Biomarker Analyses in Phase 2 Single-Agent Trials of Dasatinib for Breast Cancer.
Authors: L. Strauss, O. Sy, J. Fairchild, C. Fu, A. Rybicki, S. Yoganathan, D. Brickman, C. Harbison, L. Ploughman
Journal: Cancer Research (2009)

Abstract Background: Dasatinib (BMS-354825) is a potent SRC inhibitor being studied in several solid tumors including breast cancer. Expression profiling of breast cancer cell lines led to the identification of genes putatively correlated with dasatinib sensitivity.1,2 Inhibition of Src-family kinases may have complex effects on angiogenesis; circulating levels of VEGFR2 and collagen type IV (CollIV) are related to changes in VEGF signaling. Two Phase 2 single-agent trials of dasatinib3,4 have been performed in patients with locally-advanced or metastatic advanced breast cancers. Tumor markers may be used to predict clinical benefit and circulating biomarkers may reveal key mechanisms of action.Methods: Biomarker data from two Phase 2 trials including 114 patients were aggregated for this analysis. Archival tumor tissue from most recent prior surgery was collected in both trials; tumor samples were submitted for 38 of 44 patients with triple-negative, 39 of 46 patients with ER/PR+, and 20 of 24 patients with Her2/neu-amplified breast cancer. The initial dasatinib dose of 100 mg BID (n=46) was reduced to 70 mg BID (n=68) to improve tolerability. Based on mRNA results, immunohistochemical (IHC) procedures were developed for caveolin (Cav), phospho-Cav (p-Cav; scored as membrane vs cytoplasmic), EphA2 and IGFBP-2. Staining intensity was expressed on a scale of 0–3. Plasma was collected at baseline and after 2 and 4 weeks of dasatinib treatment and analyzed for VEGFR2 and CollIV by enzyme-linked immunosorbent assay (ELISA). Quantitative biomarker values pre-treatment and at ≥1 on-study time point for 71 of 114 patients were expressed as percent change from baseline. Tumor mRNA expression is being analyzed in all available tissue.Results: Protocol-defined clinical benefit was observed in 13 patients: 4 with triple-negative, 7 with ER/PR+, and 2 with Her2+ (which were also ER+) malignancies. Tumor tissue was prioritized and adequate for analysis in 89 tumors for Cav, 80 for p-Cav, 88 for EphA2 and 84 for IGFBP-2. Positive IHC (2-3+ intensity) was recorded for Cav in 35% of patients, with 11% and 25% positive for p-Cav in cytoplasm and membrane, respectively, and in 27% for EphA2 and 23% for IGFBP-2. No association was detected between clinical benefit and IHC results. Consistent increases in plasma biomarkers were observed in &amp;gt;90% of subjects. Median percent change (at Days 15 &amp; 29, respectively) was 22% &amp; 27% in VEGFR2 and 32% &amp; 46% in CollIV; the mechanism of this change is being further investigated. Increased CollIV on treatment was associated with drug-related Grade 3-4 adverse events in first 4 weeks and with clinical benefit, but not with tumor subtype. Data on mRNA expression will be presented.Conclusions: The selected IHC analytes did not predict clinical benefit in these trials. Consistent early increases in VEGFR2 and CollIV suggest an effect of dasatinib on vascular endothelium which appears related to both safety and efficacy.1. Huang et al. Cancer Res. 2007;67(5):2226-38.2. Finn et al. Breast Cancer Res Treat. 2007;105(3):319-26.3. Finn et al. SABCS 2008;abstract 3118.4. Mayer et al. ASCO 2009;abstract 1011. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2034.