Assessment of Her-1, Her-2, and Her-3 Expression and Her-2 Amplification in Advanced Stage Ovarian Carcinoma

Abstract

The human epidermal growth factor receptor (Her) family of receptor tyrosine kinases includes Her-1, Her-2, and Her-3. The overexpression of Her-1 and Her-2 have been reported previously in surface epithelial ovarian cancer. Although up to one-third of ovarian carcinomas have been found to have amplification or overexpression of Her-2, responses to trastuzumab therapy in these patients have been disappointing. In this study, we examined Her-1, Her-2, and Her- 3 protein expression as well as the frequency of Her-2 amplification in a series of 103 high-grade, advanced-stage (FIGO stage III or IV) ovarian surface epithelial carcinomas. Immunohistochemical staining using commercially available antibodies against Her-1-3 and fluorescence in situ hybridization (FISH) using probes against Her-2 and chromosome 17 centromere (CEP) were performed on a tissue microarray containing cores of tumor from 103 surface epithelial carcinomas (85 serous, 6 mixed surface epithelial, 5 clear cell, 3 endometrioid, 3 undifferentiated, 1 mucinous). Nine of 99 (9.1%) tumors were positive for Her-1 expression and 5 of 102 (4.9%) tumors were positive for Her-2 expression, with 1 showing strong immunoreactivity. None of the Her-1 positive tumors exhibited Her-2 immunoreactivity. There was no correlation between Her-1 or Her-2 expression and survival. Using Her-2:centromere fluorescence ratios of 2.0 or 1.5 as cutoffs in assessment of Her-2 amplification, 8 of 75 (10.7%) and 25 of 75 (33.3%) tumors, respectively, showed Her-2 amplification. Two of eight tumors that showed higher level (>2) Her-2 amplification by FISH also were positive for Her-2 by immunohistochemistry. Only 3 of 103 tumors expressed Her-3. Immunoreactivity for Her-1 and Her-2 was less frequently observed in this series than has been previously reported. The strong correlation between Her-2 immunostaining and amplification characteristic of breast carcinoma is not seen in ovarian carcinoma. These results indicated that few patients with ovarian carcinoma have tumors that would benefit from therapy targeted specifically against Her-1, Her-2, or Her-3.

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

“…Although the predictive value of c-erb-B2 in ovarian carcinomas is not clear, some studies have shown a significantly worse prognosis for patients with positive tumors, 11,12,21 whereas others did not observe this correlation. [23][24][25] Similarly, EGFR reportedly was overexpressed in 30% to 77% of ovarian carcinomas, and its association with a poor prognosis, like in our series, was not verified. 11,[25][26][27] Downstream of the growth factor receptors, there are at least 2 main biochemical routes.…”

“…[23][24][25] Similarly, EGFR reportedly was overexpressed in 30% to 77% of ovarian carcinomas, and its association with a poor prognosis, like in our series, was not verified. 11,[25][26][27] Downstream of the growth factor receptors, there are at least 2 main biochemical routes. It is known that the PI3K-AKT-mTOR pathway and the Ras-Raf-MEK-ERK pathways are activated in ovarian carcinomas.…”

High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer

“…In colorectal cancer, Kountourakis et al found no significant relationship between HER3 expression and any parameters involved with tumor progression (42), and Lee reported a relationship with patients in the early stage of the disease (43). The frequency of HER3 overexpression is low in advanced ovarian cancer (44). These discrepancies may be partially explained by the different methods used for determination of HER3 status, or by different coexpression of HER3 and another HER.…”

HER-family gene amplification and expression in resected pancreatic cancer

“…Concordantly, a very low expression of HER-3 has also been reported in advanced stage ovarian carcinoma. [39] Loss of HER-3 overexpression might be correlated with progression of pancreatic tumor stage.…”