HER2 Protein Expression Levels Research Articles

Differential spatial expression and activation pattern of EGFR and HER-2 in human breast cancer

20041 Background: Overexpression of HER family members is a well-established prognositc factor and identifies potential targets for antibody-based receptor blocking strategies. While several studies have analyzed the expression of HER-2 and other HER-family members in malignant tumors, considerably less is known about their expression and activation in non-involved breast tissue from breast cancer patients. Methods: We have therefore investigated the differential expression of EGFR, HER-2 and their tyrosinekinase activated forms (ptyr-1248 HER-2 and ptyr-845 EGFR) by using immunohistochemistry (IHC) in 64 tumor specimens containing malignant epithelium (a), non-malignant tissue located at the peritumoral margin (b), and univolved breast tissue obtained at a distance of at least more than 5 cm from the malignant tumor (c). Results: We found significantly higher HER-2 protein expression levels in malignant epithelium than in non-malignant epithelium (p = 0.000004, Fisher’s Exact Test). Stromal HER-2 was absent in any of the tissues investigated. Epithelial EGFR expression did not differ between the three tissue types, but stromal EGFR protein was significantly more common in peritumoral and non-involved distant tissues when compared to tumor tissues (p = 0.008, Fisher’s Exact Test). We only found one case of intratumoral epithelial ptyr-1248 HER-2 expression, and interestingley two cases in peritumoral and peripheral normal tissue. Furthermore, we did not observe ptyr-845 EGFR in any of the samples analyzed.We found a significant overall correlation between epithelial and stromal EGFR expression (r = 0.442; p < 0.0001; Spearman’s Rho). Furthermore, we found a significant overall correlation between stromal EGFR expression and normal tissue type (r = 0.170; p < 0.02; Spearman’s Rho), and an inverse correlation between epithelial HER-2 and normal tissue type (r = 0.492; p < 0.0001; Spearman’s Rho). Conclusion: We have found a differential expression pattern of EGFR, HER-2, and activated HER-2 that is dependent on the spatial relation to a malignant tumor. Our observation of decreased intratumoral EGFR expression and the absence of activated EGFR suggest that, in contrast to HER-2, EGFR inhibition might not be an ideal target for antibody therapy. No significant financial relationships to disclose.

Myocardial expression of HER2 and HER4 in anthracycline-pretreated breast cancer patients

652 Background: Therapeutic benefits of the powerful combination of Trastuzumab and anthracyclines in the management of HER2-overexpressing metastatic breast cancer are limited by a dramatic increase in cardiac side effects. Many data indicate an important role of HER2 and its preferred cardiac heterodimerisation partner HER4 in mediating essential myocytes survival pathways. Gene targeting of either receptor leads to cardiomyocyte apoptosis and cardiomyopathy. An interaction between Trastuzumab and HER2/HER4 mediated signaling might therefore contribute to the cardiotoxic side effects. We therefore have examined possible changes in the protein expression levels of HER2 and HER4 after anthracycline treatment. Methods: We examined HER2 and HER4 protein expression as well as HER2 gene amplification in 35 cardiac specimens obtained from autopsy material of breast cancer patients with a history of anthracycline treatment. The mean cumulative Epirubicin dose was 662 mg. In addition 10 patients with anthracycline- free pretreatment were assessed. Three of them had received immunotherapy with Trastuzumab. HER2 and HER4 expression were analyzed immunohistochemically using the HercepTest (DAKO) and the polyclonal antibody c-18 (SantaCruz) respectively. Copy numbers of the HER2 gene were determined by fluorescence in situ hybridisation (Inform-Kit Ventana). Results: In the 54 cardiac biopsies with and without anthracycline pretreatment no HER2 staining could be detected. In addition, no HER2 gene amplification was observed in all specimens. A HER4 expression could be detected in 13 of the 25 anthracycline pretreated specimens witch was not significantly different from the cases without anthracycline history (6/10). No relation of HER4 expression with the cumulative anthracycline dose could be noticed. Conclusions: This study shows that an anthracycline treatment does not result in changes of the HER2 or HER4 expression levels nor in amplification of the HER2 gene in the myocardium as suspected to probably underlie the onset of heart failure in anthracycline pretreated patients receiving Trastzumab therapy. No significant financial relationships to disclose.

HER2 and COX2 expression in human prostate cancer

COX2 and HER2 expression are associated with a poor prognosis in prostate cancer and HER2 has been linked to COX2 expression in colorectal cancer. The association between COX2 and HER2 expression was investigated in 117 patients with prostate cancer (89) or Benign prostatic hyperplasia (BPH) (28). Tissue was analysed for HER2 amplification by fluorescent in situ hybridisation, and HER2 and COX2 protein expression by immunohistochemistry (IHC). All tumours analysed expressed COX2 at a significantly higher level than BPH tissue (P=0.041). Only low levels of HER2 gene amplification (8%, 7/89) and HER2 protein expression (12%, 11/89) were observed. HER2 protein expression was rarely observed and did not correlate with HER2 amplification or COX2 expression. Although HER2 does not drive COX2 expression in prostate cancer, this study identified high levels of COX2 expressed in locally advanced prostate cancer, suggesting COX2 could be a potential therapeutic target. COX2 inhibitors are currently being used in clinical trials for the treatment of other tumour types.