Fosforilirani receptor HER-2 kao pokazatelj rezistencije karcinoma dojke na terapiju trastuzumabom [Phosphorylated HER-2 receptor as an indicator of breast cancer resistance to trastuzumab]

Ramić, Snježana (2018) Fosforilirani receptor HER-2 kao pokazatelj rezistencije karcinoma dojke na terapiju trastuzumabom [Phosphorylated HER-2 receptor as an indicator of breast cancer resistance to trastuzumab]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

About 20-25% of breast cancers have over-expressed HER2 receptor, leading to aggressive behavior of cancer and poor disease course. Implementing anti-HER2 therapy with trastuzumab improved disease outcome and survival of patients. Yet, a significant number of patients do not respond to therapy. HER1, HER2, HER3 and HER4 receptors belong to the epidermal growth factor receptors family. Bonding of growth factor to the receptor activates dimerization of HER receptors, resulting in phosphorylation on cytoplasmic domain and activating the signaling pathway. Our study was performed on 124 samples of HER2 positive breast cancer with the assumption that HER2 phosphorylation is a true marker of receptor's activity and that HER2 dimerization with other HER receptors contributes to the acquisition of trastuzumab resistance. We performed immunohistochemical staining using specific primary antibodies against phosphorylated HER2, HER1, HER3 and HER4, and investigated the correlation between their expression and correlation with the resistance. Our results found that HER2 receptor is predominantly phosphorylated (66.2% pHER2+) and positive pHER2 status is a marker of a good response to trastuzumab (P <0.001). Negative phosphorylated status of HER2 is significant in the HER2 intrinsic group where 33.3% of the patients had a disease recurrence. HER1, HER3 and HER4 receptors were expressed in 9.7%, 70.2% and 71% of HER2 positive carcinomas, retrospectively. Coexpression of pHER2 and HER3 showed a statistically significant correlation (P=0.013). Patients with negative pHER2 and positive HER3 or HER4 had poor survival, and resistance was recorded in 35.3% of pHER2‒ /HER3+/HER4+. We can conclude that the positive phosphorylation status of HER2 determines patients who will benefit from trastuzumab therapy. Negative status of pHER2 refers to patients who should undergo dual therapy in first line treatment, especially in the HER2 intrinsic breast cancer group.

Abstract in Croatian

Oko 20-25% karcinoma dojke ima prekomjerno izražene receptore HER2, što doprinosi agresivnijem ponašanju tumora i lošijem tijeku bolesti. Uvođenjem anti-HER2 terapije primjenom trastuzumaba poboljšan je ishod bolesti i preživljenje bolesnica. Unatoč visokoj specifičnosti trastuzumaba, značajan dio bolesnica ne reagira na terapiju. Receptori HER1, HER2, HER3 i HER4 pripadaju obitelji receptora za epidermalne faktore rasta. Vezanje faktora rasta na receptor aktivira proces dimerizacije članova HER obitelji te fosforilaciju na citoplazmatskom dijelu receptora, čime se aktivira signalni put. Naše istraživanje provedeno je na 124 uzoraka HER2 pozitivnih karcinoma dojke s pretpostavkom da fosforilacija HER2 predstavlja pravi biljeg receptorske aktivnosti, a dimerizacija HER2 s ostalim receptorima HER doprinosi pojavi rezistencije na trastuzumab. U istraživanju smo koristili metodu imunohistokemijskog bojenja upotrebom primarnih protutijela na fosforilirani HER2 receptor i ostale receptore HER obitelji te istražili povezanost međusobne izraženosti i korelaciju s pojavom rezistencije/progresije bolesti. Rezultati našeg istraživanja utvrdili su da se receptor HER2 uglavnom nalazi u fosforiliranom stanju (66,2% pHER2+), a pozitivan pHER2 status pokazatelj je dobrog odgovora na terapiju trastuzumabom (P<0,001). Negativan status pHER2 je značajan u HER2 intrinzičkoj skupini gdje je 33,3% bolesnica imalo povrat bolesti. Receptori HER1, HER3 i HER4 su izraženi u 9,7%, 70,2% i 71% HER2 pozitivnih karcinoma, a istovremena izraženost pHER2 i HER3 pokazuje statistički značajnu korelaciju (P=0,013). Bolesnice s negativnim pHER2, a pozitivnim HER3 ili HER4, imale su lošije preživljenje odnosno rezistencija je registrirana u 35,3% karcinoma s pHER2‒/HER3+/HER4+. Na osnovi naših rezultata možemo zaključiti da pozitivan fosforilacijski status HER2 određuje bolesnice koje će imati koristi od terapije trastuzumabom. Negativan status pHER2 upućuje na bolesnice kod kojih bi trebalo odmah uvesti dualnu terapiju, pogotovo u HER2 intrinzičkoj skupini karcinoma dojke.

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