Predictive Factors Associated with Survival in Female Gastric Cancer Patients in Southeast Asia

Introduction: Association of Southeast Asian Nations (ASEAN) countries have high Helicobacter pylori infections, and gastric cancer (GC) is a leading fatal cancer in this region, especially in female patients. This study aimed to compare clinical manifestations, histopathological subtypes, and prognostic factors associated with the overall survival rate of female GC patients in this important region. Methods: This retrospective cohort study was conducted between 2007 and 2022 at a tertiary care center in Thailand. All clinical information, endoscopic findings, and histological types were extensively reviewed. Furthermore, all qualified studies in ASEAN published in PubMed and Scopus between 2000 and 2022 were extracted and thoroughly analyzed. Young female GC patients are defined as those ≤50 years of age. Results: A total of 98 Thai female GC patients were included, with a mean age of 58.99 ± 14 years; 70.4% were elderly women. The common presenting symptoms were weight loss (69.4%) and dyspepsia (68.4%). Younger female GC patients had significantly more common diffuse-type GC than elderly female GC patients (82.8% vs. 53.6%, p-value = 0.007). Moreover, elderly female GC patients demonstrated significantly better survival than younger female GC patients (44.8% vs. 20.7%, odds ratio = 3.49; 95% confidence interval: 1.20–10.14, p-value = 0.022). Furthermore, a total of 1,491 female GC patients from ASEAN were reviewed and included in this study, aged 15 to 93 years. The top three countries with the highest proportion of female GC from ASEAN were Indonesia (66.7%), Thailand (44.9%), and Singapore (38.4%). Conclusion: GC in women is not uncommon in ASEAN and presents at an advanced stage with a grave prognosis. This study showed that ASEAN countries with the highest disease burden were Indonesia, Thailand, and Singapore. Overall, survival rates for female GC patients in ASEAN countries were relatively low, highlighting the need for proactive measures such as intensive H. pylori eradication and the development of early detection methods for GC.


Introduction
Gastric cancer (GC) is a significant global health issue, with 1 million new cases and 760,000 deaths per year, notably in the Asia-Pacific area, including the Association of Southeast Asian Nations (ASEAN), where it has a high incidence and mortality rate.Despite the fact that men are approximately twice as likely as women to be affected by GC, it continues to be the fourth leading cause of cancer-related mortality among women worldwide and the seventh leading cause in ASEAN.GC continues to impact *16,000 women annually in ASEAN, with Singapore experiencing the highest prevalence, with a 5-year prevalence of 19.8 per 100,000 individuals. 1This may be affected by the region's high prevalence of Helicobacter pylori infection, ranging from 20% to *70%. 1,2nterestingly, men had a twofold higher incidence of GC than women 2,3 ; this disparity disappears when women reach menopause. 4It is hypothesized that estrogen and progesterone produced during the menstrual cycle play a significant role as a protective factor against GC. 5 Owing to the lack of available studies, information regarding prognostic factors and survival outcomes in women with GC is limited.This will be one of the pioneer studies to compare clinical manifestations, histopathological subtype differences, and survival prognostic factors between elderly and younger female GC patients in this region.

Study design
This retrospective cohort included all female GC patients at a tertiary care center in Thailand between August 2007 and August 2022.The absence of data as a potential source of bias was controlled by excluding patients with incomplete medical records.Demographic data, comorbidities, clinical manifestations, endoscopic features, GC location, H. pylori infection status, histopathological findings, staging according to the eighth edition AJCC cancer staging manual, 6 treatment, and survival were all extracted and extensively reviewed from medical records.
The search was limited to articles containing data on patients with GC published before August 31, 2022.Two researchers evaluated and selected all relevant studies.None of the publications from Thailand utilized the same data as the patients from our center.

Definitions
Younger female was defined as those whose chronological age is £50 years.
A diagnosis of GC was made by pathological diagnosis from a gastric biopsy.
Early-stage GC was defined as primary GC with an invasion depth no further than the submucosa, regardless of lymph node involvement.According to the eighth AJCC TNM staging, 6 early GC is defined as T1 with any N.

Statistical analysis
Continuous data are shown using the mean and standard deviation.Demographic data were analyzed by the chi-squared test or Fisher's exact test, whichever was appropriate.Univariate and multivariate analyses were performed to determine the relationship between variables.All tests were two sided, and a p-value <0.05 was regarded as statistically significant.IBM SPSS Statistics version 27.0 was used for the statistical analysis (SPSS, Inc., Armonk, NY).
This study adhered to the good clinical practice guidelines and the Declaration of Helsinki.Owing to the fact that this was a retrospective study with low risk and had no effect on the participant's well-being or rights, informed consent was waived.Only authors had access to the data, which were kept exclusively confidential.The obtained data are anonymous and cannot be used to identify specific individuals.

Results
A total of 3,936 patients with GC from ASEAN were enrolled in this study.Within Thailand, 190 patients were included; among them, 98 (51.6%) were women.The mean age of female GC patients was 58.99 -14 years, and the majority (70.4%) were elderly GC patients.Common comorbidities in female GC patients were hypertension (26.5%), dyslipidemia (23.5%), and diabetes mellitus (19.4%).A subset of 28 patients (28.6%) had multiple comorbidities, and 66 patients (67.3%) had H. pylori infection.
The most prevalent presenting symptoms in female GC patients were weight loss (69.4%) and dyspepsia (68.4%).The majority of patients had diffuse-type GC (62.2%) and were in advanced stages (89.8%), with 60 patients (61.2%) having metastatic cancer.In addition, we included data from a literature review, incorporating an additional 3,746 GC patients into the total cohort of 3,936, of whom 1,491 (37.9%) were women.
Baseline patient demographic data, clinical characteristics, endoscopic findings, pathological subtype, and staging are demonstrated in Table 1.
Primary outcome: Differences between gender, younger female group, and elderly female group Men were found to be more likely to smoke than women (52.7% vs. 12.2%, p-value <0.001).Regarding clinical manifestation, women were more likely to pres-ent with dyspepsia and anemia than men (68.4% vs. 47.8%,p-value = 0.004, and 39.8% vs. 26.1%,p-value = 0.045, respectively).Moreover, women were found to have a higher incidence of diffuse-type GC than men (62.2% vs. 40.2%,p-value = 0.002).No significant differences were found in underlying diseases, endoscopic findings, and staging between the two genders.
Regarding the histopathology, even though there was more diffuse-type GC in both groups, the younger group had a significantly higher prevalence of diffusetype GC (82.8% vs. 53.6%,p-value = 0.007).Moreover, the younger group had a higher likelihood of presenting with advanced-stage GC (100% vs. 85.5%, p-value = 0.031).There was no significant difference in terms of clinical manifestations, endoscopic features, location of GC, and site of metastasis between the two age groups.

Survival outcomes and prognostic factors associated with mortality
Of the 190 GC patients, 183 were included in the survival analysis after attending follow-up visits, whereas 7 were excluded due to being lost to follow-up.Of the seven patients, five were men, and two were women, both being in the elderly female GC group.The overall 1-, 2-, and 5-year survival rates in female GC patients were 37.5%, 13.5%, and 1%, respectively.Female GC patients had better 1-year survival rates and 2-year survival rates than male GC patients (37.5% vs. 23%, p-value = 0.033, and 13.5% vs. 1.1%, p-value = 0.002, respectively).
Elderly female GC patients had significantly better 1-year survival rates than the younger female GC group (44.8% vs. 20.7%,odds ratio [OR] = 3.49; 95% confidence interval [CI]: 1.20-10.14;p-value = 0.022).However, Kaplan-Meier survival analysis revealed that there was no significant difference in median survival between elderly and younger female GC patients, as shown in Figure 1.
Regarding prognostic factors associated with mortality, several statistically significant univariate variables were analyzed in a Cox multivariate analysis.Younger female GC group (OR = 3.49; 95% CI: 1.20-10.14;p-value = 0.022) and diffuse-type GC group (OR = 3.50; 95% CI: 1.45-8.45;p-value = 0.005) were significantly associated with mortality.Univariate and multivariate analyses of prognostic factors associated with mortality are demonstrated in Table 2.

Female GC in ASEAN
Fourteen studies involving patients with GC were reported from seven different countries of ASEAN (Thailand, Brunei, Malaysia, Vietnam, Singapore, Indonesia, and the Philippines).There were 3,936 cases of GC, with 1,491 (37.9%) being women.The highest proportion of female GC patients was observed in Indonesia (66.7%), followed by Thailand (44.9%) and Singapore (38.4%), whereas the lowest proportion of female GC patients was found in the Philippines (22.2%).The mean age of female patients ranged from 58.4 -14.8 to 58.99 -14 years old.
The prevalence of diffuse-type GC varied widely across studies, ranging from 29.8% to 52.6%.Most patients were diagnosed at an advanced stage, with the majority being diagnosed at stage 4, ranging from 8.8% to 57.1%.Consequently, the mortality rates were high, with 1-and 5-year survival rates ranging from 37.5% to 46.2% and 1% to 17.8%, respectively.Chemotherapy was the most common treatment   3, and those exclusively of female GC patients in Table 4.

Discussion
GC is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide.Approximately 16,000 new cases of female GC are annually diagnosed in the region. 1 This study demonstrated a comparable ratio of male-to-female patients with GC, in contrast to the predominance of male patients in all other ASEAN studies.The male predominance in GC incidence may not solely be due to the protective effect of estrogen in women.
Other factors, such as tobacco use, variations in dietary patterns, and occupational exposure, may also contribute to the increased prevalence of GC among men. 7oreover, this study revealed that the majority of female GC patients were elderly and diagnosed at an advanced stage, which was comparable with previous studies, 2,[8][9][10][11][12][13][14][15][16][17][18][19][20][21] notably that all of the younger group presented at an advanced stage.This appears to be comparable with a study from China. 8Furthermore, this study demonstrated a significantly higher proportion of diffuse-type GC in the younger group.Estrogen has been proposed to play a role in the development of diffuse-type GC.A prior study has reported an elevated positivity rate of estrogen receptors (ERs) and tumorigenic mechanism of estrogen in the development of ER-positive diffuse-type GC in young female patients, which may account for the higher incidence of this subtype among younger female GC patients. 9oreover, our study demonstrates that having diffusetype GC and being younger have a lower survival rate.This is consistent with previous studies indicating that patients with young-onset GC and diffuse-type GC had a poor prognosis. 8,10,11This could be attributed to the absence of precancerous lesions associated with diffuse-type GC, resulting in challenges in early detection, leading to late presentation and diagnosis at a more advanced stage of the disease.Furthermore, CDH1 gene mutations may also contribute to late diagnosis.These mutations can disrupt gastric cell polarity, causing the loss of the epithelial cell adhesion protein E-cadherin, and result in diffuse-type GC without atrophic chronic gastritis or intestinal metaplasia.This can lead to hereditary diffuse GC, with an incidence of *5-10/ 100,000 births. 12These mutations are more commonly found in younger patients, 13 resulting in delayed diagnosis, rapid tumor growth, and poor treatment response.This interplay of factors can contribute to a lower 1year survival rate among younger female GC patients.
Our study compiled and analyzed 14 studies with GC patients from 7 countries throughout ASEAN.The proportion of women with GC in comparison with men with GC ranges from 22.2% to 66.7%.Among the countries analyzed, Indonesia has the highest proportion at 66.7%, followed by Thailand at 44.9% and Singapore at 38.4%.The lowest proportion was found in the Philippines at 22.2%.This contradicts the GLOBOCAN report for 2020, which indicates that the countries with the highest incidence of GC over a 5-year period are Vietnam, Brunei Darussalam, and Singapore. 1 The disparity between the findings of this study and GLOBOCAN might be attributed to differences in some factors such as number of studies conducted, study period, and population.Furthermore, this study gained more information and defined current knowledge on the incidence of GC among women in ASEAN, especially Thailand.Singapore had a high prevalence of GC among ASEAN, and Singapore's incidence rate of 38.4% reported in this study is consistent with a report from GLOBOCAN.
Therefore, Singapore remains a country of concern with growing problems with female GC.Furthermore, our study demonstrated that female diffuse-type GC is more common among both elderly and younger female GC patients and that the majority of patients were in advanced stages.This is comparable with studies from other regions in Asia, such as East Asia, 10,14 the Middle East, 15 and Europe. 16ffective screening programs, early diagnosis, and treatment of GC in young female patients may play a pivotal role in improving survival rates and treatment outcomes.Many systematic reviews and meta-analyses concluded that eradication of H. pylori in infected adults reduced the risk of developing GC. 17,18Although the optimal screening system for this particular patient population is still unknown.

Conclusion
In conclusion, GC in female patients remains a major concern in ASEAN, and differences in clinical characteristics and histopathological findings between age groups can affect prognosis.Younger female patients with diffuse-type GC are associated with higher mortality rates.This underscores the crucial need for proactive measures, including comprehensive H. pylori eradication and the development of effective screening and early detection methods for GC.
Authors' Contributions R.K.V. contributed to conceptualization, methodology, supervision, project administration, funding acquisition, writing-review and editing, and supervision.

Table 2 .
Cox Multivariate Analysis of Predictive Factors for Mortality of Female Gastric Cancer a Cox multivariate analysis adjusting from all significant variables from univariate analysis, including age £50 and diffuse-type GC.CI, confidence interval; GC, gastric cancer; OR, odds ratio.Bongkotvirawan, et al.; Women's Health Reports 2024, 5.1 http://online.liebertpub.com/doi/10.1089/whr.2023.0069option, received by 56.1% to 63.8% of patients, followed by surgery (20.7% to 35.7%).Data from Cambodia, Laos, Myanmar, and Timor-Leste were not available.All clinical characteristics and survival rates of male and female GC patients in ASEAN are demonstrated in Table

Table 3 .
Clinical Characteristics and Survival of Female and Male Gastric Cancer Patients in Association of Southeast Asian Nations

Table 4 .
Summary of Clinical Characteristics and Survival of Female Gastric Cancer Patients in Association of Southeast Asian Nations CCRT, concurrent chemoradiotherapy; CMT, chemotherapy; OS, overall survival.Bongkotvirawan, et al.; Women's Health Reports 2024, 5.1 http://online.liebertpub.com/doi/10.1089/whr.2023.0069P.B. was involved in methodology, software, formal analysis, investigation, resources, data curation, and writing-original draft.N.A. carried out validation, data curation, and writing-review and editing.B.P., S.C., S.S., P.Bh., P.N., N.I., and V.M. carried out data curation and writing-review and editing.. K.K.P. carried out writing-review and editing.Institutional Review Board Approval This study was approved by The Human Research Ethics Committee of Thammasat University with approval number MTU-EC-IM-6-211/65.