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 / S. Ughetto, C. Migliore, F. Pietrantonio, M. Apicella, A. Petrelli, L. D'Errico, S. Durando, D. Moya-Rull, S.E. Bellomo, S. Rizzolio, T. Capelôa, S. Ribisi, M. Degiuli, R. Reddavid, I. Rapa, U. Fumagalli, S. De Pascale, D. Ribero, C. Baronchelli, G. Sgroi, E. Rausa, G.L. Baiocchi, S. Molfino, S. Manenti, M. Bencivenga, M. Sacco, C. Castelli, S. Siena, A. Sartore-Bianchi, F. Tosi, F. Morano, A. Raimondi, M. Prisciandaro, A. Gloghini, S. Marsoni, A. Sottile, I. Sarotto, A. Sapino, C. Marchiò, P. Cassoni, S. Guarrera, S. Corso, S. Giordano. - In: GASTRIC CANCER. - ISSN 1436-3291. - (2021 Mar 23). [Epub ahead of print] [10.1007/s10120-021-01165-w]

Personalized therapeutic strategies in HER2-driven gastric cancer

Pietrantonio, Filippo;De Pascale, Stefano;Rausa, Emanuele;Siena, Salvatore;Sartore-Bianchi, Andrea;Raimondi, Alessandra;Prisciandaro, Michele;
2021-03-23

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.
Drug resistance; Gastric cancer; HER2; Targeted therapy; Trastuzumab;
Settore MED/06 - Oncologia Medica
GASTRIC CANCER
Article (author)
File in questo prodotto:
File Dimensione Formato  
Ughetto2021_Article_PersonalizedTherapeuticStrateg.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 6.62 MB
Formato Adobe PDF
6.62 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/827576
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
social impact