
==== Front
Chin Med J (Engl)
Chin Med J (Engl)
CM9
Chinese Medical Journal
0366-6999
2542-5641
Lippincott Williams & Wilkins Hagerstown, MD

39148190
CMJ-2024-449
10.1097/CM9.0000000000003259
00002
3
Review Article
Emerging trends in early-onset gastric cancer
Wang Xinlin 1 2
Gao Xianchun 1 2
Yu Jun 1 2
Zhang Xiaotian 1 3
Nie Yongzhan 1 2
Ji Yuanyuan
1 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Xi’an, Shaanxi 710032, China
2 National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
3 Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
Correspondence to: Dr. Xiaotian Zhang, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China E-Mail: zhangxiaotianmed@163.com;
Dr. Yongzhan Nie, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032, China E-Mail: yongznie@fmmu.edu.cn
15 8 2024
20 9 2024
137 18 21462156
07 2 2024
Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Abstract

The incidence of early-onset gastric cancer (EOGC) is consistently increasing, and its etiology is notably complex. This increase may be attributed to distinctive factors that differ from those associated with late-onset gastric cancer (LOGC), including genetic predispositions, dietary factors, gastric microbiota dysbiosis, and screening of high-risk cases. These factors collectively contribute to the onset of cancer. EOGC significantly differs from LOGC in terms of clinicopathological and molecular characteristics. Moreover, multiple differences in prognosis and clinical management also exist. This study aimed to systematically review the latest research advancements in the epidemiological characteristics, etiological factors, clinicopathological and molecular features, prognosis, and treatment modalities of EOGC.

Keywords:

Early-onset gastric cancer
Epidemiology
Etiology
Clinicopathological features
Molecular signaling
Prognosis
Clinical management
OPEN-ACCESSTRUE
==== Body
pmcIntroduction

Early-onset gastric cancer (EOGC) is a type of gastric cancer that is diagnosed in patients aging 45 years or younger, which is different from the late-onset gastric cancer (LOGC) that is diagnosed in patients aging older than 45 years.[1] Although the age threshold of 45 years old is utilized for the definition of EOGC in several studies,[123456789] some studies also used a threshold of 40[10,11] or 50 years old.[12,13] The incidence of EOGC has been consistently rising over the past half-century.[14] Nevertheless, the etiology of the disease remains elusive due to the lack of comprehensive epidemiological research. Recently, researchers have demonstrated an increasing fascination with EOGC, and several studies have emphasized its unique clinicopathological characteristics, such as later pathological staging and lower differentiation rate compared with the LOGC.[3,4] Furthermore, the molecular signaling exhibited significant differences between these two diseases,[14] and conventional treatment methods may not be optimally effective for EOGC patients.[7,12,13] Nevertheless, emerging studies suggested that the prognosis of EOGC may not be inferior to, or may even be superior to LOGC of the same stage.[2,10,11] Consequently, there is an urgent need to comprehensively investigate the factors contributing to the increasing prevalence of EOGC and the development of more potent treatment protocols, in order to ultimately improve preventive, diagnostic, and therapeutic approaches.

Epidemiology of EOGC

Over the past half-century, the incidence of EOGC has increased. This upward trend is evident globally, spanning regions with traditionally lower incidence rates, such as Europe and the Americas, as well as higher-incidence areas, such as China and South Korea.[14151617] Data from the Surveillance, Epidemiology, and End Results (SEER) database in the United States revealed a significant rise in the proportion of gastric cancer patients aging under 50 years old, escalating from 6% in 1982 to 12.5% in 2015. Moreover, when considering patients aging under 40 years, the rate has escalated from 1.7% in 1973 to 3.5% in 2015.[14] In China, prior research has found a modest increase in the incidence rate among 15- to 49-year-old gastric cancer patients from 1990 to 2019.[15] Concurrently, similar trends have been observed in the United Kingdom, Belarus, Chile, the Netherlands, and Canada.[16] According to the latest data from the Global Cancer Observatory, in 2020, there were 51,183 new EOGC patients globally, with China accounting for 16,532 of these cases, representing 32.3% of the total.[18]

It is noteworthy that this upward trend in incidence rate varies across different regions. Studies estimating the trend through annual percentage changes reported that by 2035, the incidence rate of EOGC in China will rise from 9.6 to 17.6 per 100,000, and in South Korea, from 10.9 to 21.4 per 100,000, nearly doubling in both countries.[17] The incidence of EOGC has also stabilized or decreased in some countries. Japan is anticipated to experience a decline in its EOGC incidence rate to 6.6 per 100,000 by 2028, followed by a modest increase to 7.1 per 100,000 by 2035. The incidence rate in Australia was predicted to remain stable or change only slightly until 2035.[17] These findings underscore a global upward trajectory in the incidence of EOGC, including in China and most other regions of the world. Consequently, there is an imperative need for extensive epidemiological studying on EOGC. Assessment of the intrinsic factors contributing to the increase in incidence rate is vital to promote the development of further effective prevention and control strategies.

Due to the lack of systematic epidemiological studies on EOGC, the high-risk populations for EOGC remain unclear. In the guidelines related to gastric cancer, long-term residence in areas with a high incidence, Helicobacter pylori (H. pylori) infection, precancerous lesions, and the family history are significant factors in identifying vulnerable populations of gastric cancer.[192021] The dietary and lifestyle habits associated with EOGC differ from those related to LOGC, such as higher intake of red and processed meats, lower consumption of fruits and vegetables,[22] higher alcohol intake,[23] lower salt intake,[24] and less influence from smoking.[25] These may be key factors in identifying high-risk populations for EOGC, for instance, emphasizing poor dietary habits and high alcohol consumption in screening for high-risk groups of EOGC. By integrating the common risk factors for gastric cancer and the distinct dietary and lifestyle habits associated with EOGC as opposed to LOGC, it is possible to accurately stratify the risk of gastric cancer in the younger population, thereby identifying those at high risk for screening.

Influential Factors of the Rising Incidence of EOGC

Due to the lack of reliable and extensive epidemiologic evidence, the precise reasons for the rising incidence of EOGC remain elusive. It may result from life-course exposure factors [Figure 1], such as genetic predispositions, dietary factors, gastric microbiota dysbiosis, and also from screening of high-risk cases [Table 1].

Figure 1 Life-course exposure factors and EOGC development. From infancy to young adults, individuals are encountered various exposures, encompassing genetics, poor diet and lifestyle behavior, Helicobacter pylori infection, and excessive antibiotic use. These factors begin to impact the normal gastric epithelial tissue at different stages of life, ultimately leading to the occurrence of EOGC. EOGC: Early-onset gastric cancer.

Table 1 Influential factors of the rising incidence of EOGC.

Influential factors	Detailed information	
Genetic susceptibility	Related germline mutation genes of EOGC include: CDH1, CTNNA1, APC, BRCA2, TP53, ATM, NBN, and MUTYH.[26,27,31]	
Lifestyle and dietary	Smoking: As the age of starting smoking decreases in younger populations, the total duration of smoking increases,[33] leading to an earlier age of gastric cancer onset.
Heavy alcohol consumption: Alcohol intake is the highest among individuals who aged 20–49 years, leading to the onset of EOGC.[23]
High-salt diets: Salt intake is lower among younger individuals and higher among older individuals,[24] suggesting that high-salt diets have a more significant impact on the incidence of LOGC rather than EOGC.
Unhealthy dietary: Younger populations consumed more red and processed meats with a lower consumption of fruits and vegetables.[22] These unhealthy dietary behaviors have exhibited an upward trend over time, resulting in the rising incidence of EOGC.	
Gastric microbiota imbalance and dysbiosis	Helicobacter pylori infection: It significantly correlated with EOGC.[39] Also, screening and intervention for Helicobacter pylori infection in people 20–40 years old are more cost-effective.[41]
Unhealthy dietary: Lower consumption of fruits and vegetables in EOGC may contribute to the gastric microbiota imbalance for the antioxidants found in fresh vegetables and fruits can improve it.[43]
Usage of antibiotics: The utilization of antibiotics in infancy and early childhood reduce the diversity and richness of gastrointestinal microorganisms, leading to gastric microbiota dysbiosis.[44,45]	
Screening of high-risk populations	The increase in gastric cancer screening among younger individuals leads to an earlier age of diagnosis, thereby increasing the incidence of EOGC.	
EOGC: Early-onset gastric cancer; LOGC: Late-onset gastric cancer.

Genetic susceptibility

Germline mutations associated with hereditary gastric cancer primarily include mutations in E-cadherin (CDH1), Catenin alpha 1 (CTNNA1), and APC genes.[26] It is widely accepted that genetic factors have a greater influence on the development of EOGC compared with LOGC.[1] However, genomics of gastric cancer indicated that the proportion of hereditary cases in EOGC is not noticeable. A multicenter study[27] from Spain revealed that 15.4% (18 out of 117) of the EOGC patients had a family history of the disease, and 25% (4 out of 16) had germline mutations in CDH1, BRCA2, and TP53 genes in patients with available germline DNA. Only 4.3% (5 out of 117) of the patients met the diagnostic criteria for hereditary gastric cancer. Brazilian scholars found no significant difference in the proportion of patients with a family history of gastric cancer between EOGC and LOGC patients (7.3% vs. 13.9%, P >0.05).[3] Nevertheless, it should be pointed out that the above-mentioned studies utilized the age cut-off values of 50 years and 45 years, respectively, for EOGC. In cases diagnosed at a younger age, the proportion of patients with a family history was higher. A study on the Chinese population found that 19% of gastric cancer patients under 35 years old had a family history compared with only 5.2% over 35 years old.[28]

Hereditary diffuse-type gastric cancer, an autosomal dominant syndrome mostly found in younger populations, is mainly caused by germline mutations in CDH1 or CTNNA1 gene.[29] The CDH1 gene encodes E-cadherin, and CTNNA1 gene encodes alpha-catenin. E-cadherin, a transmembrane glycoprotein in epithelial tissue, mediates cell-cell adhesion, connects to alpha-catenin and the cytoskeleton, and is involved in cell signaling, apoptosis, and invasion. Consequently, mutations causing E-cadherin dysfunction (CDH1) or alpha-catenin deficiency (CTNNA1) disrupt gastric epithelial tissue homeostasis, promoting tumorigenesis.[30] Additionally, Setia et al[31] identified potential germline mutations in high-penetrance (CDH1 and APC) and moderate-penetrance (ATM, NBN, and MUTYH) genes in EOGC, suggesting a possible association with the pathogenesis of EOGC.

Genetic factors may be more crucial in EOGC. However, the definition of EOGC is currently often set at under 45 years of age. Under this criterion, the proportion of hereditary gastric cancer is relatively low. Therefore, the influence of following other factors on EOGC may deserve greater attention.

Lifestyle and dietary factors

Existing evidence demonstrated that lifestyle and dietary factors associated with the onset and progression of gastric cancer include smoking, alcohol consumption, increased consumption of red meats and processed meats, high-salt diets, and decreased intake of fresh fruits and vegetables.[32] These risk factors are differentially distributed among young and old populations.

A previous study indicated that the risk of gastric cancer caused by smoking increases with the number of daily cigarettes and duration of smoking, and there is a significant difference in the risk of gastric cancer between smokers and non-smokers after more than 30 years of smoking.[25] Younger populations have higher smoking rates and start smoking earlier than middle-aged and older populations.[33] This reveals that although the smoking rate is higher in the young population, due to their shorter duration of smoking, smoking has a more significant impact on the LOGC. However, it is noteworthy that as the age of starting smoking decreases in younger populations, the total duration of smoking increases, leading to an earlier age of gastric cancer onset, which may be one of the reasons for the rising incidence of EOGC.

Alcohol consumption is significantly associated with the onset of gastric cancer.[34] A previous study demonstrated that alcohol intake is the highest among individuals who aged 20–49 years and the lowest in older populations.[23] Furthermore, the trend of alcohol consumption in young population varies among different countries, decreasing in high-income countries and increasing in low- and middle-income countries,[35] indicating that the impact of alcohol consumption on the incidence of EOGC varies across different countries. High-salt diets are also associated with gastric cancer.[32] Japanese scholars have found that salt intake increases with age, and it is lower among younger individuals and higher among older individuals.[24] This suggests that high-salt diets have a more significant impact on the incidence of LOGC rather than EOGC.

Additionally, an international study, utilizing a dietary health pattern score derived from 10 healthy dietary items and 7 unhealthy dietary items, revealed that younger populations exhibited suboptimal dietary habits compared with their older counterparts. This was accompanied by an elevated consumption of red and processed meats and a diminished intake of fruits and vegetables.[22] In low- and middle-income countries, these unhealthy dietary behaviors above have exhibited an upward trend over time,[22] indicating that patients with EOGC may be more affected by unhealthy dietary behaviors.

In summary, the exposure of EOGC patients to lifestyle and dietary risk factors differs from those of LOGC patients from adolescence to adulthood. The prevalence of these risk factors also varies in different countries and regions, indicating the variations in the rising trend of EOGC incidence across different countries.

Gastric microbiota imbalance and dysbiosis

Gastric microbiota imbalance and dysbiosis are crucial contributors to the development of gastric cancer. Intragastric microbiome have been proven to promote gastric cancer development through inducing DNA damage, inflammatory responses, and immunosuppression.[36] Factors, such as H. pylori infection, overuse of antibiotics, and poor dietary habits, may contribute to induce gastric microbiota imbalance, thereby promoting the development of gastric cancer.[37]

The rate of H. pylori infection, a significant risk factor for gastric cancer, increases with age and is lower in young population compared with that in the old population,[38] which may contribute to the lower incidence of EOGC. However, prior research indicated a significant correlation between EOGC and H. pylori infection,[39] with a higher infection rate than the normal population (72.5% vs. 27.5%).[40] Health economic analysis indicated that screening and intervention for H. pylori infection in people 20–40 years old are more cost-effective in reducing the risk of gastric cancer,[41] highlighting the importance of H. pylori infection as a risk factor for EOGC and the significance of early adult screening in preventing the disease. A study[42] found differences in the diversity and richness of gastric microorganisms between patients with gastric cancer, superficial gastritis, atrophic gastritis, and intestinal metaplasia. Pasteurella stomatis, Dialister pneumosintes, Spodoptera. exigua, Parvimonas micra, and Streptococcus anginosus were found to be significantly enriched in gastric cancer tissues, indicating their crucial role in gastric cancer development.

The antioxidants found in fresh vegetables and fruits can improve gastric microbiota imbalance.[43] Poor dietary habits, such as low intake of vegetables and fruits and high consumption of processed meats, are more common in younger populations.[22] Additionally, the utilization of antibiotics in infancy and early childhood reduces the diversity and richness of gastrointestinal microorganisms, with effects lasting more than two years,[44] and EOGC patients are more likely to be exposed to excessive antibiotics during infancy and adolescence.[45] This may lead to gastric microbiota imbalance and dysbiosis, promoting the development of EOGC.

These findings indicate that the gastric microbial dysbiosis in EOGC patients is not only due to H. pylori infection, but is also related to poor dietary patterns and excessive usage of antibiotics in early life, necessitating further research into the gastric microecology of EOGC.

Screening of high-risk cases among younger populations

The enhanced screening of high-risk cases for gastric cancer in younger populations may be one of the reasons for the rising incidence of EOGC. The existing guidelines from several countries recommend screening for gastric cancer in cases identified as “high-risk.” In particular, guidelines from both China and South Korea recommend commencing gastric cancer screening at the age of 40 years old.[19,20] On one hand, with the widespread dissemination of medical knowledge, elevated concentration on personal health, and expanded health insurance coverage, there is a growing inclination among young individuals, especially those with high-risk factors, such as genetic predispositions and specific dietary habits, to undergo gastric cancer screening. On the other hand, the widespread utilization of endoscopic examinations and the emergence of new gastric cancer screening technologies, such as liquid biopsy, gradually improve the accuracy of gastric cancer screening. These factors may partly contribute to the earlier diagnosis of gastric cancer, thereby increasing the incidence of EOGC. Notably, since 2018, Japan has postponed the recommended initiation age for gastric cancer screening, shifting it from 40 years to 50 years, which may justify the current downward trend for the incidence of EOGC in Japan.[21]

Clinicopathological, Molecular Signaling, and Prognostic Characteristics of EOGC

Clinicopathological characteristics of EOGC

The clinicopathological features of EOGC exhibit notable differences from those observed in LOGC, particularly in terms of gender, cell differentiation, histology, and pathological staging [Table 2]. Regarding gender, while gastric cancer is more frequent in older male patients, studies indicate that up to 45% of EOGC patients are female, compared to only about 30% in LOGC.[6,46,47] In terms of cell differentiation, EOGC has a higher proportion of poorly differentiated cancer (57.7% vs. 35.4%), while the proportions of moderately (12.4% vs. 37.3%) and well-differentiated (0.3% vs. 2.2%) cancer are lower.[4,10] Histologically, both groups are primarily adenocarcinomas, while a higher proportion of EOGC patients have signet ring cell carcinoma (19.0% vs. 10.4%), and diffuse-type gastric cancer is more frequent (25.7% vs. 15.0%).[14] Diffuse-type gastric cancer is highly associated with genetic factors, and 40% of patients have familial CDH1 mutations. This type of cancer has a strong invasive and metastatic capability and progresses rapidly, and it may occur at an earlier age.[48] Diffuse-type gastric cancer is primarily related to the mutation of the CDH1 gene, leading to dysfunction of E-cadherin and influencing intercellular adhesion. It also influences signaling pathways, including Wnt, Rho, and nuclear factor kappa-B (NF-κB), and facilitates tumor progression via the mechanism of epithelial-mesenchymal transition (EMT). Moreover, it may be associated with overexpression of fibroblast growth factor receptor (FGFR) and mutations in the APC and ras homolog family member A (RHOA) genes.[49] In terms of pathological staging, pathological Tumor-Node-Metastasis (pTNM) IV is more common in EOGC patients (59% vs. 42%), while the proportion of patients with pTNM stage I is lower (12% vs. 23%).[11] The younger the age, the higher the proportion of stage IV gastric cancer.[3,11,50] Therefore, compared with LOGC, EOGC has a higher degree of malignancy in its clinicopathological characteristics, and it is mainly diagnosed at a later tumor stage, decreasing the likelihood of successful treatment. Thus, further attention should be paid to the screening and early diagnosis of EOGC to improve its treatment rate.

Table 2 The clinicopathological and molecular characteristics of EOGC compared with LOGC.

Clinicopathological characteristics	Molecular characteristics	
Higher proportion of female patients[6,46,47]	Higher prevalence of the EBV subtype of gastric cancer[14]	
More common in stage IV[3,11,50]	Lower proportion of the MSI subtype of gastric cancer[14]	
Higher proportion of poorly differentiated patients[4,10]	Lower incidence rate of dMMR[27]	
Higher proportion of signet ring cell carcinoma[14]	Higher mutation rate of CDH1 and lower mutation rate of RHOA[5]	
More common diffuse-type gastric cancer[3,14]	Enrichment of CLDN18–ARHGAP fusion gene[56]	
	Lower positivity rate of HER2[59]	
	Higher positivity rate of PD-L1[55]	
dMMR: deficient mismatch repair; EBV: Epstein–Barr virus; EOGC: Early-onset gastric cancer; LOGC: Late-onset gastric cancer; MSI: Microsatellite instable; HER2: A tyrosine kinase receptor and member of the epidermal growth factor receptor family; PD-L1: Programmed death-ligand 1.

Molecular signaling characteristics of EOGC

The molecular signaling characteristics of EOGC significantly differ from those of LOGC [Table 2]. For instance, according to The Cancer Genome Atlas (TCGA) database based on molecular characteristics, gastric cancer can be divided into four subtypes: Epstein–Barr virus (EBV), microsatellite instable (MSI), genomically stable (GS), and chromosomal instable (CIN).[51]

The EBV subtype, mainly accompanied by programmed death-ligand 1 (PD-L1) overexpression, generally has a relatively better prognosis.[52] In EOGC, the EBV subtype is more common (7.7% vs. 5.1%, P <0.01), and it is associated with high-level mutations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway,[14] promoting development and progression of gastric cancer through inhibition of apoptosis, EMT, and angiogenesis.[53] Clinical trials of the AKT inhibitor AZD5363 in combination with paclitaxel for advanced gastric adenocarcinoma with mutations in PIK3CA have entered phase II, potentially improving survival of EOGC.[54] The EBV subtype of gastric cancers is also associated with the high-level amplification of the PD-L1 gene, and previous research found a higher rate of PD-L1-positive in EOGC (31% vs. 2.86%, P <0.01).[55] The MSI subtype of gastric cancer, caused by deficient mismatch repair (dMMR), is mainly accompanied by better survival outcomes compared with microsatellite stable subtype of gastric cancer,[52] while the proportion of MSI subtype is lower in EOGC compared with LOGC (5.6% vs. 18.6%, P <0.01).[14]

GS subtype of gastric cancer typically occurs in the distal stomach and often carries mutations in CDH1 and RHOA genes, as well as CLDN18-ARHGAP fusion gene, and it has a poor prognosis with lower benefits from chemotherapy.[52] The proportion of the GS subtype of gastric cancer is higher in EOGC (22.5% vs. 8.8%, P <0.05),[14] indicating that a greater proportion of patients with EOGC may derive lesser benefits from chemotherapy. Compared with LOGC, EOGC has a higher mutation rate of CHD1 (42.2% vs. 17.4%, P <0.01)[5] and enrichment of CLDN18–ARHGAP fusion gene (15.1%).[56]ARHGAP gene expression’s Rho-GTPase can reduce RHOA activity around CLDN18 protein sites, inhibiting the interaction between CLDN18 protein and actin-regulating protein in gastric epithelial cells, thereby promoting tumor development. Additionally, the CLDN18–ARHGAP fusion gene may be associated with later stages of EOGC, as CLDN18–ARHGAP fusion gene cases generally have larger tumors and more lymph node metastases.[56] The mutations in RHOA gene impair GTP hydrolysis and enhance interaction with ROCK gene, enhancing actin rearrangement and focal adhesion formation. By activating focal adhesion kinase (FAK), mutations in RHOA gene promote the activation of YAP/TAZ, PI3K/AKT, and β-catenin, thereby inducing the occurrence of diffuse-type gastric cancer.[57] However, EOGC has a lower proportion of mutations in RHOA gene (9.2% vs. 19.1%, P = 0.03)[5] and a higher proportion of diffuse-type gastric cancer,[14] suggesting that the pathogenesis of early-onset diffuse-type gastric cancer may be different from that of late-onset diffuse-type gastric cancer.

CIN subtype of gastric cancer is the most common molecular subtype, associated with mutations in genes involved in the receptor tyrosine kinase (RTK)/RAS pathway (EGFR, HER2, FGFR2, KRAS, MET, and VEGF),[52] with no significant difference in proportion between EOGC and LOGC.[14] HER2, a tyrosine kinase receptor and member of the epidermal growth factor receptor (EGFR) family, is involved in several signaling pathways, such as PI3K/AKT/mTOR and RAS/RAF/MAP kinase; it regulates cell growth, proliferation, differentiation, and migration, and it is overexpressed in 15–20% of gastric cancer patients.[58] However, the positive rate of HER2 in EOGC is lower, in which one study that included 108 EOGC cases and 91 LOGC cases found a significant correlation between HER2 expression and age, with a significantly lower HER2-positive rate in EOGC (1.89% vs. 19.7%, P <0.05).[59]

Furthermore, for operable gastric cancer patients, EOGC patients are more likely to test negative for traditional preoperative tumor markers, such as carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9), which is one of the reasons for its delayed diagnosis.[46] In summary, the molecular signaling characteristics of EOGC differ from those of LOGC, demonstrating a possible reason for the poor efficacy of conventional drug treatments.

Prognosis of EOGC

The prognosis of EOGC remains controversial, as varying outcomes arise due to differences in study populations and statistical methods. A study conducted in China[10] categorized gastric cancer patients using 40 years as the age cut-off (<40 years: 1146 cases; ≥40 years: 16,988 cases). The results indicated that, in pTNM stage III, EOGC patients experienced a less favorable prognosis, while in other stages, there was no significant difference in prognosis between EOGC and LOGC. Another study utilizing the National Cancer Database (NCDB) in the United States, which also set 40 years as the age cut-off (<40 years: 2615 cases; ≥40 years: 67,469 cases), compared the 5-year survival rates of EOGC and LOGC. This study found that the prognosis of EOGC was better than that of LOGC in each pathological stage. However, the overall 5-year survival rate was similar (21.1% vs. 22.1%, P >0.05).[11] This lack of difference may be due to a higher proportion of EOGC patients with stage IV (59.5% vs. 41.7%). Austrian scholars compared the prognosis of gastric cancer patients who aged ≤45 years (58 cases) and ≥65 years (827 cases). They found that patients with stages I–III EOGC had a better prognosis. When there was only one metastatic site, the prognosis of EOGC and LOGC patients was similar. However, when there were two or more metastatic sites, the prognosis of EOGC patients was worse, possibly because widely metastasized EOGC is more aggressive and less conducive to long-term survival.[2] Differences in the definition of EOGC, methods of analysis, and the racial and genetic backgrounds of the populations included in these studies could all contribute to variations in the results of prognostic analysis of EOGC. In summary, the differences in prognosis between EOGC and LOGC patients may be related to the pathological staging of the tumor, and further specific research is required for clarification.

The prognosis differences between EOGC and LOGC may be associated with treatment tolerability. Studies have demonstrated significant variations between the two groups in terms of treatment intensity, adverse reactions, and therapeutic benefits.[4,7,12,13,60,61] For patients with stage I gastric cancer, the primary treatment is surgical resection. EOGC patients mainly have better preoperative nutritional and physical conditions, which can promote postoperative recovery, reduce the incidence of complications, and improve long-term prognosis.[60] Additionally, the postoperative recurrence rate for stage I gastric cancer is low (1.5%),[62] and the main survival factors may be non-gastric cancer causes, in which younger gastric cancer patients have a lower rate of non-gastric-cancer-specific mortality (16.3% vs. 41.3%).[63] This may explain why patients with stage I EOGC have a better prognosis.[2,11]

For patients with stages II–III gastric cancer, the treatment strategy primarily involves surgery combined with adjuvant chemotherapy. EOGC patients, with better nutritional status, can tolerate more intensive treatments. Studies have found that compared with older gastric cancer patients, there is a greater percentage of younger patients undergoing postoperative adjuvant chemotherapy (74.8% vs. 56.8%),[4] receiving more intensive chemotherapy, and demonstrating superior treatment compliance.[61] However, EOGC may exhibit reduced sensitivity to the existing treatment protocols outlined in guidelines compared with LOGC. Previous research indicated that in patients with stages II–III gastric cancer, chemotherapy significantly increases older patients’ overall survival, rather than young patients.[12] Furthermore, a previous study found no improvement in the 3-year survival rate after tumor resection in patients with stage III EOGC (36.1% vs. 34.6%, P = 0.36).[7] Another study identified no significant difference in the prognosis of patients with stages II–III EOGC, who were treated with surgery combined with radiotherapy and chemotherapy compared with surgery alone, and further analysis revealed that early-onset signet ring cell carcinoma patients had longer overall survival (OS) and cancer-specific survival (CSS) with surgery alone compared with combined treatments.[13]

For patients with stage IV EOGC, the typical approach is palliative chemotherapy, which can be combined with targeted therapy or immunotherapy based on the specific molecular expression levels in the tumor tissue. Evidently, patients with EOGC are more capable of tolerating multidrug combination treatment regimens, resulting in better outcomes. Therefore, for patients with stages II–IV gastric cancer, on one hand, EOGC patients generally have a better postoperative recovery and a lower incidence of complications, enabling them to tolerate a stronger and more diverse drug therapy. On the other hand, EOGC patients are less sensitive to radiotherapy and chemotherapy than LOGC patients. This has led to controversies in the prognostic study of EOGC.

Currently, several retrospective studies have established prognostic nomograms using clinical pathological information, which can more accurately and individually assess the survival of EOGC patients, thereby facilitating the selection of appropriate treatment strategies.[646566] A multicenter study[64] utilized data of EOGC patients to develop a prognostic nomogram, showing that factors such as tumor location, tumor size, differentiation, TNM stage, the number of lymph nodes, chemotherapy, and surgery can predict the CSS rate of EOGC patients with greater accuracy than models based solely on TNM staging. Other retrospective studies, in addition to the aforementioned variables, have included factors related to prognosis such as ethnicity and sex, similarly demonstrating higher predictive accuracy.[65,66] Accurate prediction of the prognosis for EOGC may contribute to the improvement of its survival rates. The current survival prediction models for EOGC primarily incorporate clinical and pathological factors. Future studies that include the molecular characteristics of EOGC will further enhance the accuracy of prediction for its survival.

Clinical Management of EOGC

Various studies have explored the impact of age on the efficacy of gastric cancer treatments [Table 3]. Surgeons often perform more extensive surgical resections for EOGC patients with the expectation of reducing postoperative recurrence rates because of their better physical performance and fewer preoperative comorbidities. However, a study[67] has found that the overall survival of EOGC patients receiving more extensive surgery does not differ from that of LOGC. This indicated extensive surgical resection may not be necessary for EOGC patients eligible for curative resection. Another study[68] found that in metastatic EOGC patients, palliative surgical treatment significantly extended survival time (13 months vs. 6 months, P <0.01), suggesting that palliative surgery can improve survival in advanced EOGC patients. In summary, both early and advanced EOGC could improve survival through surgical treatment, but the extent of surgical resection should not be unnecessarily expanded.

Table 3 The impact of age on the efficacy of gastric cancer treatment.

Author	Stage	Age group threshold (years)	Below threshold cases (%)	Treatment regimen	Research design	Conclusion	
Rompen et al[67]	Ⅰ–Ⅳ	50	129 (17.5)	Surgery, chemotherapy and radiotherapy	Retrospective study	EOGC patients underwent more extended and multivisceral resections, yet no significant differences in overall survival were found.	
An et al[68]	Ⅳ	50	3641	Surgery and chemotherapy	Retrospective study	EOGC patients with palliative gastrectomy had a significantly longer survival time than patients without surgery.	
Huang et al[8]	Ⅳ	45	154 (2.9)	Paclitaxel/oxaliplatin	Retrospective study	In gastric cancer patients under 45 years old, paclitaxel provides greater survival benefits than oxaliplatin.	
Jiang et al[12]	Ⅱ–III	65	15,873 (43.5)	Surgery and chemotherapy	Retrospective study	Chemotherapy provides lesser survival benefits for gastric cancer patients aged 18–64 years compared to those aged 65–84 years.	
Zhang et al[13]	I–IV	50	1639	Surgery and radio-chemotherapy	Retrospective study	Gastric cancer patients under 50 years old do not benefit more from surgery combined with chemoradiation than from surgery alone.	
Sawaki et al[70]	Ⅳ	60	–	Trastuzumab and chemotherapy	Meta analysis	Trastuzumab has no significant efficacy difference between patients over 65 and those under 60 years old.	
Muro et al[9]	Ⅳ	45	114	Ramucirumab and paclitaxel	Randomized controlled trial	In advanced gastric cancer patients under 45 years old, Ramucirumab improves survival.	
Wang et al[77]	Ⅳ	45	18 (7.1)	ICIs, chemotherapy and targeted therapy	Retrospective study	Immunotherapy is less effective in advanced gastrointestinal cancer patients <45 years old.	
Kundel et al[78]	Ⅳ	65	–	ICIs	Meta analysis	There is no significant difference in the efficacy of immunotherapy between advanced gastric cancer patients ≤65 years and those >65 years.	
EOGC: Early-onset gastric cancer; ICIs: Immune checkpoint inhibitors; –: Not applicable.

Multiple retrospective studies revealed that patients with stage II–III EOGC may be insensitive to the current chemotherapy,[7,12,13] while these studies have only concentrated on whether to receive chemotherapy, without considering specific chemotherapy regimens. A retrospective study[8] conducted by Chinese researchers found that unresectable EOGC patients treated with a first-line chemotherapy regimen containing paclitaxel may have better survival outcomes compared with those treated with an oxaliplatin-based regimen (median survival time: 13 months vs. 10 months). A study compiled data from 9 phase III clinical trials on fluorouracil-based monotherapy and combination chemotherapy for advanced colorectal cancer, revealing that younger age, whether classified at 40 years or 50 years, is not associated with worse prognosis, and younger patients benefit from combination chemotherapy at the same level as older patients.[69] However, in the case of gastric cancer, due to the low prevalence of EOGC, there is a lack of evidence-based clinical research for EOGC. Consequently, there is inadequate evidence to conclusively determine the appropriateness of current chemotherapy regimens for patients with EOGC.

Because of unique molecular characteristics of EOGC, the targeted therapy for EOGC may vary compared with that utilized for LOGC. Trastuzumab, which targets HER2, has been employed as a primary treatment for gastric cancer patients with high HER2 expression level in their cancer cells. However, the HER2 positivity rate is lower in younger patients with gastric cancer.[59] A meta-analysis[70] indicated that the efficacy of Trastuzumab, a HER2-targeting drug, exhibited no significant difference between gastric cancer patients aging under 60 years and those who aged 60 or older. Nevertheless, there is a need for additional stratification by age in patients under 60 years old to evaluate its efficacy specifically in cases of EOGC. Ramucirumab, an antibody targeting vascular endothelial growth factor (VEGF) receptor-2, is a second-line treatment for advanced gastric cancer. Muro et al[9] conducted a subgroup analysis of the REGARD and RAINBOW clinical trials, demonstrating that patients with advanced gastric cancer who aged ≤45 years had improved survival with ramucirumab, supporting its application in EOGC. Patients with EOGC have a higher somatic mutation rate in CDH1 gene, which may be a target for treatment. For individuals with a mutation in CDH1 gene and a family history of diffuse-type gastric cancer, prophylactic total gastrectomy is generally recommended.[30] Furthermore, Bougen-Zhukov et al[71] found that gastric cancer cells and organoids derived from mice with a loss of CDH1 expression exhibited increased sensitivity to the allosteric AKT inhibitors Miransertib (ARQ-092) and MK2206, necessitating further clinical studies to determine the efficacy of these inhibitors in EOGC. Fukamachi et al[72] discovered that mTOR inhibitors might be effective for diffuse-type gastric cancer developed from intestinal-type gastric cancer rather than normal gastric epithelium. They also found that early-onset diffuse-type gastric cancer might originate from normal gastric epithelium, suggesting that younger patients with diffuse-type gastric cancer might have a poorer response to mTOR inhibitor treatments. In conclusion, targeted therapy strategies for EOGC still require more clinical study for support, and drug development focused on its unique molecular characteristics may potentially improve the survival of EOGC in the future.

Immunotherapy has emerged as an integral component in the pharmacological treatment of patients with advanced and locally advanced gastric cancer. At present, immune checkpoint inhibitors (ICIs), especially programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte associate protein-4 (CTLA-4) inhibitors, are extensively employed as first-line treatments for patients with advanced gastric cancer. Additionally, ICIs have been used in neoadjuvant therapy, which is used before the surgery, to enhance the treatment outcomes.[73] PD-L1 expression, tumor mutational burden (TMB), MSI, and EBV positivity rates are considered as reliable biomarkers for predicting the efficacy of ICIs.[74] Studies indicated that EOGC has a higher PD-L1 positivity rate compared with LOGC,[55] especially in young patients with metastatic gastric cancer,[75] and a higher EBV detection rate.[55] However, MSI subtype of gastric cancer is less common in EOGC,[14] and the median TMB value is significantly lower than that in older patients (3.38 mt/mb vs. 9.39 mt/mb; P <0.01).[76] Therefore, early assessment of PD-L1 expression and EBV detection in EOGC patients may guide the clinical application of immunotherapy. However, few studies have evaluated the efficacy of immunotherapy for EOGC. A previous study[77] included metastatic gastrointestinal tumors treated with ICIs and categorized patients into young (18–44 years), middle-aged (45–65 years), and older (>65 years) groups, in order to assess the efficacy of immunotherapy. This study found that younger patients responded less favorably to immunotherapy. However, it included multiple gastrointestinal malignancies with small sample size, and young gastric cancer patients only accounted for 50% (9/18) of the young group with gastrointestinal tumors, making them less representative for gastric cancer specifically. A meta-analysis on immunotherapy for gastric cancer revealed no significant differences in treatment efficacy between patients who aged over and under 65 years[78]; however, the analysis did not include further stratification for patients aging under 65 years.

Follow-up strategies for EOGC have not been recommended based on patient age stratification in domestic and international guidelines.[19,21] Due to its earlier diagnostic age and better physical performance, EOGC patients are more likely to benefit from follow-up as they can receive more intensive treatment upon recurrence detection compared to LOGC patients. Qiu et al[79] included 180 EOGC patients and 1848 LOGC patients, analyzing the dynamic changes in the risk of postoperative recurrence in gastric cancer patients. They found that the probability of recurrence was higher at 11 months and 36.5 months post-operation for EOGC, while for LOGC, the probability was higher at six months post-operation. Therefore, a more intensive postoperative follow-up strategy should be adopted for EOGC, and further research is needed to explore the differences in recurrence patterns between EOGC and LOGC, to establish individualized follow-up timing for these EOGC patients.

Due to the relatively low proportion of EOGC patients, it is challenging for the current clinical trials to enroll these patients separately. Therefore, further multicenter real-world studies on the clinical management of EOGC patients are warranted. By considering EOGC and LOGC as stratifying factors in prospective clinical trials or retrospective studies, the effectiveness-based differences between treatments may be clarified. This may contribute to provide more evidence-based support for the clinical management of EOGC.

Conclusions and Outlook

The incidence of EOGC is increasing, which may be related to genetic factors, lifestyle and dietary habits, gastric microbiota imbalance, and screening of high-risk cases. Prospective epidemiological studies are required to clarify the risk factors for the development of EOGC and provide evidence for its prevention and early screening. EOGC tends to be more aggressive in terms of its clinical and pathological features, while there is still controversy regarding its prognosis. Compared with LOGC, EOGC has exhibited a higher prevalence of PD-L1 positivity, EBV positivity, and CDH1 mutations, while a lower prevalence of HER2 positivity and MSI, suggesting the applicability of different treatment approaches for EOGC. Retrospective studies indicated that EOGC may be less responsive to the current general treatment options, and there is a lack of clinical trials that further stratify by age to assess the appropriateness of the current treatments for this type of cancer. For young gastric cancer patients, especially those with stages III and IV, second-generation sequencing is recommended for molecular profiling to provide precise combined treatment plans. Future epidemiological studies and clinical trials on gastric cancer should consider the differences between EOGC and LOGC for the stratified research, aiming to improve the survival of EOGC patients through personalized treatment.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82202837, 81730016, and 81972761).

Conflicts of interest

None.

How to cite this article: Wang XL, Gao XC, Yu J, Zhang XT, Nie YZ. Emerging trends in early-onset gastric cancer. Chin Med J 2024;137:2146–2156. doi: 10.1097/CM9.0000000000003259
==== Refs
References

1. Ma Z Liu X Paul M Chen M Zheng P Chen H . Comparative investigation of early-onset gastric cancer. Oncol Lett 2021;21 :374. doi: 10.3892/ol.2021.12635.33777198
2. Puhr HC Karner A Taghizadeh H Jomrich G Schoppmann SF Preusser M , . Clinical characteristics and comparison of the outcome in young versus older patients with upper gastrointestinal carcinoma. J Cancer Res Clin Oncol 2020;146 :3313–3322. doi: 10.1007/s00432-020-03302-x.32617700
3. Braga-Neto MB Carneiro JG de Castro Barbosa AM Silva IS Maia DC Maciel FS , . Clinical characteristics of distal gastric cancer in young adults from northeastern Brazil. BMC Cancer 2018;18 :131. doi: 10.1186/s12885-018-3995-4.29402219
4. Liu W Quan H Chen X Ouyang Y Xiao H . Clinicopathological features and prognosis of young gastric cancer patients following radical gastrectomy: A propensity score matching analysis. Sci Rep 2019;9 :5943. doi: 10.1038/s41598-019-42406-4.30976037
5. Cho SY Park JW Liu Y Park YS Kim JH Yang H , . Sporadic early-onset diffuse gastric cancers have high frequency of somatic cdh1 alterations, but low frequency of somatic RHOA mutations compared with late-onset cancers. Gastroenterology 2017;153 :536–549. doi: 10.1053/j.gastro.2017.05.012.28522256
6. LaPelusa M Shen C Gillaspie EA Cann C Lambright E Chakravarthy AB , . Variation in treatment patterns of patients with early-onset gastric cancer. Cancers (Basel) 2022;14 :3633. doi: 10.3390/cancers14153633.35892891
7. Rona KA Schwameis K Zehetner J Samakar K Green K Samaan J , . Gastric cancer in the young: An advanced disease with poor prognostic features. J Surg Oncol 2017;115 :371–375. doi: 10.1002/jso.24533.28008624
8. Huang Q Zheng X Jiao Y Lei Y Li X Bi F , . A distinct clinicopathological feature and prognosis of young gastric cancer patients aged ≤ 45 years old. Front Oncol 2021;11 :674224. doi: 10.3389/fonc.2021.674224.34513668
9. Muro K Cho JY Bodoky G Goswami C Chao Y Dos Santos LV , . Age does not influence efficacy of ramucirumab in advanced gastric cancer: Subgroup analyses of REGARD and RAINBOW. J Gastroenterol Hepatol 2018;33 :814–824. doi: 10.1111/jgh.14007.28960444
10. Niu P Huang H Zhao L Wang T Zhang X Wang W , . Clinicopathological characteristics, survival outcomes, and genetic alterations of younger patients with gastric cancer: Results from the china national cancer center and cBioportal datasets. Cancer Med 2022;11 :3057–3073. doi: 10.1002/cam4.4669.35486034
11. De B Rhome R Jairam V Özbek U Holcombe RF Buckstein M , . Gastric adenocarcinoma in young adult patients: Patterns of care and survival in the United States. Gastric Cancer 2018;21 :889–899. doi: 10.1007/s10120-018-0826-x.29691758
12. Jiang Y Xie J Huang W Chen H Xi S Li T , . Chemotherapy use and survival among young and middle-aged patients with gastric cancer. Clin Transl Gastroenterol 2020;11 :e253. doi: 10.14309/ctg.0000000000000253.
13. Zhang C Tang R Zhu H Ge X Wang Y Wang X , . Comparison of treatment strategies and survival of early-onset gastric cancer: A population-based study. Sci Rep 2022;12 :6288. doi: 10.1038/s41598-022-10156-5.35428811
14. Bergquist JR Leiting JL Habermann EB Cleary SP Kendrick ML Smoot RL , . Early-onset gastric cancer is a distinct disease with worrisome trends and oncogenic features. Surgery 2019;166 :547–555. doi: 10.1016/j.surg.2019.04.036.31331685
15. He Y Wang Y Luan F Yu Z Feng H Chen B , . Chinese and global burdens of gastric cancer from 1990 to 2019. Cancer Med 2021;10 :3461–3473. doi: 10.1002/cam4.3892.33931958
16. Arnold M Park JY Camargo MC Lunet N Forman D Soerjomataram I . Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035. Gut 2020;69 :823–829. doi: 10.1136/gutjnl-2019-320234.32001553
17. Ning FL Zhang NN Zhao ZM Du WY Zeng YJ Abe M , . Global, regional, and national burdens with temporal trends of early-, intermediate-, and later-onset gastric cancer from 1990 to 2019 and predictions up to 2035. Cancers (Basel) 2022;14 :5417. doi: 10.3390/cancers14215417.36358835
18. International Agency for Research on Cancer. Cancer today. Available from: http://gco.iarc.fr/today/home. [Last accessed on 2023 September 3].
19. Fan X Qin X Zhang Y Li Z Zhou T Zhang J , . Screening for gastric cancer in china: Advances, challenges and visions. Chin J Cancer Res 2021;33 :168–180. doi: 10.21147/j.issn.1000-9604.2021.02.05.34158737
20. Choi KS Jun JK Suh M Park B Noh DK Song SH , . Effect of endoscopy screening on stage at gastric cancer diagnosis: Results of the national cancer screening programme in Korea. Br J Cancer 2015;112 :608–612. doi: 10.1038/bjc.2014.608.25490528
21. Mabe K Inoue K Kamada T Kato K Kato M Haruma K . Endoscopic screening for gastric cancer in japan: Current status and future perspectives. Dig Endosc 2022;34 :412–419. doi: 10.1111/den.14063.34143908
22. Imamura F Micha R Khatibzadeh S Fahimi S Shi P Powles J , . Dietary quality among men and women in 187 countries in 1990 and 2010: A systematic assessment. Lancet Glob Health 2015;3 :e132–e142. doi: 10.1016/S2214-109X(14)70381-X.25701991
23. Baburin A Reile R Veideman T Leinsalu M . Age, period and cohort effects on alcohol consumption in Estonia, 1996-2018. Alcohol Alcohol 2021;56 :451–459. doi: 10.1093/alcalc/agaa115.33164062
24. Sugiura T Takase H Ohte N Dohi Y . Dietary salt intake increases with age in Japanese adults. Nutr Res 2021;89 :1–9. doi: 10.1016/j.nutres.2021.02.002.33866192
25. Praud D Rota M Pelucchi C Bertuccio P Rosso T Galeone C , . Cigarette smoking and gastric cancer in the stomach cancer pooling (stop) project. Eur J Cancer Prev 2018;27 :124–133. doi: 10.1097/CEJ.0000000000000290.27560662
26. Carneiro F . Familial and hereditary gastric cancer, an overview. Best Pract Res Clin Gastroenterol 2022;58-59 :101800. doi: 10.1016/j.bpg.2022.101800.35988963
27. Pocurull A Herrera-Pariente C Carballal S Llach J Sánchez A Carot L , . Clinical, molecular and genetic characteristics of early onset gastric cancer: Analysis of a large multicenter study. Cancers (Basel) 2021;13 :3132. doi: 10.3390/cancers13133132.34201547
28. Bai Y Li Z . Endoscopic, clinicopathological features and prognosis of very young patients with gastric cancer. J Gastroenterol Hepatol 2011;26 :1626–1629. doi: 10.1111/j.1440-1746.2011.06759.x.21557767
29. Decourtye-Espiard L Guilford P . Hereditary diffuse gastric cancer. Gastroenterology 2023;164 :719–735. doi: 10.1053/j.gastro.2023.01.038.36740198
30. Gamble LA Heller T Davis JL . Hereditary diffuse gastric cancer syndrome and the role of cdh1: A review. JAMA Surg 2021;156 :387–392. doi: 10.1001/jamasurg.2020.6155.33404644
31. Setia N Wang CX Lager A Maron S Shroff S Arndt N , . Morphologic and molecular analysis of early-onset gastric cancer. Cancer 2021;127 :103–114. doi: 10.1002/cncr.33213.33048355
32. Thrift AP Wenker TN El-Serag HB . Global burden of gastric cancer: Epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol 2023;20 :338–349. doi: 10.1038/s41571-023-00747-0.36959359
33. Pan X Cao Y Zhang W Liu Y . Trends in age of smoking initiation among the Chinese population born between 1950 and 1997. Public Health 2020;187 :127–133. doi: 10.1016/j.puhe.2020.08.013.32949883
34. Kang SJ Shin CM Han K Jung JH Jin EH Lim JH , . Impact of smoking and alcohol consumption on early-onset gastric cancer development in young Koreans: A population-based study. J Gastric Cancer 2024;24 :145–158. doi: 10.5230/jgc.2024.24.e2.38575508
35. Holmes J Fairbrother H Livingston M Meier PS Oldham M Pennay A , . Youth drinking in decline: What are the implications for public health, public policy and public debate? Int J Drug Policy 2022;102 :103606. doi: 10.1016/j.drugpo.2022.103606.35131690
36. Huang H Zhong W Wang X Yang Y Wu T Chen R , . The role of gastric microecological dysbiosis in gastric carcinogenesis. Front Microbiol 2023;14 :1218395. doi: 10.3389/fmicb.2023.1218395.37583514
37. Liatsos C Papaefthymiou A Kyriakos N Galanopoulos M Doulberis M Giakoumis M , . Helicobacter pylori, gastric microbiota and gastric cancer relationship: Unrolling the tangle. World J Gastrointest Oncol 2022;14 :959–972. doi: 10.4251/wjgo.v14.i5.959.35646287
38. Breckan RK Paulssen EJ Asfeldt AM Kvamme J Straume B Florholmen J . The all-age prevalence of Helicobacter pylori infection and potential transmission routes. A population-based study. Helicobacter 2016;21 :586–595. doi: 10.1111/hel.12316.27172105
39. Masuda G Tokunaga A Shirakawa T Togashi A Kiyama T Kato S , . Helicobacter pylori infection, but not genetic polymorphism of cyp2e1, is highly prevalent in gastric cancer patients younger than 40 years. Gastric Cancer 2007;10 :98–103. doi: 10.1007/s10120-007-0414-y.17577619
40. Koshida Y Koizumi W Sasabe M Katoh Y Okayasu I . Association of Helicobacter pylori-dependent gastritis with gastric carcinomas in young Japanese patients: Histopathological comparison of diffuse and intestinal type cancer cases. Histopathology 2000;37 :124–130. doi: 10.1046/j.1365-2559.2000.00948.x.10931235
41. Liou JM Malfertheiner P Lee YC Sheu BS Sugano K Cheng HC , . Screening and eradication of Helicobacter pylori for gastric cancer prevention: The Taipei global consensus. Gut 2020;69 :2093–2112. doi: 10.1136/gutjnl-2020-322368.33004546
42. Coker OO Dai Z Nie Y Zhao G Cao L Nakatsu G , . Mucosal microbiome dysbiosis in gastric carcinogenesis. Gut 2018;67 :1024–1032. doi: 10.1136/gutjnl-2017-314281.28765474
43. Zhou S Li C Liu L Yuan Q Miao J Wang H , . Gastric microbiota: An emerging player in gastric cancer. Front Microbiol 2023;14 :1130001. doi: 10.3389/fmicb.2023.1130001.37180252
44. Kesavelu D Jog P . Current understanding of antibiotic-associated dysbiosis and approaches for its management. Ther Adv Infect Dis 2023;10 :2018389259. doi: 10.1177/20499361231154443.
45. Fink G D’Acremont V Leslie HH Cohen J . Antibiotic exposure among children younger than 5 years in low-income and middle-income countries: A cross-sectional study of nationally representative facility-based and household-based surveys. Lancet Infect Dis 2020;20 :179–187. doi: 10.1016/S1473-3099(19)30572-9.31843383
46. Liu S Feng F Xu G Liu Z Tian Y Guo M , . Clinicopathological features and prognosis of gastric cancer in young patients. BMC Cancer 2016;16 :478. doi: 10.1186/s12885-016-2489-5.27418046
47. Sandeep B Huang X Li Y Mao L Gao K Xiao Z . Gastric carcinoma in young patients and its clinicopathological characteristics and prognosis. Gastroenterol Res Pract 2020;2020 :1–8. doi: 10.1155/2020/7378215.
48. Monster JL Kemp LJS Gloerich M van der Post RS . Diffuse gastric cancer: Emerging mechanisms of tumor initiation and progression. Biochim Biophys Acta Rev Cancer 2022;1877 :188719. doi: 10.1016/j.bbcan.2022.188719.35307354
49. Ansari S Gantuya B Tuan VP Yamaoka Y . Diffuse gastric cancer: A summary of analogous contributing factors for its molecular pathogenicity. Int J Mol Sci 2018;19 :2424. doi: 10.3390/ijms19082424.30115886
50. Kono Y Kanzaki H Tsuzuki T Takatani M Nasu J Kawai D , . A multicenter observational study on the clinicopathological features of gastric cancer in young patients. J Gastroenterol 2019;54 :419–426. doi: 10.1007/s00535-018-1525-4.30374622
51. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513 :202–209. doi: 10.1038/nature13480.25079317
52. Nakamura Y Kawazoe A Lordick F Janjigian YY Shitara K . Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: An emerging paradigm. Nat Rev Clin Oncol 2021;18 :473–487. doi: 10.1038/s41571-021-00492-2.33790428
53. Baghery Saghchy Khorasani A Pourbagheri-Sigaroodi A Pirsalehi A Safaroghli-Azar A Zali MR Bashash D . The pi3k/AKT/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021;898 :173983. doi: 10.1016/j.ejphar.2021.173983.33647255
54. Fattahi S Amjadi-Moheb F Tabaripour R Ashrafi GH Akhavan-Niaki H . Pi3k/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci 2020;262 :118513. doi: 10.1016/j.lfs.2020.118513.33011222
55. Moore A Hikri E Goshen-Lago T Barkan T Morgenstern S Brook E , . Young-onset gastric cancer and Epstein-Barr virus (EBV) – A major player in the pathogenesis? BMC Cancer 2020;20 :34. doi: 10.1186/s12885-020-6517-0.31937281
56. Nakayama I Shinozaki E Sakata S Yamamoto N Fujisaki J Muramatsu Y , . Enrichment of cldn18-arhgap fusion gene in gastric cancers in young adults. Cancer Sci 2019;110 :1352–1363. doi: 10.1111/cas.13967.30771244
57. Zhang H Schaefer A Wang Y Hodge RG Blake DR Diehl JN , . Gain-of-function RHOA mutations promote focal adhesion kinase activation and dependency in diffuse gastric cancer. Cancer Discov 2020;10 :288–305. doi: 10.1158/2159-8290.CD-19-0811.31771969
58. Palle J Rochand A Pernot S Gallois C Taïeb J Zaanan A . Human epidermal growth factor receptor 2 (her2) in advanced gastric cancer: Current knowledge and future perspectives. Drugs 2020;80 :401–415. doi: 10.1007/s40265-020-01272-5.32077003
59. Moelans CB Milne AN Morsink FH Offerhaus GJA van Diest PJ . Low frequency of her2 amplification and overexpression in early onset gastric cancer. Cell Oncol (Dordr) 2011;34 :89–95. doi: 10.1007/s13402-011-0021-0.21394646
60. Sakurai K Ohira M Tamura T Toyokawa T Amano R Kubo N , . Predictive potential of preoperative nutritional status in long-term outcome projections for patients with gastric cancer. Ann Surg Oncol 2016;23 :525–533. doi: 10.1245/s10434-015-4814-7.26307230
61. Slagter AE Tudela B van Amelsfoort RM Sikorska K van Sandick JW van de Velde CJH , . Older versus younger adults with gastric cancer receiving perioperative treatment: Results from the CRITICS trial. Eur J Cancer 2020;130 :146–154. doi: 10.1016/j.ejca.2020.02.008.32208351
62. Yago A Haruta S Ueno M Hamada Y Ogawa Y Ohkura Y , . Adequate period of surveillance in each stage for curatively resected gastric cancer: Analyzing the time and rates of recurrence. Gastric Cancer 2021;24 :752–761. doi: 10.1007/s10120-020-01147-4.33400037
63. Wu CW Chen MH Huang KH Chang SC Fang WL Lin CH , . The clinicopathological characteristics and genetic alterations between younger and older gastric cancer patients with curative surgery. Aging 2020;12 :18137–18150. doi: 10.18632/aging.103627.32961530
64. Liu H Li Z Zhang Q Li Q Zhong H Wang Y , . Multi-institutional development and validation of a nomogram to predict prognosis of early-onset gastric cancer patients. Front Immunol 2022;13 :1007176. doi: 10.3389/fimmu.2022.1007176.36148218
65. Liao F Guo X Lu X Dong W . A validated survival nomogram for early-onset diffuse gastric cancer. Aging 2020;12 :13160–13171. doi: 10.18632/aging.103406.32639946
66. Wang X Niu X Zhang F Wu J Wu H Li T , . Nomogram models for predicting overall and cancer-specific survival in early-onset gastric cancer patients: A population-based cohort study. Am J Cancer Res 2024;14 :1747–1767. doi: 10.62347/FPRM7701.38726268
67. Rompen IF Nienhüser H Crnovrsanin N Musa J Haag GM Longerich T , . Clinical characteristics and oncological outcomes of surgically treated early-onset gastric adenocarcinoma – A retrospective cohort study. J Cancer 2023;14 :1470–1478. doi: 10.7150/jca.82876.37325055
68. An H Wang P Liu Y . Palliative gastrectomy improves the survival of patients with metastatic early-onset gastric cancer: A retrospective cohort study. Curr Oncol 2023;30 :7874–7890. doi: 10.3390/curroncol30090572.37754487
69. Blanke CD Bot BM Thomas DM Bleyer A Kohne CH Seymour MT , . Impact of young age on treatment efficacy and safety in advanced colorectal cancer: A pooled analysis of patients from nine first-line phase III chemotherapy trials. J Clin Oncol 2011;29 :2781–2786. doi: 10.1200/JCO.2010.33.5281.21646604
70. Sawaki A Ohashi Y Omuro Y Satoh T Hamamoto Y Boku N , . Efficacy of trastuzumab in japanese patients with her2-positive advanced gastric or gastroesophageal junction cancer: A subgroup analysis of the trastuzumab for gastric cancer (toga) study. Gastric Cancer 2012;15 :313–322. doi: 10.1007/s10120-011-0118-1.22179434
71. Bougen-Zhukov N Nouri Y Godwin T Taylor M Hakkaart C Single A , . Allosteric AKT inhibitors target synthetic lethal vulnerabilities in e-cadherin-deficient cells. Cancers (Basel) 2019;11 :1359. doi: 10.3390/cancers11091359.31540244
72. Fukamachi H Kim SK Koh J Lee HS Sasaki Y Yamashita K , . A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors. J Exp Clin Cancer Res 2019;38 :127. doi: 10.1186/s13046-019-1121-3.30866995
73. Li S Yu W Xie F Luo H Liu Z Lv W , . Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer. Nat Commun 2023;14 :8. doi: 10.1038/s41467-022-35431-x.36596787
74. Cai H Li M Deng R Wang M Shi Y . Advances in molecular biomarkers research and clinical application progress for gastric cancer immunotherapy. Biomark Res 2022;10 :67. doi: 10.1186/s40364-022-00413-0.36042469
75. Chitapanarux T Gumrai P Kongkarnka S Wannasai K Lertprasertsuke N . Programmed death-ligand 1 expression and overall survival in Thai patients with gastric cancer. Sci Rep 2023;13 :7241. doi: 10.1038/s41598-023-34434-y.37142693
76. Kim J Kim B Kang SY Heo YJ Park SH Kim ST , . Tumor mutational burden determined by panel sequencing predicts survival after immunotherapy in patients with advanced gastric cancer. Front Oncol 2020;10 :314. doi: 10.3389/fonc.2020.00314.32232003
77. Wang Y Zhang S Zhang F Wang L Wu C Zhang X , . Young patients show poor efficacy for immune checkpoint inhibitor combined therapy in metastatic gastrointestinal cancers. Front Oncol 2023;13 :1155019. doi: 10.3389/fonc.2023.1155019.37207161
78. Kundel Y Sternschuss M Moore A Perl G Brenner B Goldvaser H . Efficacy of immune-checkpoint inhibitors in metastatic gastric or gastroesophageal junction adenocarcinoma by patient subgroups: A systematic review and meta-analysis. Cancer Med 2020;9 :7613–7625. doi: 10.1002/cam4.3417.32869544
79. Qiu WW Chen QY Zheng WZ He QC Huang ZN Xie JW , . Postoperative follow-up for gastric cancer needs to be individualized according to age, tumour recurrence pattern, and recurrence time. Eur J Surg Oncol 2022;48 :1790–1798. doi: 10.1016/j.ejso.2022.02.025.35279349
