Genomics and Targeted Therapies in Gastroesophageal Adenocarcinoma

Abstract

Gastroesophageal adenocarcinomas (GEA) are devastating diseases with stark global presence. Over the past 10 years, there have been minimal improvements in treatment approach despite numerous clinical trials. Here, we review recent progress toward understanding the molecular features of these cancers and the diagnostic and therapeutic challenges posed by their intrinsic genomic instability and heterogeneity. We highlight the potential of genomic heterogeneity to influence clinical trial outcomes for targeted therapies and emphasize the need for comprehensive molecular profiling to guide treatment selection and adapt treatment to resistance and genomic evolution. Revising our clinical approach to GEA by leveraging genomic advances will be integral to the success of current and future treatments, especially as novel targets become therapeutically tractable. SIGNIFICANCE: GEAs are deadly cancers with few treatment options. Characterization of the genomic landscape of these cancers has revealed considerable genetic diversity and spatial heterogeneity. Understanding these fundamental properties of GEA will be critical for overcoming barriers to the development of novel, more effective therapeutic strategies.

Figure 1.. Molecular classification of GEA.

Key features of the four TCGA subtypes of GEA spanning the lower esophagus to the distal stomach. Frequencies at each anatomic location are from Ref. (6).

Figure 2.. Types of genomic heterogeneity in GEA.

Figure 3.. Genomic heterogeneity impacts the molecular diagnosis and treatment response of GEA.

Potential outcomes with testing of a single tumor site, in this case, endoscopic biopsy of the primary lesion. The inset represents a scenario in which the biopsy captures both cells with Gene A amplification and cells with Gene B amplification.