Association of HER2/ErbB2 Expression and Gene Amplification with Pathologic Features and Prognosis in Esophageal Adenocarcinomas

Abstract

Purpose We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). Experimental Design HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n=713). Gene amplification was examined by fluorescence in situ hybridization (FISH) in a large subset (n=344). Most tumors were T3–4 (66%) or node-positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Results Overall, 17% of EACs were HER2-positive (ie, IHC3+ or IHC2+ with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ=.83). HER2-positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett’s esophagus (BE). EACs with BE had higher odds of HER2-positivity compared to EACs without BE, independent of pathologic features (odds ratio 1.8 [95% confidence interval (CI) 1.1–2.8], p=.014). Among all cases, HER2-positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (p for interaction=.0047). In EACs with BE, HER2-positivity was significantly associated with improved DSS (hazard ratio 0.54 [95% CI 0.35–0.84], p=.0065) and overall survival (p=.0022) independent of pathologic features, but was not prognostic among EACs without BE. Conclusions HER2-positivity was demonstrated in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2-positive and, within this subgroup, HER2-positivity was independently associated with improved survival.

Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications

“…The relevant prognostic value attributed to tumor location in the current study is consistent with previous reports suggesting worse outcomes for junctional primaries [2,23] and should rule out the superiority of adjuvant chemotherapy over perioperative chemotherapy. Our findings are in substantial agreement with those reported by Yoon et al, suggesting a strong association between HER2 positivity and better survival outcomes in patients with esophageal adenocarcinoma [24]. Also, improved survival for patients with HER2 overexpression was hypothesized in the frame of the ToGA study [20].…”

HER2 Amplification or Overexpression in Upper GI Tract and Breast Cancer with Clinical Diagnosis and Treatment

“…However, the frequency of HER2 amplification was found to be significantly higher (p=0.004) in moderately differentiated tumors (13/22) compared with poor or well differentiated tumors (1/6 and 7/61 respectively). Yoon [69](2012) study supported our finding that HER2 amplification cases were significantly associated with better differentiation, but HER2 amplification cases were not associated with age and gender. However, they also showed that HER2 amplification was associated with lower depth of tumor invasion (T stage), fewer malignant nodes, and absence of signet ring cells.…”

The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1

“…Multiple randomized trials have shown negative results for agents targeting EGFR, VEGF, MTOR, and hedgehog. To date, only two biologic therapies have been shown to improve overall survival in these patients: trastuzumab, a monoclonal antibody (mAb) targeting human epidermal growth factor 2 (HER2, ERBB2), and ramucirumab, a mAb targeting vascular endothelial growth factor receptor 2 (VEGFR2) (12)(13)(14)(15)(16)(17).…”