Genentech, of S. South Francisco, California, plans to unveil the details of the 808-women trial at this year's San Antonio Breast Cancer Symposium, in San Antonio, Texas, which kicks off on December 6. The company also plans to file for approval of the combination shortly after the presentation. It is difficult to judge at this stage whether Genentech will obtain approval solely on the basis of the Cleopatra study, which had progression-free survival as its primary end point. Recently, Genentech and the US Food and Drug Administration (FDA) have locked horns over this issue in connection with the approval of Avastin (bevacizumab) in breast cancer (Nat. Biotechnol. 29, 669, 2011). “I don't think it should be impossible, but the data will have to be really, really good,” says Elmar Kraus, analyst at DZ Bank in Frankfurt.
HER2 expression, which is associated with a poor prognosis, occurs in around 20% of invasive breast cancers (as well as in lung, ovarian, pancreatic and gastric cancers). In normal cells, the transmembrane tyrosine kinase is involved in cell survival and differentiation. Signaling events implicate four closely related HER family members. HER2 is recruited to a ligand-receptor complex comprising one of over ten neuregulin ligands and either HER1, HER3 or HER4. When aberrant expression of HER2, arising from gene amplification events, gives rise to high concentrations of HER2, this equilibrium is disrupted, leading to the protein becoming constitutively active. Thus, dimerization with other HER receptors—and subsequent signaling—can occur, even in the absence of ligand binding. “We think the oncogenic unit here is the higher order complex between HER2 and HER3,” says Genentech senior staff scientist Mark Sliwkowski, who has been part of Genentech's effort in developing HER2-targeting therapies for some 20 years.
This is a preview of subscription content, access via your institution