treat bony metastasis. Typically the regimens we give range from just one treatment to up to 10 daily fractions — or daily treatments — once a day, Monday through Friday. And what studies have shown is that the pain relief is pretty similar between these regimens, but shorter courses may not be as durable. They may not last as long, you might need re-treatment with the shorter courses.

Those are really the kind of things we’re considering when we decide how to treat and what kind of regimen to choose for an individual patient.

Side effects from radiation. Many times my patients may not have any side effects at all. It is dependent upon how large of an area we’re treating and other factors. But typically if there are side effects, they’re mild and they’re transient, they’re temporary.

The types of side effects that may occur depending on where they’re located could be some mild gastrointestinal symptoms like temporary loose stools or temporary nausea; temporary irritation with swallowing if we’re treating an area near the esophagus here; mild temporary skin changes, which usually are not bothersome to patients; mild fatigue that’s temporary; and occasionally if we’re treating large areas in the pelvis that have a lot of bone marrow, in the hip area, we could see some decreases in blood counts, so that’s something that we would monitor. And with radiation there might be a very small increase in early fracture risk, because if you think about if we’re killing tumor cells there with a tumor in some cases might be providing a little bit of stability, sometimes they respond very rapidly so there could be a small increase in early fracture risk, but actually overall radiation helps to recalcify the bone, especially when given with bisphosphonate therapy that we just heard about.

And if we, you monitor this, you typically see that by 10 to 12 weeks after radiation you can see some recalcification. Usually your doctor will tell you certain lesions might be more of a fracture risk early, but then usually overall there’s a net benefit to the bone from the radiation therapy.

When do we treat with radiation to sites of bony metastasis? If there’s symptoms, typically this would be pain. If there’s an impending fracture, we would talk to our colleagues in surgery to see whether there needs to be stabilization surgery, and if there does, sometimes we give radiation after we talk about the timing of that and work together. Also if there is impingement on nerves or spinal cord or impending, we think that that could happen based on growth of a lesion, then we would treat those lesions.

Some ongoing questions are whether or not we should be treating certain asymptomatic lesions and also whether we should be treating patients who have a few sites of disease in the bone, or it could be in other sites, that are not growing and no other sites of disease are showing and they’re on systemic therapy and are doing quite well. Is there a benefit to treating with radiation in in that situation?

I just wanted to bring to light a few studies that are newer in these areas that may change practice that aren’t quite there yet, but they may change management and practice. What about more aggressively treating bony metastasis in sites where there’s just a few areas of disease? Does that help outcomes overall? To do this we use a different radiation technique. They are known as stereotactic body radiation therapy, we sometimes call that SBRT, or stereotactic ablative body radiation, called SABR. And what we do is we treat with very high doses of radiation, very conformally, so we use a lot of different beams to come in and kind of shape this dose and it can help to, we call it ablate, those tumor cells. It really is high dose there.

This type of treatment requires a longer treatment time, more planning, it’s more expensive, and so we don’t want to use it when we don’t have to. And we don’t need to use it for pain relief. This is really talking about if it’s a benefit to ablate, or get rid, of these individual sites. Does that help the overall course of the disease?

This has been examined, this is just showing some examples of these more advanced treatments where we get around this lesion, we can get the dose much more tight with using multiple beams as opposed to some of these simpler methods.

There have been a couple of studies looking at treating with this SBRT or SABR techniques to bony metastasis or other sites of disease. One is a trial called the SABR-COMET trial that was reported in 2020. This was a randomized phase II trial of about a hundred patients, and these patients had five or fewer sites of metastatic disease. These were for all different types of tumors. The endpoint was overall survival, but they also looked at quality of life and toxicity. And they had about just over 50 months of follow up.

What we see is that there is about 20 percent of patients or so that had breast cancer in this study and about a third of them had sites that were in the bone. What they were randomized to is they got ablation of all of the lesions — the five or less lesions — with their systemic therapy, or they just had standard of care. So if there was a site that was painful, they’d get treatment, but not with the SABR, just with traditional radiation.

What they saw is that there was a statistical benefit in survival and progression-free survival, which was exciting, however there was a significant amount of severe toxicity. So it’s not without potential for severe toxicity. This is a phase randomized phase II, so we need to explore this in more detail.

The other question, are there studies just in breast cancer patients in treating in a similar method? So there was a recently reported study, it’s not published yet, but this was reported in the past year at a conference called NRG-BR002, and this was also a randomized phase II. What they did is — and these are just breast cancer patients and this is patients with four or fewer sites of disease, it didn’t have to be bone, it could be bone or other sites — but they treated all of the sites with ablative radiation therapy. And both arms got their systemic therapy. They compared and were wondering whether this improved outcomes. What they found in this study is that there’s no difference in outcomes looking at progression-free survival or overall survival. That and there is toxicity associated with it, so that has led many in our area to not be jumping to do ablative therapy in patients like this because it may not help them, it might actually cause side effects. It didn’t show a benefit in outcomes, with increased toxicity.

The last thing I wanted to touch on, which is this is an exciting trial that was just presented last fall. What about treating asymptomatic bony metastases? As I mentioned, we do treat symptomatic bone lesions, but if you think about it, there might be a benefit to treat asymptomatic bone lesions because maybe you could reduce these skeletal related events that we’ve heard about in the last lecture: pathologic fracture, cord compression, surgery for instability that might develop, or future radiation for pain.

This study was a randomized phase II, single institution study patients that enrolled patients with high-risk asymptomatic metastasis. And what they mean by high risk is if it was larger lesions, involved certain areas of the body that are higher risk, or certain spinal lesions. They’re randomized to just standard radiation — so not ablative radiation — or no radiation. And the primary endpoint was skeletal-related events and they looked at quality of life and such. There are 78 patients and about a quarter of them are breast cancer patients, so it had included other types of cancers.

What they found was that there was a statistically significant reduction in skeletal-related events with radiation from about 30 percent to about 2 percent. And if they took out the fact whether or not they needed future radiation, it still was significant about 13 percent versus less than 1 percent, I think. Other outcomes were improved as well. They actually saw improvements in disease-related outcomes and quality of life. This led to a lot of excitement in our field and wanting to do additional studies, multi-institution studies to validate these findings because that could change how we treat patients with asymptomatic lesions.

In conclusion, radiation is effective in managing metastatic bony lesions. Pain reduction is similar with different treatment regimens, and most side effects are limited and temporary. There isn’t evidence, as of yet, that’s randomized in studies, that ablative treatment with radiation improves outcomes. In the future there will be more studies on treating higher risk asymptomatic bony metastases. And I just want to highlight once again that multidisciplinary collaboration and innovation is the key to managing bony metastases.
With that I wanted to thank everyone, thank my patients as well, and thank you for attending.

Natalie (moderator) (36:19):
OK, thank you both doctors for a great and informative presentation. We have tons of questions for you, so I’m going to do my best to rapid fire.

But I want to start with a common question that’s been coming in. We have a few questions about dosing. One would be, how long is it safe or recommended to stay on these bisphosphate? A couple questions about how long should you stay on Zometa if you are stable, do you go to the minimum dose twice a year and how long can you stay on that? And also how long can you stay on Xgeva? We have one individual who was on Xgeva monthly for five years. Is that too much? So a little bit more about how long you should stay on these drugs if you’re stable.

Katherine N. Weilbaecher, MD (37:09):
OK, so great questions. Both drugs, we want to, it’s that risk benefit. A lot of the side effects —osteonecrosis of the jaw and atypical fractures — can occur the longer you’re on it and the more dose. So you’re right. And up until I would say five years ago it was, you’re on it monthly for life. We’ve now had studies that show that if your disease is stable after a year, maybe even longer it depends on your disease, we can try to go to every three months and in some cases we’ll go every six. And that’s dosing for both. I think both of them, if we can get under once a month, extend it longer for those patients that have been on it for a few years and are stable, we should.

That being said, some patients might have tumors that are a little bit active and their doctors don’t want to rock the boat. I get that.

I would say there is data now to decrease the dose. I haven’t seen it for longer than every six months for Zometa. And I haven’t seen the data for, definitely not longer denosumab every six because it wears off. And then the other piece of data I saw was, if you progress, let’s say you were on every three to six months and you progress, should you go back to every monthly as you’re getting a new treatment? Yes. When things are active, we go back to every month. If things are quiet and we can — usually we have to go at least a year six months to a year — then it is worth trying to extend it.

Natalie (moderator) (39:09):
OK. And can you just clarify the dosing of Xgeva versus Zometa? I know sometimes we get confused, but the Zomets is the infusion that’s maybe you can spread out versus the Xgeva shot is more frequent. So if you could just address.

Katherine N. Weilbaecher, MD (39:28):
OK. Zometa, you can give it for osteoporosis once a year. So it’s in the bone for a long time and there’s no rebound problem. So for breast cancer in localized breast cancer, it’s every six months to prevent bone loss and it’s every year for osteoporosis and it’s every month for bone mets. But I would say up to every six if things are stable.

Denosumab is a little tricky. For osteoporosis it’s every six months. It’s not every year, it’s every six months, because the drug wears off by six months. And so the problem is when it wears off, it rebounds and you lose all the bone you gained, and we don’t want that. So every six months is the max, you can’t go less than that. That’s the trick of that drug.

Zometa like with the pandemic, it’s OK if you don’t get it on time. Denosumab we had some worries because when people weren’t coming in, they were getting rebound.

Natalie (moderator) (40:48):
Wonderful, thank you so much.

Is there any point where you would stop taking the biphosphonates? You know, if you’ve been stable for a long time, is there ever an end point or do you just stay on them? Are there benefits versus risk to how long you should stay on these drugs? Like ultimately is there an endpoint or do we just stay on them indefinitely?

Katherine N. Weilbaecher, MD (41:13):
Well, I never say never, and I had a patient who had bones for 10 years and she was at that point we were giving it every month for 10 years because we didn’t know we could stop. In myeloma where they have all these new therapies and things are doing well, people are stopping. In breast cancer we are not stopping, but I think with some of these new exciting medicines, we’re getting there. So I will say for right now I might go to every year.
I’ve had patients I’ve had to graduate. They had HER2-positive disease, metastatic, eight years later I’m like, “OK, maybe we can.” But I would say I think we’re going to reach a time of that. Especially with, zoledronic acid is in the bones for years, so there’s hope.

Natalie (moderator) (42:09):
Great! Great. A couple questions coming in.

Various questions around bone density tests and their role in monitoring bone mets. Could you speak to bone density tests? What type of tests we should be getting on a regular basis to monitor how our bone mets are doing?

Katherine N. Weilbaecher, MD (42:30):
Yeah, so bone density we often do in the localized breast cancer, when patients are on aromatase inhibitors, they have all this bone loss and we’re giving Zometa to make sure. In the metastatic setting, bone density is tricky, because like Dr. Bergom said, when you heal a bone met it gets really calcified So it can make the bone density, the DEXA scan, difficult to interpret.

The challenge I saw in the chat was the CAT scan versus the PET scan or the bone scan. The CAT scan shows like an x-ray. You might see I might treat someone with not only Zometa but with an aromatase inhibitor and all of a sudden they’re all these dense spots and it looks like they got worse, but they actually just mean all those spots were healing up. So it can be tricky.

PET scans are nice because it’s just activity of disease and so I’ll have a negative PET scan, but the CAT scan looks bad, so it is some nuance. But for the DEXA scan, the bone density, I don’t usually follow that unless patients have stable disease because they’re going to be on these drugs. I don’t know if that answers the question.

Natalie (moderator) (43:58):
You don’t tend to use the bone density test?

Katherine N. Weilbaecher, MD (44:01):
Not in the metastatic setting. Actually, sorry, Kathy, nope, wrong.

If I’m really worried about osteoporosis. I would refer that patient to an endocrinologist because there are data now there are drugs that build the bone, romosozumab [Evenity]. Then I would get a bone density. So I stand corrected. In severe osteoporosis, I would want to follow it and then refer to an endocrinologist.

Natalie (moderator) (44:34):
I think that does adjust some questions around how do we monitor for our bone mets. There was one question about, is there anything in the blood levels that you can look out for? I know a lot of us get a lot of blood tests, or is it always looking at the PET, the CT?

Katherine N. Weilbaecher, MD (44:52):
I wish we had a good marker for that and Carmen is always up on the newest research, maybe you know. Of course we use our tumor markers as CA 15-3, the CA 19-9. People talk about like circulating tumor DNA, but that won’t tell you where it is, and the circulating tumor cells won’t tell you where. We can do a bone scan, PET scan, CAT scan. I wish we had a better marker. Yeah, we don’t have it.

Natalie (moderator) (45:33):
OK, that’s fine. That’s great.

Katherine N. Weilbaecher, MD (45:36):
One thing we’ve been wanting to do a study on is bone marrow aspirates and look for it that way, but that’s clinical trial that’s not for primetime.

Natalie (moderator) (45:46):
OK. let’s see. You guys have so many wonderful questions.

Do you have an opinion on which scans are the best to know whether there’s progression? I think you addressed that. There’s also MRI, there’s a question about FES, which I think is a new type of scan.

Do you have opinions on like what are the best scans to show progression versus healing? What are your recommendations on scans?

Katherine N. Weilbaecher, MD (46:29):
I have some thoughts. Carmen, do you have a thought, because radiation can be tricky. How do you look at that?

Carmen Bergom, MD, PhD (46:38):
I guess if there’s questions we sometimes would get MRI, but sometimes if there’s suspicion and there’s pain in that area and there’s suspicion on a scan, depending on how severe the symptom is, we sometimes empirically treat that. But if there is nothing on the scan, we would look for evidence of that and we wouldn’t treat if there’s absolutely nothing. But sometimes it’s a little bit ambivalent.

Katherine N. Weilbaecher, MD (47:06):
I think that the thing I like about PET scan, FDG PET, or FES PET is it’s a functional scan, because the problem in bone, like if I fractured my arm, my x-ray is going to look abnormal for 20 years. The bones are just going to look abnormal because the body’s trying to heal them and they overheal and they form a callous or a scar, right? You get scars in bone. So the nice thing about the FDG PET is it’s telling you there’s glucose taking up, the cells are active.

I think patients who have bone-only disease, bone metastases, it’s very challenging to know how patients are doing. In fact, a lot of clinical trials you’re not allowed on because they don’t know how to measure response. So it is a challenge. I think it’s a combination of CAT scan, but I do like the PET scan. In fact, because of insurance issues, if you can get the PET scan at diagnosis, then they’ll allow you to use it. Not all bone mets are PET positive. So unless you know it’s a PET positive bone met, insurance often won’t pay for you to follow. It’s a challenge, and that’s why we have to be care cautious. But then I have to tell my patients, live your life. We can’t worry at some point we just have to trust. But usually it’s what Dr. Bergom was saying, how patients feel is important. FES is nice because that’s for patients who are on endocrine therapy, and it tells you are you responding to estrogen. The problem is, if you’re on the fulvestrant, the SERDs, Faslodex, you can’t use FES pet. It doesn’t work.

We’ve got to come up with better monitoring, don’t we?

Natalie (moderator) (49:30):
OK! Oh my goodness.

Several questions on bone pain. I’m just going to put a few out there so you can address them.

Why does bone pain come and go? Can you tell if it’s from arthritis or from bone mets? And are there things that can be done if you radiate a spot and the pain goes away and then the pain comes back?

Just several questions around bone pain in the mets context?

Carmen Bergom, MD, PhD (50:00):
Yeah, sometimes it can be difficult to tell if the pain is related to arthritic type things or from a lesion or lesions. Usually history can help. If it’s getting worse, along with signs of say progression on scans, that would be something that we would in treat that as if it’s a progression. Sometimes if the pain is bad enough and we’ve tried everything, like treatment for arthritis and such, we might try to give radiation and see if that helps. As far as if you can re-treat after receiving radiation, typically we are able to re-treat at least once. If it’s more than that, we like to see that the first time we gave treatment if there’s a response. Typically if it comes back over time and we give radiation again, typically you get a good response. Again, that’s usual, it isn’t all the time. So we might choose to give either the same dose or a little bit different dose. There are certain tolerances, mostly around the spinal cord, that we would be really careful to not go over. But with a lot of these shorter courses you are able to re-treat without any worry about the spinal cord dose for instance. So don’t think if “I had relief for two years and now it’s back and I can’t get radiation again.” It’s really something to talk to your doctor about because typically you can.

Natalie (moderator) (51:31):
OK, great. We’re running out of time so I am going to try and squeeze in a couple more.

Opinion on, I know this is controversial, which is better, Zometa or Xgeva?

Katherine N. Weilbaecher, MD (51:43):
I tend to be a fan of Zometa to start with. Because it stays in the bone, it gets you some coverage. The problem with Xgeva, and I guess with the pandemic, the problem with Xgeva is that if you don’t, even though it’s nice and easy, it’s only subcutaneous, if you have any delays of getting it, it can be a problem.

I think they’re both equivalent in many ways. And so what I’ll do is, let’s say someone is progressing and they might have a little more pain. I might add Xgeva, and you know, I might switch.
So I use them both.

Often I will start with Zometa. That’s just my own preference. But if patients really don’t want an IV and they don’t have a port and they’re just taking the oral CDK 4/6, we’ll do Xgeva. But if someone comes from far away or they’re not very reliable, I will do Zometa. Yeah.

And what I would say about pain, real quick. I always have the two-week rule. We all have pain, right? You lift a suitcase, you get a pull. If things aren’t better after two weeks, you need to get evaluated. But it is a hard challenge. When is it just pains of life or arthritis versus the bone? That’s always a challenge.