Abstract Background: The Cyfra 21-1 epitope is a polypeptide originating from cytokeratin-19 fragments possibly released by cell death and was an interesting serum marker in small and/or retrospective studies in breast cancer. On the back of circulating tumor cell (CTC) detection, the prospective IC 2006-04 study planned serum markers (CEA, Ca15.3, Cyfra 21-1) measurements. Methods: Metastatic breast cancer patients were included in a multicentric non-interventional study before the start of the 1st line chemotherapy. Blood biomarkers, including CTC detection (CellSearch®, ≥5CTC/7.5ml), were analyzed at 4 different times: before the start of the chemotherapy, before cycle 2 (ie mostly at day 21), at first tumor evaluation (ie before cycle 3/4) and at tumor progression. Results: 191 of the 267 patients included had Cyfra 21-1 assessed at inclusion. CTC level was ≥5CTC/7.5ml in 44% of the cases. Cyfra 21-1>ULNV (in 65% of pts) was not correlated with tumor ER/PR/HER2 status but strongly correlated with PS (p=8e-04), number of metastatic sites (p=0.0001), Ca15.3 (p=0.009), CEA (p=0.005), LDH (p=7e-08) and CTC detection (p=2e-06). CTC (≥5CTC/7.5ml) and Cyfra21-1 (>ULNV) correlation (N patients) The effectiveness of curcumin in the treatment of HER-2 overexpressed breast cancer was further confirmed through in vivo BT-474 xenograft model. The comparable ability of curcumin to inhibit cell proliferation, mobility, and angiogenesis as herceptin, combined with the potential ability to overcome the herceptin resistance, curcumin may be a novel agent in the treatment of HER-2 overexressed breast cancer. Logistic regression showed that LDH (p=0.0005) and CTC (p=0.0004) were the two independent predictors of Cyfra 21-1 elevation. Baseline Cyfra 21-1 >ULNV was associated with early tumor progression (RECIST, p=0.03). In multivariate analysis including standard biomarkers (without CTC), baseline Cyfra 21-1 was independently associated with PFS (p=0.008, RR), together with PS (P<0.001), triple-negativity (P<0.001) and CEA (p=0.02). Multivariate analysis with CTC, subsequent Cyfra 21-1 analyses (cycles 2, 3-4 and progression) and correlation with tumor response and PFS will be will be shown at the meeting. Conclusion: Cyfra 21-1 is a commonly elevated serum marker in metastatic breast cancer and has an independent prognostic value. Although highly correlated, Cyfra 21-1 appears to be more frequently positive in metastatic breast cancer patients than CTC count. Multivariate analyses comparing CTC and Cyfra 21-1 at different time points will be shown at the meeting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-01-01.