title: HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research.
abstract: Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease.
authors: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. filippo.pietrantonio@istitutotumori.mi.it.
authors: F
authors: F
authors: Pietrantonio
authors: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: M
authors: M
authors: Caporale
authors: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: F
authors: F
authors: Morano
authors: Medical Oncology Department, Azienda Ospedaliera Universitaria Cagliari, Presidio Policlinico Universitario "Duilio Casula", Cagliari, Italy.
authors: M
authors: M
authors: Scartozzi
authors: Diagnostic pathology and laboratory medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: A
authors: A
authors: Gloghini
authors: Medical Oncology Department, Seconda Università degli studi di Napoli, Naples, Italy.
authors: F
authors: F
authors: De Vita
authors: Medical Oncology 1, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
authors: E
authors: E
authors: Giommoni
authors: U.O. Oncologia Medica 2 Universitaria, Ospedale S. Chiara - Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano, Tumori, Italy.
authors: L
authors: L
authors: Fornaro
authors: Medical Oncology Department, University and General Hospital, Udine, Italy.
authors: G
authors: G
authors: Aprile
authors: Medical Oncology, Università degli studi di Verona, Italy.
authors: D
authors: D
authors: Melisi
authors: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: R
authors: R
authors: Berenato
authors: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: A
authors: A
authors: Mennitto
authors: Diagnostic pathology and laboratory medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: C C
authors: CC
authors: Volpi
authors: Medical Oncology Department, Seconda Università degli studi di Napoli, Naples, Italy.
authors: M M
authors: MM
authors: Laterza
authors: Medical Oncology Department, Azienda Ospedaliera Universitaria Cagliari, Presidio Policlinico Universitario "Duilio Casula", Cagliari, Italy.
authors: V
authors: V
authors: Pusceddu
authors: Medical Oncology 1, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
authors: L
authors: L
authors: Antonuzzo
authors: U.O. Oncologia Medica 2 Universitaria, Ospedale S. Chiara - Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano, Tumori, Italy.
authors: E
authors: E
authors: Vasile
authors: Medical Oncology Department, University and General Hospital, Udine, Italy.
authors: E
authors: E
authors: Ongaro
authors: Medical Oncology, Università degli studi di Verona, Italy.
authors: F
authors: F
authors: Simionato
authors: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|Oncology Department, University of Milan, Italy.
authors: F
authors: F
authors: de Braud
authors: Oncology Department, IRCCS-Mario Negri Institute for Pharmacological Rresearch, Milan, Italy.
authors: V
authors: V
authors: Torri
authors: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: M
authors: M
authors: Di Bartolomeo
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
keywords: HER2; HER2 loss; gastric cancer; resistance; trastuzumab