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.

Background/Objectives: Standard hereditary breast cancer gene panels fail to identify causative variants in some patients meeting hereditary breast and ovarian cancer (HBOC) criteria. This exploratory, hypothesis-generating study characterised germline variants in MCPH1, functionally related DNA damage response genes, and selected low-evidence candidate genes in breast cancer patients with uninformative standard panel results. Methods: A total of 185 patients meeting NCCN/ACMG criteria, with normal 42-gene panel and BRCA1/2/PALB2 MLPA results, underwent second-tier targeted sequencing. Group 1 comprised MCPH1 and related genes (TP53BP1, MDC1, TOPBP1, UBE2N, RAD52); Group 2 consisted of Genomics England PanelApp candidates (ATRIP, ESR1, PPM1D, RAD54L, RRAS2, XRCC2). No ethnically matched control cohort was available. Variants were classified per ACMG 2015 guidelines and confirmed by Sanger sequencing. Results: Rare variants meeting reporting criteria were identified in 20/185 patients (10.8%): one likely pathogenic (LP) MCPH1 frameshift deletion (c.1869_1870del) in a luminal B invasive ductal carcinoma patient, nineteen variants of uncertain significance (VUS), and one unconfirmed copy number variant. ATRIP was the most frequently implicated Group 2 gene (4 patients), including a homozygous variant; RAD54L variants were identified in three patients, including the only male breast cancer case. Conclusions: These descriptive findings identify MCPH1, ATRIP, MDC1, TOPBP1, and RAD54L as candidates warranting evaluation in case–control studies with ancestry-matched cohorts, functional validation, and family segregation analysis before any consideration for panel inclusion.

Background/Objectives: Sarcopenia predicts increased morbidity and mortality in gastrointestinal (GI) cancer. This study evaluated the longitudinal association between changes in the skeletal muscle index (SMI) and serum procollagen type III N-terminal peptide (PIIINP), together with sarcopenia and malnutrition screening tools (SARC-F, SARC-CalF, MUST), during chemotherapy for GI cancer. Methods: In this prospective single-center study, 170 patients with GI cancer were assessed at baseline and month 6; 48 died, and longitudinal analyses included the 122 survivors. SMI was derived from bioelectrical impedance analysis (Tanita SC-330) using the Janssen equation, and serum PIIINP was measured at both time points. The primary endpoint was the association between the percentage changes in SMI and PIIINP. Results: BMI, SMI, and handgrip strength decreased and SARC-F and SARC-CalF scores increased significantly (all p < 0.001); the prevalence of low muscle mass rose from 29% to 52%, and PIIINP increased significantly. The percentage changes in SMI and PIIINP were strongly inversely correlated (ρ = −0.733, p < 0.001). In the parsimonious multivariable model, the percentage change in PIIINP (β = −0.47) and month-6 albumin (β = 0.31) were independently associated with the change in SMI (R² = 0.37); the albumin association was model-dependent and not retained in the expanded model. Conclusions: In patients with GI cancer receiving chemotherapy, progressive muscle loss over six months was accompanied by a rise in the circulating collagen turnover marker PIIINP. Because the study was observational, restricted to survivors, and based on a non-muscle-specific marker, causal and muscle-specific inferences are unwarranted; PIIINP nonetheless merits further evaluation as a monitoring biomarker.