Abstract
Abstract Introduction: Gastric cancer is the 3rd leading cause of cancer mortality worldwide. Surgery is the only curative treatment strategy and conventional chemotherapy has shown limited efficacy. Trastuzumab (a HER2 mAb), is the only therapy targeting molecular alterations approved so far in gastric cancer, for HER2+ patients with advanced disease. However only a fraction (<20%) of HER2 amplified patients benefits from treatment. Methods: We have recently generated a molecularly annotated colony of gastro-esophageal PDXs (at the moment, > 70 PDXs). The platform also comprises primary cell lines and 3D-cultured organoids derived from gastric cancer PDXs. Results and Discussion: At present, we have identified several HER2+ PDXs and generated the corresponding in vitro derivatives. Four HER2+ PDXs, showing 3+ HercepTest score and HER2 amplification > 8 copies (thus theoretically sensitive to Trastuzumab), were selected to undergo ‘xenotrials’ with the following anti-HER2 drugs/combos: Trastuzumab (T); Pertuzumab (P, anti-HER2 mAb); Lapatinib (L, a dual HER2-EGFR tyrosine kinase inhibitor). According to RECIST-like criteria, T induced tumor regression in only 1 out of 4 HER2+ PDXs. Interestingly, in all the tumors but one the combos T+P and T+L were able to bypass resistance to T monotherapy and to induce tumor regression. One tumor was resistant to all the tested therapeutic approaches. Conclusion: We identified PDXs displaying HER2 gene amplification. Only a minor fraction of them benefited from the anti-HER2 mono-therapy, despite the presence of a strong HER2 gene amplification, while the association of two HER2 inhibiting drugs resulted in intense and prolonged response. This suggests that monotherapy with T might not be the most effective therapeutic approach in gastric cancer patients. We are currently investigating the cause of resistance to anti-HER2 drugs to identify mutations/CNV in tumors showing resistance to Trastuzumab. Note: This abstract was not presented at the meeting. Citation Format: Simona Corso, Cristina Migliore, Maria Apicella, Silvia Menegon, Eirini Pectasides, Tania Capeloa, Stefania Durando, Marilisa Cargnelutti, Paola Cassoni, Anna Sapino, Maurizio de Giuli, Adam Bass, Silvia Giordano. Targeting HER2 in gastric cancer: Hints from a gastric PDX platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3851. doi:10.1158/1538-7445.AM2017-3851
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