HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer

Hanna Styczen, Iris Nagelmeier, Tim Beissbarth, Manuel Nietert, Kia Homayounfar, Thilo Sprenger, Ute Boczek, Kathrin Stanek, Julia Kitz, Hendrik A Wolff, B Michael Ghadimi, Peter Middel, Torsten Liersch, Josef Rüschoff, Lena-Christin Conradi, Hanna Styczen, Iris Nagelmeier, Tim Beissbarth, Manuel Nietert, Kia Homayounfar, Thilo Sprenger, Ute Boczek, Kathrin Stanek, Julia Kitz, Hendrik A Wolff, B Michael Ghadimi, Peter Middel, Torsten Liersch, Josef Rüschoff, Lena-Christin Conradi

Abstract

Objective: In this study, we evaluate the frequency of HER-2 and HER-3 expression in liver metastases from patients with colorectal cancer (CRLM). We analyzed the potential of HER-2 and HER-3 as therapeutic targets and evaluated their prognostic value.

Patients and methods: Overall 208 patients with CRLM were enrolled. HER-2 and HER-3 expression were determined in metastatic tissue of diagnostic punch biopsies (n = 29) or resection specimens (n = 179). The results of immunohistochemistry (IHC) scoring and In-situ-hybridization (ISH)-amplification were correlated with clinical parameters and for the 179 resected patients with cancer-specific (CSS) and overall survival (OS). The mean follow-up time was 56.7 months.

Results: Positivity of HER-2 status (IHC score 2+/ISH+ and IHC 3+) was found in 8.2% of CRLM. High expression of HER-3 (IHC score 2+ and IHC 3+) was detected in 75.0% of liver metastases. CSS after liver surgery was determined and was independent from the HER-2 status (p = 0.963); however HER-3 was prognostic with a favorable course for patients showing an overexpression of HER-3 (p = 0.037).

Conclusions: HER-2 overexpression occurs in only 8% of patients with CRLM but with 75% of cases HER-3 is frequently overexpressed in CRLM. Therefore, HER-2 and particularly HER-3 could serve as novel targets to be addressed within multimodal treatment approaches.

Keywords: HER-2; HER-3; colorectal cancer; liver metastases; targeted therapy.

Conflict of interest statement

CONFLICTS OF INTEREST

This work was supported by the Deutsche Forschungsgemeinschaft (KFO 179-2) and the BMBF consortium MetastaSys (0316173A). Roche Diagnostics provided detection kits for the immunohistochemical staining.

Figures

Figure 1. Examples of HER-2 and HER-3…
Figure 1. Examples of HER-2 and HER-3 immunohistochemical staining and Dual-ISH according to the HER-2 algorithm
This figure shows the HER-2 algorithm with examples of HER-2 and HER-3 according to the magnification rule as adopted from gastric cancer scoring for HER-2. *in ≥10% tumor cells in resection specimens.
Figure 2. HER-3 immunohistochemical staining of tissue…
Figure 2. HER-3 immunohistochemical staining of tissue samples from liver metastases
This figure pictures tissue samples from HER-3 immunohistochemical staining from CRC liver metastases with various factors of magnification.
Figure 3. Cancer-specific and overall survival after…
Figure 3. Cancer-specific and overall survival after liver surgery in correlation with HER-3 expression
Kaplan-Meier curve for CSS and OS of CRC patients with high and low HER-3 expression levels (p = 0.037, p = 0.049). The Cox model for CSS and OS based on HER-3 status from 179 resection specimens of liver metastases.
Figure 4. Cancer-specific and overall survival survival…
Figure 4. Cancer-specific and overall survival survival after liver surgery in correlation with HER-2 expression
Kaplan-Meier curve for CSS and OS of CRC patients with high and low HER-2 expression levels (p = 0.963, p = 0.747). The Cox model for CSS based on HER-2 status from 179 resection specimens of liver metastases.

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