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

Authors

Lumish MA

Walch H

Maron SB

Chatila W

Kemel Y

Maio A

Ku GY

Ilson DH

Won E

Li J

Joshi SS

Gu P

Schattner MA

Laszkowska M

Gerdes H

Jones DR

Sihag S

Coit DG

Tang LH

Strong VE

Molena D

Stadler ZK

Schultz N

Janjigian YY

Cercek A

Doi

10.1093/jnci/djad186

PMID: 37699004 · DOI: 10.1093/jnci/djad186 · Journal: JNCI: Journal of the National Cancer Institute (2024)

TL;DR

This single-institution study from MSK compared clinical and molecular features of early-onset (age <50, n=219) versus average-onset (age >=50, n=904) esophagogastric cancer. Early-onset patients were more likely to be female, have gastric primary tumors, signet ring cell/diffuse-type histology, and genomically stable TCGA molecular subtypes. Despite these differences, overall survival from time of metastasis did not differ between groups (median 22.7 vs 22.1 months, P=0.78). Somatic profiling with MSK-IMPACT revealed CCNE1 and CDH1 enrichment in early-onset tumors, while CDKN2A was enriched in average-onset tumors. Germline analysis showed no difference in moderate- or high-penetrance alterations between groups.

Cohort & data

  • 1,123 patients with esophagogastric cancer (EGC, STAD, ESCA, GEJ) treated at Memorial Sloan Kettering Cancer Center between 2005 and 2018.
  • Early-onset group: n=219 (median age 43 years, range 18-50). Average-onset group: n=904 (median age 67 years, range 50-94).
  • Somatic profiling via MSK-IMPACT (IMPACT505, up to 505 genes) available for 902 patients (196 early-onset, 706 average-onset) (PMID:27634761).
  • Germline analysis using a 76- to 88-gene MSK-IMPACT panel on 466 patients (116 early-onset, 350 average-onset).
  • Data deposited in cBioPortal as study egc_msk_2023.

Key findings

  • Early-onset EGC had a higher proportion of women (39% vs 28%, P=0.002) and patients of Asian race (16% vs 9%, P=0.002).
  • Gastric primary site was more common in early-onset (64% vs 44%, P<0.0001); esophageal site was less common (16% vs 28%, P<0.001).
  • Signet ring cell/diffuse-type histology was 3 times more common in early-onset (31% vs 9%, P<0.0001).
  • Early-onset tumors had lower TMB (median 3.3 vs 4.9 mutations/Mb, P<0.001) and lower fraction genome altered (median 0.055 vs 0.132, P<0.001).
  • Genomically stable TCGA subtype was more frequent in early-onset (31% vs 18%, P=0.0002); MSI-high was less frequent (2% vs 7%, P=0.003).
  • Among microsatellite-stable tumors, CCNE1 alterations were enriched in early-onset (16% vs 7%, P=0.001, Q=0.011) and CDH1 alterations were enriched in early-onset (12% vs 6%, P=0.004, Q=0.03).
  • CDKN2A alterations were enriched in average-onset (22% vs 11%, P<0.001, Q=0.011).
  • Peritoneal metastasis was more common in early-onset (40.3% vs 23.8%, P<0.001).
  • Overall survival from metastasis did not differ (median 22.7 vs 22.1 months, P=0.78).
  • In multivariable analysis, CDKN2A alterations were associated with worse survival (HR=1.55, 95% CI 1.21-1.98, P<0.001); ERBB2 was associated with improved survival (HR=0.65, 95% CI 0.47-0.91, P=0.01).
  • Germline moderate- or high-penetrance alterations were similar between groups (9.9% vs 9.6%, P>0.99).
  • 35% of early-onset patients were initially treated for an alternative diagnosis (vs 21% average-onset), suggesting diagnostic delay.

Genes & alterations

  • ERBB2: Amplification; trend toward higher frequency in average-onset (20% vs 15%, P=0.16). Associated with improved survival in multivariable model (HR=0.65, P=0.01).
  • CDKN2A: Loss/mutation; enriched in average-onset (22% vs 11%, P<0.001, Q=0.011). Associated with worse survival (HR=1.55, P<0.001).
  • KRAS: Oncogenic alterations; trend toward higher frequency in average-onset (15% vs 12%, P=0.23).
  • CCNE1: Amplification; enriched in early-onset (16% vs 7%, P=0.001, Q=0.011), driven by chromosomal instability esophageal/GEJ subgroup.
  • CDH1: Mutations; enriched in early-onset (12% vs 6%, P=0.004, Q=0.03), consistent with signet ring cell/diffuse-type enrichment.
  • PIK3CA: Oncogenic alterations present in >10% of patients across both groups; no significant differential frequency reported.
  • ARID1A: Oncogenic alterations present in >10% of patients across both groups; no significant differential frequency reported.

Clinical implications

  • Early-onset esophagogastric cancer represents a clinically and molecularly distinct subgroup characterized by gastric primary site, signet ring cell/diffuse-type histology, and genomically stable subtype – but outcomes from time of metastasis are similar, providing no evidence to intensify treatment for younger patients.
  • The high rate of misdiagnosis (35%) in early-onset patients highlights the need for increased clinician awareness of esophagogastric cancer in patients under 50.
  • The enrichment of CCNE1 amplification in early-onset tumors may represent a potential therapeutic target (e.g., CDK2 inhibitors).
  • ERBB2-positive status was associated with improved survival, supporting the continued role of HER2-directed therapy in this population.

Limitations & open questions

  • Single-institution cohort from MSK with relatively homogeneous racial/ethnic distribution, limiting generalizability.
  • Population was enriched for patients with ERBB2 amplification due to institutional research focus, potentially inflating median overall survival.
  • Preferential inclusion of molecularly profiled patients biases toward more advanced disease.
  • Retrospective design with chart review for symptom data introduces recall and documentation bias.
  • The role of hormonal factors (estrogen exposure) in driving the sex-specific and signet ring cell/diffuse-type predominance in early-onset disease remains hypothesis-generating rather than established.
  • Whether alternative screening strategies (beyond upper endoscopy) could improve early detection for young patients with signet ring cell/diffuse-type gastric cancer is unanswered.

Citations from this paper used in the wiki

  • “We included 1123 patients with early-onset esophagogastric cancer (n=219; median age=43 years [range=18-49years]) and average-onset esophagogastric cancer (n=904; median age=67 years [range=50-94years]) treated between 2005 and 2018.” (Abstract/Results)
  • “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).” (Abstract/Results)
  • “Early-onset tumors were more frequently genomically stable (31% vs 18%, P=.0002) and unlikely to be microsatellite instability high (2% vs 7%, P=.003).” (Abstract/Results)
  • “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).” (Results, Figure 2)
  • “CDKN2A was altered at a higher frequency in the average-onset group (22% vs 11%, P<.001, Q=0.011).” (Results)
  • “Overall survival did not differ statistically significantly between patients with early-onset disease compared with average-onset disease (median overall survival=22.7 vs 22.1months; P=.78 by log-rank test).” (Results)
  • “CDKN2A (hazard ratio=1.55, 95% confidence interval=1.21 to 1.98; P=<.001), while ERBB2 was associated with improved survival (hazard ratio=0.65, 95% confidence interval=0.47 to 0.91; P=.01).” (Results)
  • “No difference in the frequency of moderate- or high-penetrance alterations between the 2 groups (9.9% vs 9.6%, P>.99).” (Results)

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