Abstract
Abstract Background: Approximately one-half of HER2-positive breast cancer patients will respond to first-line trastuzumab-containing therapy. However, in those patients with an initial trastuzumab response, most will progress within a year with acquired resistance. Since trastuzumab treatment is also now used in the HER2-positive adjuvant breast cancer setting, trastuzumab resistance will continue to be a vexing clinical problem, and better predictive and prognostic biomarkers are urgently needed. Methods: Serum HER2, tissue inhibitor of metalloproteinase-1 (TIMP-1), urokinase-type plasminogen activator (uPA), CA9, Insulin-like growth factor-1 receptor (IGF-1R), VEGF-165, and endoglin were measured using ELISA assays in 60 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. The HER2, TIMP-1, uPA, CA9, IGF-IR, and VEGF-165 ELISAs were from Oncogene Science/Siemens Healthcare Diagnostics, Cambridge, MA; and the endoglin ELISA was from R&D Systems, Minneapolis, MN. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with continuous pretreatment serum biomarker variables. Results: Pretreatment serum HER2 (p= 0.008), TIMP-1 (p< 0.0001), uPA (p= 0.006), endoglin (p= 0.010), and CA9 (p <0.0001) were all significant as univariate continuous biomarkers for predicting PFS to first-line trastuzumab-containing therapy, but VEGF (p=0.94) and IGF-IR (p=0.11) were not. In multivariate analysis for PFS with all 7 biomarkers, only serum CA9 (p= 0.002) was a significant independent covariate. For OS, pretreatment serum HER2 (p= 0.018), TIMP-1 (P<0.0001), uPA (P<0.0001), endoglin (0.006), CA9 (P<0.0001) were all significant as univariate continuous biomarkers for prognosis, but VEGF (p=0.69) and IGF-IR (p=0.098) were not. In multivariate analysis for OS with all 7 biomarkers, only serum CA9 was a significant independent prognostic covariate (p=0.001), and TIMP-1 trended significant (p=0.069). Conclusions: Elevated pretreatment serum CA9 (a marker of hypoxia) predicts reduced progression-free survival and overall survival in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. These serum biomarkers deserve further study in larger trials of HER2-targeted breast cancer treatment. Supported by a grant from Komen for the Cure. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-07.
Published Version
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