Prognostic, predictive, and surrogate value of HER2 extracellular domain (ECD) for progression-free survival (PFS) in advanced breast cancer treated with lapatinib (lap) : a meta-analysis

Background: We performed a meta-analysis to determine the clinical utility of HER2 ECD in advanced breast cancer patients undergoing lap therapy. Methods: Data from Phase 3 clinical trials (EGF30001 , EGF30008 , EGF100151) of patients randomized to receive lap-containing or control treatments were analyzed. Baseline HER2 ECD (bECD) and tissue HER2 status were examined for associations with PFS. We also performed a landmark analysis to quantify the association between ECD change, as measured at 10 weeks post-randomization, with PFS, and assessed the extent ECD change predicted lap benefit. Results: Levels of bECD were higher in HER2+ (n=378) than HER2- (n=1060) patients (61.59 vs 14.25ng/ml, p15ng/ml), respectively. mPFS were 3.3 and 5.7 months for patients with ECD increase to >15ng/ml and ECD decrease to ≤15ng/ml, respectively. Similar finding was observed in the experimental arm (P<0.0001). In both treatment arms, there was 4% increase in risk of disease progression for every 10 unit ECD increment after adjustment of bECD and other factors (P<0.0001). Lap improved PFS over control (HR 0.83, P=0.002). Adjustment for ECD change yielded a similar result (HR 0.80, P