HER-2 gene amplification and protein overexpression has been associated wit
h increased risk of advanced-stage breast cancer and poor prognosis. Recent
ly, a single missense point mutation (Ile(655)Val) in the transmembrane dom
ain of the HER-2 gene was associated with a 40% increase in breast cancer r
isk among women 45 years of age and younger. In this analysis, we measured
the association between the Ile(655)Val variant and postmenopausal breast c
ancer among women participating in the Hawaii and Los Angeles Multiethnic C
ohort. Risk of localized breast cancer was significantly elevated among wom
en with the HER-2 variant, but not among women with regional or metastatic
disease. Women with at least one copy of the Valine variant were approximat
ely one-half as likely to have high-stage as low-stage breast cancer (P = .
02), and this effect was present across racial/ethnic groups.