MCs comprise a very heterogeneous group of neoplasms, which show immunohistochemical evidence of myoepithelial differentiation ranging from “carcinomatous types”, with strong expression of basal cell type cytokeratins, to “sarcomatoid types”, with weak or absent cytokeratin expression.3,7,8,9,10,11,12,13
The five year survival rates of MCs vary considerably within the range of 28% to 68%,11–15
and some subtypes (especially carcinosacomas) are very aggressive tumours that can present clinically as massive lesions.2
Eight of our 20 MCs were large stage pT3 or pT4 tumours (table 2). Two patients suffered a local recurrence two years after surgery of the primary tumour, and one patient presented with lung metastases after the same disease free interval. In addition, nine of the 20 MCs occurred in younger women aged between 37 and 53. Because oestrogen and progesterone receptors and Her-2 overexpression are negative in most MCs,1–3,14
adjuvant endocrine treatment or Her-2 targeted treatment with a monoclonal antibody (trastuzumab) is usually not a therapeutic option in patients with advanced disease, positive resection margins, or positive lymph nodes.
EGFR (Her-1) is homologous to other members of the EGFR/erbB family, including Her-2 (erbB2), Her-3 (erbB3), and Her-4 (erbB4). Because aberrant signalling through the EGFR is associated with neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis,6,16
it has emerged as an attractive target for anticancer treatments. Among the agents targeting EGFR (monoclonal antibodies such as cetuximab and small molecule inhibitors), the inhibitor furthest in development is gefitinib (ZD1839, Iressa). It was approved by the US Food and Drug Administration in 200317
on the basis of two randomised phase 2 trials, which reported tumour responses in patients with non-small cell lung cancer (NSCLC) who had previously been treated with at least one platinum based regimen or who had received both platinum based and docetaxel chemotherapies.18,19
Because two phase 3 trials showed no benefit for patients treated with gefitinib in combination with standard chemotherapy compared with standard chemotherapy alone,20,21
gefitinib was only recommended for use as monotherapy. The EGFR protein is expressed by a variety of normal cells, including many epithelial cell types (such as squamous epithelium) and tumours derived from these cell types.22
In breast carcinomas, EGFR expression is associated with a poor prognosis,23–25
although its prognostic value seems to be dependent on the oestrogen receptor status of the patient also.23,25,26
More recent studies that used immunohistochemical staining for EGFR instead of ligand binding assays reported positivity for EGFR in 16.4%,26
of breast carcinomas, which were mainly of the invasive ductal not otherwise specified type. In our study, EGFR was identified in 70% of MCs, whereas only one weakly expressed Her-2. Her-3, Her-4, and the androgen receptor were only detected in the spindle cells of one tumour, and progesterone/oestrogen receptors were negative in the spindle cells of all MCs. These results clearly show the difficult therapeutic situation in MCs compared with other high grade carcinomas of the breast, some of which at least have been shown to exhibit androgen receptors28
and overexpress Her-2 as potential targets for adjuvant treatment. However, the frequent expression of EGFR in the absence of steroid receptors or other receptors of the EGFR family might render MCs even more sensitive to EGFR tyrosine kinase inhibitors, because it may reflect the crucial role of this receptor for tumour progression in most MCs, whereas endocrine and Her-2 dependent stimuli do not seem to contribute to tumour cell proliferation in these high grade tumours.
“The frequent expression of epidermal growth factor receptors (EGFRs) in the absence of steroid receptors or other receptors of the EGFR family might render metaplastic breast carcinomas even more sensitive to EGFR tyrosine kinase inhibitors”
Admittedly, the assessment of gefitinib sensitive NSCLS by immunohistochemistry has been seriously questioned by recent studies reporting that specific mutations in certain EGFR exons, not simply kinase expression, render NSCLS sensitive to selective inhibitors.29–31
These results are consistent with positive responses to a protein kinase inhibitor (Imatinib) in patients suffering from gastrointestinal stromal tumours with kinase mutations.32
However, one has to remember that kinases in other tumour types might not necessarily have to be genetically altered to play a significant role in tumour cell proliferation and survival. An experimental study using breast cancer cell lines showed that EGFR overexpressing MDA-MB-231 cell lines and Her-2 overexpressing KPL-4 cell lines were more sensitive to gefitinib than other cell lines.33
Because MCs express EGFR considerably more frequently than the types of breast carcinoma investigated immunohistochemically in previous studies,25–27
they represent a promising target for future studies (especially molecular analyses) on EGFR expression in breast carcinomas. Based on our results, patients suffering from this aggressive variant of breast carcinoma might benefit from treatment with protein kinase inhibitors such as gefitinib.
Take home messages
- Metaplastic breast carcinomas express the epidermal growth factor receptor more frequently than the types of breast carcinomas investigated previously
- Women suffering from this aggressive form of breast carcinoma might benefit from treatment with protein kinase inhibitors, such as gefitinib