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

Abstract

BackgroundAdjuvant 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.MethodsMarkers 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.ResultsWhen 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.ConclusionsSerum 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.

From latency to overt bone metastasis in breast cancer: potential for treatment and prevention

“…These included serum BALP and serum or urine NTX levels, which are associated with risk reduction for death and pathological fractures upon treatment with bisphosphonates [100][101][102][103][104][105]. Patients with high serum levels of P1NP, CTX, and 1-CTP shortly after diagnosis were shown to be at high risk of bone metastasis during the course of the disease [106], confirming previous indications in breast and lung cancers. This latter evidence came from a retrospective analysis of serum from a subset of patients from a large phase III trial, the AZURE trial [107].…”

Breast cancer outcome in relation to bone mineral density and bisphosphonate use: a sub-study of the DATA trial

“…Adjustment for bisphosphonate use was not performed, patients were treated with tamoxifen instead of an aromatase inhibitor, and importantly, no information on BMD measurements was available [15]. Also a sub-study of the AZURE trial found the bone turnover markers P1NP, CTX, and TX size of tumour could not be assessed, ER: oestrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor 2 a All patients received cyclophosphamide-based chemotherapy 1-CTP to show good prognostic ability for bone-specific recurrence [16]. None of the markers were prognostic for overall distant recurrence and not predictive of treatment benefit from zoledronic acid.…”

An Assessment of Novel Biomarkers in Bone Metastatic Disease Using Multiplex Measurement and Multivariate Analysis

“… 17 Futhermore Brown J. et al studied, in a large randomized trial, the use of P1NP, CTX, and pyridinoline cross-linked CTx of type-1 collagen in early breast cancer adjuvantly treated by zoledronic acid. 18 …”