Clinical and molecular characteristics of early-onset vs average-onset esophagogastric cancer

Abstract

Background: The rate of esophagogastric cancer is rising among individuals under 50 years of age. It remains unknown whether early-onset esophagogastric cancer represents a unique entity. This study investigated the clinical and molecular characteristics of early-onset and average-onset esophagogastric cancer .

Methods: We reviewed the Memorial Sloan Kettering Cancer Center gastric, esophageal, and gastroesophageal junction cancer database. Associations between baseline characteristics and tumor and germline molecular alterations were compared between those with early-onset and average-onset esophagogastric cancer using Fisher exact tests and the Benjamini-Hochberg method for multiple-hypothesis correction.

Results: We included 1123 patients with early-onset esophagogastric cancer (n = 219; median age = 43 years [range = 18-49 years]) and average-onset esophagogastric cancer (n = 904; median age = 67 years [range = 50-94 years]) treated between 2005 and 2018. The early-onset group had more women (39% vs 28%, P = .002). Patients with early-onset esophagogastric cancer were more likely to have a gastric primary site (64% vs 44%, P < .0001). The signet ring cell and/or diffuse type was 3 times more common in the early-onset esophagogastric cancer group (31% vs 9%, P < .0001). Early-onsite tumors were more frequently genomically stable (31% vs 18%, P = .0002) and unlikely to be microsatellite instability high (2% vs 7%, P = .003). After restricting to adenocarcinoma and signet ring cell and/or diffuse type carcinomas, we observed no difference in stage (P = .40) or overall survival from stage IV diagnosis (median = 22.7 vs 22.1 months, P = .78).

Conclusions: Our study supported a preponderance of gastric primary disease sites, signet ring histology, and genomically stable molecular subtypes in early-onset esophagogastric cancer. Our findings highlight the need for further research to define the underlying pathogenesis and strategies for early detection and prevention.

Figure 1.

Clinical characteristics of early-onset (age <50 years, n = 219) and average-onset (age ≥50 years, n = 904) esophagogastric cancer. A) Comparison of the clinical and pathologic characteristics demonstrates a higher percentage of gastric primary tumor site (64% vs 44%, P < .0001), proportion of women (39% vs 28%, P = .002), Asian race (16% vs 9%, P = .002), and signet ring histology or Lauren diffuse type cancer (31% vs 9%, P < .001) in the early-onset group. B) Histologic subtype distribution in the average-onset group compared with the early-onset group demonstrates a higher proportion of signet ring cell and/or diffuse type in the early-onset gastric cancer than in the average-onset gastric cancer group. C) Presenting symptoms that occurred statistically significantly more frequently in the early-onset group included pain and change in bowel habits, while weight loss and swallowing difficulty occurred more frequently in the average-onset group. BMI = body mass index; GEJ = gastroesophageal junction; GI = gastrointestinal.

Figure 2.

Molecular characteristics of early-onset (age <50 years) and average-onset (age ≥50 years) esophagogastric cancer. A) Oncoprint demonstrates that the most frequent oncogenic alterations were similar across the early-onset and average-onset groups (n = 196 early onset, n = 706 average onset). The genes that were altered at a statistically significantly higher frequency in the early-onset group compared with the average-onset group were CCNE1 (16% vs 7%, P = .001, Q = 0.011) and CDH1 (12% vs 6%, P = .004, Q = 0.03). B) Comparison of the tumor mutational burden (mutations/megabase), fraction genome altered, and The Cancer Genome Atlas molecular subtypes demonstrates statistically significantly lower tumor mutational burden and fraction genome altered in the early-onset group than in the average-onset group (tumor mutational burden median = 3.3 vs 4.9 mutations/megabase, P < .001; fraction genome altered median = 0.055 vs 0.132, P < .001) and a higher predominance of the genomically stable subtype. C) Comparison of the frequency of gene- and pathway-level alterations after restricting to adenocarcinoma and signet ring cell/diffuse–type tumors. CDKN2A was found to be statistically significantly enriched in average-onset tumors, whereas CCNE1 and CDH1 were enriched in early-onset tumors. D) Germline genomic analysis using a 76- to 88-gene panel showed that patients in both groups were similarly likely to have high or moderate penetrance alterations (9.9% vs 9.6%, P  > .99). CIN = chromosomal instability; EBV = Epstein-Barr virus; GEJ = gastroesophageal junction; GS = gastric cancer; MSI = microsatellite instability; MSS = microsatellite stabile; NOS = not otherwise specified; ∗= P < .001.

Figure 3.

Clinical outcomes of metastatic early-onset (age <50 years) and average-onset (age ≥50 years) esophagogastric cancer, restricted to adenocarcinoma and signet ring cell/diffuse–type tumors. A) Overall survival from the time of metastasis to the time of death or last follow-up did not differ statistically significantly between patients with early-onset compared with average-onset disease (median overall survival = 22.7 vs 22.1 months; P = .78 by log-rank test). B) Overall survival stratified by disease site showed that overall survival from time of metastasis to time of death or last follow-up was statistically significantly longer in patients with early-onset esophageal/gastroesophageal junction cancers and statistically significantly shorter in patients with early-onset gastric cancer (median overall survival = 32.0 vs 19.8 months, P = .02). C) Peritoneal metastasis was statistically significantly more common in the early-onset group than in the average-onset group (40.3% vs 23.8%, P < .001) and within the early-onset group occurred much more frequently in the gastric cancer group than in the esophageal/gastroesophageal junction cancer group (56.3% vs 15.9%, P < .001). D) Multivariate model generated based on variables that were statistically significant on univariate analysis demonstrated that more than 1 metastasis site and CDKN2A alterations were associated with worse outcomes. AO = average onset; CI = 95% confidence interval; CIN = chromosomal instability; EBV = Epstein-Barr virus; EO = early onset; GEJ = gastroesophageal junction; GS = gastric cancer; met = metastasis; MSI = microsatellite instability.