Association of Baseline Serum DKK-1 Levels with Subsequent Bone Metastasis in Stage III Breast Cancer

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Abstract
Background and Objectives: Bone metastasis is the most frequent site of distant spread in breast cancer, yet reliable biomarkers capable of identifying patients at increased risk before metastatic disease becomes clinically evident remain limited. We investigated whether baseline serum Dickkopf-1 (DKK-1) and irisin levels were associated with subsequent bone and liver metastasis in patients with stage III breast cancer. Materials and Methods: Sixty-three patients with stage III breast cancer were retrospectively included. DKK-1 and irisin concentrations were measured using enzyme-linked immunosorbent assay in archived serum samples collected at the time of initial diagnosis, before the start of definitive treatment. Associations between biomarker levels and subsequent metastatic outcomes were evaluated using maximally selected rank statistics for cut-off determination, Kaplan–Meier survival analysis, restricted cubic spline analysis, and Cox proportional hazards regression models. Results: During follow-up, 29 patients developed bone metastasis. Baseline serum DKK-1 levels were significantly higher in patients who subsequently developed bone metastasis than in those who remained metastasis-free (p = 0.005), whereas irisin levels showed no significant difference. An exploratory optimal DKK-1 cut-off value of 66.75 pg/mL was identified. High baseline DKK-1 remained independently associated with bone metastasis-free survival after multivariable Cox proportional hazards regression including T stage, histological grade, Ki-67 index, lymphovascular invasion, irisin, ALP and CA15-3 (HR = 7.48, 95% CI 1.67–33.43, p = 0.008). Elevated baseline ALP was also independently associated with bone metastasis-free survival (BMFS) (HR = 4.12, 95% CI 1.35–12.53, p = 0.013). Neither DKK-1 nor irisin was significantly associated with subsequent liver metastasis. Conclusions: Elevated baseline serum DKK-1, but not irisin, was independently associated with shorter BMFS in patients with stage III breast cancer. Baseline DKK-1 may represent a candidate biomarker for identifying patients at increased risk of skeletal metastasis; however, these exploratory findings require external validation in prospective multicenter studies before any clinical implementation can be considered.

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