In the present study we have evaluated the potential relationship between HER2 expression in GCs and clinicopathologic variables. We found no significant difference in sex, age, or tumor location with respect to the overexpression of HER2. A statistically significant correlation was found between HER2 positivity and TNM stage and nodal metastasis.
High correlation between HER2 expression and intestinal histological type was reported by several authors (Tanner et al., 2005; Park et al., 2006; Kang et al., 2008). Our group observed a higher rate of HER2 overexpression in intestinal than in diffuse type (93 vs. 67%). In the study by Park et al. (2006), amplification of HER2 was strongly associated with poor carcinoma-specific survival, particularly evident in the subgroup of intestinal type of cancers (P=0.0019), which is usually considered to associate with more favorable prognosis compared with the diffuse type of gastric adenocarcinoma (Kang et al., 2008). I-GC also exhibited higher rates of HER2 amplification compared with D-GC (P<0.05) in the study by Tanner et al. (2005). Finally, in the ToGA trial, HER2 positivity differed significantly by histological subtype (intestinal 34%, diffuse 6%, mixed 20%). The reasons for the selective overexpression of HER2 in I-GC are complex and it is necessary to investigate them in depth. The association of this oncogene with a specific histological tumor type indicates that certain characteristics (e.g. HER2 overexpression and intestinal phenotype) may be expressed together preferentially. However, as not all tumors of the intestinal type overexpress HER2, this cannot be the only factor involved (Van Cutsem et al., 2009). The reasons for the selective overexpression of HER2 in I-GC are complex and unclear at present. In breast carcinomas, HER2 gene amplification is a common feature of invasive ductal carcinomas and an uncommon feature in lobular carcinomas (Ménard et al., 2000). In GC, HER2 gene amplification associates inversely with E-cadherin mutations (Yuan et al., 2009; Zhou et al., 2010); E-cadherin mutations are typical for diffuse gastric and lobular invasive breast carcinomas but rare in intestinal gastric and ductal invasive breast carcinomas (Ménard et al., 2000; Chen et al., 2003; Graziano et al., 2004; Tan and Yu, 2007). Gene amplification and protein overexpression of the growth factor receptors HER2 and K-sam may be prognostic factors for I-GC and D-GC, respectively (Li et al., 2012). Recently, germline mutations of E-cadherin have been identified that are responsible for a dominantly inherited form of D-GC (Zhang et al., 2009).
Depending on the depth of invasion (T), involvement of lymph nodes (N), and the presence of distant metastasis (M), the TNM stage is the most important prognostic parameter for GC in clinical practice (Yamashita et al., 2008). Previous studies including all pathological stages have also reported no correlation between pathological stage and HER2 overexpression (Yamashita et al., 2008; Yuan et al., 2009). In a series of 260 GCs, Okegawa et al. (2006) found that HER2 overexpression was an independent factor and correlated with serosal invasion and lymph node metastases. Aggressive biological behavior, such as lymphovascular invasion and lymph node metastasis, usually leads to poor prognosis. Our study confirmed that HER2 positivity was associated with lymphovascular invasion and lymph node metastases (including pN stage) in agreement with previous studies. Our results demonstrated that HER2 overexpression was statistically higher in phase III–IV lesions than in phase I–II lesions (P<0.05).
There are no conflicts of interest.
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