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Haffner, I.* ; Schierle, K.* ; Raimúndez, E.* ; Geier, B.* ; Maier, D.* ; Hasenauer, J. ; Luber, B.* ; Walch, A.K. ; Kolbe, K.* ; Riera Knorrenschild, J.* ; Kretzschmar, A.* ; Rau, B.* ; Fischer von Weikersthal, L.* ; Ahlborn, M.* ; Siegler, G.* ; Fuxius, S.* ; Decker, T.* ; Wittekind, C.* ; Lordick, F.*

HER2 expression, test deviations, and their impact on survival in metastatic gastric cancer: Results from the prospective multicenter VARIANZ study.

J. Clin. Oncol. 39, 1468-1478 (2021)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
PURPOSE: Trastuzumab is the only approved targeted drug for first-line treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic gastric cancer (mGC). However, not all patients respond and most eventually progress. The multicenter VARIANZ study aimed to investigate the background of response and resistance to trastuzumab in mGC. METHODS: Patients receiving medical treatment for mGC were prospectively recruited in 35 German sites and followed for up to 48 months. HER2 status was assessed centrally by immunohistochemistry and chromogenic in situ hybridization. In addition, HER2 gene expression was assessed using qPCR. RESULTS: Five hundred forty-eight patients were enrolled, and 77 had HER2+ mGC by central assessment (14.1%). A high deviation rate of 22.7% between central and local test results was seen. Patients who received trastuzumab for centrally confirmed HER2+ mGC (central HER2+/local HER2+) lived significantly longer as compared with patients who received trastuzumab for local HER2+ but central HER2- mGC (20.5 months, n = 60 v 10.9 months, n = 65; hazard ratio, 0.42; 95% CI, 8.2 to 14.4; P < .001). In the centrally confirmed cohort, significantly more tumor cells stained HER2+ than in the unconfirmed cohort, and the HER2 amplification ratio was significantly higher. A minimum of 40% HER2+ tumor cells and a HER2 amplification ratio of ≥ 3.0 were calculated as optimized thresholds for predicting benefit from trastuzumab. CONCLUSION: Significant discrepancies in HER2 assessment of mGC were found in tumor specimens with intermediate HER2 expression. Borderline HER2 positivity and heterogeneity of HER2 expression should be considered as resistance factors for HER2-targeting treatment of mGC. HER2 thresholds should be reconsidered. Detailed reports with quantification of HER2 expression and amplification levels may improve selection of patients for HER2-directed treatment.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Gastroesophageal Cancer; Gene Amplification; Trastuzumab; Adenocarcinoma; Therapy; Heterogeneity; Sensitivity; Resistance; Prognosis
ISSN (print) / ISBN 0732-183X
e-ISSN 1527-7755
Quellenangaben Band: 39, Heft: 13, Seiten: 1468-1478 Artikelnummer: , Supplement: ,
Verlag American Society of Clinical Oncology
Verlagsort Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Begutachtungsstatus Peer reviewed
Förderungen German Federal Ministry for education and research (BMBF)