The Predictive and Prognostic Significance of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 Expression in Hepatocellular Carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) is the fifth most common fatal cancer and an important healthcare problem worldwide. There are many studies describing the prognostic and predictive effects of epidermal growth factor receptor 2 (c-erb-B2) and epidermal growth factor receptor 1 (EGFR), transmembrane tyrosine kinases that influence cell growth and proliferation in many tumors.ObjectivesThe current study aimed to investigate the expression levels of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 in hepatocellular carcinoma (HCC) and their correlation with other clinicopathologic features.Patients and MethodsFifty HCC cases were stained immunohistochemically with these markers. Correlations between the markers and clinicopathologic characteristics and survival rates were analyzed.ResultsNo membranous c-erb-B2 staining was seen, whereas cytoplasmic positivity was present in 92% of HCC samples, membranous EGFR was observed in 40%, PI3K was found in all samples, and mTOR was seen in 30%, whereas reduced or absent PTEN expression was observed in 56% of samples and loss of p27 was seen in 92% of the cases. c-erb-B2 and mTOR overexpression, as well as reduced expression of p27, all correlated with multiple tumors (P = 0.041, P < 0.001, and P < 0.001, respectively). P27 loss, and mTOR and EGFR positivity were significantly correlated with AFP (P = 0.047, P = 0.004, and P = 0.008, respectively). Angiolymphatic invasion was more commonly seen in EGFR- and ERCC1-positive cases (P = 0.003 and P = 0.005). EGFR was also correlated with histological grade (P = 0.039). No significant correlations were found among PTEN , PI3K, and the clinicopathological parameters. Disease-free or overall survival rates showed significant differences among therapy modalities, AFP levels, angiolymphatic or lymph node invasions, and ERCC1 and p27 expression levels (P < 0.05).Conclusionsc-erb-B2, EGFR, mTOR, ERCC1 overexpression levels, and loss of p27 may play roles in hepatocarcinogenesis and may be significant predictors of aggressive tumor behavior. These markers were found to be correlated with certain clinicopathologic features, therapy modalities, and survival rates in the current study. These findings may help in planning new, targeted treatment strategies .

Genetic alterations in hepatocellular carcinoma: An update

“…A recent study identified PIK3CA mutations in 14% of patients.These mutations were strongly correlated with tumor size, suggesting that PIK3CA mutations could be used as prognostic markers in HCC[283]. However, other more recent studies have shown that hot spot mutations in PIK3CA are completely absent or rare in HCC[263,284-287]; PI3K mutations were not associated with either hepatic carcinogenesis or the postoperative prognosis of HCC patients[284,285,288]. …”

SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma

“…8,9 The epidermal growth factor receptor (EGFR) pathway has been implicated in the pathogenesis of HCC. 10,11 EGFR activation may interfere with HCC response to sorafenib, [11][12][13] suggesting that EGFR inhibition may enhance tumor response. Erlotinib is an orally active inhibitor of EGFR tyrosine kinase 14,15 approved to treat patients with advanced nonsmall-cell lung and pancreatic cancers.…”

Crosstalk between EGFR and p53 in Hepatocellular Carcinoma

“…Several EGFR agents such cetuximab panitumumab, gefitinib and erlotinib gained U.S. Food and Drug Administration (FDA) approval in recent years for different cancers (Bassullu et al, 2012).…”