Sex Disparity in Patients with Gastric Cancer: A Systematic Review and Meta-Analysis

Objective This systematic review and meta-analysis aimed to ascertain whether sex-based differences influence clinicopathological characteristics and survival outcomes of gastric cancer patients. Background Gastric cancer in females has received less attention than in males. Clinicopathological features and survival outcomes of females with gastric cancer have been reported in several studies with controversial results. Methods We systematically reviewed clinical studies from PubMed, Cochrane Library, Embase, and Web of Science published up to June 2022. The effect sizes of the included studies were estimated using odds ratios (ORs). Heterogeneity was investigated using the χ2 and I2 tests, while sensitivity analyses were performed to identify the source of substantial heterogeneity. All data used in this study were obtained from previously published studies obviating the need for ethical approval and patient consent. Results Seventy-six studies with 775,003 gastric cancer patients were included in the meta-analysis. Gastric cancer patients were less likely to be females (P < 0.00001). Female patients were younger in age (P < 0.00001) and showed a higher percentage of distal (P < 0.00001), non-cardia (P < 0.00001), undifferentiated (P < 0.00001), diffuse (P < 0.00001), and signet-ring cell carcinoma (P < 0.00001). Female patients showed better prognosis in both 3-year (P = 0.0003) and 5-year overall survival (OS) (P < 0.00001), especially White patients. However, females were associated with lower 5-year OS relative to males in the younger patients (P = 0.0001). Conclusions In conclusion, gender differences were observed in clinicopathological characteristics and survival outcomes of gastric cancer. Different management of therapy will become necessary for different genders.


Introduction
Gastric cancer is the ffth most common cancer globally and the fourth leading cause of cancer-related mortality [1]. Gastric cancer is more common in males than females [2]. Many studies have concluded that exposure to estrogen reduces the risk of gastric cancer [3][4][5][6]. Some studies showed sex disparity may play a special role in the development of cardia and intestinal type of gastric cancer [7,8]. As research on sex-related diferences in gastric cancers has progressed, there has also been a concomitant interest in female gastric cancer research.
As such, the aim of the current study was to compare the clinicopathological characteristics and survival outcomes of female and male patients with gastric cancer through systematic review and meta-analysis, thus providing evidence suggesting the need for specifc treatments optimized for female and male gastric cancer patients.

Search Strategy.
Two investigators independently and systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases for clinical studies using the following search terms: "gastric" or "stomach," "cancer" or "neoplasm," "women" or "females" or "girls," "sex" or "gender." All articles published in English were included since the establishment of the database until the end of June 2022. Reference lists of the relevant systematic reviews and meta-analyses were also screened for other potential articles that might have been missed in the database search.

Inclusion and Exclusion
Criteria. Te eligibility criteria for inclusion were as follows: (I) studies compared females and male patients with gastric cancer; (II) studies contained quantitative clinicopathological characteristic information; and (III) studies involved at least one of the survival outcomes mentioned.
Te exclusion criteria were as follows: (I) abstract form only, letters, editorials, expert opinions, case reports, and studies lacking control groups; (II) duplicate research based on author or center; (III) data were inappropriate or unextractable; (IV) studies of benign lesions and special types of gastric cancer; (V) patients in the study had other diseases or cancers that afected their hormone levels; and (VI) studies involved other strong confounding factors.

Data Extraction.
All data from the included studies were independently extracted by two investigators. We extracted data on studies' authors, year of publication, study sites, document type, sample size, date sources, design, and quality assessment. Te clinicopathological characteristics extracted from patients included sex, age, tumor size, tumor location, diferentiation, histologic grading, Lauren type, Borrmann classifcation, the state of lymph node metastasis, pathologic tumor-node-metastasis (pTNM) stage, history of Helicobacter pylori (HP) infection, and family history. Te survival outcomes included short or long-term survival rates on total population, diferent ethnic group, and diferent age group. Some data were extracted by Engauge Digitizer version 11.3 from the graphical survival plots when data were only available as Kaplan-Meier curves. Te stage of gastric cancer in the systematic review and meta-analysis was performed according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system. Discrepancies in data extraction were resolved through discussion by the two investigators.

Quality Assessment.
Two investigators used the Newcastle-Ottawa Quality Assessment Scale (NOS) to evaluate the methodological quality of the included studies [26]. Te NOS scores range from 0 to 9 and studies with NOS score ≥6 are considered high-quality studies. Discrepancies in quality assessment were resolved through discussion by the two investigators.

Statistical Analysis.
We assessed heterogeneity between studies using both the I 2 test and the χ 2 test. Te I 2 test and χ 2 test were the methods to test for heterogeneity in multiple independent studies and were often used in meta-analysis.
Heterogeneity was considered signifcant when I 2 values over 50% and the χ 2 test with a P value < 0.10 [27] were obtained. Review Manager V.5.4.1 (Cochrane Collaboration, Oxford, United Kingdom) was used to conduct the systematic review and meta-analysis by generating forest plots. We set confdence intervals (CIs) at 95%. Results were expressed as odds ratios (ORs) with corresponding 95% CI by using the Mantel-Haenszel method for dichotomous outcomes and weighted mean diference (WMD) with corresponding 95% CI for continuous variables. Hazard ratio (HR) with corresponding 95% CI was used to assess the survival outcomes. Te random efects model was used when signifcant heterogeneity obviously existed; otherwise, the fxed efects model was used [28,29]. It was necessary to identify sources of signifcant heterogeneity by sensitivity analysis. Figure 1 shows the fow sheet of the search process. A total of 30,765 relevant clinical studies were identifed with our search strategy. After initial screening of titles and abstracts, 120 potentially eligible articles were retrieved by a full-text review. Articles were then based on exclusion and inclusion criteria. Finally, 76 studies with 775,003 gastric cancer patients were included in the systematic review and meta-analysis for further investigation, of which two were prospective studies, twentynine were observational studies, and the rest were retrospective comparative studies. Table 1 shows the essential characteristics and the NOS scores of the included studies. Table S1 shows the clinicopathological characteristics of the included studies.
We also divided female and male patients into two groups by age. Due to the limitation of meta-analysis, diferent articles have diferent age criteria. So, the age group was blurred in this paper. Te patients were divided into two groups with 40-50 years old as the dividing line based on previously published studies and data. Most articles used 40 or 45 years old as the dividing line [24,31,55,61,69,86]. One article used 50 years old as the cutof [71]. Only patient data from those older than 55 years were used from the article by Bando et al. [45]. In older patients, the pooled 6 and 8 studies, respectively, showed that females had a better prognosis in both 3-year and 5-year OS (HR � 0.91, 95% CI: 0.86, 0.97, P � 0.002, I 2 � 17%; HR � 0.85, 95% CI: 0.76, 0.95, P � 0.005, I 2 � 78%) ( Figure 4). In contrast, females were associated with lower 5-year OS relative to males in young patients (HR � 1.39, 95% CI: 1.18, 1.65, P � 0.0001, I 2 � 43%) ( Figure 5).
Our study showed that the incidence of gastric cancer is lower in females than in males. While the exact physiological mechanism is unclear, it had been suggested that female hormones could reduce the risk of gastric cancer. Te prevailing view of the past was that frequent exposure to environmental carcinogens might lead to a predominance of gastric cancer in males, such as cigarettes [90]. But as the research went on, diferential exposure to established risk factors cannot totally explain the diferences. Several studies revealed that the use of exogenous hormones also played a protective role in gastric cancer risk, which suggested a high correlation between gastric cancer and hormones [3][4][5]. Our study found that females with gastric cancer were younger in age compared with males. Other studies have also reported higher incidence of gastric cancer in younger females [24,55,91]. Tis trait was also believed to be related to hormonal factors. Higher estrogen levels and a higher proportion of estrogen receptor positive cells have been found in younger females [30,35,92]. Terefore, more studies are needed to explore the role of hormones in gastric cancer.          Some fndings of clinicopathological features in the meta-analysis were consistent with previous studies, including a higher proportion of distal, non-cardia, undifferentiation, difuse histology, and signet-ring cell carcinoma in female patients. Many studies suggested a possible suppressive role of female sex hormones on cardia cancer and intestinal gastric cancer [7,8,93]. However, it has recently been suggested that estrogen can promote the development of undiferentiated and difuse gastric cancer. Te estrogen receptor (ER) positive rate has been reported to be slightly higher in young females and in poorly diferentiated gastric cancer. Tis may be the reason that poorly diferentiated histological results have been found more common in female gastric cancer patients [30,35,94,95]. One study detailed the tumorigenic mechanism of estrogen in the development of ERα-positive difuse-type gastric adenocarcinoma [94]. In addition, HP infection seemed to be involved in this process. CagA + HP infection is associated with an increased risk of distal gastric cancer [96][97][98]. A study of 917 patients with gastric cancer reported a higher titer of HP antibody in difuse gastric cancer than in intestinal type, suggesting that HP might be more closely related to difuse gastric cancer [99]. Furthermore, one study showed that HP could secrete a type of toxin called CagA,        Journal of Oncology which might enhance the efect of estrogen on difuse gastric cancer [94]. Tis may explain why studies found no sexrelated diferences in HP infection; however, our study found that female gastric cancer patients were more likely to have a history of HP infection. Terefore, young females with physiologically high levels of estrogen showed a higher percentage of distal, non-cardia, undiferentiation, difuse, and signet-ring cell carcinoma under the infuence of HP.
For postoperative complications, our study showed that being male was a risk factor for an adverse outcome. One study found that men are more likely to get infections after surgery [100]. Some research found that postoperative complications may be related to difering female/male patterns of adipose tissue distribution [53]. Visceral obesity but not general obesity was signifcant independent factor associated with postoperative complications in males [66]. Furthermore, the higher postoperative complications in males might be due to higher preoperative complications and more extensive surgical procedures [84]. However, other studies showed that the level of sex hormones was related with postoperative complications rather than sexrelated diferences. In both sexes, higher levels of 17β-estradiol predicted a poor prognosis [101,102]. Terefore, more studies are needed to research the relationship between Total events Heterogeneity: Chi 2 = 6.05, df = 5 (P = 0.30); I 2 = 17% Test for overall effect: Z = 3.07 (P < 0.002)    sex and postoperative complications in the future. If differences do indeed exist, diferent management of therapy will become necessary for the diferent genders [101].
Female gastric cancer patients had a better prognosis, and this fnding was consistent with most previous studies [9][10][11][12][13][14][15][16][17][18]. Tere are many possible reasons for this phenomenon. Firstly, females were more likely to have non-cardia and distal gastric cancer than males. Many studies have found that cardiac and proximal gastric cancer were more advanced and showed a poorer prognosis [103][104][105]. Secondly, our study included a large number of White gastric cancer patients, and White females have been shown to have a better prognosis in previous studies [17,80]. Tirdly, one study found that the ATRX gene was found to mutate more frequently in female gastric cancer patients. Te ATRX gene is a protein coding gene associated with alpha-thalassemia myelodysplasia syndrome and intellectual disability-hypotonic facies syndrome, X-linked. Female patients with ATRX mutation obtained signifcantly better survival benefts after treatment with immune checkpoint inhibitors [106]. Fourthly, survival was signifcantly increased in females receiving neoadjuvant chemotherapy, especially in females with microsatellite instability-high (MSI-H) tumors [15]. In terms of tumor metastasis, females were less likely to develop hepatic metastasis, consistent with previous studies [13]. One possible reason could be that estrogen has an anti-cancer efect in some non-target organs such as the liver and colon, but more research is needed to prove the exact mechanism [107].
Other studies have found that sex-related diferences have diferent infuences on the prognosis of gastric cancer patients in diferent racial groups, and this study reached the same conclusion. Te reason for this phenomenon can be explained by the diferences in molecular mechanisms between the two sexes among gastric cancer patients of different ethnic groups [80]. Moreover, female gastric cancer patients might have a worse prognosis under the infuence of HP as previously mentioned. Tis phenomenon could also be explained by the higher prevalence of HP infection in under-developed and developing countries than in developed countries [108]. Note, however, that in one previous study, females showed a worse prognosis compared with males among Asian gastric cancer patients [80]. In our metaanalysis, there was no signifcant diference in survival outcomes between Asian males and females, which was consistent with another study [17]. Terefore, the efect of sex-related diferences on the prognosis of Asian gastric cancer patients needs to be further studied.
In this study, younger female gastric cancer patients were found to have a lower 5-year OS relative to younger male patients. Many studies reached similar conclusions when age was analyzed [23,24,55,69]. Poorly diferentiated adenocarcinoma was more likely to be identifed in younger women, which might be related to hormone levels [69,84]. Te poorly diferentiated tumor types in females might partly explain the poor prognosis. Studies have also found that younger female patients had larger tumors and more advanced TNM staging and were also likely to develop lymph node metastases [72,79]. Another study found that young female patients showed lower OS than male patients in both signet-ring cell and non-signet-ring cell histological types, which partly supports this view [69].
Tere were several limitations in our meta-analysis. First of all, most of the studies we included were retrospective studies with some limitations, which were at risk of publication bias and heterogeneity. Secondly, we were not able to analyze information from Black gastric cancer patients because most of the studies meeting inclusion criteria used in this study were only related to clinical characteristics and survival outcomes in White and Asian patients. Tirdly, the lack of available patient data did not allow our analysis to assess disease-specifc survival and disease-free survival, and we could only deal vaguely with diferent versions of TNM stages. Furthermore, heterogeneities in the included studies' female/male ratios, tumor location, Lauren type, and other variables were all signifcant. Despite these limitations, this meta-analysis to our knowledge is the frst to evaluate differences in clinicopathological characteristics and prognosis between female and male patients. Moreover, we assessed the efect of sex-related diferences on postoperative complications and metastasis. In addition, all clinical studies included in this meta-analysis were of high quality, which may provide clinicians with more valuable resources for patient management and decision making.

Conclusions
In conclusion, gender diferences were found in clinicopathological characteristics and survival outcomes of gastric cancer patients. Female patients with gastric cancer were more often diagnosed with distal, non-cardia, undiferentiated, and signet-ring cell carcinoma. Te clinicopathological type of tumor in female patients with gastric cancer was more aggressive than that found in males. Female patients showed better prognosis especially in the White patients' group. However, the results were reversed in younger patients. We expect to see more studies researching the molecular mechanisms and pathophysiological process relationships between gastric cancer prognosis in female and male populations. We will further analyze sex-related differences among diferent regions and ethnic groups (including Black, White, and Asian) in our next study. Furthermore, we will distinguish sex-related diferences among diferent age subgroups of gastric cancer in subsequent studies, so as to explore the impact of those differences in gastric cancer between young, middle-aged, and elderly groups on prognosis and explore the impact on women before and after menopause on prognosis. We also look forward to the publication of studies with larger sample sizes in the future to confrm our fndings.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request. Figure S1: meta-analysis of female ratio of total patients. Figure S2: meta-analysis of age between female and male groups. Figure S3: the proportion of clinicopathologic feature between female and male groups-(A) meta-analysis of proximal cancer; (B) meta-analysis of distal cancer; (C) meta-analysis of cardia cancer; (D) meta-analysis of noncardia cancer; (E) meta-analysis of diferentiation; (F) metaanalysis of undiferentiation; (G) meta-analysis of intestinal type; (H) meta-analysis of difuse type; (I) meta-analysis of signet-ring cell carcinoma. Figure S4: meta-analysis of the proportion of HP infection history between female and male groups. Figure S5: meta-analysis of the proportion of postoperative complications between female and male groups. Figure S6: the 3-year and 5-year overall survival for gastric cancer between female and male groups among Asian gastric cancer patients-(A) the 3-year overall survival of Asian patients; (B) the 5-year overall survival of Asian patients. Figure S7: meta-analysis of the proportion of hepatic metastasis between female and male groups. Table S1: clinicopathological characteristics of the included studies. (Supplementary Materials)