Kathy D. Miller, MD; Alexander H.G. Paterson


December 19, 2011

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Kathy D. Miller, MD: Hello. I am Kathy Miller, associate professor of medicine at Indiana University School of Medicine in Indianapolis. Welcome to Medscape Oncology Insights in Breast Cancer, coming to you from the 2011 San Antonio Breast Cancer Symposium.

Joining me today is Dr. Alexander Paterson, chair of the Alberta Breast Cancer Program at the Tom Baker Cancer Center and professor of medicine and oncology at the University of Calgary in Calgary, Alberta. Welcome, Sandy.

Alexander H.G. Paterson, MBChB, MD, FRCP: Thank you.

Bisphosphonates in the Adjuvant Setting

Dr. Miller: Today I want to talk to you about the use of bisphosphonates in the adjuvant setting, in general, and specifically about the B34 trial. This trial looked at the incorporation of clodronate into the adjuvant setting. We have been waiting for these results for a long time. What have you finally found?

Dr. Paterson: This was an event-driven trial, so we had to wait for 596 events. What has happened over the last 10 years since we started to design this study is that the event rate has dropped in women with node-negative breast cancer. This is a trial predominately in women with axillary node-negative disease, about three fourths of the patients were in that group and two thirds were 50 years of age and older. The event rate has dropped. We originally thought it was going to be about 3.5/100 patients, now it is actually 2.5%, so that took us an extra 3 years.

Dr. Miller: If you start talking about women over age 50, those with lymph-node negative disease are the most common demographic group of patients that we see. It is great news for patients overall that the subgroup is doing better, but you are keeping me in suspense here. Was adding clodronate helpful?

Dr. Paterson: Yes, it was. One thing that was clear, the primary endpoint [chosen for this study] may not be appropriate for this kind of agent. The endpoint was disease-free survival, an endpoint that is really good for cytotoxic drugs. You have to look at all events (for example, contralateral breast cancer, second primaries, deaths, intervening deaths up to the time of any recurrence, or recurrence-free death), and when you are using an agent that actually has its primary effect on bone, many of these events that occur may dilute the results a bit, and that is what happened. So the primary endpoint was not met, but there was about a 9% reduction in events, so we thought, "All right, let's have a look at this." Looking at the results, the incidence of second primaries was exactly the same between the clodronate and the placebo groups; the incidence of contralateral breast cancers was exactly the same; and the incidence of local regional recurrences was exactly the same. The difference was in distant metastases. We saw a reduction in distant metastases in the women in this trial. Looking at it more closely, in the stratification variables (this is a reasonable statistical approach to take when you are looking for any group that might have had an advantage), we found a reduction in the instance of bone metastases and nonbone metastases in women age 50 and older but not in those under age 50. You may say that is just a chance finding. No, it isn't, because we now have 4 trials that show the same thing -- 4 fingers pointing in the same direction. The benefits of bisphosphonates, if you look at the history of these kinds of trials, have all been in postmenopausal women over the age of 50, 55, or 60, and/or women who were made menopausal by the use of goserelin (luteinizing hormone releasing hormone [LHRH] analog).

Digging Deeper Into B34

Dr. Miller: I want to ask you about a couple of points here.

Dr. Paterson: Yes.

Dr. Miller: This starts to get a little complicated. I understand that this is an agent where you really thought the money was going to be on bone metastases, so I tend to agree that focusing on the bone events might most directly reflect the benefits of the agent, but I could make the same argument about chemotherapy. I don't give women chemotherapy to prevent contralateral breast cancers. There has never been any evidence that it does, yet we do focus on overall disease-free survival, so I am not sure they are quite as different as you were suggesting.

Dr. Paterson: That is a fair point. We are going to have to discuss this more, because with cytotoxic drugs, you do want to make sure that you are not causing second primaries. You may have an effect on contralateral breast cancers (it is not unreasonable to expect that could happen), and you are very likely to have an effect on local regional recurrences. I know of no animal studies that have shown that using a bisphosphonate will reduce the incidence of cancers at any site other than bone; that is the first thing. The second thing is that there may be an effect on nonbone metastases. I think there is an effect, although I am not sure that we really understand it. So yes, you can use that argument and I would mull it around, but I think that with an agent like a bisphosphonate, the primary effect is actually on bone turnover. It is not a cytotoxic drug at all.

Dr. Miller: I want to ask you a little bit more about this subset. This gets into some of the nuances of how we describe clinical trials and report them. When the overall trial does not meet its primary endpoint, we have to say it is a negative trial.

Dr. Paterson: When you say a negative trial, there are implications that there is nothing in it. The primary endpoint was not met.

Dr. Miller: No, I wouldn't make that leap. Merely that for consistency, if we have a predefined primary endpoint that [was not] met, then by definition it is a negative trial. There may be lots of useful information and evidence of benefit that we need to talk about, but it becomes a nice way to ensure that we are being honest in our reporting. There is sometimes a temptation to focus entirely on a subset and to do a bit of "subset diving," to see whether we can find a group that may not be biologically based and may be spurious. I don't mean to suggest that is the case with the bisphosphonates because of the consistency across the subsets, but there is sometimes a tendency to do lots of subsets, stumble across one that looks encouraging, and focus all the discussion on that one.

Dr. Paterson: Fair enough, but as you said, we now have a number of pointers in the same direction, and B34 is certainly pointing to that as well. Some trials are selecting co-primary endpoints -- disease-free survival and bone metastases-free. The D-CARE study is doing this. I am not sure there is a huge difference between a primary and a secondary endpoint. Obviously, they are different endpoints, but with respect to the primacy of the results, if you have preplanned, predetermined secondary endpoints in your protocol and they come up positive, you have to consider what is happening.

What Is Happening in the Bone?

Dr. Miller: I want to ask you more about what is happening here, because not being a bone maven by any means, I find the biology a little bit confusing. The consistent subgroup, for which 4 trials have found a benefit, are in -- to put it in very broad strokes -- women with very low estrogen levels (either naturally postmenopausal, particularly the older groups, so there is no question of perimenopausal women and stuttering ovarian function) or premenopausal women essentially rendered in a very low estrogen state [by means of] an LHRH analog. What is so different about the bone environment in the absence of estrogen that makes the bisphosphonates useful, or perhaps allows the bisphosphonates to be useful? Or, said a different way, how does having estrogen screw up the effects of the bisphosphonate?

Dr. Paterson: I don't know. That is the short answer. There are a number of possibilities, because what happens, as you know, with menopause and declining estrogen levels, is an enhancement of bone turnover. In natural menopause, the first 2-3 years, bone turnover is accelerated and then over time, it slows down so that women in their 60s have a 2% per year turnover in bone loss. The control mechanisms are quite different. When you give a woman goserelin or do an oophorectomy, the control of bone turnover is with the hormone inhibin. When an oophorectomy is done, or medical oophorectomy with goserelin, inhibin levels drop and the control of bone turnover moves peripherally to the marrow and bone spaces. We know that, for example, activin is a mediator that controls bone turnover in postmenopausal women (noggin is another one), and so it is a different situation. In short, I don't think we know, but it may well be different.

Dr. Miller: Could we use measures of bone turnover? Several measures of bone turnover can already be done as standard assays. Could they be used as a way of more clearly defining the subset, rather than the sort of arbitrary age cutoffs that have been used in some of the analyses?

Dr. Paterson: Yes, we are going to look at that -- markers of bone turnover such as P1NP or even CTX -- because if you can show that bone turnover levels are high (and you will, in most of these patients) and you can bring them down with bisphosphonates, that is likely to be reasonably effective in inhibiting the vicious cycle that is going on in bone with bone metastases. It looks as if merely stopping osteoclast function isn't quite the complete answer that we were looking for -- if you could block osteoclast function, then you can stop the cancer cells growing. It seems that by reducing osteoclast function (and you can certainly almost wipe it out with zoledronate), doing that may have a small effect in older women. I think AZURE showed this, pretty much the same as we did, that in older women, for some reason there may be an inhibition of the vicious cycle that we cannot see in younger women.

Putting Bisphosphonates Into Practice

Dr. Miller: How should we put the results of the B34 trial and the other bisphosphonate trials that came before it, into practice? You practice in Canada, where clodronate, the agent used in the B34 trial, is available.Are you using it in the adjuvant setting in anyone or in this subgroup of patients?

Dr. Paterson: There are more similarities than differences between bisphosphonates. Many of the differences are marketing differences. I will use a bisphosphonate, certainly in the adjuvant setting, particularly in a woman with low bone density. That is a normal indication. I use bisphosphonates in the adjuvant setting in women on aromatase inhibitors. We have an agent here that is nontoxic -- we didn't see any osteonecrosis, except one possible case -- it is very easily taken, and it looks like we may get a reduction in metastases. Some clinicians may be looking to use bisphosphonates. You could use zoledronate.

Dr. Miller: Those of us on the other side of the parallel, who would need to use a different agent, would it trouble you?

Dr. Paterson: Not at all, no.

Dr. Miller: If we used the agent that was available, particularly in this low estrogen environment group of patients?

Dr. Paterson: If you are considering zoledronate, the every 6-month regimen is a good one, because it isn't associated with much risk for osteonecrosis of the jaw developing, whereas the monthly regimen might be problematic.

Dr. Miller: Where are we going with this collection of results now? You are going to be looking at the bone turnover markers and so forth, but what is the next study you have in mind?

Dr. Paterson: We are doing the denosumab trial. This is an agent that is highly specific and inhibits the RANK ligand, which is the mediator between the osteoblast and the osteoclast. It looks like it is a very effective agent. There aren't many trials comparing bisphosphonate A vs bisphosphonate B; in fact, very few. In patients with bone metastases, [the use of] denosumab showed an improvement over [the use of] zoledronate in the numbers of skeletal-related events and the time to the first event. If we bring this drug in to the adjuvant setting, this might be an agent that we can give easily subcutaneously. It doesn't seem to cause any kidney problems. I am looking for that one.

Dr. Miller: Thank you, Sandy, for coming in and going through these long-awaited results for us, and thanks to you, our audience, for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller at the 2011 San Antonio Breast Cancer Symposium.


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