Gastroesophageal Adenocarcinoma: History
Subjects: Oncology
Contributors:

The aims of the review are to describe the novel pathways implicated in the development and progression of gastro-esophageal tumors illustrating the results of the molecular matched therapies.

  • Advanced Gastroesophageal cancer
  • Precision Medicine
  • New Drug development

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1. Summary 

Gastroesophageal adenocarcinoma (GEA) represents the fifth most frequent tumor and the third leading cause of cancer-related deaths worldwide. In 2018 GEA was diagnosed in about 1,000,000 people, causing death in 783,000 patients. Despite concerted efforts to develop comprehensive molecular classifications for GEA aimed at offering a precision approach to patients, only a few drugs have been approved, and also the epidermal growth factor receptor 2 (HER2) and microsatellite instability have been recognized as predictive biomarkers. The improvement in the molecular analysis due to the application of high throughput technologies based on DNA and RNA sequencing has opened a novel scenario leading to the personalization of treatment. However, several compounds, such as anti-EGFR or MET monoclonal antibodies, as well as tyrosine kinase inhibitors, were no longer able to improve clinical outcomes. Moreover, among the anti-HER2 agents, only trastuzumab when combined to platinum-based chemotherapy was able to improve progression-free survival and overall survival in HER2 amplified tumors, suggesting that tumor characteristics, such as heterogeneity and the co-presence of further molecular alterations could negatively impact a precision medicine approach. Nevertheless, the possibility to target with novel more specific agents, the HER2, Claudine, Fibroblast Growth Factor Receptors (FGFR), and other alterations with a molecular matched novel therapy could significantly improve clinical outcomes over advanced gastric cancer patients. On the other hand, the development of immunotherapy could also represent a promising strategy in a selected population. 

3. Conclusions

GEA presents as a very heterogeneous disease. The high number of molecular alterations, as reflected in the percentage of tumors belonging to the CIN subtype, makes a precision approach complicated. Nevertheless, the possibility of identifying certain drivers due to the implementation of omics in recent years has opened up novel opportunities in cancer patients. Among HER2-amplified tumors, more active molecules are leading to significantly improved benefits in these patients. The growing interest in the tumor microenvironment, together with the development of novel immunotherapies and combinations could also herald new approaches. The road towards a personalized approach is long, requiring further studies and breakthroughs in current knowledge.

 

This entry is adapted from the peer-reviewed paper 10.3390/jcm9093049