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Br J Cancer
2014 Feb 18;1104:1045-52. doi: 10.1038/bjc.2013.794.
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Triple negative breast carcinoma EGFR amplification is not associated with EGFR, Kras or ALK mutations.
Secq V
,
Villeret J
,
Fina F
,
Carmassi M
,
Carcopino X
,
Garcia S
,
Metellus I
,
Boubli L
,
Iovanna J
,
Charpin C
.
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BACKGROUND: The amplification of epidermal growth factor receptor (EGFR) in triple negative breast carcinomas (TNBC) suggests its potential therapeutic application, as for HER-2, using standardised methods of measurement. In this regard, we aimed to compare several methods for evaluating EGFR amplification along with potential mutations for suitability in clinical practice.
METHODS: Tissue sections of 138 TNBCs were used (1) to compare EGFR amplification and expression by silver in situ hybridisation (SISH) to qPCR and immunohistochemistry (IHC) and (2) to search for EGFR mutations, along with Kras, PI3K, Braf and HER-2 mutations and echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) translocation.
RESULTS: (1) Amplification of EGFR was observed in well-characterised TNBCs (up to 92%); (2) qPCR correlated with SISH with 94% specificity and 75.6% sensitivity; (3) IHC correlated with SISH with 97% sensitivity and 78% specificity; (4) no EGFR, Kras mutations or EML4-ALK translocations were found, but PI3K and Braf mutations were observed in 26% of cases; and (5) small, acentric circular extrachromosomal DNA similar to 'double minutes' in glioblastomas was observed in 18% of SISH sections.
CONCLUSIONS: SISH and IHC are methods that are suitable in clinical practice to screen for EGFR amplification and overexpression, which are frequently observed in TNBC. Patients with TNBC are potential candidates for EGFR-targeted therapy combined with PI3K and Braf inhibitors.
Figure 1. Positive anti-EGFR immunohistochemical reaction in TMA spot of ductal triple negative breast carcinoma.
Figure 2. Positive in situ hybridisation with black dot clustering within the cell nucleus.
Figure 3. Positive in situ hybridisation appearing as separated tiny dots distributed in the nucleus of many cells.
Figure 4. Positive in situ hybridisation within some cells in a triple negative breast carcinoma contrasting with the clustering distribution observed in Figure 2.
Figure 5. In situ hybridisation showing the double minutes chromosome (arrow) appearing as arciform pattern of positive dots within the cytoplasm close to nuclear membrane.
Figure 6. EGFR immunohistochemical positive expression in current large-tissue sections of triple negative breast carcinoma.
Figure 7. PI3K mutations were observed in 35.3% (12/34) tumours. Overall exons 9 and 20, 10 PI3K mutations are exclusive of all other mutations (5/exon 9 and 5/exon 20), seven are found in TNBC-like with E545K mutation. H1047R mutations are distributed between both the tumour profiles. Braf mutations were observed in 13.8% (4/29) cases, two are exclusive of all other mutations and are distributed between both tumour profiles. HER-2 mutations were detected in 5.9% cases (2/34), one is exclusive of all other mutations and is found in TNBC-like. One classified TNBC-like patient has concomitant mutations for Braf and PI3K and another one for Braf, PI3K and HER-2. In total 66.6% (10/15) of TNBC-like are significantly (P<0.044) mutated compared with 26.3% (5/19) of the TNBC. No EGFR and Kras mutation was detected. wt: Wild type; Association between qualitative variables was assessed with Fisher's exact test.
Bhargava,
EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations.
2005, Pubmed
