Investigating Differences Between Esophagogastric Cancers Across Age Groups

Early-onset esophagogastric cancer has demonstrated an alarming rise in incidence, with some studies suggesting an increase of up to 30% in recent decades, according to Ryan H. Moy, MD, PhD.

This trend, which mirrors the rise observed in other gastrointestinal (GI) malignancies such as colorectal cancer, generally defines the early-onset population as patients under the age of 50 years. Clinical data derived from real-world datasets reveal that patients with early-onset disease often present with a more advanced stage and are more likely to have diffuse-type gastric cancer. Furthermore, this cohort is frequently enriched for women and specific minority racial and ethnic populations.

During a site visit to Columbia University, CancerNetwork® spoke with Moy, an assistant professor of medicine at Columbia University Irving Medical Center, about some of his research and other hot topics in GI cancers.

Biologically, early-onset esophagogastric cancer is characterized by distinct molecular signatures that differentiate it from later-onset disease. Investigators have identified an increase in mutations within genes such as CDH1 and a decrease in P53 mutations, suggesting a more genomically stable tumor phenotype. Additionally, these tumors often exhibit increased amplifications in FGFR2, CCNE1, and MYC. At the transcriptional level, there is a higher enrichment for signatures related to epithelial-to-mesenchymal transition (EMT) pathways, which Moy noted suggests a “more invasive phenotype” at the time of diagnosis.

While the underlying causes for this epidemiological shift remain under investigation, the enrichment of specific genomic alterations such as FGFR2 amplifications underscores the importance of a multidisciplinary approach to early detection and precision treatment. By utilizing comprehensive genomic profiling, clinicians can better navigate the unique landscape of early-onset esophagogastric cancer and identify potential avenues for targeted interventions and clinical trial enrollment.

Transcript:

CancerNetwork: Are there distinct molecular characteristics in patients with esophagogastric and GI cancers under age 45 that suggest they need different therapeutic backbones than the traditional older population?

We're seeing an alarming rise in early-onset esophagogastric cancers, which we generally define as patients under the age of 50 years. We aren't exactly sure of the reasons for this rise, but some studies suggest that this is even up to a 30% increase in recent decades and nears the increase we see in other GI cancers, like colorectal cancers. We've looked at the differences between early-onset and late-onset esophagogastric cancer from real-world data sets, and we see some distinct differences between early-onset and late-onset disease. Early-onset patients tend to present at more advanced stage, have diffuse-type gastric cancer, and are enriched for women as well as certain ethnic and racial populations, such as Hispanic, Black, and Asian patients.

In addition, biologically, there are some key differences. For example, there's an increase in mutations in genes like CDH1 in early onset disease and decreased P53 mutations, so a more genomically stable tumor phenotype. In addition, there are increased amplifications in genes like FGFR2, CCNE1, and MYC. On the transitional level, there are also differences with higher enrichment for signatures related to epithelial to mesenchymal transition pathways in early onset disease, suggesting a more invasive phenotype at this time. We don't have enough data to suggest that patients with early onset disease should be treated differently than [those with] later onset disease. Treatment is still guided by biomarkers such as PD-L1, HER2, MSI, and CLDN18, but these data reinforce the need to perform comprehensive genomic profiling in younger patients, particularly to identify targetable alterations that may guide treatment selection.