Prognosis and distant metastasis patterns of early-onset gastric cancer compared to late-onset: A large-scale, cross-population retrospective study

doi:10.21203/rs.3.rs-5267904/v1

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Prognosis and distant metastasis patterns of early-onset gastric cancer compared to late-onset: A large-scale, cross-population retrospective study

https://doi.org/10.21203/rs.3.rs-5267904/v1

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Background

Early-onset gastric cancer (EOGC, ≤ 45 years) exhibits distinct clinicopathological characteristics, and its incidence is rising. This study aims to offer insights into treatment strategies for gastric cancer patients across different age groups by retrospectively analyzing the clinicopathological features, distant metastasis patterns, and prognostic factors of EOGC patients.

Methods

We performed a retrospective analysis of data from 33,675 gastric cancer patients in the Surveillance, Epidemiology, and End Results database and Zhejiang Cancer Hospital, including 3,208 EOGC patients and 30,467 late-onset gastric cancer (LOGC) patients. Restricted cubic spline analysis was applied to evaluate the nonlinear relationship between age and mortality risk. Propensity score matching (PSM) was employed to balance baseline differences between groups. Survival analysis was conducted using Kaplan-Meier curves, subgroup analysis, and Cox regression analysis.

Result

Despite EOGC patients presenting with unfavorable clinicopathological features, survival analysis revealed that EOGC patients had better overall survival than LOGC patients both before and after PSM. Subgroup analysis further indicated that EOGC patients exhibited a significant survival advantage with smaller tumor size, SRCC subtype, and stages I-III. Additionally, the distant metastasis pattern in EOGC patients differed from LOGC patients, with EOGC patients more frequently developing bone and ovarian metastases, while liver metastasis was less common. EOGC patients with peritoneal metastasis had poorer outcomes than LOGC patients. Prognosis was relatively better for EOGC patients with distant lymph node metastasis, but poorer for those with peritoneal metastasis.

Conclusion

Surgically treated EOGC patients have significantly better prognoses than LOGC patients. Furthermore, the distant metastasis patterns of EOGC differ from LOGC, carrying distinct prognostic implications for different metastatic sites.

Biological sciences/Cancer

Health sciences/Diseases

Health sciences/Gastroenterology

Health sciences/Medical research

Health sciences/Oncology

Early-onset gastric cancer

Prognosis

Distant metastasis

SEER

Gastric cancer ranks as the fifth most prevalent malignancy worldwide and stands as the fifth leading cause of cancer-related death ^[1]. Although the overall incidence of gastric cancer has been steadily declining in recent years, the proportion of early-onset gastric cancer (EOGC) has been rising, now comprising 4.6–14.8% of cases ^[2]. In the United States, EOGC represents over 30% of newly diagnosed gastric cancer cases ^{[3, 4]}. EOGC typically refers to gastric cancer diagnosed at a younger age, though the specific age cutoff varies across studies. Some set the threshold at under 40 years ^[4], while others define it as below 50 years ^[5] or 45 years and younger ^[6–9]. In this study, we adopted 45 years and younger as the age threshold for EOGC, consistent with our clinical experience.

EOGC patients generally exhibit better overall health, stronger organ function, and greater treatment tolerance. However, due to its subtle early symptoms, EOGC is often overlooked ^[10]. Previous studies suggest that EOGC is often associated with a higher proportion of female patients, poor differentiation, and greater aggressiveness, though findings remain inconsistent across studies ^{[8, 11, 12]}. Furthermore, while EOGC presents several clinicopathological features linked to poor prognosis, it remains uncertain whether these features serve as definitive risk factors for poor outcomes. Recent studies, however, suggest that EOGC patients may have a better survival rate than late-onset gastric cancer (LOGC) patients ^[13–15]. Overall, EOGC represents a distinct subtype of gastric cancer, characterized by controversial clinicopathological features, prognosis, and treatment, necessitating further clarification through large-scale, high-quality studies to investigate potential mechanisms.

This study utilizes data from 33,675 gastric cancer patients from Zhejiang Cancer Hospital and the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified into two groups: EOGC (≤ 45 years) and LOGC (> 45 years), aiming to systematically compare clinicopathological characteristics, patterns of distant metastasis, and prognostic factors across age groups. We applied restricted cubic spline (RCS) analysis to evaluate the nonlinear relationship between age and mortality risk, and propensity score matching (PSM) to adjust for baseline differences between the two groups, ensuring robust comparisons. Additionally, we performed subgroup analysis to assess survival differences across various clinical variables between EOGC and LOGC patients. This study aims to provide valuable insights to guide treatment strategies for gastric cancer patients across different age groups.

Patient selection

In this study, we comprehensively reviewed a cohort comprising 33675 cases of gastric adenocarcinoma. Of these, 27,948 cases were extracted from the SEER database (2010–2019) using SEER*Stat software. The remaining 5,727 cases were collected from Zhejiang Provincial Cancer Hospital, China, spanning 2007 to 2019. Eligibility criteria included: (1) a pathological diagnosis of adenocarcinoma with histological types specified in the SEER database (codes 8140, 8142–8145, 8210, 8211, 8221, 8230, 8231, 8255, 8260, 8062, 8263, 8310, 8480, 8481, 8490); (2) patients with only one primary tumor; (3) documented age at diagnosis. Exclusion criteria were: (1) survival time of less than one month or insufficient survival data; (2) unknown TNM stage; (3) missing critical clinical and pathological data. The detailed screening methodology is depicted in Fig. 1.

Variable definition

The clinicopathological data collected for the patients in SEER cohort included a range of variables: race, gender, age, tumor location, differentiation, pathological type, TNM stage (AJCC 8th edition), T stage, N stage, M stage, surgical method, the count of examined lymph nodes (ELNs), chemotherapy status, radiotherapy status, and distant metastasis sites. The clinicopathological data collected for the patients in Chinese cohort included variables: gender, age, BMI, family history, tumor size, tumor location, differentiation, pathological type, TNM stage (AJCC 8th edition), T stage, N stage, M stage, vascular tumor thrombus, nerve invasion, the count of ELNs, chemotherapy status, postoperative complications, postoperative recurrence and metastasis, distant metastasis sites, carbohydrate antigen50 (CA50), carcinoembryonic antigen (CEA), Alpha-fetoprotein (AFP), carbohydrate antigen 242 (CA242), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), and carbohydrate antigen 724 (CA724).Tumors were classified by site into upper (cardia, gastric fundus), middle (gastric body, lesser curvature and greater curvature of stomach), lower (gastric antrum, gastric sinus, pylorus), and others (> 2/3 stomach). Positive levels for the tumor markers were defined as follows: CA242 ≥ 20 U/ml, CA199 ≥ 37 U/ml, CEA ≥ 5 ng/ml,CA50 ≥ 25 U/ml, CA724 ≥ 6.9 U/ml, and CA125 ≥ 35 U/ml.

Follow-up and outcome

Follow-up data for the SEER cohort and the Chinese cohort were last updated in November 2023 and December 2023, respectively. In the SEER cohort, the median follow-up duration was 77 months, ranging from 2 to 143 months. In the Chinese cohort, the median follow-up duration was 87 months, ranging from 2 to 157 months. Overall survival (OS) was defined as the time from diagnosis of gastric adenocarcinoma to death from any cause.

Statistical analysis

Restricted cubic spline (RCS) regression was used to describe the non-linear relationship. Kaplan-Meier curves were used to plot survival distributions, and differences were assessed with the Log-rank test. Cox proportional hazards models were used for univariate and multivariate analyses to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for OS. Subgroup analysis was performed with age as the grouping variable, and the p-value for interaction was calculated to assess the potential interaction effect of age. A two-sided p-value of less than 0.05 was considered statistically significant. All analyses were performed using R software (version 4.3.3).

Ethics

The ethics Committee of Zhejiang Provincial Cancer Hospital approved this retrospective study (IRB-2022-371).

The clinicopathological characteristics of EOGC and LOGC differ significantly.

The SEER database included 27,948 patients, with 2,698 diagnosed with EOGC and the remaining 25,250 with LOGC (Table 1). We compared the clinicopathological characteristics between the two groups. EOGC patients were characterized by a higher proportion of females, fewer tumors in the upper third of the stomach, a higher incidence of poorly differentiated carcinoma and signet ring cell carcinoma (SRCC), and increased rates of lymph node and distant metastasis, as well as more frequent use of chemotherapy and radiotherapy. Table 1 presents the detailed baseline characteristics of the SEER cohort.

Table 1

Clinicopathological characteristics between EOGC and LOGC patients in the SEER cohort.
Variable	EOGC(<=45)	LOGC(>45)	p-value
N (%)	n = 2698	n = 25250	p-value
Race:			0.083
Black	295 (10.9%)	2943 (11.7%)
Other	501 (18.6%)	4597 (18.2%)
Unknown	23 (0.85%)	128 (0.51%)
White	1876 (69.6%)	17585 (69.6%)
Sex:			< 0.001
Female	1245 (46.2%)	8759 (34.7%)
Male	1450 (53.8%)	16494 (65.3%)
Tumor Location:			< 0.001
Lower	537 (19.9%)	5602 (22.2%)
Middle	693 (25.7%)	5129 (20.3%)
Others	279 (10.4%)	1930 (7.64%)
Unknown	434 (16.1%)	2697 (10.7%)
Upper	752 (27.9%)	9895 (39.2%)
Tumor size:			< 0.001
>4cm	591 (21.9%)	7178 (28.4%)
<=4cm	826 (30.6%)	8616 (34.1%)
Unknown	1278 (47.4%)	9459 (37.5%)
Differentiation:			< 0.001
Moderately	286 (10.6%)	6188 (24.5%)
Poorly	1910 (70.9%)	14123 (55.9%)
Undifferentiated	37 (1.37%)	280 (1.11%)
Unknown	409 (15.2%)	3584 (14.2%)
Well	53 (1.97%)	1078 (4.27%)
Pathological type:			< 0.001
Adenocarcinoma	1644 (61.0%)	20574 (81.5%)
SRCC	1051 (39.0%)	4679 (18.5%)
TNM stage:			< 0.001
I	309 (11.5%)	5836 (23.1%)
II	405 (15.0%)	5232 (20.7%)
III	479 (17.8%)	4675 (18.5%)
IV	1502 (55.7%)	9510 (37.7%)
T stage:			< 0.001
T1	235 (19.6%)	3487 (27.4%)
T2	130 (10.9%)	1550 (12.2%)
T3	432 (36.1%)	4714 (37.0%)
T4	381 (31.8%)	2892 (22.7%)
TX	19 (1.6%)	92 (0.7%)
N stage:			< 0.001
N0	974 (36.1%)	10871 (43.0%)
N1	700 (26.0%)	6758 (26.8%)
N2	285 (10.6%)	2655 (10.5%)
N3	342 (12.7%)	2714 (10.7%)
NX	394 (14.6%)	2255 (8.93%)
M stage:			< 0.001
M0	1193 (44.3%)	15743 (62.3%)
M1	1502 (55.7%)	9510 (37.7%)
Gastrectomy:			< 0.001
No	1497 (55.5%)	12468 (49.4%)
Unknown	1 (0.04%)	50 (0.20%)
Yes	1197 (44.4%)	12735 (50.4%)
NACT:			0.002
No/unknown	2158 (80.1%)	20824 (82.5%)
Yes	537 (19.9%)	4429 (17.5%)
ELNs:			0.057
<16	1870 (69.4%)	17986 (71.2%)
>=16	730 (27.1%)	6534 (25.9%)
Unknown	95 (3.53%)	733 (2.90%)
Chemotherapy:			< 0.001
No/Unknown	432 (16.0%)	8752 (34.7%)
Yes	2263 (84.0%)	16501 (65.3%)
Radiotherapy:			< 0.001
No/Unknown	2001 (74.2%)	17788 (70.4%)
Yes	694 (25.8%)	7465 (29.6%)
SRCC: Signet-ring cell carcinoma; NACT: Neoadjuvant chemotherapy; ELNs: examined lymph nodes;

In the Chinese cohort of 5,727 patients, 510 were diagnosed with EOGC, while 5,217 were diagnosed with LOGC (Table 2). The findings from the SEER cohort were validated in the Chinese cohort. Additionally, we found a higher incidence of vascular tumor thrombus in EOGC patients. In terms of serum tumor markers, EOGC patients had lower positivity rates for CEA and CA242, but a higher positivity rate for CA125. Table 2 presents detailed baseline characteristics of the Chinese cohort.

Table 2

Clinicopathological characteristics between EOGC and LOGC patients in the Chinese cohort.
Variable	EOGC(<=45)	LOGC(>45)	p-value
N (%)	n = 510	n = 5217	p-value
Sex:			< 0.001
Female	263 (51.6%)	1374 (26.3%)
Male	247 (48.4%)	3843 (73.7%)
BMI:			0.141
<18.5	61 (12.0%)	503 (9.64%)
18.5–23.9	308 (60.4%)	3346 (64.1%)
>=24	141 (27.6%)	1368 (26.2%)
Family history:			0.409
No	407 (79.8%)	4247 (81.4%)
Yes	103 (20.2%)	970 (18.6%)
Tumor location:			< 0.001
Lower	320 (62.7%)	2929 (56.1%)
Middle	122 (23.9%)	855 (16.4%)
Total	17 (3.4%)	133 (2.6%)
Upper	51 (10.0%)	1300 (24.9%)
Tumor size:			< 0.001
>4cm	254 (49.8%)	2254 (43.2%)
<=4cm	242 (47.5%)	2892 (55.4%)
Unknown	14 (2.7%)	71 (1.4%)
Differentiation:			< 0.001
Moderate	87 (17.1%)	2610 (50.0%)
Poor	417 (81.8%)	2506 (48.0%)
Well	6 (1.1%)	101 (2.0%)
Pathological type:			0.018
Adenocarcinoma	301 (59.0%)	2787 (53.4%)
SRCC	209 (41.0%)	2430 (46.6%)
Vascular tumor thrombus:			0.018
No	301 (59.0%)	2787 (53.4%)
Yes	209 (41.0%)	2430 (46.6%)
Nerve invasion:			0.351
No	242 (47.5%)	2594 (49.7%)
Yes	268 (52.5%)	2623 (50.3%)
TNM stage:			< 0.001
I	156 (30.6%)	1330 (25.5%)
II	82 (16.1%)	962 (18.4%)
III	227 (44.5%)	2700 (51.8%)
IV	45 (8.8%)	225 (4.31%)
T stage:			0.001
T1	153 (30.0%)	1140 (21.9%)
T2	55 (10.8%)	622 (11.9%)
T3	32 (6.3%)	351 (6.7%)
T4	270 (52.9%)	3104 (59.5%)
N stage:			0.068
N0	173 (33.9%)	1799 (34.5%)
N1	77 (15.1%)	894 (17.1%)
N2	89 (17.5%)	1046 (20.0%)
N3	171 (33.5%)	1478 (28.3%)
M stage:			< 0.001
M0	465 (91.2%)	4992 (95.7%)
M1	45 (8.8%)	225 (4.3%)
ELNs:			0.560
<16	49 (9.61%)	550 (10.5%)
>=16	461 (90.4%)	4667 (89.5%)
NACT:			0.159
No/unknown	446 (87.5%)	4673 (89.6%)
Yes	64 (12.5%)	544 (10.4%)
Chemotherapy:			< 0.001
No/Unknown	173 (33.9%)	2584 (49.5)
Yes	337 (66.1%)	2633 (50.5%)
Complication:			0.181
No	484 (94.9%)	4865 (93.3%)
Yes	26 (5.1%)	352 (6.7%)
Postoperative recurrence:			0.107
No	507 (99.4%)	5133 (98.4%)
Yes	3 (0.6%)	84 (1.6%)
Distant metastasis (Pre-and Postoperative):			< 0.001
No	405 (79.4%)	4548 (87.2%)
Yes	105 (20.6%)	669 (12.8%)
Postoperative recurrence and metastasis:			0.138
No	462 (90.6%)	4827 (92.5%)
Yes	48 (9.4%)	390 (7.5%)
CEA:			< 0.001
Negative	469 (92.0%)	4155 (79.6%)
Positive	41 (8.0%)	1062 (20.4%)
CA199:			0.080
Negative	426 (83.5%)	4184 (80.2%)
Positive	84 (16.5%)	1033 (19.8%)
CA125:			< 0.001
Negative	459 (90.0%)	4909 (94.1%)
Positive	51 (10.0%)	308 (5.9%)
AFP:			0.429
Negative	484 (94.9%)	4900 (93.9%)
Positive	26 (5.1%)	317 (6.1%)
CA242:			0.003
Negative	470 (92.2%)	4566 (87.5%)
Positive	40 (7.8%)	651 (12.5%)
CA724:			0.689
Negative	417 (81.8%)	4222 (80.9%)
Positive	93 (18.2%)	995 (19.1%)
SRCC: Signet-ring cell carcinoma; NACT: Neoadjuvant chemotherapy; ELNs: examined lymph nodes;

The prognosis of EOGC patients is better than that of LOGC patients.

Since approximately 50% of patients in the SEER cohort either did not undergo surgery or had unknown surgical status, while all patients in the Chinese cohort had undergone surgery (either curative or palliative), we included only 13,932 post-surgical patients from the SEER cohort in the prognostic analysis (Table S1). RCS analyses revealed a significant nonlinear relationship between age and HR in both the SEER and Chinese cohorts (P-non-linear < 0.001). In the SEER cohort, 66 years was identified as the cut-off point, after which HR significantly increased (Fig. 2A); in the Chinese cohort, 61 years served as the cut-off point, showing a similar upward trend in HR (Fig. 2B). This suggests that as the age at gastric cancer diagnosis increases, mortality risk gradually rises and then significantly accelerates after a specific age threshold. These two cut-off points reveal the staged impact of diagnosis age on gastric cancer mortality risk: early changes in mortality risk are relatively slow, but increase rapidly after the cutoff, underscoring the importance of diagnosis age in assessing mortality risk for gastric cancer.

Prognostic analyses of the SEER and Chinese cohorts demonstrated that EOGC patients had significantly better OS compared to LOGC patients (p < 0.001). In the SEER cohort (Fig. 2C), the 5-year OS rate for EOGC patients was 48.7%, significantly higher than the 45.4% for LOGC patients (HR = 0.82, p < 0.001). In the Chinese cohort (Fig. 2D), the 5-year OS rate for EOGC patients was 72.2%, again significantly higher than the 62.8% for LOGC patients (HR = 0.65, p < 0.001).

Given the significant baseline differences between EOGC and LOGC, we performed 1:2 PSM to adjust for potential confounding factors affecting prognosis. In the SEER cohort, PSM resulted in a total of 3,434 matched patients, comprising 1,158 EOGC and 2,276 LOGC patients (Table S2). In the Chinese cohort, PSM yielded 1,353 matched patients, with 469 EOGC and 884 LOGC patients (Table S3). In the PSM-adjusted SEER cohort (Fig. 2E), the 5-year OS rate for EOGC patients was 48.3%, compared to 43.1% for LOGC patients, with EOGC continuing to show a significant survival advantage (HR = 0.83, p < 0.001). Similarly, in the PSM-adjusted Chinese cohort (Fig. 2F), the 5-year OS rate for EOGC patients was 72.6%, significantly higher than the 64.3% for LOGC patients (HR = 0.71, p < 0.001). These results suggest that in both the SEER cohort of Western populations and the Chinese cohort, EOGC patients maintain a survival advantage even after adjusting for baseline differences, further validating the relatively favorable prognosis of EOGC across different populations.

We subsequently performed univariate and multivariate Cox regression analyses on EOGC patients to identify independent prognostic factors. In the SEER cohort, multivariate analysis identified independent prognostic factors for EOGC patients, including tumor size, differentiation, T stage, N stage, distant metastasis, radiotherapy, and the number of ELNs (Table S3). In the Chinese cohort, independent risk factors for prognosis included tumor size, nerve invasion, T stage, N stage, distant metastasis, as well as the tumor markers CA199, CA125, and CA724 (Table S4).

Subgroup analyses of clinicopathological features in EOGC and LOGC patients and the impact of chemotherapy on prognosis

We performed a subgroup analysis of the PSM-adjusted SEER cohort to investigate EOGC and LOGC patients (Fig. 3). The results revealed significant subgroup effects (p for interaction < 0.05) in four variables: tumor size, pathology type, TNM stage, and chemotherapy. Specifically, EOGC patients with smaller tumor size (HR = 0.63, p < 0.001), SRCC pathology (HR = 0.72, p < 0.001), and stage I-III (HR = 0.76, p < 0.001) demonstrated a survival advantage over LOGC patients. In evaluating the impact of chemotherapy on prognosis, although EOGC patients receiving chemotherapy still had a survival advantage (HR = 0.59, p < 0.001), this advantage was significantly weaker compared to those who did not undergo chemotherapy (HR = 0.88, p = 0.022). This suggests that although chemotherapy benefits EOGC patients, the relative survival benefit they gain is less than that of LOGC patients.

In the subgroup analysis of the PSM-adjusted Chinese cohort (Fig.S1), we similarly identified significant subgroup effects in sex, tumor size, TNM stage, T stage, and chemotherapy (P for interaction < 0.05). EOGC patients with smaller tumors and stage I-III had significantly better prognosis compared to LOGC patients, consistent with the findings in the SEER cohort. Regarding the impact of chemotherapy, the Chinese cohort once again validated the SEER cohort findings: EOGC patients who did not undergo chemotherapy had a significant survival advantage over LOGC patients (HR = 0.34, p < 0.001), while those who received chemotherapy still showed a survival advantage, though reduced (HR = 0.79, p = 0.032). This further supports the conclusion that EOGC patients derive relatively less survival benefit from chemotherapy.

Analyses of differences in distant metastasis sites and prognosis in EOGC and LOGC patients

The incidence of distant metastasis in EOGC patients was significantly higher than in LOGC patients, a finding validated across both cohorts. To further investigate the characteristics of distant metastasis in EOGC and LOGC patients and its impact on prognosis, we included 11,012 patients with distant metastasis from the SEER cohort and 774 from the Chinese cohort for analysis. We first compared the differences in metastasis sites between EOGC and LOGC patients. In the SEER cohort, bone and other metastasis sites were more common in EOGC patients, while liver and lung metastasis occurred more frequently in LOGC patients (Table 3). Similar results were observed in the Chinese cohort (Table 4), where liver and lung metastasis were more common in LOGC patients, while ovarian metastasis was more frequent in EOGC patients.

Table 3

Distribution of distant metastasis sites between EOGC and LOGC patients in the SEER cohort
Variable	EOGC(<=45)	LOGC(>45)	p-value
N (%)	n = 1502	n = 9510	p-value
D.M-distant.LN:			0.194
No	439 (29.2%)	2666 (28.0%)
Unknown	623 (41.5%)	3838 (40.4%)
Yes	440 (29.3%)	3006 (31.6%)
D.M-liver:			< 0.001
No	1111 (74.0%)	5327 (56.0%)
Unknown	49 (3.2%)	286 (3.0%)
Yes	342 (22.8%)	3897 (41.0%)
D.M-bone:			0.009
No	1226 (81.6%)	8038 (84.5%)
Unknown	56 (3.8%)	342 (3.6%)
Yes	220 (14.6%)	1130 (11.9%)
D.M-brain:			0.935
No	1416 (94.3%)	8975 (94.4%)
Unknown	61 (4.1%)	370 (3.9%)
Yes	25 (1.6%)	165 (1.7%)
D.M-lung:			< 0.001
No	1303 (86.8%)	7851 (82.6%)
Unknown	65 (4.3%)	409 (4.3%)
Yes	134 (8.9%)	1250 (13.1%)
D.M-others:			< 0.001
No	559 (37.2%)	5679 (59.7%)
Unknown	14 (0.9%)	86 (0.9%)
Yes	929 (61.9%)	3745 (39.4%)
D.M-distant.LN: Distant.metastasis-distant lymph nodes; D.M-others: Distant.metastasis-other sites.
D.M-multiple: Distant.metastasis-multiple organs.

Table 4

Distribution of distant metastasis sites between EOGC and LOGC patients in the Chinese cohort
Variable	EOGC(<=45)	LOGC(>45)	p-value
N (%)	n = 105	n = 669	p-value
DX-distant.LN:			0.669
No	87 (82.9%)	540 (80.7%)
Yes	18 (17.1%)	129 (19.3%)
DX-bone:			0.107
No	92 (87.6%)	621 (92.8%)
Yes	13 (12.4%)	48 (7.2%)
DX-brain:			0.607
No	105 (100%)	661 (98.8%)
Yes	0 (0.00%)	8 (1.2%)
DX-lung:			0.018
No	103 (98.1%)	607 (90.7%)
Yes	2 (1.9%)	62 (9.3%)
DX-ovary:			< 0.001
No	77 (73.3%)	638 (95.4%)
Yes	28 (26.7%)	31 (4.63%)
DX-liver:			0.006
No	90 (85.7%)	486 (72.6%)
Yes	15 (14.3%)	183 (27.4%)
DX-peritoneum			0.160
No	87 (82.9%)	586 (87.6%)
Yes	18 (17.1%)	83 (12.4%)
DX-others:			0.076
No	101 (96.2%)	605 (90.4%)
Yes	4 (3.8%)	64 (9.6%)
D.M-distant.LN: Distant.metastasis-distant lymph nodes; D.M-other: Distant.metastasis-other sites.
D.M-multiple: Distant.metastasis-multiple organs.

We subsequently performed subgroup analyses on the prognosis of EOGC and LOGC patients with different metastasis sites. In the SEER cohort, aside from other metastasis sites, no statistically significant difference in prognosis was observed between EOGC and LOGC patients for each metastasis site (Fig. 4A). Notably, EOGC patients with metastasis to other sites exhibited a better prognosis than LOGC patients (HR = 0.91, p = 0.031). In the Chinese cohort, the prognosis of EOGC patients differed (Fig. 4B): those with peritoneal metastasis had significantly worse prognosis than LOGC patients (HR = 2.23, P = 0.031), whereas those with multiple organ metastasis had significantly better prognosis than LOGC patients (HR = 0.70, p = 0.044). This suggests that the impact of different metastasis sites on prognosis varies between EOGC and LOGC patients across the two populations.

Additionally, we performed univariate COX regression analyses on EOGC patients with distant metastasis to examine prognostic differences by metastasis site. In the SEER cohort, the prognosis for distant lymph node, liver, and other single metastasis sites was significantly better than for multiple organ metastasis, with distant lymph node metastasis demonstrating the greatest survival advantage (Fig. 4C). In the Chinese cohort, peritoneal metastasis had the worst prognosis, while single organ metastasis, bone metastasis, liver metastasis, distant lymph node metastasis, and ovarian metastasis all had better prognoses than peritoneal metastasis (Fig. 4D). These findings highlight significant prognostic differences for EOGC patients based on metastasis site, suggesting that the metastasis pattern plays a crucial role in survival outcomes.

This study, utilizing data from gastric cancer patients in the SEER database and Zhejiang Cancer Hospital in China, systematically compared clinicopathological characteristics, distant metastasis patterns, and prognostic differences between EOGC (≤ 45 years) and LOGC (> 45 years) patients. The results demonstrated that EOGC patients had significantly better overall survival than LOGC patients in both the predominantly Western cohort and the Chinese cohort. Even after adjusting for baseline differences using PSM, EOGC patients maintained a significant survival advantage. However, it is important to note that all patients in the Chinese cohort underwent surgery (curative or palliative). Therefore, for the prognostic analysis in the SEER cohort, we included only post-surgical patients and excluded those who were ineligible for surgery and received only medical treatment due to advanced disease. These findings align with previous studies. Wang et al., in a retrospective analysis of 3,930 gastric cancer patients who underwent curative gastrectomy, found that the 342 younger patients (≤ 40 years) had a higher 5-year survival rate ^[16]. Similarly, Wu et al. analyzed 1,661 stage I-III gastric cancer patients, including 317 aged ≤ 45 years, and reported better survival rates for younger patients ^[17]. Liu et al. further confirmed this trend in a study of 5,046 gastric cancer patients who underwent gastrectomy, showing that EOGC patients had significantly better overall survival than non-EOGC patients ^[18].

In the subgroup analysis, EOGC patients showed a significant survival advantage over LOGC patients across several key variables, providing partial insight into EOGC's better prognosis. Signet ring cell carcinoma (SRCC), a type of diffuse tumor, is highly aggressive and often metastasizes to lymph nodes and distant sites ^[19]. Despite the higher proportion of poorly differentiated tumors and SRCC, which are usually associated with worse prognosis, subgroup analysis revealed that EOGC patients had better survival rates than LOGC patients in both the poorly differentiated and SRCC groups (SEER cohort: HR = 0.72, p < 0.001). This is consistent with the findings reported by Huang et al. and Ren et al ^{[9, 19]}. This suggests that the biological behavior of EOGC may differ from LOGC, or that the younger physical condition of EOGC patients may reduce the negative impact of these pathological features. Additionally, subgroup analysis showed that EOGC patients with tumors smaller than 4 cm had significantly better survival than LOGC patients (SEER cohort: HR = 0.48, p = 0.002; Chinese cohort: HR = 0.63, p < 0.001), suggesting that smaller tumor size may be a key factor in EOGC's better prognosis. Smaller tumors are more easily controlled through surgery or other treatments. Furthermore, multivariate Cox regression identified tumor size as an independent prognostic factor for EOGC, further supporting this conclusion. Additionally, a higher proportion of EOGC patients were diagnosed with TNM stages I-III. Subgroup analysis showed that EOGC patients in the I-III stages had significantly better prognoses than LOGC patients in both cohorts, while no significant survival difference was observed among stage IV patients. This finding aligns with the results of Liu et al ^[20]. This suggests that EOGC patients are more likely to be diagnosed and treated early, contributing to a better prognosis. Even in stage IV patients, the survival difference between the two groups was not significant, further suggesting that EOGC's survival advantage primarily occurs in early and locally advanced stages. In conclusion, EOGC patients' advantages in tumor differentiation, pathology type, tumor size, and TNM stage may explain their better survival outcomes. Despite its more aggressive behavior, smaller tumor size, earlier stage diagnosis, and potential biological differences likely contribute to EOGC's better prognosis compared to LOGC. These results suggest that for operable EOGC patients, aggressive intervention should be pursued despite many clinicopathological features associated with poor prognosis, as it may still lead to favorable outcomes.

According to the Chinese guidelines for gastric cancer, the standard treatment for patients with locally advanced gastric cancer is D2 surgery combined with postoperative adjuvant chemotherapy. SOX (oxaliplatin plus S-1) and XELOX (oxaliplatin plus capecitabine) are the first-line recommended regimens ^[21]. In the subgroup analysis of chemotherapy’s impact on the prognosis of EOGC and LOGC patients, we observed an intriguing phenomenon. Although a significantly higher proportion of EOGC patients received chemotherapy compared to LOGC patients, the subgroup analysis revealed a relatively lower survival benefit from chemotherapy in EOGC patients. Specifically, the survival advantage was more pronounced in EOGC patients who did not receive chemotherapy (SEER cohort: HR = 0.59, p < 0.001; Chinese cohort: HR = 0.34, p < 0.001). While EOGC patients who received chemotherapy still showed a survival benefit (SEER cohort: HR = 0.88, p = 0.022; Chinese cohort: HR = 0.79, p = 0.032), this advantage was notably reduced (p for interaction < 0.05). This suggests that although chemotherapy provides some benefit to EOGC patients, their relative survival benefit is lower compared to LOGC patients. This phenomenon may be linked to the biological characteristics of EOGC. EOGC patients typically have stronger organ function and a higher tolerance for surgery, allowing them to achieve favorable prognoses even without chemotherapy ^{[22, 23]}. In contrast, LOGC patients, who are generally older with declining organ function and increased comorbidities, derive greater therapeutic benefit from chemotherapy. Additionally, we speculate that the higher proportion of SRCC in EOGC patients may contribute to this difference. SRCC is generally considered less responsive to chemotherapy, particularly to 5-FU and platinum-based drugs, and is more prone to drug resistance ^{[4, 24]}. Several studies have demonstrated that postoperative adjuvant chemotherapy does not significantly improve survival in SRCC patients ^{[25, 26]}. These findings warrant further consideration of treatment strategies for EOGC patients. Future research should explore the sensitivity of EOGC patients to various treatment modalities and focus on developing individualized treatment plans to optimize therapeutic outcomes for this patient population.

Previous studies have established the crucial role of serum tumor markers, such as CEA, CA125, CA199, and CA724, in diagnosing, monitoring disease progression, and evaluating prognosis in gastrointestinal malignancies ^[27]. The elevation of these preoperative serum markers is strongly linked to tumor progression and poor prognosis ^{[28, 29]}. In this study, we found that EOGC patients had lower positivity rates for CEA and CA242 compared to LOGC patients, while the positivity rate for CA125 was higher. Previous research has indicated that elevated CA125 is often associated with tumors located in the middle and lower parts of the stomach ^{[28, 30]}, aligning with our findings that EOGC patients primarily presented with tumors in the middle and lower stomach. Additionally, CA19-9, CA125, and CA72-4 were identified as independent prognostic factors for EOGC patients, marking the first report of this association.

Previous studies have also shown that distant metastasis is significantly more common in EOGC patients than in LOGC patients ^{[8, 11, 20, 31]}. Therefore, we explored the patterns of distant metastasis across different age groups in gastric cancer patients. Our results indicated that bone and ovarian metastases were more frequent in EOGC patients, while liver and lung metastases were more common in LOGC patients. These findings are consistent with those reported by Wu et al ^[28], who also found that EOGC is a protective factor against liver metastasis, while LOGC is an independent risk factor for liver metastasis. This further supports the lower rate of liver metastasis observed in EOGC patients. In terms of prognosis, subgroup analysis revealed significant survival differences between EOGC and LOGC patients based on metastasis sites. For instance, EOGC patients had better survival than LOGC patients when metastasis occurred at other sites or involved multiple organs. However, EOGC patients had significantly worse prognosis in cases of peritoneal metastasis compared to LOGC patients (HR = 2.23, p = 0.031). These results suggest that metastasis to different sites has varying impacts on the prognosis of EOGC and LOGC patients. Furthermore, this study revealed additional prognostic differences among EOGC patients based on metastasis sites. In the SEER cohort, patients with distant lymph node and liver metastases had significantly better survival compared to those with multiple organ metastasis, with distant lymph node metastasis offering the greatest survival advantage. This suggests that distant lymph node metastasis may represent a relatively "manageable" pattern of metastasis in EOGC patients. Similarly, results from the Chinese cohort showed that peritoneal metastasis was associated with the worst prognosis, likely due to its high invasiveness and treatment challenges, while prognosis was relatively better for other single metastasis sites, such as distant lymph node, liver, and ovarian metastasis.

This study has several limitations. First, certain key clinical variables were missing from the SEER database, including information on peritoneal and ovarian metastasis as well as serum tumor marker levels, which limited our ability to perform a more comprehensive analysis of these potential prognostic factors. Second, as a retrospective cohort study, confounding and selection biases cannot be completely eliminated.

Despite these limitations, this study has several important strengths. First, as a large-scale retrospective study combining data from the SEER and the Chinese database, it systematically investigates the prognosis of EOGC, with results validated in both Western and Asian populations. This enhances the generalizability and applicability of the findings. Second, we are the first to provide a detailed analysis of prognostic differences in distant metastasis patterns between EOGC and LOGC, offering new insights into the heterogeneity between these patient groups. This large-scale, cross-regional, and cross-population study provides a strong scientific foundation for future clinical practice and personalized treatment approaches.

This study demonstrates that although EOGC presents with several unfavorable clinicopathological features, operable EOGC patients have a significantly better prognosis than LOGC patients, especially those with smaller tumors, SRCC subtype, and stages I-III. Additionally, the patterns of distant metastasis in EOGC patients differ significantly from those in LOGC patients, and these variations are associated with distinct prognostic outcomes.

EOGC

early-onset gastric cancer

LOGC

late-onset gastric cancer

SEER

Surveillance, Epidemiology, and End Results

RCS

restricted cubic spline

PSM

propensity score matching

ELNs

examined lymph nodes

SRCC

signet ring cell carcinoma CA50:carbohydrate antigen 50

CEA

carcinoembryonic antigenCA242:carbohydrate antigen 242

CA199

carbohydrate antigen 199

CA125

carbohydrate antigen 125

CA724

carbohydrate antigen 724

AFP

Alpha-fetoprotein

overall survival

hazard ratio

confidence interval

S-1

Tegafur-Gimeracil-Oteracil

SOX

oxaliplatin plus S-1

XELOX

oxaliplatin plus capecitabine

Ethics approval and consent to participate
This study was approved by the Ethics Committee of Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) and conformed to the principles of the Declaration of Helsinki (revised in 2013) (Ethical ID: IRB-2022-371). All patients gave their informed consent.

Consent for publication
Not applicable.

Competing interests

The authors declare no competing interests.

Funding

This research was supported by several foundations. That included: National Key R&D Program of China (2021YFA0910100), National Natural Science Foundation of China (92259302, 82074245, 82204828, 82374544), Chinese Postdoctoral Science Foundation (2022M713203), Program of Zhejiang Provincial TCM Sci-tech Plan (GZY-ZJ-KJ-230003, GZY-ZJ-KJ-23048), Medical Science and Technology Project of Zhejiang Province (2022KY114, WKJ-ZJ-2104), Natural Science Foundation of Zhejiang Province (HDMY22H160008), Healthy Zhejiang One Million People Cohort (K-20230085).

Author Contribution

Li yuan and Xiangdong cheng conceived the study and acquired the funding. Yukai wang, Kailai yin and Dujiang Liu carried out clinical research, collected clinical samples, analyzed clinical data and wrote the paper. Chuhong Pang , Yang Pan, Xuanhong Jin, Yubo Ma, Yingsong Zheng, Kang liu, Zhengchen Jiang, Ruihong Xia, Yizhou Wei participated in clinical samples collection. All authors have read and approved the final manuscript.

Acknowledgement

Thanks to the follow-up room of Zhejiang Cancer Hospital for its contribution to this article.

Data Availability

Due to the privacy of patients, the data related to patients cannot be available for public access but can be obtained from the corresponding author on reasonable request approved by the institutional review board of all enrolled centers.

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Prognosis and distant metastasis patterns of early-onset gastric cancer compared to late-onset: A large-scale, cross-population retrospective study

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Abstract

Background

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Introduction

Method

Patient selection

Variable definition

Follow-up and outcome

Statistical analysis

Ethics

Result

Analyses of differences in distant metastasis sites and prognosis in EOGC and LOGC patients

Discussion

Conclusion

Abbreviations

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Not applicable.

Competing interests

Funding

Author Contribution

Acknowledgement

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1

Prognosis and distant metastasis patterns of early-onset gastric cancer compared to late-onset: A large-scale, cross-population retrospective study

Status:

Version 1

Abstract

Background

Methods

Result

Conclusion

Figures

Introduction

Method

Patient selection

Variable definition

Follow-up and outcome

Statistical analysis

Ethics

Result

Analyses of differences in distant metastasis sites and prognosis in EOGC and LOGC patients

Discussion

Conclusion

Abbreviations

Declarations

Consent for publication Not applicable.

Competing interests

Funding

Author Contribution

Acknowledgement

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1

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Not applicable.