Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial

Abstract

Background: Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis.

Methods: Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided.

Results: When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell's c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI = 0.51 to 0.62), and 1-CTP of 0.57 (95% CI = 0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid.

Conclusions: Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study.

Figure 1.

Hazard ratios and 95% confidence intervals for adjusted continuous analyses of log-transformed data for baseline N-terminal propeptide of type-1 collagen, C-telopeptide of type-1 collagen, and pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen and disease outcomes. P values were calculated using the likelihood ratio χ² test statistic, and tests were two-sided. 1-CTP = pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen; CI = confidence interval; CTX = C-telopeptide of type-1 collagen; HR = hazard ratio; P1NP = N-terminal propeptide of type-1 collagen.

Figure 2.

A) Cumulative incidence function for time to bone metastasis at any time for categorical analysis of N-terminal propeptide of type-1 collagen (P1NP) level ≥ or < 70 ng/mL (hazard ratio [HR] for adjusted analyses = 1.61, 95% confidence interval [CI] = 1.07 to 2.42, P = .03). B) Cumulative incidence function for time to bone metastasis at any time by treatment arm for participants with high P1NP (≥70 ng/mL; HR for adjusted analyses = 0.989, 95% CI = 0.517 to 1.895, P_interaction = .69 for the interaction between P1NP and treatment; ie, to assess for differing effects of treatment within the two groups of high or normal P1NP). P values were calculated using the likelihood ratio χ² test statistic, and tests were two-sided. 1-CTP = pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen; CTX = C-telopeptide of type-1 collagen; P1NP = N-terminal propeptide of type-1 collagen; ZOL = zoledronate 4 mg (19 doses over 5 years).

Figure 3.

χ² values from adjusted Cox proportional hazards model, analyzing bone metastasis at any time by N-terminal propeptide of type-1 collagen (P1NP), with differing high vs normal P1NP cut-points. Optimum cut-point observed at 64 ng/mL with a corresponding P value of .003. P values were calculated using the likelihood ratio χ² test statistic, and tests were two-sided. P1NP = N-terminal propeptide of type-1 collagen.