Avaliação do HER2 em Câncer gástrico: correlação entre expressão proteica, amplificação gênica e características clinicopatológicas

Abstract

Introduction: Gastric cancer is usually diagnosed in an advanced stage of disease and treatment options are sparse. Trastuzumab was recently approved for patients with HER2-positive gastric tumors. Although anti-HER2 treatment is indicated for metastatic carcinomas, HER2 testing is performed in the primary tumor. Moreover, data on HER2 status among Brazilian patients are limited. Objective: Our aim was to characterize HER2 status in a series of Brazilian patients with gastric cancer, report any associations with clinicopathological data and obtain the concordance rate for HER2 expression between primary tumors and paired metastatic lymph nodes. Methods: Histological slides from 137 primary gastrectomies and lymphadenectomies were reviewed and their pathological reports were retrieved from the files at a Brazilian university hospital. Immunohistochemistry was performed on whole-tissue sections from each gastric tumor using two primary anti-HER2 antibodies and from paired lymph node metastases in 85 cases. HER2-equivocal cases in primary tumors were submitted to automated dual in situ hybridization for gene amplification. HER2 status was confronted with clinicopathological features to assess statistically significant associations. Results: Using the 4B5 anti-HER2 antibody, immunohistochemistry analysis revealed that 13/124 cases (10.5%) were HER2 positive (3+), 10/124 cases (8.1%) were equivocal (2+) and 101/124 cases (81.4%) were negative, being 7/124 cases 1+. None of the equivocal cases showed gene amplification. The overall HER2 positivity rate was 10.5%. There was an association between HER2-positive status and Lauréns intestinal subtype (P=0.048), low-grade tumors (P=0.004) and presence of lymphovascular invasion (P=0.031). No association was found with tumor topography. Using the HercepTest kit, immunohistochemistry analysis revealed that 17/137 primary tumors (12.4%) and 12/85 metastatic lymph nodes (14.1%) showed HER2 overexpression (3+ or 2+). The concordance rate was of 88.2% (-value of 0.515, indicative of a moderate agreement). There were 10 discordant cases, from which five cases (5.9%) were HER2 positive in the primary cancer and negative in nodal metastases, while five cases (5.9%) showed a negative result in the surgical resection specimen and HER2 positivity in metastatic deposits. Conclusions: Confronted with data published by other authors, the lower percentage of HER2-positive cases in our series might be partially explained by the lower number of tumors from the gastroesophageal junction in comparison with distal gastric carcinomas in Brazilian patients. This could also account for the lack of statistically significant association with tumor topography. Furthermore, since eligible patients for anti-HER2 treatment may remain undetected if immunohistochemistry is performed only in primary tumors, HER2 testing in lymph node metastases is encouraged as HER2 status can change between primary and corresponding metastatic samples. Keywords: HER2; gastric cancer; immunohistochemistry; gene amplification; clinicopathological features; lymph node metastasis.