EGFR amplification and lack of activating mutations in metaplastic breast carcinomas

Abstract

Metaplastic breast carcinomas are reported to harbour epidermal growth factor receptor (EGFR) overexpression in up to 80% of the cases, but EGFR gene amplification is the underlying genetic mechanism in around one-third of these. In this study, EGFR gene amplification as defined by chromogenic in situ hybridization and protein overexpression was examined in a cohort of 47 metaplastic breast carcinomas. Furthermore, the presence of activating EGFR mutations in exons 18, 19, 20, and 21 was investigated. Thirty-two cases showed EGFR overexpression and of these, 11 (34%) harboured EGFR gene amplification. In addition, EGFR amplification showed a statistically significant association with EGFR overexpression (p < 0.0094) and was restricted to carcinomas with homologous metaplasia. Ten cases, five with and five without EGFR amplification, were subjected to microarray-based CGH, which demonstrated that EGFR copy number gain may occur by amplification of a discrete genomic region or by gains of the short arm of chromosome 7 with a breakpoint near the EGFR gene locus, the minimal region of amplification mapping to EGFR, LANCL2, and SEC61G. No activating EGFR mutations were identified, suggesting that this is unlikely to be a common alternative underlying genetic mechanism for EGFR expression in metaplastic breast carcinomas. Given that metaplastic breast carcinomas are resistant to conventional chemotherapy or hormone therapy regimens and that tumours with EGFR amplification are reported to be sensitive to EGFR tyrosine kinase inhibitors, these findings indicate that further studies are warranted to explore EGFR tyrosine kinase inhibitors as potential therapeutic agents for metaplastic breast carcinomas harbouring amplification of 7p11.2.

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

“…We [31,42,55] and others [39,43] have previously demonstrated that genes significantly overexpressed when amplified are likely amplicon drivers, as the expression of these genes is required for the survival of cells harbouring amplification of their genomic region. Our integrated analysis has not only identified genes previously shown to be potential drivers of amplicons 8p11.2 (FGFR1), 8q24 (MYC), 11q13 (CTTN, FADD), 17q12 (ERBB2) and 20q13 (AURKA), but also identified a list of 269 that should be investigated as potential therapeutic targets in the amplicons on chromosomes 1q, 3q, 6p, 8q, 13q, 14q, 17q, 19q and 20q (Table 4; Supplementary Table S6).…”

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

“…EGFR gene amplification and high polysomy were reported in up to 24% and 27% of triple-negative breast cancer, respectively (Table 8). 10,11,13,14,19,25 However, the frequency of EGFR gene amplification is quite variable, even though most studies used the same, University of Colorado Cancer Center criteria. 30,31 We also assessed EGFR amplification by the University of Colorado Cancer Center criteria and found that EGFR amplification was quite rare, being present in only 2% of cases, which is consistent with some previous studies.…”

“…8 EGFR is a well-established treatment target for colorectal cancer, non-small cell lung cancer, and squamous cell carcinoma of the head and neck. In breast cancer, EGFR overexpression has been reported in up to 78% of triple-negative breast cancers, [9][10][11][12][13][14][15][16][17][18][19][20] more than in non-triple-negative breast cancers, 12,15 suggesting that EGFR is a potential therapeutic target for triple-negative breast cancer. EGFR tyrosine kinase inhibitors have yielded insignificant response rates in breast cancer, [21][22][23] possibly due to the lack of patient selection in these studies; they were not restricted to breast cancers with EGFR overexpression or triple-negative breast cancers.…”

“…24 EGFR gene amplification, one of the mechanisms of EGFR overexpression, is highly variable and found in up to 24% of triple-negative breast cancer. 10,11,13,14,19,25 EGFR gene mutation, another mechanism of EGFR overexpression, has been reported to be rare, 11,17,19,25,26 although a recent study reported that it was present in 11% of triplenegative breast cancers. 16 EGFR immunoreactivity has been presented as an independent indicator of poor prognosis in patients with triple-negative breast cancer.…”

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…5 More recently, a subgroup of lobular carcinomas has been shown to express high-molecular-weight cytokeratins, 41 however it remains to be determined whether these cases truly show a basal-like transcriptome. The majority of basal-like breast cancers lack or show low levels of ER and PR, lack HER2 protein overexpression and HER2 gene amplification, whereas they express genes and proteins usually found in 'basal'/myoepithelial cells of the normal breast including high-molecular-weight cytokeratins (5/6, 14 and 17), 17,19,21,42 P-cadherin, 43 caveolins 1 and 2, 44,45 nestin, 46 aB crystallin, 47,48 CD109, 49,50 and EGFR 17 and, in a minority of cases, harbor EGFR gene amplification 51 or aneusomy. 52 p53 immunohistochemical expression or TP53 gene mutations is observed in up to 85% of cases, 53,54 and alterations of the pRB and p16 G1/S cell-cycle checkpoint are remarkably prevalent in these cancers.…”