Stefano Ughetto1,2, Cristina Migliore1,2, Simona Corso1,2, Silvia Giordano3,4, Filippo Pietrantonio5,6, Maria Apicella2, Annalisa Petrelli2, Laura D'Errico1,2, Stefania Durando2, Daniel Moya-Rull2, Sara E Bellomo1,2, Sabrina Rizzolio2, Tania Capelôa2,7, Salvatore Ribisi2, Maurizio Degiuli8, Rossella Reddavid8, Ida Rapa8, Uberto Fumagalli9,10, Stefano De Pascale9,10, Dario Ribero2, Carla Baronchelli11, Giovanni Sgroi12, Emanuele Rausa12, Gian Luca Baiocchi13, Sarah Molfino13, Stefania Manenti11, Maria Bencivenga14, Michele Sacco14, Claudia Castelli15, Salvatore Siena6,16, Andrea Sartore-Bianchi6,16, Federica Tosi6,16, Federica Morano5, Alessandra Raimondi5, Michele Prisciandaro5,6, Annunziata Gloghini17, Silvia Marsoni18, Antonino Sottile2, Ivana Sarotto2, Anna Sapino2,19, Caterina Marchiò2,19, Paola Cassoni19, Simonetta Guarrera2,20. 1. Department of Oncology, University of Torino, Candiolo, Italy. 2. Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo, 10060, Turin, Italy. 3. Department of Oncology, University of Torino, Candiolo, Italy. silvia.giordano@unito.it. 4. Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo, 10060, Turin, Italy. silvia.giordano@unito.it. 5. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 6. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy. 7. Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium. 8. Department of Oncology, University of Torino, Orbassano, Italy. 9. Chirurgia Generale 2, Spedali Civili, Brescia, Italy. 10. Digestive Surgery, European Institute of Oncology, IRCCS, Milan, Italy. 11. Department of Pathology, ASST Spedali Civili, Brescia, Italy. 12. Surgical Oncology Unit, Surgical Science Department, ASST Bergamo Ovest, Treviglio, BG, Italy. 13. Department of Clinical and Experimental Sciences, Surgical Clinic, University of Brescia, Brescia, Italy. 14. Section of Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy. 15. Section of Pathology, Department of Diagnostics and Public Health University of Verona, Verona, Italy. 16. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. 17. Pathology and Laboratory Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 18. Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy. 19. Department of Medical Sciences, University of Torino, Turin, Italy. 20. Italian Institute for Genomic Medicine, IIGM, Candiolo, Italy.
Abstract
BACKGROUND: Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors. METHODS: We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. RESULTS: Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. CONCLUSION: These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.
BACKGROUND: Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors. METHODS: We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. RESULTS: Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. CONCLUSION: These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.
Entities:
Keywords:
Drug resistance; Gastric cancer; HER2; Targeted therapy; Trastuzumab
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