Voracious,

No, Gnant's study clearly states:

Among patients > 40 yr of age (n = 1,390) with presumed complete ovarian blockade, ZOL significantly reduced the risk of DFS events by 34% (HR = 0.66; Cox P = .014) and the risk of death by 49% (HR = 0.51; Cox P = .020); however, there were no significant DFS or OS benefits in patients <40 yr of age. 

http://www.sabcs.org/PressReleases/Documents/Gnant.pdf (the details come after the press release part.) 

The overall population benefitted, but when you separate out the olders and youngers, the youngers did not benefit (meaning the benefits of the olders were overwhelming the non-benefits to the youngers.) 

In other words... The results were STATISTICALLY significant for everyone... However, they "presume" that the 40 year and older women had an even better response because they think they had a more complete estrogen shutdown.

I think if the under 40 crowd had no statistical benefit it would have said that in the first paragraph. That's also why they are referring to the more complete ovarian shutdown of the women over 40. The under 40 women had some benefit, but NOT significant and they surmise that the reason why the over 40 year old women did overwhelming better was due to the O/S doing a better job. I think you need to put all the pieces of the press release together because it is so poorly written.

Also.... If you read the last paragraph the conclusion says the protocol should be given to ALL early stage ER+ women. It doesn't say just to the over 40 women..

Beep... I agree we have to look closer at the details. But if you look at what we have right now... The conclusion says for women over 40.. The data is "highly" significant. The under 40 crowd are benefitting too! I believe this is positive knews for ALL ER + women!

Voracious,

We'll have to agree to disagree.

From this, and the other studies out there on Zometa, there's no evidence that it helps very young women with breast cancer. In fact, the AZURE trial showed that premenopausal women taking zometa did *worse* than those who did not get it. And that trial was much larger (and most of the women had chemo first).

Also, in this trial, none of the women got chemo. That's pretty significant. It may be that OS + tam or AI + zometa is better than OS with tam or AI but not Zometa (which is exactly the design of Gnant's study), but not better than chemo + hormonal therapy. That's an important question to address (not sure if it has been or if there are ongoing trials?)

Anyway, if I were a 30-something diagnosed with ER+ breast cancer tomorrow, depending on my nodal status, I would go with chemo + hormonals, but not zometa. The evidence just isn't there that it would help that person! Wish it would.

P.S. I took Statistics in college too. 

I would love to hear our oncs weigh in on this one. But I won't see mine for awhile. If anyone else is going to, please let us know what they say!

Beeb, I have an appointment with my MO on Monday, and I will definitely ask for his take. 

For anyone reeeeeaaaaalllllyyyy interested in this topic, here's a podcast where the head of the AZURE trial, and Gnant, and a few other experts discuss their seemingly conflicting results.

The downloadable powerpoint slides are really interesting too:

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

Upshot: Zometa seems to prevent some BC recurrences and deaths in very low estrogen environments, which are not achievable by very young women (unless they have an ooph, maybe?). Secondly, it isn't clear that Zometa adds any benefit for women who've had chemotherapy.

http://www.youtube.com/watch?v=twlFII2YtBo

Above is a recent video of Coleman discussing AZURE.

Thanks for the additional videos, Voracious.

What concerns me about the AZURE update video is that Coleman reports that Zometa actually had an *adverse* effect on younger women. Meaning they actually did worse in terms of disease-free and overall survival if they got Zometa. 

Also, as an aside, I've heard that women who hope to become pregnant should be cautious about taking bisphosphonates, because it can affect the developing bones of a fetus, even years after you take it. 

Can We Predict Who's at Risk for Developing Bone Metastases in Breast Cancer?Larissa A. Korde and                      Julie R. Gralow⇓+ Author AffiliationsUniversity of Washington School of Medicine, Seattle, WACorresponding author: Julie R. Gralow, MD, University of Washington/Seattle Cancer Care Alliance, 825 Eastlake Avenue East,                        G3-630, Seattle, WA 98116, 206-288-7722 (206-288-2054); e-mail: pink@u.washington.eduBone metastases are common in patients with advanced breast cancer. Bone is the first site of distant disease in 25% to 40%                  of patients with metastatic breast cancer, and up to 60% to 80% of patients with recurrent breast cancer eventually show evidence                  of skeletal involvement.¹ The process of breast cancer metastasis, including tumor cell seeding, tumor dormancy, and metastatic growth, is only partly                  understood. Circulating breast cancer cells have been shown to demonstrate affinity for bone and exhibit chemotactic responses                  to areas of bone undergoing resorption.² Disseminated tumor cells have been reported in the bone marrow of 30% to 40% of patients with early-stage breast cancer at                  the time of diagnosis.³ The majority of these disseminated tumor cells die, but some are capable of micrometastatic proliferation or remain dormant,                  only to grow later. The development of established bone metastases involves complex, reciprocal interactions between cancer                  cells and the bone microenvironment, with a resultant vicious cycle of tumor cell growth and bone destruction.⁴ The rich supply of mitogenic factors released during bone resorption can lead to increased survival and proliferation of                  disseminated breast cancer cells.⁵ It is possible that elevated rates of bone remodeling during early breast cancer growth and dissemination could increase                  the risk of bone metastases, and that adjuvant antiosteoclast therapy, through reduction of bone turnover and interference                  with tumor cell-bone microenvironment interaction, could decrease cancer recurrence. Based in part on this hypothesis, several                  large, randomized clinical trials of adjuvant osteoclast-targeted therapies have been undertaken in early-stage breast cancer,                  with conflicting results reported to date and no definitive conclusion as to which patients might benefit from such a strategy.^6-11 A better understanding of the interaction between breast cancer, bone turnover, and the skeletal microenvironment could provide                  useful insights in determining which patients and which cancers are at increased risk for developing bone metastasis, and                  in tailoring therapy to prevent or reduce the occurrence of bone metastases.               Several studies have explored patient and primary tumor factors associated with bone-specific distant recurrence in breast                  cancer. Disseminated tumor cells found in the bone marrow of patients with early-stage breast cancer without other clinically                  detectable metastatic disease appear to have prognostic importance, but these patients do not appear to be at higher risk                  of future bone recurrence versus all sites of relapse.^3,12-15 The International Breast Cancer Study Group analyzed recurrence data in over 6,000 patients treated in seven adjuvant breast                  cancer trials to identify patients at high risk for bone metastases.¹⁶ Factors associated with higher rates of bone recurrence included higher numbers of involved lymph nodes, larger tumor size,                  and tumor estrogen receptor (ER) expression. In a study of the distribution of organ site-specific relapse within the intrinsic                  breast cancer molecular subtypes, an association was seen between the ER-positive luminal subtypes and bone as a site of relapse.¹⁷ Interestingly, when bone relapse occurred in the human epidermal growth factor receptor 2 subtype, the genes upregulated                  were entirely different from those in luminal tumors, suggesting that metastasis to bone occurs via different processes in                  different intrinsic subtypes. In addition to ER, many genes and proteins associated with the primary tumor have been studied                  as predictors of bone metastasis, including parathyroid hormone-related protein and its receptor, osteopontin, ostenectin,                  several interleukins including IL-8, receptor activator of nuclear factor kappa beta (RANK) and RANK ligand, C-X-C chemokine                  receptor type 4, bone sialoprotein, tumor cell surface integrins, and Fas/Fas-ligand.^16-32 Recently, several groups have published microarray multigene expression profiles that are predictive for bone metastases                  in breast cancer.^33-35 We are clearly gaining an increased understanding of factors associated with osteotropic metastases in early-stage breast                  cancer, but there is still no validated, reliable marker or assay to predict an elevated risk of future bone metastasis.               Biochemical markers of bone turnover, released as a result of normal bone maintenance and repair as well as malignant bone                  involvement, can provide insight into ongoing rates of bone metabolism.³⁶ Bone markers have the potential for use in assessing overall skeletal health, osteoporotic fracture risk, and monitoring                  response to antiresorptive therapies in managing osteoporosis.³⁷ In patients with cancer, markers of bone turnover have been evaluated in screening for development of bone metastases, predicting                  risk of skeletal-related events and survival in patients with bone metastases, and monitoring response to antiosteoclast therapy.^38-41 Several serum and urine tests for bone resorption and formation have been used to evaluate and follow bone remodeling activity.                  Most markers of bone metabolism have diurnal, and in some cases seasonal, variations. Many are significantly influenced by                  sex, age, and renal function, and most bone resorption markers are increased in postmenopausal women with osteopenia or osteoporosis.⁴²Based on preclinical studies demonstrating that increased bone resorption creates an environment that promotes growth of breast                  cancer cells, and that substances released from resorbing bone have a chemotactic effect on these tumor cells, it has been                  hypothesized that circulating markers of bone turnover may help identify patients with early-stage breast cancer at increased                  risk for development of bone metastasis.^2,5 In an early study of this association, Diel et al⁴³ showed a relationship between high preoperative serum levels of bone sialoprotein and the future development of bone metastases.                  In the article that accompanies this editorial, Lipton et al⁴⁴ ask whether it is possible to identify a subset of patients with breast cancer with a predilection to bone as a first site                  of distant recurrence by using a serum assay for the carboxyterminal peptide of type I collagen (CTx), a marker of bone turnover                  released during bone resorption. The authors examined the association between CTx and bone as a first site of relapse on the                  National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) adjuvant phase III MA.14 study. Six hundred sixty-seven                  postmenopausal patients with stage I/II, predominantly ER-positive breast cancer enrolled on the MA.14 study between 1996                  and 2000, and were randomly assigned to adjuvant tamoxifen alone or in combination with octreotide. The study reported no                  benefit in event-free or recurrence-free survival for the addition of octreotide to tamoxifen.⁴⁵ In order to explore whether increased bone resorption creates an environment that promotes development of breast cancer bone                  metastases, serum CTx concentrations before initiation of endocrine therapy were determined for 621 of 667 patients. Ninety-two                  patients (15%) were found to have elevated bone resorption, as determined by high serum CTx levels. At 8 years of follow-up,                  there were a total of 123 relapses (approximately 20% of patients), of which 19 (3.1% of patients, 15% of recurrences) were                  within the bone only, and 47 (7.5%) were within bone plus other sites. The investigators report that higher serum CTx predicted                  for bone-only relapse, but not for bone plus other sites of recurrence, or relapse in general.               While this study is interesting and hypothesis-generating, the strength of the findings is limited by several factors. The                  number of patients with bone-only relapse was quite small, and the number of patients with elevated serum CTx was much larger,                  indicating that many patients with elevated CTx did not relapse in the bone. Because the NCIC MA.14 study did not require                  evaluation of site of recurrence in a systematic way at the time of relapse (by mandating bone scans in all relapsed patients,                  for example), the strength of the classification of recurrence sites is limited. For the group categorized as having relapse                  in "bone plus other sites," it's not clear how many had bone-predominant disease (with perhaps minimal additional distant                  or locoregional disease) and how many had visceral-dominant disease (with minor bone involvement). These are likely different                  groups of patients. Elevated bone resorption at the time of study entry, as reflected in baseline serum CTx levels, could                  have been due to normal physiologic forces associated with bone loss, such as osteoporosis, or alternatively it could have                  been due to early bone metastases. Evaluation for metastatic disease at the time of trial enrollment included a chest x-ray                  and routine blood work, and did not include a specific bone metastasis work-up. Osteoporosis and bone density were not specifically                  assessed at baseline or while on study, and data on bisphosphonate use, which was permitted at enrollment and during follow-up                  and which could have affected CTx level, was not collected by the study.               If validated in future studies, the exciting possibility suggested by Lipton et al⁴⁴ that elevated bone turnover markers can predict which patients with early-stage cancer are at increased risk for bone-specific                  relapse could lead to the selective addition of antiresorptive therapies to the adjuvant breast cancer treatment plan. Bisphosphonates                  and RANK ligand inhibitors have been shown to reduce both normal physiologic bone loss in osteoporotic patients, and cancer                  treatment-related bone loss in postmenopausal patients with breast cancer receiving aromatase inhibitor therapy and premenopausal                  women undergoing ovarian suppression or experiencing chemotherapy-induced premature ovarian failure.^46-55 In patients with breast cancer with established bone metastases, these antiosteoclast therapies can reduce complications                  of malignant bone involvement, including the incidence of skeletal-related events.^56-61 In early-stage breast cancer, conflicting data from several randomized clinical trials suggest that adjuvant bisphosphonate                  treatment may reduce recurrence risk, at least in a subset of patients.^6-11 Recent reports suggest that adjuvant bisphosphonate benefit may be restricted to women with the lowest estrogen state, those                  who are most likely to have the highest rates of ongoing physiologic bone resorption at the time of their breast cancer diagnosis                  and treatment. The promising, yet somewhat contradictory, results of three older adjuvant clodronate studies suggested that                  bisphosphonates might impact disease recurrence, but were inconclusive.^6-8 More recent results from several large adjuvant trials of zoledronic acid have also been conflicting. The Austrian Breast                  Cancer Study Group (ABCSG) -12 study investigated the adjuvant use of zoledronic acid in premenopausal patients with ER-positive                  breast cancer receiving ovarian suppression for 3 years in combination with either tamoxifen or anastrozole. The study reported                  an improvement in disease-free survival in the group receiving zoledronic acid (given every 6 months for 3 years), in addition                  to favorable benefits on bone mineral density.^10,53 Interestingly, and somewhat contrary to the hypothesis that adjuvant bisphosphonates would preferentially reduce bone-specific                  metastases, the ABSCG-12 study reported decreases not only in bone but also in visceral and locoregional recurrences, as well                  as contralateral disease. While the primary mechanism of action of bisphosphonates is on the osteoclast, there is some evidence                  of direct antitumor effects of amino-bisphosphonates in laboratory models.⁶² A recent subgroup analysis of ABCSG-12 suggested that the disease-free survival benefit of adjuvant zoledronic acid appeared                  to be driven by patients who were older than 40 years of age. Although all patients got ovarian suppression in this study,                  patients older than 40 years at baseline likely achieved more substantial estrogen deprivation, which would be expected to                  be associated with more significant rates of bone loss.⁶³ The Zometa-Femara Adjuvant Synergy Trials (Z-FAST, ZO-FAST, and EZO-FAST) enrolled postmenopausal women with ER-positive                  tumors receiving letrozole, an aromatase inhibitor known to increase bone loss due to its antiestrogen effects, and randomized                  to immediate versus delayed zoledronic acid. A combined analysis showed lower recurrence rates in the group receiving upfront                  zoledronic acid.¹¹ The large, phase III Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer (AZURE) study randomly assigned                  women with stage II or III breast cancer receiving standard adjuvant therapy to zoledronic acid or not for 5 years, given                  at a more intensive dosing schedule than that used in ABSCG-12.⁹ For the overall study population there was no significant difference in disease-free or overall survival in the two study                  arms. In a planned subset analysis, women who were older than 60 years of age or known to be postmenopausal for longer than                  5 years had a significant improvement in overall survival with the addition of zoledronic acid. This supports the hypothesis                  that adjuvant bisphosphonates might be most effective at reducing breast cancer recurrence in a low estrogen, high bone resorptive                  environment. We await the results of several additional large, randomized trials of adjuvant bisphosphonates and the RANK                  ligand inhibitor, denosumab. The Southwest Oncology Group (SWOG) S0307 trial, comparing adjuvant clodronate, ibandronate,                  and zoledronic acid in patients with early-stage breast cancer, collected baseline serum and primary tumor blocks for correlative                  studies aimed at defining who is at risk for developing bone metastases and most likely to benefit from adjuvant bisphosphonate                  therapy. This study, and others soon to report, will provide additional information to help us better understand the relationship                  between breast cancer cells, the bone microenvironment, and antiosteoclast therapy.               The hypothesis and data presented by Lipton et al⁴⁴ are intriguing. While it is unlikely that a single marker will hold all the answers, this study highlights the possibility                  of moving toward a more tailored approach to predicting metastatic behavior. Data presented in this study do not conclusively                  tell us that we should be using bone turnover markers at the time of breast cancer diagnosis to define the anticancer treatment                  plan. There is no question, however, that many patients with breast cancer are at increased risk of bone loss due to their                  age and menopausal status, as well as their anticancer therapies, leading to increased rates of osteoporosis and associated                  fracture. That fact, in and of itself, is reason enough to monitor and maintain the bone health of our patients with early-stage                  breast cancer, including assessment of bone mineral density, supplementation with adequate calcium and vitamin D, and, in                  selected cases, initiation of antiresorptive drug therapy.⁶⁴There is complicated interplay between breast cancer cells and the bone microenvironment. Accurately teasing out which patient                  and tumor characteristics can be used to predict who is likely to recur in the bone, and which patients are most likely to                  benefit from bone-targeted therapy, will require more complex analyses. If adjuvant bisphosphonates and other antiosteoclast                  therapies are found to be effective in reducing bone recurrences in breast cancer, they will likely be of benefit in only                  a subset of patients, since the majority of women with early-stage breast cancer will not develop bone or other distant metastases                  and will not die of their disease. Identifying predictors of bone metastases will allow for selective use of bone-targeted                  therapy in patients who would benefit from them most, while avoiding the adverse effects and cost in patients unlikely to                  benefit. We are entering an era in which we will be increasingly tailoring therapy to individual tumor and patient characteristics.                  Identifying which patients and which tumors are at highest risk for bone recurrence holds great promise in the management                  of early-stage breast cancer.               Next SectionAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAlthough all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest                        that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those                        for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description                        of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author                        Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Larissa A. Korde, Amgen; Julie R. Gralow, Amgen, Roche, Novartis Expert Testimony: None Other Remuneration: None                  Previous SectionNext SectionAUTHOR CONTRIBUTIONS

Voracious, 

You say "Then he goes on to say, "IN GENERAL," which I believe is referring to the entire group, "THE OVERALL SURVIVAL IS EXCELLENT....""

I agree that he is referring to the entire group, but my interpretation is that he is saying the overall survival is good for early stage patients using only hormonal treatment with or without Zometa, so maybe women in this group do not need chemo. I'd likely agree.

The question I'm getting at is simply, does Zometa help women under 40, and all the available data thus far says: No, it does not (whether they get chemo or instead only do ovarian suppression + tam or AI). Wish it were different.  

beeb...To answer your question, "Does Zometa help women under 40?"  The answer is, "Yes...BASED ON GNANT'S STUDY...just NOT AS MUCH AS WOMEN OVER 40."

So, if you are Stage 1 or 2 and DID NOT RECEIVE CHEMO AND you are ER+ and are doing Tamoxifen or an AI, AND doing ovarian suppression and taking Zometa 2X a year for three years, you will benefit. 

JSwan... That is a great question. Folks like you and I, who don't have traditional type of bc often wonder if the data applys to our specific types. At first blush, that type of data isn't usually broken down. Usually in retrospective analysis we get our answers. You might try doing a search at pubmed.org to see if there is some data. I'd be curious to know.