Human Epidermal Growth Factor Receptors 1 and 2 (EGFR/HER1 and HER-2/NEU) status in invasive apocrine carcinoma of the breast

Vranić, Semir (2012) Human Epidermal Growth Factor Receptors 1 and 2 (EGFR/HER1 and HER-2/NEU) status in invasive apocrine carcinoma of the breast. PhD thesis, Sveučilište u Zagrebu.

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Abstract

The study was undertaken to investigate EGFR and HER-2/neu expression in a cohort of apocrine carcinomas of the breast with emphasis on the classification of the breast carcinomas with apocrine morphology. In total, 55 breast carcinomas morphologically diagnosed as apocrine were evaluated for steroid receptor expression profile characteristic of normal apocrine epithelium (ER-/PR-/AR+), and for the expression of EGFR and Her-2/neu proteins, and the copy number ratios of the genes EGFR/CEP7 and HER-2/CEP17. Another cohort composed of 72 invasive ductal carcinomas of no-special-type was used to further determine the impact of CEP17 polysomy on the interpretation of HER-2/neu testing. Our study confirms that apocrine carcinomas of the breast are molecularly diverse group of carcinomas. Strictly defined, pure apocrine carcinomas (ER-, PR-, AR+) (38 cases, 69%) are either HER-2 overexpressing breast carcinomas (52%) or triple-negative breast carcinomas (48%). Apocrine-like carcinomas (ER+/-, PR+/-, AR+/-) (17 cases, 31%) belong predominantly to the luminal phenotype (76%). Pure apocrine carcinomas show consistent over-expression of either EGFR or Her-2/neu. EGFR gene amplification was observed in two pure apocrine carcinomas and one apocrine-like carcinoma. CEP7 polysomy (defined as three or more CEP7 signals) was seen in 61% pure apocrine carcinomas and 27% of apocrine-like carcinomas and showed a weak positive correlation with EGFR protein expression. HER-2/neu gene amplification is the primary mechanism of Her-2/neu activation and is found in 52% of all apocrine carcinomas. CEP17 polysomy (defined as three or more CEP17 signals) was observed in 10 pure apocrine carcinomas (32%) and 8 apocrine-like carcinomas (50%). CEP17 polysomy may be seen without HER-2/neu gene amplification. Further exploration on a cohort of invasive ductal carcinomas of no-special-type confirmed that increased CEP17 signals may lead to discordant interpretation of HER-2/neu gene amplification in a significant proportion of the cases, depending on which criterion (ratio versus absolute number) is used for interpretation. However, increased gene dosage (>6 HER-2/neu genes or HER-2/CEP17 ratio>2.2), regardless of the evaluation method, is positively correlated with Her-2/neu protein expression.

Abstract in Croatian

Cilj istraživanja je bio ispitati ekspresiju EGFR i Her-2/neu proteina u skupini apokrinih karcinoma dojke s posebnim osvrtom na klasifikaciju karcinoma dojke s apokrinom morfologijom. Ukupno 55 karcinoma dojke s apokrinom morfologijom testirano je na karakteristični profil steroidnih receptora koji se susreće kod normalnog apokrinog epitela (ER-/PR-/AR+), ekspresiju Her-2/neu i EGFR proteina, te broj kopija i odnos HER-2/CEP17 i EGFR/CEP7. Dodatna skupina sastavljena od 72 karcinoma dojke (opći tip) poslužila je za daljnje ispitivanje utjecaja polisomije CEP17 na status i interpretaciju HER-2/neu gena. Rezultati istraživanja pokazuju da su apokrini karcinomi dojke molekularno heterogena skupina tumora. Striktno definirani, tzv. čisti apokrini karcinomi (ER-/PR-/AR+) (38 slučajeva, 69%) su ili HER-2 pozitivni (52%) ili “trostruko-negativni” karcinomi (48%). “Apocrine-like” karcinomi dojke (ER+/-, PR+/-, AR+/-) (17 slučajeva, 31%) pripadaju pretežno luminalnom fenotipu (76%). Čisti apokrini karcinomi pokazuju konzistentnu ekspresiju ili EGFR ili HER-2/neu. Amplifikacija EGFR gena je bila utvrđena kod 2 čista apokrina i jednog „apocrine-like“ karcinoma dojke. Polisomija CEP7 (definirana kao tri i više CEP7 signala) je bila prisutna kod 61% čistih apokrinih i 27% „apocrine-like“ karcinoma dojke. Polisomija CEP7 je pokazivala statistički slabu pozitivnu korelaciju s ekspresijom EGFR proteina. Amplifikacija HER-2/neu gena je osnovni mehanizam aktivacije Her-2/neu proteina i pronađena je kod 52% svih apokrinih carcinoma. Polisomija CEP17 (definirana kao tri ili više CEP17 kopija) je bila prisutna kod 10 čistih apokrinih karcinoma (32%) i 8 „apocrine-like“ karcinoma dojke (50%). Polisomija CEP17 se može javiti i bez amplifikacije HER-2/neu gena. Daljnja analiza utjecaja polisomije CEP17 na kohorti invazivnih karcinoma dojke (opći tip) potvrdila je da povećani broj CEP17 signala može utjecati na proturječnu interpretaciju amplifikacije HER-2/neu gena kod signifikantnog broja karcinoma dojke, ovisno koji kriterij za interpretaciju se primjenjuje (odnos HER-2/CEP17 naspram apsolutnog broja kopija HER-2/neu gena). Ipak, povećana količina gena (>6 kopija HER-2/neu gena ili odnos HER-2/CEP17>2.2), bez obzira na način interpretiranja je pozitivno korelirala s ekspresijom Her-2/neu proteina.

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