Abstract P2-10-16: Quantitative HER3 protein expression and PIK3CA mutation status in matched samples from primary and metastatic breast cancer tissues and correlation with time to recurrence

Abstract

Abstract Background: HER3 is thought to play a prominent role in resistance to HER2-directed breast cancer therapies. Recent data suggest that HER3 levels also influence HER2-normal breast tumor biology. HER3 and PI3K signaling are linked in that in HER3 signaling activates PI3K and inhibition of PI3K activity can upregulate HER3 expression. Here, we measured quantitative HER3 protein expression levels and PIK3CA mutation status in matched tissues from the primary tumor and site of metastasis to assess correlations with time to recurrence. Methods: 44 pairs (8 HER2+ by HERmark®) of matched tissues from the primary tumor and the site of metastasis were evaluated for HER3 protein expression using a sensitive, quantitative assay for HER3 protein expression in FFPE tissue sections (VeraTag®). Matched samples were also evaluated for quantitative HER2 expression (HERmark) and for PIK3CA mutations at exon 9 (E542K and E545K) and exon 20 (H1047R). Results: HER3 protein expression at the metastatic site was largely independent of HER3 levels at the primary site (Spearman p = 0.50) in contrast to HER2 expression (Spearman p = 0.0004). HER3 expression in the primary tumor correlated with time to recurrence (TTR) (HR = 2.0 per 2-fold increase in HER3; p < 0.0001). Conversely, HER3 expression measured at the site of metastasis was not correlated with TTR (p = 0.55). Estrogen receptor negative tumors were less likely to have PIK3CA mutations (p = 0.023). In cases of primary tumors with PIK3CA mutations, no reversions to wild-type PIK3CA were observed in the metastatic sites. In metastatic tumors, mutations detected in the primary tumor as well as new mutations were observed. A gain of an exon 9 mutation at the metastatic site correlated with shorter TTR (HR = 2.5; p = 0.043). Excluding the 8 samples that were HER2+ by HERmark, longer TTR was observed for patients with PIK3CA mutations in the primary tumor (HR = 0.47; p = 0.042), which is consistent with previous reports. Interestingly, the longer TTR for those with PIK3CA mutations appeared to be dependent on quantitative HER3 protein level (interaction p = 0.065). Conclusions: HER3 protein expression in matched primary and metastatic breast cancer tissues were unrelated. This may indicate that HER3 protein is influenced by the different tumor microenvironments of the primary and metastatic sites. PIK3CA mutations were either maintained or acquired at metastatic sites. Both low HER3 protein expression and the presence of PIK3CA mutations in the primary tumor but not the metastatic tumor were associated with longer TTR. These observations suggest that HER3 protein expression may be an important prognostic factor for breast cancer progression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-16.