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CONFIDENTIAL

IN PRESS IN ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY. NOT FOR

PUBLICATION OR CITATION

Bisphosphonates and Breast Cancer Prevention

Rowan T. Chlebowski, MD, PhD1; Nananda Col, MD, MPP, MPH, FACP2

1Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA; 2Maine Medical

Center, Portland, ME

Target Journal: Anti-cancer Agents in Medicinal Chemistry

Previous Journal Submission: None

Address correspondence and reprint requests to

Rowan T. Chlebowski, MD, PhD

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center

1124 W. Carson St.

Torrance, CA 90502

Phone: 310-222-2219

Facsimile: 310-320-2564

E-mail: [email protected]

Source(s) of support (in the form of grants, equipment, drugs, or all of these):

Running Title (limit: none): Bisphosphonates in Preventing Breast Cancer

Word Counts:Manuscript (limit 27,000 words) = 3,254Abstract (limit: 250 words) = 219

Number of Figures (limit: none) = 1

Number of Tables (limit: none) = 3

Number of References (limit: none) = 57

BP Anti-cancer RA DRAFT NPC ZOM 6148 2/23/11

ABSTRACT

Bisphosphonates are commonly used in patients with breast cancer to reduce skeletal-related events in

metastatic disease and to mitigate bone loss associated with cancer therapy in early stage disease. In addition,

adjuvant breast cancer trials evaluating the oral bisphosphonate clodronate suggested a reduction in cancer

recurrence, but the findings were mixed, with 2 positive and 1 negative report. In the Austrian Breast and Colorectal

Cancer Study Group (ABCSG) 12 study, adding the intravenous bisphosphonate zoledronic acid to endocrine

therapy in premenopausal breast cancer patients significantly prolonged disease-free survival versus endocrine

therapy alone (hazard ratio = 0.68; p = 0.008) at 62 months, and reduced local, regional, and distant recurrences.

Clinical trial findings from other adjuvant trials (Z-FAST, ZO-FAST), neoadjuvant studies, and studies involving

disseminated tumor cells (DTCs) are generally supportive of the ABCSG-12 conclusion, and recent data from

AZURE suggest the importance of menopausal status. Preclinical studies provide data on the mechanisms of action

that could mediate bisphosphonate direct and indirect anti-cancer effects. Recently, several observational studies (2

cohort studies and 2 case-control analyses) have associated oral bisphosphonate use with a lower breast cancer

incidence. Such reports require cautious interpretation because confounding by indication is an issue:

bisphosphonates are prescribed for women with low bone mineral density, and women with low bone density are at

decreased breast cancer risk.

Key words: adjuvant treatment, anti-cancer, bisphosphonates, early breast cancer, prevention, zoledronic acid

CONFIDENTIAL — Working Draft


INTRODUCTION

Bisphosphonates have come into increasingly common use for preventing and treating osteoporosis [1].

Although the concept that bisphosphonates could also potentially influence breast cancer outcome is actually several

decades old [2], several recent clinical reports have prompted renewed interest in the question of bisphosphonate

impact on breast cancer prevalence in healthy women [3-5].

The potential for bisphosphonates to influence breast cancer outcome has preclinical support (as reviewed

by Winter [6]), with an increasing body of evidence supporting anti-cancer properties for bisphosphonates (as

reviewed by Green and Lipton [7]). These properties include cell apoptosis and proliferation, reduction of

angiogenesis, inhibition of tumor-cell invasion, activation of the immune system against cancer cells, synergy with

anti-cancer agents, as well as bone-mediated effects inhibiting osteoclast activity and preventing the release of tumor

growth factors [8-10]. As a result, adjuvant trials involving zoledronic acid (ZOL) were initiated that target not only

bone mineral density (BMD) maintenance but also breast cancer recurrence and overall survival.



BISPHOSPHONATES AND CANCER TREATMENT-INDUCED BONE LOSS

Interest in the potential of bisphosphonates to reduce not only breast cancer recurrence but also breast

cancer incidence was kindled by results from the more recently reported trials evaluating adjuvant bisphosphonate

treatment in breast cancer. Previously, bisphosphonates such as pamidronate, clodronate, ibandronate, and ZOL

were shown to reduce the risk of skeletal-related events (SREs) in patients with bone metastases. Also, they have

been shown to increase BMD in women with bone loss [11-14]. More recently, aromatase inhibitors (AIs), which

substantially reduce circulating estrogen levels, have been associated with increased fracture risk, and were found to

be superior as adjuvant treatment compared with tamoxifen in postmenopausal women with early stage, hormone-

receptor–positive breast cancer [15]. However, the use of AIs is associated with decreases in BMD and increased

risk of fractures [15]. As a result, interest in mitigating the aromatase inhibitor-associated bone loss (AIBL) with

bisphosphonates emerged. In a series of trials with ibandronate [16,17], risedronate [18,19], and ZOL [20-22], and

the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor denosumab [23], all demonstrated an

ability to prevent and/or reverse AIBL.



BISPHOSPHONATES AND BREAST CANCER RECURRENCES: CLODRONATE TRIALS

Initial clinical studies exploring the potential influence of bisphosphonates on breast cancer outcome were

directed at recurrence and progression. In 1987, Elomaa and colleagues described fewer new metastases after

administration of clodronate in a controlled but not randomized study in patients with breast cancer who had

established bone metastases [2]. The initial study of bisphosphonates in the adjuvant setting was reported by Diel

and colleagues in 1998 [24]. This study randomized 302 women with resected early breast cancer, to the oral

bisphosphonate clodronate (1,600 mg/day) or no bisphosphonate for 2 years. All patients received standard systemic

adjuvant therapy based on country guidelines, which could have included tamoxifen, CMF chemotherapy

(cyclophosphamide, methotrexate, and 5-fluorouracil), and/or goserelin. After 36 months of follow-up, the

clodronate group had a significant reduction in the number of bone metastases (p = 0.003) and distant metastases (p

= 0.003) compared with the control arm. Additionally, there was an overall survival benefit with clodronate (p <

0.001). Long-term follow-up (median, 103 months) demonstrated that only 20% of patients in the clodronate group

had died compared with 41% in the control group (p = 0.04) [25].

In contrast, a second similarly-sized study evaluating adjuvant clodronate reported substantially different

results. Saarto and colleagues examined the effects of clodronate (1,600 mg/day) versus no bisphosphonate for 3

years in 299 women with node-positive, early stage, resected breast cancer [26]. In this study, CMF chemotherapy

was administered to all premenopausal patients and tamoxifen to all postmenopausal patients. No differences in

bone metastasis frequency were reported between the treatment arms. Additionally, overall survival was lower in the

clodronate group (70% vs 83%, respectively; p = 0.009). This negative result is at least partially explained by an

imbalance in treatment patterns as well as estrogen receptor status between the groups (negative receptor status, 35%

vs 23%, respectively, for the clodronate and control groups). As a result of this, at least 12% more women in the

clodronate group received no effective adjuvant therapy, because their cancers most likely would not have

responded to endocrine therapy compared with women in the no-bisphosphonate group, potentially confounding the

study results.

In a third and the largest of the adjuvant clodronate trials, Powles and colleagues randomized 1,079 patients

with early stage breast cancer to standard adjuvant therapy and placebo or clodronate (1,600 mg/day) for 2 years



[27]. They reported a decrease in the incidence of bone metastases during the initial 2 years (p = 0.01) and increased

survival in the clodronate arm after a median follow-up of 5.6 years versus placebo (HR = 0.77, p = 0.048) [28].

Given these divergent clodronate results, the National Surgical Adjuvant Breast and Bowel Project (NSABP) is

currently conducting a fourth trial in which 3,200 early stage breast cancer patients receiving standard adjuvant

therapy have been randomized to placebo or clodronate (1,600 mg/day) for 3 years [29]. Accrual was completed in

March 2004, and results are awaited.



BISPHOSPHONATES AND BREAST CANCER RECURRENCE: ZOLEDRONIC ACID TRIALS

Zoledronic acid has several studies that evaluated disease-free survival (DFS) and breast cancer recurrence

(as reviewed further by Gnant on page X). The ABCSG-12 trial randomized 1,803 premenopausal patients with

early stage breast cancer who all received goserelin 3.6 mg every 28 days plus tamoxifen (20 mg/day) or anastrozole

(1 mg/day), with or without ZOL (4 mg intravenously [IV] every 6 months) for 3 years [4]. Disease-free survival

was the primary endpoint. There was no DFS difference between anastrozole and tamoxifen. However, the women

receiving ZOL experienced significantly improved DFS (HR = 0.64; 95% confidence interval [CI] = 0.46, 0.91; p =

0.01) at 48 months’ median follow-up, and there was also a trend for increased overall survival with ZOL

administration (HR = 0.60; p =.011) [4]. There were also fewer bone metastases, distant metastases, local or regional

recurrences, and contralateral breast cancers with ZOL versus no ZOL.

Other recently reported clinical study results are generally supportive of a favorable association between

ZOL and breast cancer outcome. Three similarly designed randomized trials (Zometa-Femara Adjuvant Synergy

Trials: Z-FAST, ZO-FAST, and E-ZO-FAST) are evaluating upfront versus delayed use of ZOL in postmenopausal

patients with hormone-receptor–positive, early stage breast cancer [30]. These studies randomized patients to the AI

letrozole (2.5 mg/day) together with upfront ZOL (4 mg IV every 6 months) or letrozole together with delayed ZOL

(administered if BMD declined or fracture occurred) for 3 years. In Z-FAST, ZO-FAST, and E-ZO-FAST, upfront

ZOL mitigated loss of BMD associated with letrozole use [20,31]. In an early combined analysis of the Z-FAST and

ZO-FAST trials, upfront ZOL also had a favorable effect on DFS (defined as time to first appearance of breast

cancer recurrence or death from any cause) [3]. Fewer patients receiving upfront ZOL experienced disease

recurrence (7 patients [0.84%]) compared with patients receiving delayed ZOL (17 patients [1.9%]; p = 0.04) [3].

Eidtmann and colleagues have reported similar BMD benefits and a significant improvement in DFS for upfront

versus delayed ZOL (HR = 0.59; p = 0.031 at 36 months) [31]. However, when Coleman and colleagues reported a

combined analysis that included updated results and the similar E-ZO-FAST study [32], a Gail-Simon test was

statistically significant for heterogeneity in treatment effects between studies. Therefore, combining Z-FAST,

ZO-FAST, and E-ZO-FAST study results was felt not to be statistically appropriate [33]. In contrast, Mauri and

colleagues, using a somewhat earlier dataset and incorporating results from ABCSG-12, Z-FAST, ZO-FAST, E-ZO-



FAST, and including an additional small randomized trial, found a significant reduction in breast cancer recurrence

with ZOL use (odds ratio = 0.68; 95% CI = 0.48, 0.95; p = 0.025) [34,35]. As an exploratory analysis for this

commentary, we used updated results from the previously identified ZOL trials to generate a new meta-analysis

(Figure 1) [5,20,31-33,35]. We used MetaAnalyst software (Tufts-New England Medical Center, Boston, MA) to

pool data based on the random effects model of DerSimonian and Laird [36], and found no heterogeneity by

calculating the Q-statistic. Although the overall odds ratio was 0.79 for the risk of DFS events, favoring ZOL, these

pooled analyses did not reach statistical significance. However, duration and type of follow-up varied between these

datasets. It is recognized that 3 trials (Z-FAST, ZO-FAST, E-ZO-FAST) [33] are evaluating early versus delayed

ZOL, and all but 1 dataset [4,5] represent early reports.

Adjuvant treatment with ZOL in patients with breast cancer received additional evaluation in the AZURE

trial (BIG 01/04), and initial results were recently presented at the 2010 San Antonio Breast Cancer Symposium

[37]. The AZURE trial enrolled 3,360 patients with stage II-III invasive breast cancer who had no evidence of

metastases and who had not received prior bisphosphonate therapy during the last year. Participants were

randomized to standard therapy including chemotherapy and or hormone therapy at investigator discretion, or

standard therapy plus ZOL 4 mg at a schedule of every 3 to 4 weeks × 6 doses, then every 3 months × 8 doses, then

every 6 months × 5 doses, thus completing 5 years of therapy. The prospectively defined primary endpoint was

DFS, and secondary endpoints included OS. In the overall population, baseline characteristics, including distribution

of therapy, were well balanced between groups. Notably, more than 95% received adjuvant chemotherapy. At a

median follow-up of approximately 59 months, there was no significant difference in DFS in the overall population

(HR = 0.98; 95% CI = 0.85, 1.13; p = 0.79). However, there was a trend toward improved OS with ZOL versus no

ZOL (HR = 0.85; 95% CI = 0.72, 1.01; p = 0.07).

In pre-planned analyses, there was heterogeneity of ZOL effect on DFS by menopausal status

(heterogeneity p = 0.02) [37]. Among patients who were postmenopausal for > 5 years, ZOL significantly reduced

the risk of DFS events compared with control (HR = 0.76; 95% CI = 0.60, 0.98), and this benefit was not seen in the

remaining participants who were premenopausal, < 5 years postmenopausal, or of unknown status (HR = 1.13; 95%

CI = 0.95, 1.35). Similarly, ZOL significantly reduced the risk of death compared with control among patients who

were postmenopausal for > 5 years or > 60 years of age (HR = 0.71; 95% CI = 0.54, 0.94; p = 0.02). Overall, the



combination of adjuvant therapy plus ZOL was generally well tolerated; however, 17 confirmed cases of

osteonecrosis of the jaw were reported in the ZOL group (1.16%).

The AZURE investigators concluded that adjuvant use of ZOL at this dose and schedule did not improve

DFS in breast cancer patients treated with adjuvant chemotherapy [37]. However, a trend favoring ZOL use for OS

emerged. In addition, heterogeneity of effect by menopausal status suggested that ZOL significantly improved DFS

and OS in those > 5 years from their last menstrual period. These findings, in conjunction with those of ZO-FAST

and ABCSG-12, support the hypothesis that ZOL’s beneficial effect on breast cancer outcomes may be dependent

on a low estrogen concentration in the bone microenvironment.

Other smaller randomized trials have reported on the influence of ZOL on breast cancer. In a neoadjuvant

substudy (n = 205) of the larger Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) clinical trial (N =

3,360), patients with breast cancer randomized to ZOL (4 mg IV with each chemotherapy cycle) had smaller tumors

at resection and increased frequency of pathologic complete response compared with patients who received

chemotherapy alone [38]. In 3 translational studies, ZOL reduced residual cancer burden by reducing disseminated

tumor cells [39-41].



BISPHOSPHONATES AND BREAST CANCER INCIDENCE

Against the background of information such as the ABCSG-12 results presented in 2008, 4 separate groups

decided to conduct analyses of the association between bisphosphonate use in the osteoporosis setting and breast

cancer incidence in observational studies. However, as bisphosphonates are prescribed for women with low BMD, a

potential confounding problem arises. Perhaps because of the correlation between estrogen levels and BMD, women

with bone loss are at substantially lower breast cancer risk [42,43], and bisphosphonate use would be expected to be

associated with lower breast cancer risk because of this correlation. Thus, a means of adjusting for differences in

BMD between bisphosphonate use and non-use is needed, if reliable risk estimates are to be established.

Chlebowski and colleagues were able to address this issue in their analysis in the Women’s Health Initiative

(WHI) cohort of 154,768 postmenopausal women [44]. Of these participants, 10,418 women had a BMD assessment

at study entry as part of a substudy conducted at 4 of the 40 WHI clinical centers. The WHI investigators then

compared a hip fracture prediction score calculated from a validated analytic model, which incorporated clinical

findings but not overall BMD to total-hip BMD, in participants who had both determinations [45]. A strong

statistically significant (p < 0.001) correlation was seen between hip fracture prediction score and BMD. Thus, in a

multivariate analysis, the hip fracture prediction score, which was available in the entire WHI cohort, was used to

adjust for potential BMD differences between bisphosphonate use and non-use. After 7.8 mean years of follow-up,

invasive breast cancer incidence was 32% lower in participants who received bisphosphonates after adjusting for hip

fracture prediction score, menopausal hormone therapy use, and breast cancer risk factors (p < 0.01). Interestingly, a

similar lower incidence of both estrogen-receptor–positive and estrogen-receptor–negative breast cancers was

observed in participants who received bisphosphonates, although the latter association was not statistically

significant. In contrast, the incidence of ductal carcinoma in situ was significantly greater in participants who

received bisphosphonates. The authors concluded that oral bisphosphonate use was associated with significantly

lower invasive breast cancer incidence, suggesting that bisphosphonates may have inhibiting effects on breast cancer

[44].

Two case-control studies examining the association between bisphosphonate use and breast cancer

incidence were also recently reported [46,47]. Newcomb and colleagues, in their analysis of women with breast



cancer and age-matched controls, made adjustments for body mass index and postmenopausal hormone therapy use

[46]. To address potential BMD differences, adjustments were made for adult height loss and reported physician-

diagnosed osteoporosis. These variables would likely allow incomplete adjustment for BMD differences because

height loss is a late finding in the course of bone loss, and physician-reported osteoporosis would not account for

women not seeking assessment of their BMD. Nevertheless, the incidence of breast cancer was decreased with

bisphosphonate use versus no bisphosphonate use (4.4% vs 6.2%, respectively; odds ratio = 0.67; 95% CI = 0.51,

0.89) [46]. In the case control study of Rennert and colleagues, body mass index and breast cancer risk factors were

incorporated in the analyses, but no variables allowing for more direct adjustment of BMD differences were

available [47]. This study also reported fewer breast cancer cases in patients who received bisphosphonates (odds

ratio = 0.72; 95% CI = 0.57, 0.90).

An additional cohort study provides somewhat mixed results. From Danish registers, Vestergaard et al

collected records for 87,104 female bisphosphonate recipients; each patient in this cohort was compared with 3 age-

matched controls from the general population who were not receiving bisphosphonates (n = 261,322) [48].Reduced

risk of breast cancer was observed after patients initiated alendronate (HR = 0.53; 95% CI = 0.38, 0.73) or etidronate

(HR = 0.80; 95% CI = 0.73, 0.89). However, as no dose-response relationship was seen with the 2 agents, the

authors concluded that “no causal relationship seemed to be present” [48]. No adjustment for potential BMD

difference was made in this analysis. The comparable findings of the 3 observational studies and the 1 study with

somewhat mixed results are outlined in Table 1 [44,46-48].



ADJUVANT BISPHOSPHONATE CLINICAL TRIALS ANALYZING FOR BREAST CANCER

PREVENTION

Despite the promising results cited above, it will likely be difficult to conduct a full-scale bisphosphonate

primary prevention study given the current broad use of bisphosphonates for bone health indications, especially in

the United States. However, the ongoing randomized clinical studies using bisphosphonates in the breast cancer

adjuvant therapy setting provide an opportunity to evaluate bisphosphonate influence on contralateral breast cancer

as a surrogate for primary breast cancer risk reduction. In addition to the previously reported ABCSG-12 trial, 4

additional randomized trials are evaluating ZOL in a variety of schedules for patients with early stage resected breast

cancer (AZURE, SUCCESS, SWOG 0307, and NATAN) [5,49,50]. These adjuvant trials will enroll more than

14,000 breast cancer patients and provide ample opportunity to assess clodronate, ibandronate, and ZOL influence

on contralateral breast cancer development (Table 2) [5,49,50].

There are also 3 phase III trials evaluating other antiabsorptives versus placebo in early breast cancer

(Table 3) [5,49,50]. The NSABP B-34 study randomized 3,323 patients with early stage, resected breast cancer

receiving standard adjuvant therapy to placebo or oral clodronate (1,000 mg/day) [29]. The German Breast Group

(GBG) trial 33 (GAIN) will randomize 3,000 patients with node-positive stage II-III breast cancer receiving

standard adjuvant therapy to either oral ibandronate or placebo [50]. ABCSG-18 (NCT00556374) is randomizing

3,400 postmenopausal women with endocrine-responsive breast cancer and adjuvant aromatase inhibitor treatment

to receive either placebo or the RANKL inhibitor denosumab. Finally, the D-CARE trial is in the process of

randomizing 4,500 patients with early stage breast cancer receiving standard adjuvant therapy to either placebo or

denosumab [51].



CONSIDERATIONS WITH BISPHOSPHONATE USE IN BREAST CANCER PREVENTION

Although preclinical and clinical results suggest that several bisphosphonates may influence breast cancer

outcome, a question can be raised regarding whether a bisphosphonate class effect will emerge. Only 1 of the

previously presented studies involves an active comparison of different bisphosphonates (SWOG 0307, comparing

ZOL, clodronate and ibandronate). However, in a phase III trial in multiple myeloma, patients with stage I, II, or III

disease were randomized to either ZOL (4 mg every 3 to 4 weeks) or daily oral clodronate. Patients who received

ZOL had significantly longer (p = 0.01) survival than patients who received clodronate, suggesting that differences

may also emerge in the breast cancer setting [52].

Despite the range of potential mediating mechanisms identified in preclinical studies, the well-described

influence on bone turnover could be a major factor in the observed bisphosphonate influences on breast cancer

incidence and outcome. In this regard, it is noteworthy that the 2 agents approved for breast cancer risk reduction in

the United States, tamoxifen and raloxifene, both result in reduced bone turnover [53-55]. As bisphosphonates and

selective estrogen receptor modulators share this common bone influence, their relative influence on breast cancer

outcomes will be addressed in ongoing trials. In ABCSG-12, early results suggest that ZOL may add to tamoxifen’s

favorable influence on breast cancer DFS [5].

Finally, bisphosphonates are not free of risk, with the potential for renal toxicity [13], osteonecrosis of the

jaw [56], and, rarely, atypical femoral fractures [57]. Oral bisphosphonate are commonly associated with

gastrointestinal problems [13]. The ongoing, full-scale, randomized, controlled bisphosphonate adjuvant trials will

provide important information regarding the risk-to-benefit ratio of moderate-term bisphosphonate use to influence

breast cancer outcome.



CONCLUSIONS

In randomized adjuvant breast cancer trials, ZOL likely reduces breast cancer recurrence risk, suggesting

breast tumor inhibitory effects. Preclinical studies provide several potential mechanism of action for the direct breast

tumor inhibitory effects of bisphosphonates (as reviewed by Clezardin on page X). Three recent observational

studies provide consistent reports associating bisphosphonate use with lower breast cancer incidence, but 1 cohort

study reported somewhat inconsistent findings. Ongoing randomized clinical trials evaluating bisphosphonates and

other antiresorptive agents may provide more definitive evidence regarding bisphosphonate use and breast cancer

incidence based on contralateral breast cancer findings.



LIST OF ABBREVIATIONS

ABCSG = Austrian Breast and Colorectal Cancer Study Group

AI = aromatase inhibitor

AIBL = aromatase inhibitor-associated bone loss

AZURE = Adjuvant Zoledronic Acid to Reduce Recurrence

BMD = bone mineral density

CI = confidence interval

CLO = clodronate

CMF = cyclophosphamide, methotrexate and 5-fluorouracil

DFS = disease-free survival

DOC = docetaxel

FEC = 5-fluorouracil, epirubicin, cyclophosphamide

GBG = German Breast Group

GEM = gemcitabine

IBAN = ibandronate

IV = intravenous(ly)

NSABP = National Surgical Adjuvant Breast and Bowel Project

OR = odds ratio

RANKL = receptor activator of nuclear factor kappa B ligand

SWOG = Southwest Oncology Group

WHI = Women’s Health Initiative

Z-FAST, ZO-FAST, E-ZO-FAST = Zometa-Femara Adjuvant Synergy Trials

ZOL = zoledronic acid



CONFLICT OF INTEREST

Rowan Chlebowski is a consultant for Novartis and on their speakers bureau. He also is a consultant for Amgen and

has grant funding support from that company.

ACKNOWLEDGMENTS

Financial support for formatting assistance was provided by Novartis Pharmaceuticals. Dr. Chlebowski takes

responsibility for the content of the manuscript. He provided the initial draft of the manuscript and provided critical

revisions of the manuscript for important intellectual content. We thank ProEd Communications, Inc., for their

assistance with formatting and submitting this manuscript.



REFERENCES



FIGURE LEGEND

Figure 1. Risk of disease-free survival (DFS) events between zoledronic acid and control groups in recent trials

[5,20,31-33,35]. Disease-free survival was defined as breast cancer recurrence or death from any cause. Squares

represent odds ratio with the size proportional to the trial size. The 95% confidence intervals (CIs) are represented

by horizontal bars. Odds ratios < 1 favor zoledronic acid. Abbreviations: ABCSG, Austrian Breast and Colorectal

Cancer Study Group; Z-FAST, ZO-FAST, E-ZO-FAST, Zometa-Femara Adjuvant Synergy Trials.



TABLES

Table 1. Association Between Bisphosphonate Use and Breast Cancer Incidence in Observational Studies

Study Study Design Breast Cancer Association (95% CI)

Rennert G, et al [47] Case-control OR = 0.72 (0.57, 0.90)

Newcomb PA, et al [46] Case-control OR = 0.67 (0.51, 0.89)

Chlebowski RT, et al [44] Cohort HR = 0.68 (0.52,0.88)

Vestergaard P, et al [48] Cohort HR = 0.53 (0.38, 0.73), alendronate; HR = 0.80 (0.73, 0.89), etidronate; but no dose-response relationship seen

Abbreviations: CI, confidence interval; HR, hazard ratio; OR, odds ratio.



Table 2. Randomized Clinical Trials Evaluating Zoledronic Acid (ZOL) in Women With Early Stage Breast Cancer

Trial Patients, n Treatment Arms Primary Endpoint

ABCSG-12 [5] 1,803 (stage I, II)

TAM; ANA; TAM + ZOL; ANA + ZOL

DFS at 5 yr

AZURE [49] 3,360 (stage II, III)

Standard therapy ± ZOL DFS at 5 yr

SUCCESS [50] 3,754 (stage I, II, III)

FEC + DOC then endocrine therapy + ZOL; FEC + DOC + GEM then endocrine therapy + ZOL

DFS at 5 yr

SWOG-0307 [50] 4,500 (stage I, II, III)

ZOL; CLO; IBAN DFS at 3 yr

NATAN [50] 654 (stage II, III)

Standard therapy ± ZOL EFS at 5 yr

Abbreviations: ABCSG, Austrian Breast and Colorectal Cancer Study Group; ANA, anastrozole; AZURE, Adjuvant Zoledronic Acid to Reduce Recurrence; CLO, clodronate; DFS, disease-free survival; DOC, docetaxel; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; GEM, gemcitabine; IBAN, ibandronate; SWOG, Southwest Oncology Group; TAM, tamoxifen.



Table 3. Randomized Clinical Trials Evaluating Clodronate, Ibandronate, and Denosumab in Women With Early Breast Cancer

Trial Patients, n Treatment Arms Primary Endpoint Status

NSABP-B34 [29] 3323 (stage I, II)

Clodronate vs placebo

DFS Active, not recruiting

D-CARE [51] 4500 (stage II, III)

Denosumab vs placebo

BMFS Recruiting

GAIN GBG33 [50] 3000 (stage II, III)

Ibandronate vs placebo

DFS Recruiting

Abbreviations: BMFS, bone-metastases–free survival; DFS, disease-free survival; GBG, German Breast Group; NSABP, National Surgical Adjuvant Breast and Bowel Project.


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