Abstract 2615: Heterogeneity of HER2 expression in gastric cancer (GC) leads to high deviation rates between local and central testing and hampers efficacy of anti-HER2 therapy: Survival results from the VARIANZ study
Authors: Lordick Florian , Haffner Ivonne , Luber Birgit , Maier Dieter , Raimundez Elba , Hasenauer Jan , Kretzschmar Albrecht , Weikersthal Ludwig Fischer von , Ahlborn Miriam , Knorrenschild Jorge Riera , Siegler Gabriele , Rau Beate , Fuxius Stefan , Decker Thomas , Schierle Katrin , Wittekind Christian 
Published: August 2018

Abstract
Background: HER2 is a membrane-bound receptor tyrosine kinase that belongs to the epidermal growth factor receptor family. The anti-HER2 directed monoclonal antibody trastuzumab is approved for 1st-line treatment of stage IV HER2+ GC, while other drugs addressing HER2 (pertuzumab, TDM1, lapatinib) failed to improved survival outcomes. Until today, resistance against HER2-directed treatment of GC is poorly understood. The VARIANZ study aims to assess the biologic background of resistance to anti-HER2 therapy in GC.
Methods: This academic network study funded by the German Federal Ministry of Education and Research (BMBF 01ZX1610E) recruited patients (pts) who received medical treatment for stage IV GC in 34 sites. HER2 expression was verified centrally by two dedicated GI pathologists using immunohistochemistry (DCS, HI608C0I) and chromogenic in situ hybridization (Zytomed Systems, C-3022-40). Treatment and survival outcomes were reported by investigators.
Results: 502 pts were enrolled from May 2014 to Oct 2017. At present, 442 samples were fully characterized for HER2. According to criteria from the ToGA study, 73 of 442 samples were found HER2+ in central testing. In 57 samples with a HER2+ status diagnosed by local pathologists, HER2 positivity could not be confirmed centrally. Deviation rate between local and central testing was 23%. Centrally confirmed HER2-positive GC displayed a higher percentage of tumor cells staining positive for HER2 (49.72 ± 28.58% [SD] vs. 11.35 ± 17.74% [SD]; p&lt;0.001) and a higher HER2/CEP17 ratio (5.78 ± 2.55 [SD] vs. 1.43 ± 0.41 [SD]; p&lt;0.001). Survival outcomes indicate that only pts with centrally confirmed HER2+ status benefit from trastuzumab with an overall survival of 30.7 months (95%-CI 10.7 - 50.8; n=28) versus 7.9 months (95%-CI 2.8 - 12.9, n=33); HR for death was 3.9 in pts with unconfirmed vs. confirmed HER2+ GC receiving trastuzumab plus chemotherapy; p&lt;0.0001.
Conclusions: Variability between local and central HER2 assessment in GC is significant. Pts with centrally unconfirmed HER2+ status have no benefit from anti-HER2 therapy. HER2 status should be assessed in highly qualified laboratories and cut-offs for defining HER2+ should be reconsidered. Alternative treatment options–other than trastuzumab–should be investigated in pts with unconfirmed or borderline HER2 expression.
Citation Format: Florian Lordick, Ivonne Haffner, Birgit Luber, Dieter Maier, Elba Raimundez, Jan Hasenauer, Albrecht Kretzschmar, Ludwig Fischer von Weikersthal, Miriam Ahlborn, Jorge Riera Knorrenschild, Gabriele Siegler, Beate Rau, Stefan Fuxius, Thomas Decker, Katrin Schierle, Christian Wittekind. Heterogeneity of HER2 expression in gastric cancer (GC) leads to high deviation rates between local and central testing and hampers efficacy of anti-HER2 therapy: Survival results from the VARIANZ study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2615.