6348 Full
6348 Full
CCR-12-1397
Clinical
Cancer
Imaging, Diagnosis, Prognosis Research
Abstract
Purpose: Survival is highly variable in women with bone metastases from breast cancer and prognostic
factors are needed. We analyzed data from a phase III trial comparing zoledronic acid (ZOL) with pamidro-
nate in patients with breast cancer and bone metastases to identify variables prognostic for overall survival.
Experimental Design: Patients who received ZOL (n ¼ 435) with bone marker assessments and complete
baseline data were included. Relative risks (RR) of death over 24 months were assessed using a stratified Cox
regression analysis. A reduced model was generated using stepwise backward elimination until only
significant (P < 0.05) variables remained.
Results: Only 5 of 19 variables analyzed remained significantly prognostic for survival in the reduced
multivariate model. These included age more than 50 years (RR 1.78–2.53, P 0.01 for each decade >50
versus 50); Functional Assessment of Cancer Therapy-General (FACT-G) score less than 65 units (P < 0.05
vs. 75 units); impaired (PS 1) versus fully active (PS ¼ 0) Eastern Cooperative Oncology Group (ECOG)
performance status (RR 1.74, P < 0.01); prior versus no prior chemotherapy (RR 1.97; P < 0.01), and lactate
dehydrogenase (LDH) levels. Lactate dehydrogenase upper limit of normal (ULN) but < 2 ULN
correlated with a two-fold increased risk of death, and LDH > 2 ULN correlated with a six-fold increased
risk of death versus LDH < ULN (P < 0.0001 for both). Baseline bone marker levels were not significantly
correlated with survival after adjustment for other significant covariates.
Conclusions: This retrospective analysis shows that LDH levels correlate strongly with survival in patients
with bone metastases from breast cancer and confirms the relevance of previously described prognostic
factors. Clin Cancer Res; 18(22); 6348–55. 2012 AACR.
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Brown et al.
6350 Clin Cancer Res; 18(22) November 15, 2012 Clinical Cancer Research
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Published OnlineFirst September 4, 2012; DOI: 10.1158/1078-0432.CCR-12-1397
Table 2. Univariate and multivariate models for overall survival in patients with bone metastases from
breast cancer
breast cancer and bone metastases] showed a strong corre- between-group differences were apparent throughout the
lation with risk of death. Patients with LDH levels 2 course of the study (P < 0.0001; Fig. 2). Patients with LDH
ULN had an almost 6-fold increased risk of death compared levels < ULN had the best OS, and approximately 65% of
with patients whose LDH levels were below the ULN (RR patients were still alive at 24 months’ follow-up. In contrast,
5.937; P < 0.0001). the median survival among patients with LDH levels ULN
but <2 ULN was approximately 17 months, and those
LDH as a prognostic marker of survival in advanced patients with LDH levels 2 ULN had the worst OS
breast cancer (median 5 months). At the 12-month time point, Cox
Using the ULN and 2 ULN as cutoff points, the resulting regression analyses showed that significant prognostic fac-
3 LDH populations had significantly different survival, and tors predictive of >30% risk of death included high LDH,
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Brown et al.
Figure 1. Forest plot of significant prognostic variables in reduced multivariate Cox model for death in patients with bone metastases from breast cancer.
Horizontal lines represent the 95% confidence interval. Global P values are for all categories versus the reference category and are derived from the
full Cox multivariate analysis.
weight < 60 kg, albumin < 35 g/L, FACT-G < 65 units, and Other prognostic variables that remained significant in
SGOT ULN. Notably, baseline LDH levels were a consis- multivariate models included age, ECOG performance sta-
tent predictor of mortality throughout the study (e.g., at the tus, prior chemotherapy, and FACT-G score. Because these
6-, 12-, and 18-month time points). variables have been well recognized as factors prognostic for
survival in patients with metastatic breast cancer (14, 31),
they provide validation for the methodology used in the
Discussion current analyses. Univariate and multivariate analyses have
The registration trial comparing ZOL with pamidronate identified baseline bone biomarker levels such as NTX and
in patients with bone metastases from breast cancer BSAP as prognostic factors for occurrence of SREs in patients
generated an extensive database of demographic charac- with bone metastases (24, 32). However, although both
teristics, concomitant therapy, and clinical outcomes, NTX and BSAP were significantly correlated with risk of
including survival and laboratory parameters that provide death in the univariate model in the current analysis, this
a rich data source for exploratory analyses. All patients in statistically significant correlation was not maintained for
the current analysis received ZOL therapy, which remains either biomarker in the multivariate model (Table 2).
a standard of care for patients with bone metastases from Notably, LDH is a key enzyme in energy production in
solid tumors (25). Access to this database has permitted many tissues and cell types, and LDH serum concentrations
this large, multicenter, multivariate analysis of factors become elevated following tissue injury or during disease
prognostic for survival in patients with bone metastases states. The potential role of LDH as a prognostic biomarker
from breast cancer (30). A key finding from these analyses in oncology has long been recognized. In patients with
is the emergence of LDH as a significant and powerful Ewing’s sarcoma of bone (N ¼ 618), baseline serum LDH
prognostic variable for risk of death in patients with levels were significantly higher in patients with metastatic
advanced breast cancer. disease (P < 0.0001) and prognostic of shorter disease-free
6352 Clin Cancer Res; 18(22) November 15, 2012 Clinical Cancer Research
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Published OnlineFirst September 4, 2012; DOI: 10.1158/1078-0432.CCR-12-1397
Brown et al.
absolute measurements. Also, the possibility of false pos- be incorporated into future large breast cancer studies, and
itive LDH results would actually reduce the chance of LDH also may be an important stratification factor in the
showing an association when one exists. Thus, if false design of future randomized trials.
positives were present in the data, the model would more
likely yield conservative estimates of the association Disclosure of Potential Conflicts of Interest
between LDH and survival. J. Brown has received honoraria from speakers bureau from Novartis
There are potential limitations in this study worthy of and Amgen and is a consultant and/or advisory board member for
Novartis, Amgen, Roche, and Bristol-Myers Squibb. R. Cook is a consul-
note. Laboratory-specific ULNs for LDH were used to tant/advisory board member for Abbott, Amgen, and Novartis. A. Lipton
specify cut-off points, in preference to an absolute LDH has received commercial research grants from Novartis, Monogram Bios-
value as the cutoff. This was considered appropriate to ciences, and Oncogene Science; has received honoraria from speakers
bureau from Novartis, Amgen, and Genentech; is a consultant/advisory
reflect local factors and because some variation in abso- board member for Novartis, Amgen, Galapagos, and Acceleron Pharm;
lute reference ranges was reflected in the ULN across and has given expert testimony for Novartis. R. Coleman has received
other commercial support from Novartis; honoraria from speakers bureau
centers. Consequently, it is difficult to directly compare from Novartis and Amgen; is a consultant/advisory board member for
data obtained in this study with those previously reported Novartis and Amgen; and has previously given expert testimony on the
for patients with advanced cancer with or without bone behalf of Novartis.
metastases. If LDH is to be used in the future as a
prognostic factor for survival for breast cancer patients Authors' Contributions
with bone metastases, it is desirable to agree on a com- Conception and design: J.E. Brown, A. Lipton, R.E. Coleman
Development of methodology: J.E. Brown, R.J. Cook, A. Lipton
mon way of expressing LDH values across centers. This Analysis and interpretation of data (e.g., statistical analysis, biosta-
study had a limited follow-up period and duration of tistics, computational analysis): J.E. Brown, R.J. Cook, A. Lipton
bisphosphonate use, being confined to the duration of Writing, review, and/or revision of the manuscript: J.E. Brown, R.J. Cook,
A. Lipton, R.E. Coleman
the original phase III study. The LDH assessment was Study supervision: R.E. Coleman
recorded at study entry and not at the time of diagnosis of
bone metastases (median difference 3.75 months). How- Acknowledgments
ever, given that the average survival for patients with The authors thank Cancer Research UK for support for J.E. Brown. The
advanced breast cancer was typically 18 to 26 months authors thank Michael Hobert, ProEd Communications, Inc., for medical
editorial assistance with this article.
after diagnosis of bone metastases, depending on hor-
monal therapy (23), the limited follow-up is not likely to
have any substantial impact on the survival data. Grant Support
Financial support for medical editorial assistance was provided by Novar-
On the basis of the current study, the combination of tis Pharmaceuticals Corporation, East Hanover, New Jersey.
LDH with other prognostic factors into a weighted prog- The costs of publication of this article were defrayed in part by the
nostic score for survival in patients with bone metastases payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
from breast cancer would be a valuable next step. Such a this fact.
score would then require confirmation and validation in a
future prospective study before adoption into new man- Received May 7, 2012; revised August 21, 2012; accepted August 21, 2012;
agement guidelines. Assessment of LDH should, therefore, published OnlineFirst September 4, 2012.
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