P. Dettmar

Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1

Intrinsic or acquired resistance to chemotherapy is responsible for failure of current treatment regimens in breast cancer patients. The Y‐box protein YB‐1 regulates expression of the P‐glycoprotein gene mdr1, which plays a major role in the development of a multidrug‐resistant tumor phenotype. In human breast cancer, overexpression and nuclear localization of YB‐1 is associated with upregulation of P‐glycoprotein. In our pilot study, we analyzed the clinical relevance of YB‐1 expression in breast cancer (n = 83) after a median follow‐up of 61 months and compared it with tumor‐biologic factors already used for clinical risk‐group discrimination, i.e., HER2, urokinase‐type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI‐1). High YB‐1 expression in tumor tissue and surrounding benign breast epithelial cells was significantly associated with poor patient outcome. In patients who received postoperative chemotherapy, the 5‐year relapse rate was 66% in patients with high YB‐1 expression. In contrast, in patients with low YB‐1 expressions, no relapse has been observed so far. YB‐1 expression thus indicates clinical drug resistance in breast cancer. Moreover, YB‐1 correlates with breast cancer aggressiveness: in patients not treated with postoperative chemotherapy, those with low YB‐1 expression are still free of disease, whereas the 5‐year relapse rate in those with high YB‐1 was 30%. There was no significant correlation between YB‐1 expression and either HER2 expression or uPA and PAI‐1 levels. Risk‐group assessment achieved by YB‐1 differed significantly from that by HER2 or uPA/PAI‐1. In conclusion, YB‐1 demonstrated prognostic and predictive significance in breast cancer by identifying high‐risk patients in both the presence and absence of postoperative chemotherapy, independent of tumor‐biologic factors currently available for clinical decision making.

Invasion Factors uPA/PAI-1 and HER2 Status Provide Independent and Complementary Information on Patient Outcome in Node-Negative Breast Cancer

PURPOSE The independent clinical relevance of invasion factors urokinase-type plasminogen activator (uPA)/PAI-1 and HER2 status was evaluated in lymph node-negative breast cancer patients (N = 118) without adjuvant systemic therapy after long-term follow-up of more than 10 years (median, 126 months). PATIENTS AND METHODS Levels of uPA and its inhibitor PAI-1 were prospectively measured by enzyme-linked immunosorbent assay in primary tumor tissue extracts. HER2 gene amplification (HER2_AMP) was evaluated by fluorescence in situ hybridization (FISH; Ventana Medical Systems HER-2/neu probe; Tucson, AZ), and HER2 protein overexpression (HER2_EXP) was evaluated by immunohistochemistry (IHC; Oncogene Science antibody Ab-3; Cambridge, MA) on parallel-cut formalin-fixed paraffin-embedded tissue sections. RESULTS uPA/PAI-1 was high (either one or both factors were high) in 44% of the tumors. HER2_AMP was detected by FISH in 33% of the patients, and HER2_EXP was found by IHC in 44% of the patients. In a multivariate analysis of established and tumor-biologic prognostic factors, uPA/PAI-1 was the only independent prognostic factor for disease-free survival ([DFS]; P <.001; relative risk [RR], 8.3; 95% confidence interval [CI], 3.4 to 20.4). Although HER2_AMP and HER2_EXP did not reach significance for DFS, they were significant for overall survival (OS), even in multivariate analysis (HER2_AMP: P =.004; RR, 3.7; 95% CI, 1.5 to 9.2; HER2_EXP: P =.009; RR, 3.4; 95% CI, 1.4 to 8.7). CONCLUSION After long-term follow-up, uPA/PAI-1 levels in primary tumor tissue reliably and strongly indicate an aggressive course of disease in lymph node-negative breast cancer independent of HER2 status. The particular prognostic effect of HER2 status on OS may reflect its ability to predict resistance to systemic therapy.