<i>HER2</i> Heterogeneity Affects Trastuzumab Responses and Survival in Patients With HER2-Positive Metastatic Breast Cancer

다국어 초록 (Multilingual Abstract)

<P><B>Objectives:</B></P><P>Heterogeneity of <I>HER2</I> gene amplification is found in a subset of breast cancers. We investigated the impact of <I>HER2</I> heterogeneity on trastuzumab responses and clinical outcomes in 112 patients with HER2-positive metastatic breast cancer.</P><P><B>Methods:</B></P><P>Regional and genetic heterogeneity of <I>HER2</I> gene amplification was determined in three different areas of each tumor by immunohistochemistry and silver in situ hybridization. We also assessed the overall levels of <I>HER2</I> amplification and the proportion of tumor cells with a <I>HER2</I>/CEP17 ratio of more than 2.2 or strong and complete membranous (3+) expression of HER2 protein.</P><P><B>Results:</B></P><P><I>HER2</I> regional and genetic heterogeneity based on the <I>HER2</I>/CEP17 ratio was confirmed in 8.7% and 2.7% of cases, respectively. Poor response to trastuzumab was associated with overall low-level or equivocal amplification, <I>HER2</I> regional heterogeneity by the <I>HER2</I>/CEP17 ratio, the <I>HER2</I>/CEP17 ratio of more than 2.2 in less than 80% of tumor cells, and <I>HER2</I> immunohistochemical expression of 3+ in less than 75% of tumor cells. In survival analyses, low-level or equivocal <I>HER2</I> amplification, <I>HER2</I> regional heterogeneity based on the <I>HER2</I>/CEP17 ratio, and the <I>HER2</I>/CEP17 ratio of more than 2.2 in less than 80% of tumor cells were associated with shorter time to progression and lower overall survival in univariate and multivariate analyses.</P><P><B>Conclusions:</B></P><P>These results suggest that accurate assessment of <I>HER2</I> status, including <I>HER2</I> heterogeneity, is important in predicting trastuzumab responses and outcomes in patients with HER2-positive metastatic breast cancer.</P>