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