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Breast Cancer

Zoledronic Acid and Survival in Breast Cancer Patients with Bone Metastases and Elevated Markers of Osteoclast Activity

^aMilton S. Hershey Medical Center, Penn State Cancer Institute, Hershey, Pennsylvania, USA; ^bUniversity of Waterloo, Department of Statistics and Actuarial Science, Waterloo, Canada; ^cJuravinski Cancer Centre, Hamilton, Canada; ^dMassachusetts General Hospital Cancer Center, Boston, Massachusetts, USA; ^eUniversity of Sheffield, Weston Park Hospital, Cancer Research Centre, Sheffield, United Kingdom

Key Words. Biologic markers • Breast neoplasms • Survival rate • Zoledronic acid

Correspondence: Allan Lipton, M.D., Milton S. Hershey Medical Center, Penn State Cancer Institute, 500 University Drive, Hershey, Pennsylvania 17033, USA. Telephone: 717-531-5960; Fax: 717-531-5076; e-mail: alipton{at}psu.edu

Received March 28, 2007; accepted for publication June 28, 2007.

Disclosure: R.J.C. has acted as a consultant to and performed contract work for Novartis Pharmaceuticals Corporation.P.M. has acted as a consultant to Novartis Oncology. M.R.S. has acted as a consultant to and has a financial interest in Novartis Oncology. R.E.C. has acted as a consultant to and has a financial interest in Novartis. A.L. has acted as a consultant to Novartis, Merck, Amgen, and GlaxoSmithKline, and he has a financial interest in Novartis, Amgen, and Pfizer.

	Learning Objectives

Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

 
After completing this course, the reader will be able to:

1. Describe the benefits of bisphosphonate treatment in patients with bone metastases from breast cancer.
   
2. Summarize the association between decreases in elevated urinary NTX levels during the first 3 months of zoledronic acid treatment and clinical outcomes such as survival, time to disease progression, and time to first SRE.
   
3. Describe the association, if any, between bone marker levels and an impending SRE.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

 
Objective. Most breast cancer patients with bone metastases will receive bisphosphonate treatment. This post hoc analysis investigated whether early normalization of urinary N-telopeptide of type I collagen (NTX) levels during bisphosphonate therapy correlates with a long-term reduction in skeletal-related event (SRE) risk and mortality in patients with breast cancer.

Methods. This was a retrospective subset analysis of a phase III randomized trial comparing i.v. zoledronic acid with pamidronate treatment in patients with bone metastases from breast cancer or multiple myeloma. Patients with breast cancer who had NTX assessments at baseline and at months 1 and 3 (n = 342) were classified as normal (NTX <64 nmol/mmol creatinine) or elevated (NTX 64 nmol/mmol creatinine). The relative risk for an SRE or death was estimated with Cox regression models.

Results. Among the 328 evaluable patients treated with zoledronic acid, 196 patients (59.7%) had elevated baseline NTX, with 149 of those patients (76.0%) having normalized NTX levels and 31 patients (15.8%) having persistently elevated NTX levels at 3 months. The normalized NTX group had significantly lower risks for a first SRE, a first fracture or surgery to bone, or death than the group that had persistently elevated NTX levels.

Conclusions. These results suggest that early normalization of elevated baseline NTX while receiving zoledronic acid is associated with longer event-free and overall survival times compared with persistently elevated NTX. Further analyses in cancer patients with elevated marker levels are warranted to confirm the implications of these findings.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

 
Bone metastases are common in patients with advanced breast cancer. In a retrospective study of breast cancer patients, bone was the most common site of metastatic spread (70% of patients) [1]. The median survival duration after the diagnosis of bone metastases is approximately 2 years, and survival may increase with new treatment regimens [2]. Bone metastases are associated with skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, the need for palliative radiation therapy to bone, and hypercalcemia of malignancy. These complications may substantially reduce a patient's quality of life [3].

Malignant bone disease is typically associated with marked increases in bone metabolism. Clinical studies have suggested that levels of bone resorption markers, especially N-telopeptide of type I collagen (NTX), correlate with the presence and extent of bone metastases [4, 5]. Small preliminary studies in patients with bone metastases have suggested that normalization of NTX levels during bisphosphonate treatment is associated with palliative responses [6], a significant lower rate of bony disease progression [7], and a trend for a lower incidence of fractures [7]. Exploratory analyses of three large, randomized phase III trials of zoledronic acid in patients with multiple myeloma or bone metastases from breast cancer, prostate cancer, or other solid tumors have provided further evidence of the prognostic value of bone markers. In these analyses, NTX and bone-specific alkaline phosphatase (BALP) levels were shown to significantly correlate with clinical outcomes, including SREs, disease progression, and death [8, 9]. Therefore, among cancer patients with bone metastases and elevated NTX levels, normalization of NTX may have prognostic value for the clinical benefit of zoledronic acid treatment.

Over the past decade, zoledronic acid has become the most widely used i.v. bisphosphonate for the treatment of bone metastases in patients with breast cancer. Additionally, a recent Cochrane review found that, among approved bisphosphonates, zoledronic acid was the most effective in patients with metastatic breast cancer [10].

The primary objective of the present study was to assess the association between the normalization of elevated baseline NTX and clinical outcomes, including event-free and overall survival, in breast cancer patients treated with zoledronic acid. This analysis aims to provide insight into the clinical meaning of early changes in NTX levels.

	PATIENTS AND METHODS

Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

 
Patients and Study Design
Protocol 010 was a randomized, international, multicenter phase III trial comparing zoledronic acid with pamidronate that included 1,130 patients with bone metastases from breast cancer (online supplementary Figure 1) [11]. Zoledronic acid (Zometa®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, and Novartis Pharma AG, Basel, Switzerland; 4 mg or 8 mg via a 15-minute infusion) and pamidronate (Aredia®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, and Novartis Pharma AG, Basel, Switzerland; 90 mg via a 2-hour infusion) were administered every 3–4 weeks for up to 24 months. During the course of the trial, the 8-mg zoledronic acid dose was reduced to 4 mg to ensure renal safety in all patients. Details of this study design have been published previously [11]. All patients provided written informed consent, and the protocol was conducted in accordance with the review boards of the participating institutions and with the Declaration of Helsinki. Bone marker analyses were performed in a substudy of this trial that included all patients enrolled in the U.S. and Canada. This post hoc analysis included only the subset of patients with breast cancer who were treated with zoledronic acid and had NTX and BALP assessment information at baseline, month 1, and month 3 available.

Study Assessments
The primary endpoint of study 010 was the proportion of patients who developed an SRE (defined as a pathologic fracture, surgery to bone to treat or prevent an impending fracture, palliative radiation therapy to bone, or spinal cord compression). Secondary endpoints included time to first SRE, time to progression of disease in the skeleton, and survival. Assessments included radionuclide bone scans and bone radiographic surveys; these assessments were performed at baseline and repeated quarterly throughout the study. Disease progression in bone was defined as the appearance of any new bone lesions or the progression of existing bone metastases. The present analyses were restricted to patients who had complete bone marker assessments (NTX and BALP) over the first 3 months. Only deaths occurring on study were considered. Clinical parameters throughout the 25-month trial were included in the current analysis.

Biochemical markers of bone metabolism, including urinary NTX levels, were assessed at baseline and at months 1, 3, 6, 9, and 12 during the study. The current analysis included baseline and 3-month assessments of NTX levels. Assessments of NTX levels were performed at central laboratories (Mayo Medical Laboratories, Rochester, MN; Bio Analytical Research Corporation, Ghent, Belgium; Laboratoria Bioquimica Medica, Buenos Aires, Argentina; Fleury Laboratories, Sao Paulo, Brazil; Bio-Imaging Technologies, Inc., Newtown, PA). Urine was obtained as a morning second-void sample, and NTX levels were normalized according to urinary creatinine levels.

Statistical Methods
Urinary NTX was characterized as normal (NTX <64 nmol/mmol creatinine) or elevated (NTX 64 nmol/mmol creatinine). This cutoff value for NTX was chosen because it reflects the approximate upper limit of normal for disease-free premenopausal women [12]. Patients were grouped by their baseline and 3-month NTX levels: patients with elevated baseline and normalized 3-month NTX levels were the E-N group, patients with elevated baseline and 3-month NTX levels were the E-E group, and patients with normal baseline and 3-month NTX levels were the N-N group.

Clinical outcomes and biochemical responses to treatment (e.g., NTX levels) were similar in both the 4- and 8/4-mg zoledronic acid treatment groups [13]. Therefore, for the present analyses, the 4- and 8/4-mg zoledronic acid treatment groups were pooled to increase the sample size, improve the statistical power to detect effects, and increase the precision of the estimated relative risks.

Logistic regression was used to identify factors that predicted normalization of NTX over the first 3 months of treatment [14]. The proportion of patients with at least one SRE on study for each NTX group was estimated by cumulative incidence plots because of the competing risk for death [15]. Time to death was estimated by Kaplan-Meier analysis [16]. Multivariate Cox regression models using marker levels for each study endpoint were developed with the baseline NTX groups. Variables that were not significant at the 5% level were removed by backward elimination to generate a reduced multivariate model. All statistical tests were two-sided with a significance level of 0.05. Tests of the proportional hazards assumption were performed to assess the validity of the model assumptions in time-to-event analyses [17].

	RESULTS

Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

 
Patient Demographics and Baseline Characteristics
Bone resorption marker data were available for 328 patients treated with zoledronic acid. Patient demographic and baseline disease characteristics are shown in Table 1. In general, patient demographics were well balanced between patients with elevated and with normal NTX levels at baseline. Mean baseline NTX levels were 43 nmol/mmol creatinine in the normal group and 213 nmol/mmol creatinine in the elevated group. Patients with elevated baseline NTX levels tended to have a lower performance status and a higher frequency of prior SREs. Patients with elevated NTX levels also tended to have higher baseline BALP levels.

Characteristics of Patients with Persistently Elevated Versus Normalized NTX Levels at 3 Months
Patient baseline characteristics were assessed to determine whether any characteristics were associated with a failure to normalize NTX after 3 months. In univariate analyses, the baseline Functional Assessment of Cancer Therapy–General quality-of-life total score, the Brief Pain Inventory score, the use of analgesics, and a baseline NTX level >150 nmol/mmol creatinine were independently associated with persistently elevated NTX levels at 3 months (Table 2). Time since cancer diagnosis, SRE history, type of antineoplastic therapy, and nature of bone metastases (osteolytic or osteoblastic) were not significantly correlated with persistently elevated NTX levels. In the reduced multivariate analysis, a baseline NTX level >150 nmol/mmol creatinine was the strongest predictor for persistently elevated NTX (E-E group; p = .0036) at 3 months (Table 2). The Functional Assessment of Cancer Therapy–General total score and Brief Pain Inventory score were not significant covariates in the multivariate analysis.

View larger version (12K): [in this window] [in a new window]   Figure 1. Kaplan–Meier estimates of survival by baseline and 3-month N-telopeptide of type I collagen (NTX) level. Abbreviations: E-N, patients with elevated baseline NTX who had normalized NTX at 3 months; E-E, patients with persistently elevated NTX; N-N, patients with normal baseline and 3-month NTX.

View larger version (9K): [in this window] [in a new window]   Figure 2. Relative risks for death and first skeletal-related event (SRE) among breast cancer patients with persistently elevated levels of N-telopeptide of type I collagen (NTX) versus normalized NTX levels at 3 months. Lengths of the horizontal lines represent 95% confidence intervals (CIs).

View larger version (11K): [in this window] [in a new window]   Figure 3. Radiation therapy to bone among breast cancer patients with persistently elevated levels of N-telopeptide of type I collagen (NTX) versus normalized NTX levels at 3 months. Abbreviations: E-N, patients with elevated baseline NTX levels who had normalized NTX at 3 months; E-E, patients with persistently elevated NTX levels.

View larger version (19K): [in this window] [in a new window]   Figure 4. Relative risks of clinical outcomes among breast cancer patients stratified by N-telopeptide of type I collagen (NTX) decrease. (A): Time to death. (B): Time to first skeletal-related event. (C): Time to bone disease progression. a((Baseline NTX – 3-month NTX) ÷ baseline NTX) x 100. Top x-axis shows patients with maximum NTX change corresponding with value on lower x-axis. Baseline NTX of 50 nmol/mmol creatinine, 25th percentile; 77 nmol/mmol creatinine, median percentile; 127 nmol/mmol creatinine, 75th percentile.

Tests of the proportional hazards assumptions did not reveal any evidence of model violations.

NTX Increases Do Not Always Precede SREs and Death in Patients with Normal or Normalized NTX Levels
Patients in the E-N group were evaluated for SRE-free survival after the 3-month time point. Of the 149 patients for whom follow-up data were available, 71 experienced an SRE and 28 died (Fig. 5A). Only seven patients experienced NTX elevations. Similarly, among 132 patients with normal NTX levels at baseline, 49 patients experienced an SRE, 28 died, and only seven patients experienced NTX elevations during the study (Fig. 5B).

View larger version (15K): [in this window] [in a new window]   Figure 5. N-telopeptide of type I collagen (NTX) increases do not always precede skeletal-related events (SREs) and death in patients with normal or normalized NTX levels. (A): Breast cancer patients with elevated baseline NTX levels that normalized after 3 months of zoledronic acid who had an SRE, an NTX elevation (64 nmol/mmol creatinine), or died on study. (B): Breast cancer patients with normal baseline NTX who had an SRE, an NTX elevation, or died on study.

	DISCUSSION

Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

In recent years, assessments of biochemical markers of bone metabolism have become more widely available. The peptide-bound collagen type I crosslinked NTX is a degradation product of mature collagen, and its presence in the urine reflects increased bone resorption. Furthermore, this biochemical marker of bone turnover correlates with the presence and extent of skeletal metastases [18], and levels of urinary NTX correlate with negative clinical outcomes in patients with bone metastases from a variety of solid tumors [8] and in patients receiving zoledronic acid therapy [9]. Zoledronic acid is an inhibitor of osteoclast-mediated bone destruction, and in most trials maximum suppression of NTX is achieved within a few weeks after treatment initiation. The results of the present analysis are consistent with these previous observations and extend our understanding of the relationship between suppression of NTX after initiation of zoledronic acid therapy and clinical outcomes. The results of this analysis suggest that measurement of urinary NTX levels 3 months after the initiation of bisphosphonate therapy might provide useful information on treatment effects. Moreover, although further analyses are needed, the correlations between percent reduction in NTX level and bone lesion progression suggest that monitoring NTX levels may provide important insight into the status of bone lesions without the need for radiographic evaluations.

Over the past two decades, bisphosphonates have become widely used for the prevention of SREs in breast cancer patients with bone metastases. Pamidronate decreases the incidence of SREs by approximately 30% compared with placebo [19, 20], and zoledronic acid reduces the risk for SREs by an additional 20% compared with pamidronate [13]. Furthermore, preclinical data in animal models have revealed direct and indirect antitumor effects of bisphosphonates [21, 22]. For example, zoledronic acid suppressed bone, lung, and liver metastases in a murine model of breast cancer [23]. Zoledronic acid also prevented the development of osteolytic bone disease, decreased the tumor burden in bone, and increased survival in a murine model of multiple myeloma [24]. Moreover, a small, open-label study (n = 40) for the prevention of bone metastases randomized patients with a broad range of recurrent solid tumors who did not have bone metastases to receive either zoledronic acid or no treatment [25]. The results demonstrated that zoledronic acid produced significantly lower proportions of patients with bone metastases at 12 and 18 months (p < .0005 and p = .0002, respectively). These analyses suggest that bisphosphonate therapy may provide a survival advantage for patients who respond to therapy.

Forty percent of patients began therapy with a urinary NTX level within the normal range. However, despite normal levels of bone resorption, many still developed clinical sequelae of their bone disease (SREs). As the present analysis focused primarily on patients with elevated baseline NTX levels, additional analyses are necessary to provide insight into the development of SREs in patients with normal NTX levels. This group could reflect a population with lower bony disease burden or accumulated focal structural bone damage that may not be detectable by systemic bone marker levels. These patients would still be expected to have some risk for SREs, and this could represent a background rate of SREs for patients with bone metastases. In that case, the SRE risk could be reduced by initiation of bisphosphonate treatment before cancer-induced damage to bone or use of agents that stimulate bone repair afterwards. Evidence from a recently published study in patients with breast cancer receiving clodronate as an adjuvant treatment with standard therapy suggests that early bisphosphonate treatment before the development of bone lesions might reduce the burden of SREs from bone metastases that subsequently develop, although the mechanism behind this is unknown [26]. Moreover, the lack of an NTX increase before an SRE in patients with normal or normalized NTX levels suggests that other factors should be considered when assessing a patient's risk for an SRE and the benefits of bisphosphonate therapy. Further evaluations of risk factors in these patient populations are ongoing.

This analysis also provides insight into the role of NTX in predicting aggressive disease. Patients who had persistently elevated NTX levels had an unfavorable prognosis. Often these were patients with extremely elevated baseline NTX levels (>150 nmol/mmol creatinine), which may represent a very large tumor burden in bone or extremely aggressive disease with a very high rate of bone destruction. For example, a higher percentage of patients with persistently elevated NTX also had a history of SREs, and there is a higher risk for death in patients with metastatic breast cancer who experience pathologic fractures [27]. New strategies should be investigated for these patients, such as alternative administration schedules of zoledronic acid or investigational treatments localized to the site of bone lesions.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

 
The results of this subset analysis suggest that early normalization of elevated baseline NTX while receiving zoledronic acid is associated with longer event-free and overall survival times than in patients with persistently elevated NTX levels. Further studies are warranted to confirm this hypothesis and to validate the clinical utility of bone markers in the management of malignant bone disease. Ongoing studies of marker-directed therapy will provide further clarification in this regard.

	ACKNOWLEDGMENTS

Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

 
Research and technical support were provided by a grant from Novartis Pharmaceuticals Corporation. Funding for medical editorial assistance was provided by Novartis. We thank Tamalette Loh, Ph.D., ProEd Communications, Inc., for her medical editorial assistance with this manuscript.

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Top Learning Objectives Abstract Introduction Patients and Methods Results Discussion Conclusions Acknowledgments References

 

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This Article Abstract Full Text (PDF) Supplemental Data eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lipton, A. Articles by Coleman, R. E. Search for Related Content PubMed PubMed Citation Articles by Lipton, A. Articles by Coleman, R. E.