Abstract P4-09-09: Serum SDF-1: Biomarker of Bone Relapse in the NCIC MA.14 Adjuvant Breast Cancer Trial

Abstract

Background: Massague et al have shown that breast cancer cell line subpopulations with elevated bone metastatic activity overexpress chemokine receptor 4 (CXCR4), interleukin 11 (IL11), osteopontin (OPN) and connective tissue growth factor (CTGF) (Cancer Cell 3:537, 2003). CXCR4 overexpression results in bone-homing and extravasation of tumor cells in bone. In MA.14, we found that serum β-CTx was associated with bone-only relapse while Basik et.al showed that higher serum stromal cell-derived factor 1 (SDF-1) (ligand for CXCR-4) levels were associated with worse overall event-free survival (EFS) (ASCO 2010). In this study, we examined concurrently the association of both β-CTx and serum SDF-1 with bone relapse. Methods: Serum β-CTx (Serum CrossLaps, Nordic Biosciences, Copenhagen, DN) was determined in pretreatment sera from 621 of 667 NCIC CTG MA.14 patients. SDF-1 (CXCL12) (R&D Systems, Minneapolis, MN) levels were successfully determined in the 4 month post-treatment serum (SDF-1) for 508 (76%) of the patients. Trial stratification was by administration of adjuvant chemotherapy, axillary lymph node status, and ER and/or PR status. Recurrence-free survival (RFS) was defined as the time from randomization to the time of recurrence of the primary disease. Adjusted and unadjusted Cox step-wise forward multivariate analyses were used to assess the effects of β-CTx, SDF-1, trial therapy and baseline patient characteristics on non-bone, all bone and bone-only RFS; a factor was added if p<=0.05. Results: Joint assessment of β-CTx and SDF-1 was possible for 493 (74%) of the 667 patients. Imbalances in who was, or was not, included in this subset led to the trial arm of Tamoxifen + Octreotide LAR having a significant longer unadjusted ITT non-bone RFS (p=0.03-0.06). There was shorter time to bone metastasis of any type with higher lymph node involvement (p=0.001), larger T (p=0.02), and higher log SDF-1 (p=0.03). Meanwhile, high categorical and continuous β-CTx was associated multivariately with shorter bone-only RFS (p=0.04 and 0.01, respectively); higher log SDF-1 was only associated with shorter bone-only RFS (p=0.02) when the number of strata were reduced to 2 categories per factor. Conclusions: Higher serum SDF-1 level may be associated with bone metastasis, although there is less evidence of its relevance in bone-only relapse than there is for the biomarker β-CTx. Serum SDF-1 deserves further study as a promising predictive factor of bone relapse in breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-09.