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Retrospective analysis of antitumor effects of zoledronic acid in breast cancer patients with bone-only metastases
Version of Record online: 2 DEC 2011
Copyright © 2011 American Cancer Society
Volume 118, Issue 8, pages 2039–2047, 15 April 2012
How to Cite
Niikura, N., Liu, J., Hayashi, N., Palla, S. L., Tokuda, Y., Hortobagyi, G. N., Ueno, N. T. and Theriault, R. L. (2012), Retrospective analysis of antitumor effects of zoledronic acid in breast cancer patients with bone-only metastases. Cancer, 118: 2039–2047. doi: 10.1002/cncr.26512
- Issue online: 6 APR 2012
- Version of Record online: 2 DEC 2011
- Manuscript Accepted: 4 AUG 2011
- Manuscript Revised: 26 JUN 2011
- Manuscript Received: 1 MAY 2011
- zoledronic acid;
- breast cancer;
- bone-only metastases;
Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis, but have not been shown to prevent bone metastasis or to prolong survival time in metastatic breast cancer patients. The aim of this study was to determine whether the progression-free survival (PFS) and overall survival (OS) of patients with bone-only breast cancer metastasis differed based on whether patients received zoledronic acid, pamidronate, or no bisphosphonate upon diagnosis of their metastases.
PATIENTS AND METHODS:
We retrospectively identified 314 patients diagnosed with bone-only metastasis at the time of initial staging or who developed bone metastasis as the first recurrence site during follow-up from January 1, 1997 to December 31, 2008, at The MD Anderson Cancer Center. Univariate and multivariate Cox hazards models were used to assess the effects of each treatment on PFS and OS.
Patients who had more than 1 bone metastasis and Eastern Cooperative Oncology Group (ECOG) performance status of 2 and 3 were more likely to receive zoledronic acid in this analysis. Compared with no bisphosphonate use, the use of zoledronic acid was not significantly associated with longer PFS (hazard ratio [HR] = 0.72, P = .058 in univariate analysis, and HR = 0.80, P = .235 in multivariate analysis) nor with longer OS (HR = 1.04, P = .863 in univariate analysis and HR = 1.34, P = .192 in multivariate analysis).
Our study demonstrates that for patients with bone-only metastases, zoledronic acid did not prolong PFS or OS. In patients with bone-only metastasis, we could not demonstrate antitumor effects of zoledronic acid. Cancer 2012. © 2011 American Cancer Society.
Bone is the most common site of metastatic spread (70% of patients) in advanced breast cancer.1 Bone-only metastatic breast carcinoma, defined as metastatic disease limited to the bone at the time of initial diagnosis of metastasis, has been reported to occur in 17% to 37% of women.2-4 Patients with bone-only metastases have long survival and substantial numbers of skeletal-related events (SREs).4-9
Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis.10-16 However, bisphosphonates have not been shown to prevent bone metastasis or to prolong survival in breast cancer patients. Preclinical data in animal models have revealed direct and indirect antitumor effects of bisphosphonates.14, 17 For example, zoledronic acid suppressed bone, lung, and liver metastases in a murine model of breast cancer.18 Zoledronic acid has been suggested to have synergistic antitumor effects with chemotherapy,19, 20 to promote antiangiogenesis21 and apoptosis,22 and to have immunomodulatory effects.23
Based on this preclinical evidence and the potent antitumor effects of bisphosphonates in preclinical models, it remains controversial whether bisphosphonates may confer a survival benefit.24-27 Zoledronic acid prolongs survival in other metastatic diseases.28 Zoledronic acid is being investigated in the adjuvant setting to try to prevent metastasis and prolong survival. Findings from the ABCSG-12 trial showed that zoledronic acid combined with endocrine therapy in the adjuvant setting significantly improved disease-free survival (DFS) and recurrence-free survival (RFS) beyond that achieved with endocrine therapy alone.29 In the metastatic setting, pamidronate has not been shown to provide a survival benefit in previous studies.10-13, 30
It is important to identify groups of breast cancer patients who are most likely to benefit from bisphosphonate treatment. Patients with bone metastasis have different prognoses based on whether they also have visceral metastases.3, 4, 6, 8, 9 Therefore we focused on bone-only metastasis in this study.
We hypothesized that patients with bone-only metastasis treated with standard therapeutic agents plus zoledronic acid or pamidronate at the time of initial diagnosis of metastases would survive longer than patients treated with standard agents without zoledronic acid or pamidronate. The aim of this retrospective study was to compare the progression-free survival (PFS) and overall survival (OS) time of patients with bone-only metastasis who received zoledronic acid or pamidronate treatment with those who did not.
PATIENTS AND METHODS
Inclusion and Exclusion Criteria
We retrospectively identified patients diagnosed with bone metastasis at the time of initial staging or who developed bone metastasis as the first recurrence site during follow-up. Patients diagnosed from January 1, 1997 to December 31, 2008, at The University of Texas MD Anderson Cancer Center were included in this analysis, and their records were retrieved from the Department of Breast Medical Oncology prospectively maintained computerized database. Of the 2254 patients diagnosed with bone metastasis with or without nonskeletal metastasis from breast cancer, 756 (33.5%) were diagnosed with bone-only metastasis. Patients were eligible for the study if they had been treated in the Breast Medical Oncology Department at The MD Anderson Cancer Center from the time of bone metastasis diagnosis and had been followed up for more than 3 months. We excluded patients who had another malignant tumor and patients who received zoledronic acid or pamidronate more than 6 months after the diagnosis of bone metastasis. Of the 756 patients with bone-only metastasis, 442 were excluded because the patients did not undergo follow-up at MD Anderson (n = 140), were lost to follow-up (n = 42), had treatment at another hospital before coming to our institution (n = 208), received zoledronic acid or pamidronate more than 6 months after the diagnosis of bone metastases (n = 43), and/or had another malignant tumor in addition to breast cancer (n = 15). This retrospective study was approved by the institutional review board at MD Anderson.
Definition of Bone-only Metastasis and Treatment Groups
We defined patients with bone-only metastasis as patients with bone metastasis demonstrated by appropriate imaging and/or biopsy and without nonskeletal distant metastasis at the time of their initial diagnosis of metastatic breast cancer. We defined “initial stage IV” as bone-only metastasis detected at the time of the patient's initial diagnosis of breast cancer, and we defined “secondary stage IV” as bone-only metastasis detected after the completion of definitive curative management of the primary breast tumor (including neoadjuvant and/or adjuvant systemic treatment). We defined single metastasis as 1 bone metastasis based on reports of bone scan and/or positron emission tomography/computed tomography (PET/CT) imaging, and multiple metastases as 2 or more metastatic sites. We defined 3 groups of patients: patients who received zoledronic acid within 6 months of diagnosis of bone metastasis and continued more than 2 months (ZA), patients who received pamidronate within 6 months of diagnosis of bone metastasis and continued more than 2 months (PA), and patients who did not receive bisphosphonates during clinical follow-up (no-ZA/PA). The reason for the cutoff of 6 months was that some patients received chemotherapy for 6 months and then received bisphosphonate. We categorized patients who were started on pamidronate and changed to zoledronic acid as members of the PA group.
Staging and Pathology Review
Primary breast cancer had been staged according to the sixth edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual.31
Metastatic bone disease had been confirmed by histopathologic analysis when available. Patients with multiple sites of suspected metastasis had undergone biopsy of the metastatic lesion that had been considered most likely to represent metastatic disease.
Grading of tumors was determined by dedicated breast pathologists according to the modified Black's nuclear grading system;32 histologic classification of tumors had been done according to the World Health Organization criteria.33 A patient was considered to have human epidermal growth factor receptor 2 (HER2)-positive disease if the primary or metastatic tumor had a score of 3+ by HER2 immunohistochemical staining or amplification (ratio ≥2.2) of the HER2 gene by fluorescence in situ hybridization.34 A patient was considered to have estrogen receptor (ER)- or progesterone receptor (PR)-positive disease if there was at least 10% positive tumor staining. Hormone receptor-positive disease was defined as ER- and/or PR-positive disease.
Means and standard deviations were used to summarize age at diagnosis. Frequencies and proportions were used to present the categorical clinical characteristics. Pearson chi-square tests and Fisher exact tests were used to test association of treatments and categorical clinical characteristics. Analysis of variance (ANOVA) was used to determine differences in mean age among patients in various treatment groups. Progression was defined as demonstration of a new metastatic lesion. PFS was defined as the time interval from diagnosis of metastasis to progression, death, or last follow-up date, whichever occurred first. Patients who were alive without progression at the last follow-up were censored in the PFS analyses. OS was defined as the length of time from diagnosis of metastasis to death or last follow-up date if patients were alive at the last follow-up. Patients who were alive at the last follow-up were censored in the OS analyses. PFS and OS were estimated by the Kaplan-Meier product-limit method. Kaplan-Meier curves were used to present PFS and OS over time for patients in each group. Univariate and multivariate Cox proportional hazards (Cox PH) regression models were used to assess the effect of treatment and other predictive factors. The analyses were performed in SAS 9.1 for Windows (Copyright © 2002-2003 by SAS Institute Inc., Cary, NC).
Table 1 shows the 314 evaluable patients and tumor characteristics classified by the treatments that patients received at initial diagnosis of bone disease (ZA, PA, or no-ZA/PA). The ZA group had a higher percentage of patients with more than 1 bone metastasis compared with the no-ZA/PA group or the PA group, and the ZA group had a higher proportion with ECOG performance status of 2 or 3 compared with the no-ZA/PA group or the PA group. Among 314 patients with bone-only metastasis, 161 patients experienced disease progression before death, 101 patients experienced progression but were alive at last follow-up, 3 patients died without progression, and 49 patients were alive without progression at the last follow-up. In 101 (32%) patients, metastatic disease was confirmed by histopathologic analysis. The median follow-up time was 33 months.
|Characteristic||ZA N = 172 (%)||PA N = 77 (%)||No ZA/PA N = 65 (%)||P|
|Mean age at primary diagnosis, y (SD)||51.5 (12.9)||51.2 (11.2)||53.0 (13.5)||.653|
|Pre||74 (43%)||29 (38%)||19 (29%)|
|Post||98 (57%)||46 (60%)||43 (66%)||.229|
|Unknown||0 (0%)||2 (2%)||3 (5%)|
|Positive||153 (89%)||66 (86%)||56 (86%)||.801|
|Negative||19 (11%)||10 (13%)||9 (14%)|
|Unknown||0 (0%)||1 (1%)||0 (0%)|
|Positive||111 (64%)||48 (62%)||37 (57%)||.631|
|Negative||58 (34%)||22 (29%)||24 (37%)|
|Unknown||3 (2%)||7 (9%)||4 (6%)|
|Positive||27 (16%)||15 (20%)||10 (15%)||.299|
|Negative||138 (80%)||44 (57%)||38 (59%)|
|Unknown||7 (4%)||18 (23%)||17 (26%)|
|Number of bone mets|
|Single||27 (16%)||20 (26%)||28 (43%)||<.001|
|Multiple||145 (84%)||57 (74%)||37 (57%)|
|ECOG performance status|
|0,1||150 (87%)||71 (92%)||63 (97%)||.063|
|2,3||22 (13%)||6 (8%)||2 (3%)|
In the PA group, a total of 77 patients received pamidronate during initial treatment for bone metastases; 30 of these patients changed treatment for bone metastases to zoledronic acid. Pamidronate was used for a median duration of 16 months (range, 2-42 months) in patients who changed bisphosphonates.
In Table 2, we show the univariate analyses of PFS by treatment in all patients and in subgroups (single metastases, multiple metastases, hormone receptor-positive, HER2-positive, and triple-negative). We tested overall and pairwise comparisons. The overall tests showed that none of the 3 treatment groups had significantly longer PFS among all patients or among patients with hormone receptor-positive disease (P = .007 and P = .014, respectively). Among patients with hormone receptor-positive disease, the ZA group had longer PFS than the PA group (hazard ratio [HR] = 1.37, P = .040). In patients with hormone receptor-positive tumors, the no-ZA/PA group had longer PFS than either the ZA group (HR = 0.67, P = .025) or the PA group (HR = 0.49, P < .001). In all patients, PFS was longer for the no-ZA/PA group than for the PA group (HR = 0.57, P = .002). Figure 1A shows the Kaplan-Meier curves for PFS among all patients by treatment. Table 3 shows the multivariate Cox PH model results for PFS. The use of zoledronic acid at the time of first diagnosis of bone disease was not associated with significantly longer PFS (HR = 0.80, P = .235) after adjusting for menopausal status (pre- vs postmenopausal), timing of metastasis diagnosis (initial stage IV vs secondary stage IV), performance status (0, 1 vs 2, 3), ER status (positive vs negative), number of bone metastases (single vs multiple), and bone pain (symptomatic vs asymptomatic).
|No. with Progression||Compared with Zoledronic Acid||Compared with Pamidronate||Overall|
|Treatment||or Death/N (%)||HR (95%CI)||P Value||HR (95%CI)||P Value||P Value|
|ZA||141/172 (82%)||—||—||0.77 (0.59-1.03)||.077||.007|
|PA||74/77 (96%)||1.29 (0.97-1.71)||.077||—||—|
|No ZA/PA||50/65 (77%)||0.72 (0.53-1.01)||.058||0.57 (0.39-0.82)||.002|
|ZA||22/27 (81%)||—||—||0.78 (0.41-1.45)||.429||.165|
|PA||18/20 (90%)||1.29 (0.69-2.41)||.429||—||—|
|No ZA/PA||21/28 (75%)||0.70 (0.39-1.28)||.250||0.55 (0.29-1.03)||.061|
|ZA||119/145 (82%)||—||—||0.73 (0.53-1.01)||.058||.126|
|PA||56/57 (98%)||1.36 (0.99-1.87)||.058||—||—|
|No ZA/PA||29/37 (78%)||0.93 (0.61-1.40)||.722||0.68 (0.43-1.07)||.097|
|ZA||131/157 (83%)||—||—||0.73 (0.55-0.99)||.040||.014|
|PA||66/67 (99%)||1.37 (1.01-1.84)||.040||—||—|
|No ZA/PA||45/57 (79%)||0.67 (0.47-0.95)||.025||0.49 (0.33-0.73)||<.001|
|ZA||20/27 (74%)||—||—||0.65 (0.33-1.32)||.233||.496|
|PA||13/15 (87%)||1.54 (0.76-3.11)||.233||—||—|
|No ZA/PA||7/10 (70%)||1.08 (0.46-2.56)||.864||0.70 (0.28-1.77)||.452|
|PA||3/3 (100%)||0.91 (0.24-3.45)||.885||1.10 (0.29-4.20)||.885||.601|
|No ZA/PA||5/6 (83%)||1.74 (0.55-5.46)||.344||1.92 (0.44-8.42)||.388|
|Variable||No. with Progression or Death/N (%)||HR (95% CI)||P|
|No ZA/PA||50/65 (77%)||0.80 (0.55-1.16)||.235|
|Post||110/141 (78%)||1.03 (0.76-1.40)||.858|
|Initial stage IV||87/113 (77%)||Ref||—|
|Secondary stage IV||104/124 (84%)||1.23 (0.90-1.68)||.195|
|2,3||20/24 (83%)||0.81 (0.49-1.36)||.429|
|Negative||20/28 (71%)||1.34 (0.83-2.18)||.234|
|Number of metastases|
|Multiple||148/182 (81%)||1.49 (1.03-2.15)||.036|
|Symptomatic||108/127 (85%)||1.33 (0.96-1.84)||.089|
In Table 4, we show the univariate analyses of OS by treatment in all patients and in subgroups (single metastases, multiple metastases, hormone receptor-positive, HER2-positive, and triple-negative). We tested overall and pairwise comparisons. Among all 314 patients, no significant difference in OS was found between the ZA, PA, and no-ZA/PA groups. Figure 1B shows the Kaplan-Meier curves for OS by treatment group among all patients. There were no significant differences in OS among treatment groups. In the next analysis, we separately considered patients with a single metastasis and those with multiple metastases. No significant difference in OS between treatments was found in either group. Moreover, we considered separately patients with hormone receptor-positive tumors, HER2-positive tumors, and triple-negative tumors. In all 3 groups, no significant difference in OS between treatments was found. Table 5 shows the multivariate Cox PH model for OS. The use of zoledronic acid at the time of first diagnosis of bone disease was not associated with significantly longer OS (HR = 1.34, P = .192) after adjusting for menopausal status (pre- vs postmenopausal), timing of metastasis diagnosis (initial stage IV vs secondary stage IV), performance status (0, 1 vs 2, 3), ER status (positive vs negative), number of bone metastases (single vs multiple), and bone pain (symptomatic vs asymptomatic). We analyzed the subgroups of hormone receptor-positive, premenopausal and post-menopausal patients because of the AZURE and ABCSG12 trials' results. However, our data showed no difference in OS among patients in the ZA, PA, and no-ZA/PA treatment groups based on menopausal status.
|Compared with Zoledronic Acid||Compared with Pamidronate||Overall|
|Treatment||No. Deaths/N (%)||HR (95%CI)||P Value||HR (95%CI)||P Value||P Value|
|ZA||71/172 (42%)||—||—||0.85 (0.60-1.22)||.373||.663|
|PA||57/77 (74%)||1.18 (0.82-1.68)||.373||—||—|
|No ZA/PA||36/65 (55%)||1.04 (0.69-1.56)||.863||0.88 (0.58-1.34)||.554|
|ZA||7/27 (26%)||—||—||0.87 (0.33-2.30)||.777||.956|
|PA||12/20 (60%)||1.15 (0.44-3.05)||.777||—||—|
|No ZA/PA||12/28 (43%)||1.05 (0.41-2.71)||.914||0.92 (0.41-2.07)||.831|
|ZA||64/145 (44%)||—||—||0.79 (0.54-1.17)||.244||.311|
|PA||45/57 (79%)||1.26 (0.85-1.86)||.244||—||—|
|No ZA/PA||24/37 (64%)||1.38 (0.86-2.22)||.179||1.10 (0.67-1.81)||.710|
|ZA||64/157 (41%)||—||—||0.87 (0.59-1.27)||.455||.728|
|PA||49/67 (73%)||1.15 (0.79-1.69)||.455||—||—|
|No ZA/PA||32/57 (56%)||1.01 (0.65-1.55)||.978||0.87 (0.56-1.36)||.542|
|ZA||11/27 (40%)||—||—||1.01 (0.40-2.55)||.976||.921|
|PA||9/15 (60%)||0.99 (0.39-2.48)||.976||—||–|
|No ZA/PA||6/10 (60%)||1.21 (0.44-3.28)||.713||1.22 (0.42-3.55)||.710|
|ZA||6/12 (50%)||—||0.81 (0.20-3.33)||.766||.164|
|PA||3/3 (100%)||1.24 (0.30-5.12)||.766||—||—|
|No ZA/PA||4/6 (67%)||3.91 (1.04-14.73)||.044||3.16 (0.62-16.05)||.166|
|Variable||No. Deaths/N (%)||HR (95% CI)||P Value|
|No ZA/PA||36/65 (55%)||1.34 (0.86-2.15)||.192|
|Post||60/141 (43%)||1.16 (0.77-1.73)||.479|
|Initial stage IV||45/113 (40%)||Ref||—|
|Secondary stage IV||62/124 (50%)||1.05 (0.69-1.59)||.816|
|2,3||14/24 (58%)||1.47 (0.77-2.81)||.240|
|Negative||14/28 (50%)||1.60 (0.87-2.93)||.131|
|Number of metastases|
|Multiple||88/182 (48%)||2.06 (1.21-3.53)||.008|
|Symptomatic||73/127 (57%)||1.60 (1.02-2.51)||.043|
We found that the use of zoledronic acid in bone-only metastasis did not prolong OS when compared with the use of pamidronate or no bisphosphonate in this group of patients with bone-only metastatic breast cancer. The same was true for each subgroup analyzed. The use of zoledronic acid improved PFS when compared with the use of pamidronate in hormone receptor-positive breast cancer, but the PFS for patients who received the zoledronic acid was shorter than that of the patients with no bisphosphonate use.
It is standard treatment for zoledronic acid to be used to treat patients with bone-only metastatic disease to delay or prevent SREs. However, its use has not been shown to prolong survival.
It is possible to define groups of patients with advanced breast cancer at different risks of complications from skeletal disease. Patients with bone-only disease at the time of diagnosis of skeletal metastases were almost 3 times more likely to develop pathological long-bone fractures than those with bone and liver disease.4 The previous study identified groups of patients most at risk of these complications from skeletal metastatic disease. The results might be used to select patients for treatment with bisphosphonates and might improve the cost-benefit analysis.4
It is still controversial whether bisphosphonates confer a survival benefit. Three trials using clodronate in the adjuvant setting have been published. Two reported that clodronate had beneficial effects on both bone metastasis and survival.24-26 In contrast, the third trial reported that clodronate had no effect on metastasis and a negative effect on survival.27 Gnant et al29 showed that zoledronic acid significantly improved PFS among premenopausal women with early breast cancer. Recent results from the neoadjuvant subgroup analysis of the AZURE trial35 showed a significant increase in pathological complete responses in patients treated with zoledronic acid. On the other hand, Aft et al36 reported that pathological complete response rates were not significantly different between treatment groups. The ZO-FAST study showed that patients who received adjuvant letrozole plus immediate zoledronic acid had a statistically significant 41% relative reduction in the risk of DFS events when compared with patients who received delayed zoledronic acid (log-rank P = .0314).37 In the metastatic setting, pamidronate did not provide a survival benefit compared with placebo treatment.10-13 Rosen et al16 reported that the median survival times were comparable between the pamidronate and zoledronic acid groups. Park et al30 reported in a retrospective study that bisphosphonate treatment may provide a survival benefit in patients with metastatic breast cancer, particularly patients with hormone receptor-negative tumors. However, in that study, only 27.5% of patients in the bisphosphonate group received zoledronic acid. The study lacked the power to confirm antitumor effects of zoledronic acid in metastatic tumors. In our study, zoledronic acid did not improve survival; the apparent negative impact of bisphosphonates on PFS when compared with the no-ZA/PA group is likely the reflection of better prognostic characteristics of the no-ZA/PA group: more than 80% of patients in the ZA group had multiple bone metastases, whereas only 57% had multiple metastases in the bo-ZA/PA group, and the patients in the no-ZA/PA group had better performance status. Based on these data, zoledronic acid did not appear to have antitumor effects. The reasons for zoledronic acid not having demonstrable antitumor effects in bone-only metastases may include the biologic behavior of the metastatic tumor, which may be fundamentally different from that of primary breast cancers.
Recently investigators have reported markers that may be effective in selecting patients who may benefit from bisphosphonate treatment. N-telopeptide (NTX) and bone-specific alkaline phosphatase (BALP) levels have been shown to correlate significantly with clinical outcomes, including SREs, disease progression, and death.38, 39 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.40 Aft et al36 reported that fewer women had detectable disseminated tumor cells (DTCs) after neoadjuvant chemotherapy with concurrent zoledronic acid than did women who had chemotherapy alone, and zoledronic acid appeared to decrease the rate at which DTC-negative breast cancer patients developed subsequent micrometastatic disease at 3 months. We tried to find a subgroup that benefits from zoledronic acid treatment. Zoledronic acid improved PFS better than pamidronate among patients with hormone receptor-positive tumors. However, in all subgroups, the ZA group did not have prolonged survival when compared with the no-ZA/PA group.
Our study has some limitations. First, this study was a retrospective evaluation. Our data were collected from patients' charts; therefore, this study suffers from the biases associated with any retrospective study, including selection bias. Patients were given zoledronic acid based on the clinical decision to try to delay or prevent skeletal-related complications. The no-ZA/PA group included a higher percentage of patients with single bone metastases and good performance status than did the ZA and PA groups. Therefore, the no-ZA/PA group included many more patients who had long survival durations.
In the adjuvant and neoadjuvant setting, zoledronic acid showed antitumor effects.29, 41 However, our results may not support the hypothesis that zoledronic acid has antitumor effects in metastatic tumors. Zoledronic acid might prevent bone micrometastases but not have an effect on macrometastasis of bone disease. Based on our results, it is possible that if zoledronic acid is to have optimal effects in treating breast cancer, it should be given before metastases are extant.
In summary, at present, the use of zoledronic acid for patients with bone metastases is the gold standard because it significantly reduces or prevents skeletal-related events. However, in patients with bone-only metastases, we did not demonstrate an antitumor effect (prolonged PFS or OS) of zoledronic acid in this retrospective study. The potential antitumor effect of zoledronic acid remains controversial. Patients and physicians should have a clear understanding of the potential benefits of bisphosphonate treatment.
This research was supported in part by the National Institutes of Health through The MD Anderson's Cancer Center Support Grant, CA016672, and by the Nellie B. Connally Breast Cancer Research Fund.
CONFLICT OF INTEREST DISCLOSURES
Naoto T. Ueno has received honorarium from Novartis. Gabriel N. Hortobagyi receives research support from Novartis and is a consultant to Novartis. The other authors made no disclosures.
- 10Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of 2 randomized, placebo-controlled trials. Cancer. 2000; 88: 1082-1090., , , et al.
- 33The World Health Organization. Histological typing of breast tumors. Neoplasma. 1983; 30: 113-123.
- 35The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumour activity in breast cancer. Cancer Res. 2009; 69: abstr 5101., , , .