Invasive poorly differentiated gastroesophageal junction adenocarcinoma with signet ring cell features - NEGATIVE for HER2 (immunohistochemistry)
HER2 gene amplification and/ or HER2 protein overexpression have been demonstrated in colon, bladder, ovarian, endometrial, lung, cervical, head and neck, esophageal, and gastric carcinomas, which represent non-mammary candidate targets for Herceptin therapy. The need for Herceptin therapy is augmented in aggressive, high stage cancers for which highly effective drugs are not available.
The recent Trastuzumab for Gastric Cancer (or so-called ToGA) clinical trial established benefit from Herceptin (trastuzumab) in combination with chemotherapy as first-line therapy for HER2 positive gastric or gastroesophageal junction carcinomas.
As for many predictive assays, technical considerations and interpretive guidelines are critical. The ToGA trial demonstrated superiority for immunohistochemistry over the FISH assay in predicting response to drug. In gastric cancer, immunohistochemistry is more predictive than FISH in selection of patients for Herceptin therapy. Based on the ToGA data, only immunohistochemical 2+ gastric cancers should be reflexed to HER2 FISH testing. Herceptin benefit was essentially limited to immunohistochemically 3+ gastric cancers or IHC2+ and FISH+ cancers.
Immunohistochemical scoring criteria are different for gastric cancer. In gastric cancers, positive membranous-pattern staining can be basolateral, lateral, or complete; but unlike breast cancer, does not have to be complete. In gastric cancer biopsies, an allowable tumor focus should have at least five stained cells. In surgical resection specimens, >10% of tumor cells must be stained. In the ToGA trial, strict application of breast cancer interpretation guidelines would have resulted in a 50% false-negative rate for scoring gastric cancer.
The ToGA trial utilized the DAKO Herceptest immunohistochemical stain. However, two large comparison studies have shown high correlation between this system and the Ventanna PATHWAY system, both FDA approved for breast cancer testing. Without strict attention to gastric-specific interpretation guidelines, one could falsely interpret granular pattern staining of small cellular groups, positive staining of benign intestinal metaplasia, or diffuse cytoplasmic tumor cell staining as HER2 positivity.
A 62 year-old male with abdominal pain underwent upper gastrointestinal endoscopic evaluation with biopsies of gastric antrum, gastric body, and gastroesophageal junction.
The gastroesophageal biopsy revealed an ulcerated squamcolumnar junction with invasive poorly differentiated carcinoma showing partial glandular differentiation and focal signet ring cell features. Biopsies of gastric antrum and body were unremarkable.
Automated paraffin immunohistochemistry using anti-HER2 rabbit monoclonal antibody (clone 4B5) revealed no membranous pattern tumor cell stain. Many tumor cells showed strong diffuse cytoplasmic and nuclear pattern staining, which can be falsely interpreted as positive staining if guidelines are not strictly followed.
Bang J et al. (2010).Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 376: 687-97.