HER-2/neu (c-erbB-2) Evaluation in Primary Breast Carcinoma by Fluorescent In Situ Hybridization and Immunohistochemistry With Special Focus on Intratumor Heterogeneity and Comparison of Invasive and In Situ Components

Abstract

We have studied the intratumor HER-2/neu heterogeneity in 78 consecutive and population-based primary invasive breast carcinomas. Within the invasive component, heterogeneity was detected in only 1 of 78 tumors. In 48 tumors (62%), we found both in situ and invasive components in analyzed tissue sections. Twelve of these 48 tumors had a difference of at least 2 arbitrary units in the in situ compared with the invasive part of the tumor with regard to the HER-2/neu status analyzed by HercepTest (immunohistochemistry). Eight of these 12 tumors were reanalyzed with fluorescent in situ hybridization and immunohistochemistry with and without a new Automated Cellular Imaging System. In this limited material, immunohistochemistry in combination with the Automated Cellular Imaging System seemed to have a better correlation with fluorescent in situ hybridization than immunostaining analyzed manually. In conclusion, HER-2/neu expression is not seldom heterogeneous in invasive compared with in situ components within a tumor. This finding should be considered in the choice of evaluation method. To avoid heterogeneity as a confounding factor in HER-2/neu analyses, detection methods such as immunohistochemistry and fluorescent in situ hybridization, which can provide evaluation in a preserved tissue architecture, should be used. Perhaps the intratumor HER-2/neu heterogeneity can explain some of the unexpected failures of trastuzumab therapy.

Breast Cancer Intra-Tumor Heterogeneity: One Tumor, Different Entities

“…In some cases, diverse gene copy aberrations were found 18 . Intra-tumor heterogeneity also has been observed in breast cancer biomarkers (ER, PR, HER2), where tumors with spatial areas will exhibit high or low expression of these biomarkers [54][55][56][57][58] .…”

Comparison of the expression levels of molecular markers among the peripheral area and central area of primary tumor and metastatic lymph node tumor in patients with squamous cell carcinoma of the lung

“…RTKs are transmembrane proteins that serve as receptors for many growth factors, and activation of the RTK signaling pathways lead to cell proliferation and anti-apoptotic activity. Heterogeneous expression of RTKs in cancer cells has also been reported (Andersson et al 2004). Taken together, determination of the expression heterogeneity of these biomarkers would be required for the identification of clinically relevant biomarkers.…”

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

“…8,13,14 Intratumoral heterogeneity of HER2 gene amplification has been demonstrated in a subset of breast cancers. [15][16][17][18][19][20][21][22][23] However, as the previous studies targeted different sets of samples, the frequency of intratumoral HER2 heterogeneity was quite variable and was not comparable between the studies. Andersson et al 15 found HER2 heterogeneity within the invasive components of breast cancers in only 1 of 78 tumors.…”