Abstract B250: Clinical benefit of lapatinib-based therapy in patients with HER2-positive breast tumors expressing p95HER2

Abstract

Abstract Purpose: A subgroup of HER2 overexpressing tumors also express p95HER2, a truncated fragment of the HER2 receptor that lacks the extracellular domain, retains kinase activity and correlates with intrinsic trastuzumab resistance. We tested the hypothesis that the small molecule lapatinib, an EGFR/HER2 dual tyrosine kinase inhibitor, would be active in these tumors. We studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinic [lapatinib monotherapy (Study EGF20009) or lapatinib in combination with capecitabine (Study EGF100151)]. Patients and Methods: Expression of p95HER2 in primary tumors was evaluated by immunofluorescence and correlated with clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) and progression-free survival using logistic regression and Cox-proportional hazard models. Results: Lapatinib was efficacious in inhibiting tumor growth and HER2 downstream signaling of p95HER2 expressing tumors in two different animal models. In human samples, expression of p95HER2 was evaluable in 76% (105/138) and 56% (223/399) of patients from EGF20009 and EGF100151 studies, respectively. The percentage of p95HER2 positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In neither study there was a statistically significant difference in progression-free survival between p95HER2-positive and p95HER2-negative patients. Similarly, in both studies the clinical benefit rate was not significantly associated with p95HER2 expression. Conclusions: Lapatinib as a monotherapy or in combination with capecitabine is equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B250.