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.

Personalized therapeutic strategies in HER2-driven gastric cancer

Ughetto S.
Co-first
;
Migliore C.
Co-first
;
Petrelli A.;Bellomo S. E.;Degiuli M.;Reddavid R.;Rapa I.;Sapino A.;Marchio' C.;Cassoni P.;Corso S.
Co-last
;
Giordano S.
Co-last
2021

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.
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4
897
912
Drug resistance; Gastric cancer; HER2; Targeted therapy; Trastuzumab
Ughetto S.; Migliore C.; Pietrantonio F.; Apicella M.; Petrelli A.; D'Errico L.; Durando S.; Moya-Rull D.; Bellomo S.E.; Rizzolio S.; Capeloa T.; Ribisi S.; Degiuli M.; Reddavid R.; Rapa I.; Fumagalli U.; De Pascale S.; Ribero D.; Baronchelli C.; Sgroi G.; Rausa E.; Baiocchi G.L.; Molfino S.; Manenti S.; Bencivenga M.; Sacco M.; Castelli C.; Siena S.; Sartore-Bianchi A.; Tosi F.; Morano F.; Raimondi A.; Prisciandaro M.; Gloghini A.; Marsoni S.; Sottile A.; Sarotto I.; Sapino A.; Marchio' C.; Cassoni P.; Guarrera S.; Corso S.; Giordano S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1795119
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