HER2-low and gastric cancer: A prognostic biomarker?
Authors: Uchôa Bruno Cezar de Mendonça , Pirolli Rafaela , Mendes Gomes Siqueira Luciana Beatriz , Moura Francisca Giselle Rocha , Correa Ana Paula Rondina , Rosado Jose Ecio Batista , Chinelato Juliana Rosa , Felismino Tiago , Jesus Victor Hugo Fonseca , Donadio Mauro Daniel Spina , Melo Éverton , Cesca Marcelle Goldner 
Published: June 2021

e16086

Background: The role of HER2 positive (HER2+) as a prognostic biomarker for gastric/gastroesophageal junction cancer (G-GEJC) is controversial. Recently, the HER2-low (HER2l) concept has emerged and proved to predict response to trastuzumab deruxtecan in metastatic scenario. Data on HER2l prognostic value are missing. Methods: All consecutive patients with metastatic G-GEJC, tested for HER2 in the primary tumor or in the metastatic tissue before initiating first-line therapy at A.C. Camargo Cancer Center, were retrospectively recruited. The primary objective was to compare the overall survival (OS: from the metastasis diagnosis to death by any cause) between HER2l and HER2 negative (HER2-) populations. Secondarily, we aimed to compare the first-line progression-free survival (PFS) between HER2l and HER2-, to analyze prognostic factors associated with OS and to compare the OS between HER2+ and HER2l/HER2-. The HER2 immunohistochemistry (IHC) tests were performed with the Ventana anti-HER2/neu kit, by specialized gastrointestinal pathologists of the study center, using the AJCC HER2 scoring criteria for gastric cancer. In situ hybridization (ISH) was done when IHC 2+ was detected. HER2+ were IHC 3+ or 2+ amplified by ISH; HER2l, 1+ or 2+ non-amplified; HER-, 0+. Kaplan-Meier curves, Log-Rank test and Cox regression were used for survival analysis. Cox regression was used for uni and multivariate analysis. Results: From June, 2008 to July, 2020, 398 patients were included (48 HER2+; 103 HER2l; 247 HER2-). The median follow-up was 31 months (m). Median age at diagnosis was 58 years; the majority were men (62.8%), caucasian (50.8%), with gastric (81% vs 19% GEJ), diffuse (50.3%), de novo metastatic (57.0%) tumors. In comparison to HER2l/HER2-, HER2+ group had superior rates of men, GEJC, intestinal subtype and non-visceral metastasis. Central nervous system metastases were uncommon, and proportionally higher in HER2+ tumors (HER2+: 6.2%; HER2l: 2.9%; HER2-: 2.0%; p = 0.27). There were no imbalances between HER2l and HER2- groups. The median OS was similar for HER2l and HER2- (13m for both; HR 1.0, 95%CI 0.76-1.31; p = 1.0), as it was the PFS (5m for both; HR 0.84, 95%CI 0.65-1.08; p = 0.18). These results did not vary on dependence of IHC + (0 vs 1 + vs 2+). HER2+ tumors had a superior median OS (17m vs 13m for HER2l/HER2-; HR 0.70, 95%CI 0.49-0.99; p = 0.046). When ungrouping HER2l/HER2-, this numerical difference remains, with a loss of statistical significance (17m vs 13m vs 13m; HR 0.87, 95%CI 0.74-1.02; p = 0.12). HER2+, > 1 line of treatment and metastasectomy were predictive for improved OS in multivariate analysis. HER2l was neither predictive for OS nor PFS. Conclusions: Although HER2-low emerged as a new predictive biomarker in metastatic gastric cancer, its prognostic value could not be proved in this study, with an absence of impact in OS. HER2+, however, was associated with improved survival.