Clinicopathologic Characteristics of Patients With Stage III/IV (M0) Advanced Gastric Cancer, According to HER2 Status Assessed by Immunohistochemistry and Fluorescence In Situ Hybridization

Abstract

Despite recent advances in chemotherapy, the prognosis for patients with advanced gastric cancer (GC) or gastroesophageal junction cancer remains poor. Human epidermal growth factor receptor 2 (HER2) is a novel target for biologic therapy in metastatic GC. We analyzed the association between HER2 overexpression and the clinicopathologic characteristics of advanced GC. Formalin-fixed, paraffin-embedded tumor samples were collected from patients with stage III or to IV (M(0)) GC who subsequently underwent curative surgery followed by adjuvant chemotherapy with 5-fluorouracil and cisplatin. All the samples were analyzed for HER2 status by immunohistochemistry (IHC) and fluorescence in situ hybridization. Of 142 samples analyzed, 7.1% scored IHC 2+ and 8.6% scored IHC 3+, whereas 9.3% were HER2-amplified. Of HER2-amplified cases, 76.9% (10/13) scored IHC 3+, showing the correlation between HER2 amplification and overexpression (P=0.01). HER2 IHC 3+ cases were more common in the intestinal-type tumors compared with diffuse-type tumors (16.7% vs. 5.1%, respectively; P=0.049), and a nonsignificant trend was observed using fluorescence in situ hybridization (14.3% vs. 9.2%, respectively; P=0.399). HER2 gene amplification was more frequent in stage IV (M(0)) than stage III disease (15.4% vs. 4.0%, respectively; P=0.037). Interestingly, HER2-amplified disease was more common than nonamplified disease in patients with nodal stage 3 tumors (76.9% vs. 38.6%, respectively; P=0.009); a similar pattern was observed using IHC. HER2 overexpression correlated with nodal stage, and a lymph node ratio greater than 0.5 was more common in HER2-amplified tumors than HER2-nonamplified tumors (69.2% vs. 43.3%, respectively; P=0.086). These findings suggest that further investigations of adjuvant therapy with HER2-targeted therapy for advanced GC are warranted.

Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population

“…Similarly, in the ToGA trial, tumor with HER2 overexpression was reported to be more common in patients with a well-differentiated tumor histology [17][18][19]21]. Actually, well-differentiated tumor histology was significantly related to greater age, male gender, and an expansive growth pattern of the tumor in the present study (data not shown).…”

“…Despite the increasing importance of this relationship, the relationship between HER2 overexpression and tumor biology in cases of gastric cancer still remains to be elucidated. Based on the results of the ToGA trial, several studies have evaluated HER2 overexpression in esophagogastric cancer using validated criteria [17][18][19][20][21][22]. The frequency of HER2 overexpression has been reported to be 9-16 %, consistent with the results of two major reviews of previous studies [4,9].…”

“…On the other hand, lymph node metastasis was significantly more frequent in patients with poorly differentiated tumor histology (data not shown). Several previous studies have reported the existence of a relationship between the presence of lymph node metastasis and tumor HER2 overexpression [18,19]. This finding suggests that tumor biology in the subgroup of patients with tumor HER2 overexpression predisposes to spread via the lymphatic system.…”

Is Her-2 Status in the Primary Tumor Correlated with Matched Lymph Node Metastases in Patients with Gastric Cancer Undergoing Curative Gastrectomy?

“…In the study carried out by Orita et al (1997) HER2 positivity was associated with poorer survival results in gastric cancer patients. Another study further confirmed the shorter survival of HER2-positive patients, which had a 5-year survival of 29% compared to 47% HER2-negative patients (Im et al, 2011). Other studies reported similar findings (Czyzewska et al, 2009, Nakajima et al, 1999.…”

“…Trastuzumab is a monoclonal antibody targeted against the HER2 protein (Im et al, 2011). The ToGA study confirmed the survival benefits of trastuzumab in combination with chemotherapy compared with chemotherapy alone as a first line of treatment for patients overexpressing HER2 in advanced gastric or GEJ cancer (Bang et al, 2010).…”