Zometa - Latest News out of San Antonio Meeting

voraciousreader · December 2010

Zometa Didn't Prevent Breast Cancer From Coming Back By Charlene Laino
WebMD Health News Reviewed by Laura J. Martin, MD 60-ish woman

Dec. 9, 2010 (San Antonio) -- The bone-building drug Zometa does not appear to prevent breast cancer from coming back in most women, researchers report.

Adding Zometa to standard therapy, usually chemotherapy, also did not extend lives, according to results of the study of more than 3,000 women.

In women who were at least five years past menopause, however, the addition of Zometa improved overall survival rates by 29%, compared with standard treatment alone.

"This wasn't a small subgroup; 1,101 women fell into the category," says Robert Coleman, MD, professor of medical oncology at the University of Sheffield in England.

"The benefit was so great we don't think it's a chance finding," he tells WebMD.
Still, the results of a subgroup analysis cannot be considered conclusive, Coleman says.

Based on the findings, Novartis Pharmaceuticals, which makes the drug and funded the study, will withdraw U.S. and European applications for approval of Zometa to prevent breast cancer recurrences.

Coleman presented findings of the study, dubbed AZURE, at the San Antonio Breast Cancer Symposium.

A Visual Guide to Breast Cancer

Earlier Studies Raise Hopes

Zometa, given as an infusion, is a member of a class of drugs called bisphosphonates that help maintain bone strength.

Animal and lab research suggests that bisphosphonates may fight breast cancer in a number of ways -- by directly killing tumor cells, by cutting off their blood supply, or by stimulating the immune system to mount an attack against the tumor, says Rowan Chlebowski, MD, PhD, a medical oncologist at Harbor-University of California, Los Angeles Medical Center.

The new research builds on a study presented at the 2008 breast cancer meeting showing that Zometa appears to prevent breast cancer from coming back.

Then, last year, Chlebowski presented an analysis of data on more than 150,000 women that showed that there were 31% fewer cases of breast cancer among women who took bisphosphonate pills than among women who didn't.

Zometa Does Not Appear to Prevent Breast Cancer Relapses

The new five-year study involved 3,360 patients with breast cancer that had spread to the lymph nodes.

A total of 404 women given Zometa plus standard therapy and 403 of those given standard treatment alone had a recurrence, developed a new cancer, or died before they had a recurrence.

Altogether, 243 women on Zometa and 276 on standard treatment alone died, a difference so small it could be due to chance.

Twenty-six women on Zometa had confirmed or suspected cases of osteonecrosis of the jaw, a side effect of bisphosphonates that causes the jawbone to decay.

Routine Use of Zometa for Breast Cancer Treatment Not Warranted

Since only women who were well into menopause appeared to benefit from the drug, Coleman says he suspects it works best in an environment of little or no estrogen.

Commenting on the findings, Sharon Giordano, MD, MPH, of the University of Texas M.D. Anderson Cancer Center in Houston, says the scientific community has been waiting to hear these results.

The bottom line, she tells WebMD, is that the routine use of Zometa to prevent breast cancer recurrence is not warranted at this time.

As for its apparent benefit in postmenopausal women, Giordano says, "Those findings are very intriguing, but not definitive."

Four trials are under way that should better define bisphosphonates' role in breast cancer prevention, she says.

The results do not affect Zometa and other bisphosphonates' "important role in treating bone loss among women with breast cancer," Giordano says.

Zometa is approved for the reduction or delay of bone complications across a broad range of cancers that have spread to the bone and multiple myeloma. It costs about $1,000 an infusion.

This study was presented at a medical conference. The findings should be considered preliminary as they have not yet undergone the "peer review" process, in which outside experts scrutinize the data prior to publication in a medical journal.

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SOURCES:

San Antonio Breast Cancer Symposium, San Antonio, Dec. 8-12, 2010.

Robert Coleman, MD, professor of medical oncology, University of Sheffield, England; consultant, Novartis Pharmaceuticals.

Rowan Chlebowski, MD, PhD, Harbor-University of California, Los Angeles Medical Center.

Sharon Giordano, MD, MPH, University of Texas M.D. Anderson Cancer Center, Houston.

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KerryMac · December 2010

Well, sh*t....not the news I was hoping for.

littletower · December 2010

Not the news I was hoping for either. Oh well, I'm in the clinical trial, so I'll go with it. My onc is in the "pro" column.

Celtic_Spirit · December 2010

As my onc always tells me, don't put a lot of weight on one study.

mcsushi · December 2010

I just read this and now I'm depressed...

clariceak · December 2010

Not the best news, but I'm curious to hear what Jen's onc says. He seems to be on the cutting edge of research and she received it during chemo.

Meanwhile, there is more motivation to keep taking your aspirin (safety coated for you Sharon) and exercise!

Husband11 · December 2010

Just one study. We just had this published in November:

Efficacy of Zoledronic Acid in Postmenopausal Women With Early Breast Cancer Receiving Adjuvant Letrozole: 36-Month Results of the ZO-FAST Study Ann Oncol. 2010 Nov 1;21(11):2188-2194, H Eidtmann, R de Boer, N Bundred, A Llombart-Cussac, N Davidson, P Neven, G von Minckwitz, J Miller, N Schenk, R ColemanAfter a 36-month follow-up period, early initiation of ZOL provided significant benefits in bone health and improved DFS in postmenopausal women receiving adjuvant AI therapy for early hormone-receptor...TAKE-HOME MESSAGEAfter a 36-month follow-up period, early initiation of ZOL provided significant benefits in bone health and improved DFS in postmenopausal women receiving adjuvant AI therapy for early hormone-receptor positive breast cancer.Abstract SUMMARYOncologySTAT Editorial TeamAromatase inhibitors (AIs) have greater efficacy than tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive early breast cancer. Bisphosphonates such as zoledronic acid (ZOL) have been demonstrated to prevent bone loss and reduce the risk of fracture associated with AIs, and have also been demonstrated to improve cancer outcomes. Eidtmann et al reported the results of a 36-month follow-up of the Zometa-Femara Adjuvant Synergy Trial (ZO-Fast). Patients for whom ZOL treatment was initiated immediately after randomization (immediate ZOL group) experienced improved bone health and disease-free survival (DFS) compared with those for whom ZOL treatment was delayed (delayed ZOL group). In this open-label multicenter randomized trial, patients were postmenopausal women or women who were recently menopausal because of chemotherapy or ovarian suppression for hormone-receptor positive early breast cancer. Baseline lumbar spine (LS) and total hip bone mineral density (BMD) T-scores were required to be > -2.0. Patients were randomly assigned to receive immediate or delayed ZOL treatment. All patients received oral daily letrozole for 5 years and daily calcium and vitamin D supplements. In the immediate ZOL group, ZOL was provided beginning immediately after randomization. In the delayed ZOL group, ZOL was provided if the patient's T-score became < -2.0 after a nontraumatic bone fracture or if an asymptomatic fracture was detected by spinal x-ray.A total of 1065 patients were randomly assigned in the original ZO-Fast trial. Baseline and 36-month BMD data were available for 314 patients in the immediate ZOL group and 319 in the delayed ZOL group. From baseline to 36 months, LS BMD increased by 4.39% (95% confidence interval [CI], 3.69%-5.11%) in the immediate ZOL group, and decreased by 4.9% (95% CI, -5.54% to -4.25%) in the delayed ZOL group (least squares mean difference between groups, 92.9%; 95% CI, 8.37%-10.20%; P < .0001). Slightly smaller but still significant changes were observed for total hip BMD (P < .0001). More patients in the immediate ZOL group than in the delayed ZOL group with baseline lumbar T-scores between -2.0 and -1.0 transitioned to normal BMD (P < .001), and more patients in the delayed ZOL group than in the immediate ZOL group developed severe osteopenia/osteoporosis (P < .001). However, similar proportions of patients in the immediate and delayed ZOL groups experienced fractures (5.0% vs 6.0%; P = .502).A total of 506 of 532 immediate ZOL patients and 489 of532 delayed ZOL patients were disease free and alive, corresponding to an absolute difference of 3.2% between the two groups and a relative reduction of 41% in the risk of having a DFS event (hazard ratio [HR] = 0.588; 95% CI, 0.361-0.959; P = .0314). Compared with the delayed ZOL group, the immediate ZOL group had fewer local (0.4% vs 1.9%) and distant (3.8% vs 5.6%) recurrences, and fewer immediate than delayed ZOL patients developed bone metastases (1.7% vs 3.2%). Adverse events were similar between groups. Influenza-like symptoms were more common in the immediate than in the delayed ZOL group. Renal failure or impairment was less common in the immediate than in the delayed ZOL group (0.2% vs 0.6%). Osteonecrosis of the jaw occurred in 2 patients in the immediate ZOL group.The results of this analysis showed that early initiation of ZOL provided significant benefits in bone health and improved DFS in postmenopausal women receiving adjuvant AI therapy for early hormone-receptor positive breast cancer.Access this article » Community CommentsTotal comments to date: 0 View Comments Post A Comment(maximum 2000 characters: 2000 remaining)

KerryMac · December 2010

Timothy, I love you

kim40 · December 2010

Thank Goodness! I read this thread earlier this morning and got really down about it all. Then I come back and read Timothy's study and Whew! I love you too Timothy!! My next Zometa (my third infusion) is set for January 3rd! Thank you so much!!

Pure · December 2010

sooo I called my breast cancer consultant. She is in San Antonio-she was going to go to the session that covers this study. She said she would call me afterwards so as soon as I hear I will let you know. My breast cancer consultant funds research and knows some of the top researchers in the field of breast cancer. She will be a good resource for finding out more on this. Once I hear I will let you know,

chrishat · December 2010

i hope that insurance will continue to cover it. my diagnosis anniversary was yesterday and it was a yucky day, and i have a lot of emotional investment in zometa being a weapon in my arsenal! ugh! and didn't i just see something that questions the helpfulness of vitamin D as well? damn damn damn. better go take my aspirin.

Gitane · December 2010

This link is to a teleconference held by the presenters of this data at the 2010 SABCS on December 9 (updated on December 10). It has links to the slides they presented as well as an interview. What I found most interesting was the overview of the difference between the study populations in the ABCSG trial and the AZURE trial. The presenter slides from the Austrian group make a strong case for the efficacy of Z. acid in premenopausal patients being treated with endocrine therapy. There is also a slide showing the different effect in the Austrian trial on women below 40 years of age and those above 40 years of age. Finally, I noticed in one slide of the AZURE trial that Z acid lead to a reduction of 5% in bone mets in the overall population. I don't know if this was only in postmenopausal women or not. I couldn't tell.

http://www.aacr.org/home/public--media/multimedia-/aacr-podcasts/ctrc-aacr-2010-sabcs-teleconferences-and-podcasts/results-of-the-azure-trial-teleconference.aspx

I'm sorry I am unable to paste a link here, my computer just won't do it.

Husband11 · December 2010

No mention of the Zofast trial's positive results? Why so much weight placed on Azure? ABCSG involved premenopausal women treated with goserilin, a drug that suppresses the ovaries. It compared tamoxifen, an aromatase inhibitor, with or without zolodronic acid. It found a positive effect of using zolodronic acid, and no difference between the tamoxifen and AI groups.

KerryMac · December 2010

What worries me is that this new study was funded by Norvatis, and they have withdrawn their request for approval of it's being used as a preventative. So it seems Norvatis themselves believe there is not benefit??

It is so confusing, as every study up unti now has shown such promise.

voraciousreader · December 2010

I was scheduled to have my 6 month infusion on Monday. I called my oncologist at 9 am on Friday and spoke to the physician assistant. I wanted to know if I should keep my appointment. I'm stage 1. She called the oncologist who was at the conference. When we first discussed treating me with the infusions, he mentioned he was a close colleage and friend of Dr. Gnant and thought his data was "strong." Based on that, and myself looking at the Austrian study, I thought I was EXACTLY the type of patient that would do well with Zometa therapy. Anyway, the PA called me back at 10:30 and said, there were going to be additional discussions held on that day, Friday, to further discuss the latest study. She said that I SHOULD NOT keep my Monday appointment. She added, that when the oncologist returns, he would cull over all of the data further and then advise me as to what to do next.

I wish to add that my niece is also a medical oncologist and I spoke to her before my first infusion. She concurred with my oncologist that I was a good candidate for the Zometa infusions. I have repeatedly heard from my oncologist, my niece and so many others that before long, Zometa would become the "Standard of Care."

I remain hopeful that Zometa will become a first line treatment. I will post when I hear further from my physician. Until then, I appreciate hearing from EVERYONE.

voraciousreader · December 2010

Experts disagree on why the new results differ from those of the 2009 study.

Some scientists suspect it's because the patient groups and treatments were slightly different. Women in the Austrian trial had an earlier-stage disease than those in the AZURE trial, and most did not undergo chemotherapy, unlike the patients in the AZURE study.

In addition, the women in the Austrian study received drugs to stop estrogen production and put them into menopause. The level of estrogen in bones could affect how well bisphosphonates work to prevent cancer recurrence, said the lead author of the AZURE study, Dr. Robert Coleman, professor of medical oncology at the University of Sheffield in England.

"We need to understand why" the two studies differed, Coleman said. "I don't believe one is right and one is wrong."

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KerryMac · December 2010

So, basically, if I have no estrogen in my bones (thanks to ooph and Arimidex) I could still receive benefit?? This is so confusing, it just seems like they are ignoring all the previous studies because of this one. .

voraciousreader · December 2010

Kerry- That's exactly what I want to know! I'm doing ovarian suppression and take tamoxifen and am early stage. One of the parts that I find confusing is that in the Azure group they refer to women PAST menopause. So, what I want to know is, is this group of women who benefitted, a group of women who were FIRST 5 years past menopause when they were diagnosed and THEN were given the Zometa?

So many variables and differences between the two studies... I hope to learn more next week.

1Athena1 · December 2010

Gitane, thank you for that great link. I am borrowing it and taking it to the stage I/II forum if you don't mind :-)

I'm going to cross-post on this and the stage I/II forum:

If you listen to the audio of the press conference comparing AZURE vs. the Austrian study (see Gitane's link), differences do emerge:

--In the Austrian study, Gnant, the lead investigator there, said that NO women were given chemotherapy. In AZURE, most women got it and the study wasn't even controlling for that. Women could choose any of the usual treatments so long as they had no prior history of bisphosphonate use. I wonder if chemo is the elephant in the room. Could the chemo have interfered with the Zometa? That's an unanswered question.

--All women in the Austrian study were premenopausal but on Goserelin; the AZURE study, as we know, had a diversity.

--I thought the discussion at the press conference was interesting about what it means to be post menopausal. The reason why those with most benefit from Zometa in the AZURE trial were at least five years out from menopause is because estradiol levels take years to really dip, so the estrogen environment may be different five years out than at immediate menopause. That is the hypothesis discussed by Coleman, the lead researcher in AZURE, that to me is most significant. There was hypothesizing that true menopause may have to be redefined. This says to me that IF this hypothesis is correct, the goserelin-treated women of the Austrian study, with induced menopause and only a total of three years out, may have had a more pre-menopausal looking environment in their bodies.

--Most of the women in the Austrian study were stage I and the rest were stage II. In AZURE, the patients were stage II/III.

Note also that at the press conference it was revealed that the Austrian study continued to show a strong protective effect for Zometa for its patients, both in terms of disease free survival and overall survival, in 5 year follow-up findings.

As someone who did not do chemo, I am feeling a bit better about this today than I did yesterday.

AgentMo · December 2010

@Athena1: Regarding the difference in stages, it should be noted that the Austrian study still used old staging. Stage II in that case meant 10 or less involved lymph nodes and not only up to three lymphnodes.

Regardless, the results are a big disappointment for me. I hope I will receive Zometa in the future despite these results, in particular because I am exactly the patient that took part in the Austrian study group (33, hormone-receptor positive, taking goserelin and tamoxifen though of course I had chemo). I so hoped to better my chances with Zometa because chance for people of my age are dismal anyway. Unfortunately, it seems 35 is the age where chances tend to improve. Before you are up to die before you know it.

weety · December 2010

I was SUPPOSED to start zometa next week. Now I don't know what to do (or if my onc will even let me) . . . I'm a year out from chemo, so I've been in menopause for a full year (first chemo-induced, and then ooph) so I don't think my estrogen levels are anywhere close to premenopausal. I'm also on an AI. Don't know what to do, or even how to angle my argument this time--do I push for it still? I hope more discussion about these differences in the studies sheds some light on this before my appt next week (I know--wishful thinking--but hey, it's okay to wish, right?)

Whoops, just realized this was a Stage3 forum, but I'll leave it anyways. Hope it's okay.

mcsushi · December 2010

This is so confusing/frustrating! I'm premenopausal, on tamoxifen, and supposed to get lupron injections starting February. I had my first Zometa in November with my second scheduled in May. I feel like every time I try something "promising," it winds up being not beneficial as soon as I start it. I did a clinical trial for Avastin for my chemo. I wound up with a serious reaction that landed me in the hospital for a week, on high dose steroids for 3 months (BOO!!!) and I was unable to complete 11 out of 12 Taxol infusions. A week after my hospitalization, a study came out saying Avastin use in non-metastatic cancer was of no benefit. Super. You can imagine how that went over like a lead balloon. Now this. I'm 31 and I want to do everything possible, but sometimes it is so disheartening. I fill up with hope just to be deflated. I'm so over it. Sorry for the rant... Yell

maryannecb · December 2010

Shoot

JudyO · December 2010

When I was dx 2 1/2 years ago my onc was certain that zometa would soon be part of the standard care. My husband is a dentist so I was familiar with the possible negatives of zometa. We talked several times with my onc. After I completed chemo he agreed to submit to my insurance for the zometa. Of course it was denied since it is not the current approved treatment. I offered to pay for the zometa out of pocket but my onc said no. He said it would probably be a waste of money and he didn't feel would change my outcome so he would not give it to me.

Anonymous · December 2010

Well that's just great. All this time I've been thinking the Zometa infusions are a good insurance policy against recurrence. I'm scheduled for my 6 month infusion on Wednesday morning. I'm going to talk to my onc and see what he's thinking on this. I'm confused and frustrated by the way studies keep flip flopping. It's like this with everything.

Barb

Gitane · December 2010

When I listen to the presenters at the teleconference they seem to be saying that in postmenopausal women recurrence risk is lowered 29% with Zometa. In premenopausal women over 40 who had their estrogen production shut down by Goserlin there was also a 30% recurrence risk reduction with Zometa. In women younger than 40 it seems Goserlin does not lower their estrogen levels enough for Zometa to be effective on its own. I understand them to say that their hypothesis is that estrogen deprivation kills some cells and that the effect of Zometa on the bone microenvironment may keep remaining cells from getting the growth factors they need to survive and spread. It seems that women under 40 may need an ooph and/or some other mechanism beyond Goserlin to stop all estrogen production in their bodies in order to benefit from Zometa. This is what I am understanding from what I have heard and read so far.

1Athena1 · December 2010

mcsushi,

It's a sickening feeling, isn't it? That's awful that you should be going through this at age 31. This Zometa news just makes me sick to my stomach. That's why I changed my signature. :-)

orange1 · December 2010

Since this seems to be the zometa forum...

[P5-13-04] Use of Bisphosphonates in the Adjuvant Setting for Breast Cancer - A More Than 10 Years Single Centre Experience.

Jakob A, Groh U, Schwoerer D, Schattenberg A, Siebers JW

Background: Adjuvant therapies for early breast cancer are associated with substantial decrease in bone mineral density. Bisphosphonates are antiresorptive agents that have an established role in preventing skeletal morbitity in patients with bone metastases and in the treatment of osteoporosis. It has also been shown that these agents are active in preventing cancer treatment induced bone loss in women with early stage breast cancer. Recently, several trials have demonstrated that bisphosphonates may exert anticancer effects in the adjuvant setting.
Patients and methods: Since 1997 we treated an increasing number of unselected patients with early breast cancer with bisphosphonates (up to 2009: 1144 out of 1876 patients). There was no significant difference in the two patient groups concerning tumour size, nodal status, hormone receptor (HR) expression, HER-2 expression and adjuvant treatment modalities. In most cases we used zoledronic acid, but also clodronate ibandronate or alendronate.
Results: Disease-free survival (DFS) was significant better in patients treated with bisphosphonates (p = 0.009). This was also true in the subgroup of patients with hormone receptor positive disease (p=0.0011) and even more striking in patients with N+ disease (p=0.00003). There was no significant difference in DFS in patients with hormone receptor negative disease. In our analyses especially patients with N+ and ER/PR+ disease showed a significant advantage from treatment with bisphosphonates.
Conclusion: This large single centre experience demonstrates a significant improvement of disease-free survival in patients with breast cancer treated with bisphosphonates in the adjuvant setting. The benefit was more pronounced in the subgroup of nodal positive and hormone receptor positive disease.

mcsushi · December 2010

1Atnena1:

You crack me up girl! I think my future tx should also include small animal sacrifice and rain dances; at this point, I'm ready to try anything! Well, off I go to hunt pigeons and squirrels...

voraciousreader · December 2010

AZURE Results Show No Effect of Zolendronic Acid on Breast Cancer
Zosia Chustecka
December 9, 2010 (San Antonio, Texas) - Long-awaited results from the AZURE trial in breast cancer patients show no effect from the bisphosphonate zolendronic acid (Zometa, Novartis) on the recurrence of breast cancer or on overall survival. However, a subset analysis showed a significant effect on both recurrence and survival in postmenopausal women (more than 5 years after menopause), but no effect on premenopausal women.

The overall negative results from the AZURE trial have led the manufacturer to withdraw its application for zolendronic acid use in breast cancer risk reduction. But they do not appear to be deterring experts who are already using this strategy on the basis of previous positive results.

The most positive findings to date come from the Austrian ABCSG trial reported 2 years ago, and subsequently published in the New English Journal of Medicine (2009;360:679-691). This study found that zolendronic acid reduced breast cancer recurrence and breast cancer death by one third.

This Austrian trial sparked great interest from the whole medical community, and led some clinicians to prescribe zolendronic acid, which is indicated for osteoporosis, to women with breast cancer to increase their chance of survival.

However, such use is not recommended in any clinical guidelines, and the scientific community urged physicians to wait for results from the AZURE trial, said Sharon Giordano, MD, MPH, associate professor in the Department of Breast Medical Oncology at the University of Texas M.D. Andersen Cancer Center in Houston.

She was one of several experts speaking at a press conference today here at the 33rd Annual San Antonio Breast Cancer Symposium to highlight the results from AZURE. They will be presented at the meeting tomorrow by principal investigator Robert Coleman, MD, professor of oncology at the University of Sheffield, United Kingdom.

Routine use of zolendronic acid to prevent breast cancer recurrence is not indicated.
In light of the new and contradictory findings from AZURE, she said, "the routine use of zolendronic acid to prevent breast cancer recurrence is not indicated." The drug has a use in osteoporosis and other bone disorders, which are approved indications.

The finding of a significant effect in postmenopausal women in a subgroup analysis is "intriguing but not definitive," she said.

However, several experts disagreed and said that they were already prescribing the drug and would continue to do so.

Michael Gnant, MD, professor of surgery at the Medical University of Vienna, who led the positive Austrian trial, said after those results came out that he would use zolendronic acid in patients who were similar to the participants of that trial (premenopausal women who were treated with goserelin to induce artificial menopause). Now, on the basis of the positive subgroup findings, he said he would also use zolendronic acid in postmenopausal women.

"Before I would say that I would treat my wife, who is 42. Now I would also treat my mother, who is 82," he said.

Rowan Chlebowski, MD, PhD, medical oncologist at the Harbor-University of California in Los Angeles, told Medscape Medical News that he would also use zolendronic acid in postmenopausal women with breast cancer to reduce their risk for recurrence. "Many states cover use of zolendronic acid to prevent bone loss in the patient population, so I prescribe it for that," he said.

Last year, Dr. Chlebowski reported a large observational study that showed that women who were taking oral bisphosphonates (which did not include zolendronic acid, which is administered intravenously) for osteoporosis had a significantly lower risk for breast cancer. Two other observational studies have reported similar findings. In all of these studies, the women were postmenopausal, Dr. Chlebowski noted.

The effect of zolendronic acid on breast cancer is only seen when estrogen levels are very low, Dr. Chlebowski explained. It is seen in postmenopausal women more than 5 years after menopause (as in the AZURE subset) and in younger premenopausal women who have been pushed into artificial menopause by goserelin (as in the Austrian trial), he pointed out. Dr. Gnant noted that the best reduction effects were seen in women who were older than 40 years; younger women in whom the induced menopause was "less than perfect" had less favorable outcomes.

Zolendronic acid does not have an effect on breast cancer that is being driven by estrogen, Dr. Chlebowski said.

The latest results have led the experts to speculate that zolendronic acid does not have a direct anticancer effect - which had been suspected at one point - but rather that it has an effect on the host, specifically on the bone marrow environment, which prevents the cancer from returning.

Dr. Gnant explained that zolendronic acid is administered by injection once every 6 months, and that a healthy individual would clear the drug from the system in about 24 hours. But the drug persists in bone and changes the bone marrow environment, Dr. Gnant told Medscape Medical News. There is good reason to believe that breast cancer cells collect within the bone marrow, forming a "stem cell sanctuary," particularly in early disease. They can be dormant there, sometimes for years, before they escape and cause breast cancer recurrence, he said. It now appears that zolendronic acid is altering the bone marrow environment in such a way that the breast cancer cells are less likely to escape and cause a recurrence, he said.

Details of AZURE Results

The AZURE study was designed after the positive results from the Austrian trial came out and zolendronic acid began to be used in the wider breast cancer population, Dr. Coleman explained. It was an academic study, he emphasized, conducted in 3360 women from 174 centers worldwide (but mostly in the United Kingdom).

These women had stage II or III breast cancer. Nearly all were treated with adjuvant chemotherapy (93% anthracyclines, 23% taxanes), and some also received endocrine therapy. Half of them were randomized to receive zolendronic acid 4 mg intravenously over 3 to 4 weeks for 6 doses, and then every 3 months for 8 doses and every 6 months for 5 doses.

All of these details are different from the Austrian trial, Dr. Gnant noted, where all of the women were stage I, none received chemotherapy, and zolendronic acid was used once every 6 months.

Dr. Coleman explained that the more intensive administration schedule in AZURE was used because at the time the trial was designed, it was thought that zolendronic acid had a direct anticancer effect.

The differences in dosing schedule might also be related to the fact that osteonecrosis of the jaw, a known adverse effect of bisphosphonates, was not seen in the Austrian study, but was reported in 17 patients (1.16%) in the AZURE trial.

The overall results from AZURE, after a median follow-up of 59 months, show no significant effect from zolendronic acid on either disease-free or overall survival, although there was a positive trend for overall survival.

Significant Effect in Subgroup

However, in a preplanned subset analysis based on menopausal status, zolendronic acid did show a significant effect on overall survival in a subgroup of women (n = 1101) with well-established menopause (more than 5 years postmenopausal), reducing the risk for death by 29%. There were 86 deaths in the zolendronic acid groups, compared with 120 in the other group (hazard ratio, 0.71; P = .017).

There was no significant effect in younger women who were premenopausal or perimenopausal.

"To see a survival advantage like this is quite remarkable, and the difference in outcome between this group and the younger population is unlikely to be a chance finding. We will clearly want to investigate further in this population," he said.

However, he also emphasized that this result came from a subgroup analysis, so it should be considered "hypothesis-generating."

"This was an unexpected finding," he told Medscape Medical News, "and now we have to go back to see why there is an effect when there is no estrogen and why there isn't one when estrogen is present."

Dr. Gnant was more enthusiastic, and highlighted the fact the reduction in death was nearly a third, which is similar to what was reported in the Austrian study. He also pointed out that women who are in established menopause constitute a large part of the breast cancer patient population.

Dr. Coleman, however, was rather reserved in his conclusions. "Adjuvant use of bisphosphonates like zolendronic acid is widespread among women with breast cancer. The results of this trial will help answer many questions, as well as invite new ones," he said.

He also suggested that the latest findings "will likely dissuade clinicians from giving adjuvant bisphosphonates on a routine basis to younger women taking adjuvant chemotherapy because, although the drug is generally well tolerated, there is a small risk of osteonecrosis of the jaw."

Dr. Giordano has disclosed no relevant financial relationships. Dr. Coleman reports consultancy and being on the speakers' bureau for Novartis and Amgen. Dr. Gnant reports consultancy for Novartis, AstraZeneca, and Amgen, and receiving funding from Novartis and AstraZeneca. Dr. Chlebowksi reports being on the speakers' bureau of Novartis and Amgen, and receiving grants from Amgen.

33rd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S4-5. Presented December 10, 2010.

Anonymous · December 2010

Today I went for my Zometa infusion and saw my Onc. I mentioned my concern about the latest studies on Zometa. He said he was glad I asked and I am the only one of his patients who has asked him, and he's been updating them. So here's what he told me. He wants me to remain on it every 6 months because the studies are showing that in post menopausal women who have not had periods for 5 or mor years, it is promising in preventing recurrence. Pre menopausal women it's not so good.

Barb

Zometa - Latest News out of San Antonio Meeting

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