Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: A randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer

Introduction: The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1).Methods: Patients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n = 70) or T-DM1 (n = 67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction.Results: HER2 mRNA levels were obtained for 116/137 patients (HT = 61; T-DM1 = 55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR) = 0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA ≥ median (HR = 0.39; 95% CI 0.18 to 0.85) versus < median (HR = 0.85; 95% CI 0.44 to 1.67). In the T-DM1 arm, median progression-free survival (PFS) was not reached in patients with HER2 mRNA ≥ median and was 10.6 months in patients with HER2 mRNA < median. In the HT arm, PFS was 8.8 versus 9.8 months in patients with HER2 mRNA ≥ median versus < median, respectively. The effect of HER2 mRNA expression on objective response rates was less pronounced.Conclusions: This exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median. Trial registration: ClinicalTrials.gov NCT00679341.