Abstract
Background:
Gastric cancer remains one of the most common malignancies and a leading cause of cancer-related mortality worldwide. Human epidermal growth factor receptor 2 (HER2) status is a key biomarker influencing both prognosis and treatment selection. While HER2-positive patients benefit from trastuzumab, outcomes for HER2-low and HER2-zero groups remain less clearly defined.
Methods:
In this retrospective cohort study, we reviewed 507 patients diagnosed with metastatic gastric adenocarcinoma between 2015 and 2023. Patients were classified as HER2-zero (n = 134), HER2-low (n = 303), or HER2-positive (n = 70) based on immunohistochemistry and in situ hybridization results. Clinicopathologic features, treatment strategies, and survival outcomes were analyzed. Kaplan-Meier methods estimated progression-free survival (PFS) and overall survival (OS), whereas Cox regression identified independent prognostic factors.
Results:
The HER2-positive group achieved a median PFS of 9.0 months and OS of 20.0 months, superior to HER2-zero patients (PFS: 6.1; OS: 14.5; P < .001). HER2-low patients demonstrated intermediate outcomes (PFS: 6.7; OS: 16.6 months). Group distribution was HER2-zero 26.4%, HER2-low 59.8%, and HER2-positive 13.8%. All HER2-positive patients received trastuzumab-based therapy. Multivariate analysis confirmed HER2-positive status as an independent predictive factor for both progression (hazard ratio [HR] = 0.65) and mortality (HR = 0.62).
Conclusions:
HER2 status is a strong predictive determinant in metastatic gastric cancer. Trastuzumab provided significant real-world benefit for HER2-positive patients, validating the impact of targeted therapy. Notably, HER2-low patients had better outcomes than HER2-zero, supporting the recognition of HER2-low as a distinct subgroup with potential eligibility for future HER2-directed treatments.
Introduction
Gastric cancer ranks fifth globally in both incidence (~968 000 new cases, 4.9%) and mortality (~660 000 deaths, 6.8%), with approximately 20 million new cancer cases and 9.7 million cancer-related deaths reported worldwide in 2022. 1 While gastric cancer has long survival results in early stages, it has very low survival results especially in advanced inoperable and metastatic stages.2-5 Therefore, despite ranking fifth in incidence, it remains one of the leading causes of cancer-related deaths. Although high incidence rates are seen especially in regions such as East Asia, Eastern Europe and Central/South America, it continues to be a major health problem worldwide. It is 2 to 3 times more common in men than in women. 6 Risk factors such as Helicobacter pylori infection, high-salt diet, smoking and genetic predisposition play an important role in the epidemiology of the disease.7,8 The disease is a highly heterogeneous malignancy, mostly in the form of adenocarcinoma, and traditional morphology-based classifications do not fully reflect the molecular heterogeneity of the disease. 9 Systemic chemotherapy remains the mainstay of treatment for metastatic gastric cancer.2-5 Over the last 2 decades, there have been significant advances in the treatment of metastatic gastric cancer. As a result, the role of targeted agents has become more prominent. Despite this, the average overall survival (OS) is still around 12 to 17 months.10-13 Innovative approaches such as molecular classifications and targeted therapies increase personalized treatment options, especially in advanced patients, and offer promise for the future.14-16
Human epidermal growth factor receptor 2 (HER2) overexpression has historically been associated with poor prognosis in breast cancer. 17 HER2 overexpression or amplification is a proven prognostic and predictive biomarker in breast and gastric cancers.18,19 With the demonstration of the efficacy of trastuzumab, a HER2-targeted therapy, in the first-line treatment of metastatic gastric cancer, trastuzumab has become an important part of standard treatment in HER2-positive metastatic gastric cancer. 12 In recent years, significant advances have been seen in HER2-targeted therapies and trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate, is increasingly gaining ground in the treatment of metastatic gastric cancer.4,20 With the demonstration of T-DXd’s efficacy in HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH] negative) patients, the HER2-low concept has become an important factor considered when planning treatment.21,22 Moreover, the combination of trastuzumab with immune checkpoint inhibitors (ICIs), particularly pembrolizumab, has emerged as a promising first-line strategy in HER2-positive gastric cancer. A recent systematic review and meta-analysis demonstrated that the addition of ICIs to trastuzumab and chemotherapy significantly improved OS (hazard ratio [HR]: 0.73; 95% CI: 0.64-0.84; P < .0001) and progression-free survival (HR: 0.69; 95% CI: 0.60-0.80; P < .0001), with a manageable toxicity profile. 23 Although it is accepted that HER2-zero, HER2-low and HER2-positive patients have very different clinicopathologic features, it has not yet been fully clarified.24-26
Comprehensive studies comparing the clinicopathologic factors affecting survival in HER2-zero, HER2-low and HER2-positive patient groups are limited in the literature. Furthermore, the prognostic and predictive values of molecular classifications in clinical practice and the differences in the treatment responses of these groups have not been fully determined. This study aims to fill the knowledge gap in this field by systematically analyzing the prognostic significance and survival outcomes of patient groups defined according to HER2 status.
Materials and Methods
Study Population and Sample
This study was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 27 All patient details were de-identified prior to analysis, ensuring that no individual could be identified.
This retrospective study included 11 centers. The names of the centers are as follows: Kartal Dr. Lütfi Kırdar City Hospital Medical Oncology Clinic, Sancaktepe Martyr Prof. Dr. İlhan Varank Training and Research Hospital, Marmara University Faculty of Medicine Medical Oncology Clinic, Kahramanmaraş Necip Fazıl City Hospital Medical Oncology Clinic, Tekirdağ Namık Kemal University Faculty of Medicine Medical Oncology Clinic, Kocaeli City Hospital Medical Oncology Clinic, Afyonkarahisar S.B. University Faculty of Medicine Medical Oncology Clinic, Dokuz Eylül University Faculty of Medicine Hospital Medical Oncology Clinic, Kocaeli University Faculty of Medicine Hospital Medical Oncology Clinic, Necmettin Erbakan University Faculty of Medicine Hospital Medical Oncology Clinic, Medeniyet University Göztepe Prof. Dr. Süleyman Yalçın City Hospital Medical Oncology Clinic.
This retrospective cohort study analyzed patients diagnosed with metastatic gastric cancer who presented to 11 centers included in the study between January 2015 and December 2023. The researchers determined a minimum sample size of 70 patients for each group to detect a survival difference of at least 5 months in the HER2-positive group with 80% power and 5% type I error. Patients were identified through a retrospective review of medical records and were selected consecutively from the hospital information management systems of the participating centers. The study included patients who had histopathologically confirmed metastatic gastric adenocarcinoma and were at least 18 years old with Eastern Cooperative Oncology Group (ECOG) performance status scores 28 between 0 and 2 and normal organ function and at least 3 months of follow-up. The study excluded patients who received previous systemic treatment for metastatic disease and those with concomitant malignancies and unknown HER2 status and missing follow-up data. Patients with positive PD-L1 expression status were also excluded from the study to minimize potential confounding effects of immunotherapy eligibility on treatment decisions and outcomes. The research included 507 patients who were divided into 3 groups: the HER2-zero group with 134 patients and the HER2-low group with 303 patients and the HER2-positive group with 70 patients (Figure 1). HER2-zero patients were classified as IHC 0, HER2-low patients as IHC 1+ or IHC 2+ but ISH negative, and HER2-positive patients as IHC 3+ or IHC 2+ and ISH-positive.
Patient flow diagram. HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; PD-L1, programmed death-ligand 1.
Study Procedures
The researchers obtained data retrospectively through hospital information management system records and patient documentation. The laboratory protocol required initial HER2 status determination through IHC followed by ISH confirmation for cases with IHC 2+ results. HER2 IHC was performed using anti-HER2/neu (4B5) rabbit monoclonal primary antibody on the Ventana Bench Mark platform (Ventana Medical Systems, Tucson, Arizona). HER2 scoring was performed according to the standardized gastric cancer scoring criteria: IHC 0 (no staining or <10% membrane staining), IHC 1+ (faint membrane staining in ⩾10% of tumor cells), IHC 2+ (weak to moderate complete or basolateral membrane staining in ⩾10% of tumor cells), and IHC 3+ (strong complete or basolateral membrane staining in ⩾10% of tumor cells). For equivocal cases (IHC 2+), fluorescence in situ hybridization (FISH) or silver-enhanced in situ hybridization was performed to confirm HER2 gene amplification status. A HER2/CEP17 ratio of ⩾2.0 was considered positive for gene amplification. In most cases, HER2 testing was performed on biopsy specimens. In patients with a history of surgery, testing was performed on resection specimens. The microsatellite instability (MSI) status was determined through immunohistochemical tests which checked for MLH1, MSH2, MSH6 and PMS2 protein expression loss.
Overall Survival
Overall survival was defined as the duration between the date of initiation of first-line systemic treatment and the date of death from any cause or last follow-up visit for patients who were still alive at the time of analysis.
Progression-Free Survival
Progression-free survival was defined as the duration between the date of initiation of first-line systemic treatment and the date of first documented disease progression or death from any cause, whichever occurred first. For patients who were alive without documented progression, PFS was censored at the date of last follow-up. Disease progression was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). 29
The data collection tools were cross-checked by 2 different researchers for reliability, and standardized forms were used for validity.
Intervention Protocol
The patients received their HER2 status classification into 3 distinct categories which included HER2-zero and HER2-low and HER2-positive. The selection of treatment depended on physician preference together with the patient’s general condition and clinical characteristics rather than randomization. The treatment protocol for HER2-positive patients included FOLFOX + Trastuzumab and FOLFIRI + Trastuzumab and CF + Trastuzumab, whereas standard chemotherapy protocols FOLFOX, FOLFIRI, CF, DCF, FLOT and XELOX were used for HER2-zero and HER2-low patients. The NCI-CTCAE v4.0 criteria assessed treatment responses and toxicities while second-line treatments began after disease progression. The multidisciplinary oncology council evaluated all patients to develop personalized treatment plans for each patient.
Statistical Analysis
Statistical analyses were performed using SPSS Statistics 28.0 (IBM Corp., Armonk, New York) software. Continuous variables are presented as median (minimum-maximum) and categorical variables are presented as number and percentage. For intergroup comparisons, Kruskal-Wallis test was used for continuous variables and χ2 test was used for categorical variables. Survival analyses were performed by Kaplan-Meier method and log-rank test was used for intergroup comparisons. Univariate and multivariate Cox regression analyses were performed to determine prognostic factors; variables with P < .20 in the univariate analysis were included in the multivariate analysis. The missing data rate remained below 5% so complete case analysis was conducted. Subgroup analyses were presented with forest plot and interaction test was performed. Statistical significance level was accepted as P < .05.
Units of Measure
The tumor markers were reported as carcinoembryonic antigen (CEA) ng/mL, CA19-9 U/mL (conversion factors to SI units: [ng/mL] → 1.0 for CEA [U/mL] → 1.0 for CA19-9). Age was expressed in years and follow-up periods were expressed in months. Laboratory values were evaluated according to the normal ranges of our hospital and ⩽5 ng/mL for CEA and ⩽37 U/mL for CA19-9 were considered normal.
Ethical Considerations
This multicenter retrospective study was approved by the Kartal Dr. Lütfi Kırdar City Hospital Scientific Research Ethics Committee (approval no: 2025/010.99/12/14, date: January 24, 2025). Permissions for data use were obtained under the primary ethical approval covering all participating centers involved in this national multicenter study. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki (1975), as revised in 2024. Due to the retrospective design of the study and the use of anonymized patient data, the requirement for obtaining informed consent was waived by the Ethics Committee. The study team had exclusive access to encrypted computers and databases which maintained data security.
Results
Patient Demographics and Key Characteristics
The research included 507 patients with metastatic gastric cancer who were separated into 3 HER2 status groups. The patient population consisted of 134 HER2-zero patients (26.4%) and 303 HER2-low patients (59.8%) and 70 HER2-positive patients (13.8%). The median age was 64 years and most patients were men (64.1%). In terms of performance status, 63.5% of the patients had an ECOG performance score of 2 (Table 1).
Demographic and Clinical Characteristics According to HER2 Status.
All patients in the HER2-positive group (n = 70, 100%) received trastuzumab-based therapy.
Abbreviations: CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; ECOG, Eastern Cooperative Oncology Group; CF, cisplatin and 5-fluorouracil; DCF, docetaxel, cisplatin, and 5-fluorouracil; FLOT, 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; MSI, microsatellite instability; MSI-H, microsatellite instability-high; NOS, not otherwise specified; 5-FU, 5-fluorouracil; XELOX, capecitabine and oxaliplatin.
Kruskal-Wallis test.
χ2 test.
Tumor Pathological Characteristics
The most prevalent tumor pathology characteristic was adenocarcinoma NOS which appeared in 70.4% of patients. Remarkably, signet-ring cell adenocarcinoma was more common in the HER2-low group (22.4%), whereas it was the lowest in the HER2-positive group (11.4%). Similarly, the presence of signet-ring cell component was significantly different between the groups (P = .010). In terms of histologic grade, poorly differentiated tumors constituted 59.0% of the general population, whereas the proportion of well-to-moderately differentiated tumors was higher in the HER2-positive group (50.0%). The general population showed MSI-H status in 16.2% of cases, whereas the HER2-zero group had the highest rate at 20.4%. The rate of de novo metastatic disease reached 62.3% when analyzed by disease stage. The treatment methods between groups showed substantial differences because HER2-positive patients received trastuzumab-based treatments in every case but other groups selected classical chemotherapy regimens more often (Table 1).
Prognostic Factors for PFS
In the univariate Cox regression analysis for PFS, age, ECOG performance status, signet-ring cell pathology, presence of signet-ring component, poor differentiation, HER2 positivity, MSI status, presence of liver metastasis and high CEA/CA19-9 levels were determined as significant prognostic factors. The multivariate analysis showed that ECOG performance status (HR: 1.52, 95% CI: 1.16-1.99, P = .002), HER2-positive status (HR: 0.65, 95% CI: 0.46-0.91, P = .013), presence of liver metastasis (HR: 1.28, 95% CI: 1.00-1.64, P = .047) and high CEA level (HR: 1.34, 95% CI: 1.03-1.74, P = .028) remained independent prognostic factors. The risk of progression was 35% lower in HER2-positive patients compared with HER2-zero patients (Table 2).
Univariate and Multivariate Cox Regression Analysis for PFS.
Variables with P < .2 in univariate analysis were included in the multivariate analysis.
Abbreviations: CI, confidence interval; HR, hazard ratio.
Prognostic Factors for OS
Age, ECOG performance status, signet-ring cell pathology, signet-ring component, poor differentiation, HER2 status, MSI status, stage, presence of liver and peritoneal metastasis and tumor markers were found to be significant factors for OS in univariate analysis. In multivariate analysis, ECOG performance status (HR: 1.68, 95% CI: 1.28-2.21, P < .001), poor differentiation (HR: 1.28, 95% CI: 1.00-1.64, P = .048), HER2-positive status (HR: 0.62, 95% CI: 0.44-0.87, P = .006), presence of liver metastasis (HR: 1.32, 95% CI: 1.03-1.69, P = .029), high CEA level (HR: 1.42, 95% CI: 1.08-1.87, P = .012) and high CA19-9 level (HR: 1.35, 95% CI: 1.05-1.73, P = .019) remained independent prognostic factors. The risk of death was 38% lower in HER2-positive patients (Table 3).
Univariate and Multivariate Cox Regression Analysis for OS.
Variables with P < .2 in univariate analysis were included in the multivariate analysis.
Abbreviations: CI, confidence interval; HR, hazard ratio.
Survival Analysis Results
Survival analysis results clearly revealed the prognostic importance of HER2 status. Median PFS was calculated as 6.1 months in HER2-zero group, 6.7 months in HER2-low group and 9.0 months in HER2-positive group. The 12-month PFS rates were 23.8%, 30.9% and 46.4%, respectively. A similar pattern was observed in terms of OS; median OS was 14.5 months in HER2-zero group, 16.6 months in HER2-low group and 20.0 months in HER2-positive group. The 24-month OS rates were 26.3%, 32.1% and 45.2%, respectively. The difference between the groups was statistically significant for both survival parameters (Table 4).
Progression-Free Survival (PFS) and Overall Survival (OS) According to HER2 Status.
Abbreviation: CI, confidence interval.
Log-rank test.
χ2 test.
Kaplan-Meier Survival Curve Analysis
Kaplan-Meier survival curves visually supported this marked difference between HER2 groups. Progression-free survival curves showed later progression times in HER2-positive patients, whereas OS curves similarly showed a continuous divergence in favor of the HER2-positive group. The log-rank test results for both analyses were statistically significant (P < .001) (Figure 2).
Kaplan-Meier survival curves by HER2 status: progression-free survival (panel A) and overall survival (panel B) stratified by HER2 expression levels in patients with metastatic gastric cancer. HER2-positive patients demonstrated superior survival outcomes compared to HER2-low and HER2-zero groups in both analyses. HER2, human epidermal growth factor receptor 2; n, number of patients.
Subgroup Analyses
The prognostic impact of HER2 status was evaluated in subgroup analyses for different pathology categories and metastasis sites. Forest plot analysis showed a lower risk of death in HER2-low and HER2-positive patients in the NOS subgroup of adenocarcinoma compared with the HER2-zero group. A similar pattern was observed in signet-ring cell adenocarcinoma, but confidence intervals showed a wider distribution. In terms of metastasis sites, HER2-positive status showed a protective effect in all subgroups with liver, peritoneal and lung metastases, but these differences did not reach statistical significance (Figure 3).
Forest plot of hazard ratios for overall survival by HER2 status and subgroups: comparison of HER2-low and HER2-positive groups versus HER2-zero reference group across overall cohort and various subgroups including histological subtypes and metastatic sites. Points represent hazard ratios with 95% confidence intervals; the vertical dashed line at HR = 1.0 indicates no difference between groups. Points to the left of the line favor better survival in the comparison group. Adeno, adenocarcinoma; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; n, number of patients; Pos, positive.
Discussion
The research examined how HER2 status affects survival rates in patients with metastatic gastric cancer and discovered that HER2-positive patients experienced better survival outcomes. The research demonstrated that patients with HER2-zero, HER2-low and HER2-positive status showed distinct survival patterns in both progression-free and OS measurements. The 100% use of trastuzumab-based therapies in HER2-positive patients together with their superior clinical results demonstrates the effectiveness of HER2-targeted therapies. The HER2-low group demonstrated superior survival results compared with the HER2-zero group according to our research findings.
It is important to note that all HER2-positive patients in this study received trastuzumab-based therapy. Therefore, the superior survival outcomes observed in the HER2-positive group likely reflect the predictive benefit of targeted therapy rather than an inherent prognostic advantage of HER2-positive status itself. The observed survival difference should be interpreted as the combined effect of HER2 biology and trastuzumab treatment response, and not as evidence that HER2-positive status is independently prognostically favorable.
The survival results obtained in HER2-positive patients with metastatic gastric cancer in this study are consistent with the literature and even more preliminary. In our study, the median PFS was 9.0 months and median OS was 20.0 months in the HER2-positive group, which is better than the PFS 8.4 months and OS 16.7 months in IHC 3+ patients reported by Bang et al. 30 Similarly, in another study conducted in HER2-positive patients, the median OS of 13.8 months for chemotherapy combined with trastuzumab was below our findings. 31 The identification of HER2-positive status as an independent predictive factor for both PFS (HR: 0.65) and OS (HR: 0.62) in multivariate analysis supports the clinical efficacy of HER2-targeted therapy. The results of PFS 6.0 months and OS 12.3 months reported in a study examining progression after trastuzumab are consistent with the expected results after first-line treatment. 32 In addition, the 24-month OS rate of 45.2% in the HER2-positive group in our study indicates promising results in terms of long-term survival in this patient group.
The clinical and histopathologic characteristics of the HER2-low group show unique features when compared with the findings in the literature. In our study, the rate of mucinous adenocarcinoma in the HER2-low group was 11.0%, which is significantly higher than the 2.9% reported by Angerilli et al. 33 In terms of the signet-ring component, the 27.2% rate in our findings is higher than the 11.1% rate of signet-ring cell carcinoma reported by Angerilli et al. It is thought that this difference may be due to regional and demographic differences. 33 In terms of MSI-H status, a rate of 13.8% was found in the HER2-low group in our study, which is lower than the rate of 33.3% reported by Angerilli et al. 33 In terms of demographic characteristics, the median age of 65 years and 65.2% male patients in the HER2-low group reported by Narita et al 24 are similar to our findings. In terms of grade, the 59.0% rate of poorly differentiated tumors in the HER2-low group in our study suggests that this group exhibits an aggressive phenotype.
In our study, the utilization rate of trastuzumab-based therapies in HER2-positive patients with metastatic gastric cancer was found to be 100%, which shows an excellent targeted therapy application compared with the literature. The 58.6% preference for FOLFOX + Trastuzumab combination in the distribution of treatment regimens is similar to the 83.3% use of oxaliplatin-based chemotherapy regimen in Cohort A reported by Deng et al.
34
As stated by Scheck et al,
35
the
Research indicates that patients with HER2-low expression tend to survive longer than patients with HER2-zero expression. The combination of large-scale meta-analyses and cohorts for metastatic or early-stage breast cancer shows that patients with HER2-low expression achieve superior OS and disease-free survival rates. The subgroup of hormone receptor–positive patients demonstrates the most pronounced survival benefit from HER2-low expression.37-39 The real-life cohort study conducted by Ünal et al analyzed metastatic gastric cancer survival between HER2-low and HER2-zero groups without finding any significant difference. The HER2-low group presented more low-grade tumors, but the HER2-zero group contained more high-grade tumors. Both groups showed equivalent responses to chemotherapy treatment. 40 The analysis of extensive patient data indicates that tumors with HER2-low expression tend to be less aggressive biologically which leads to improved survival rates. The main factors contributing to improved survival in the HER2-low group include higher estrogen receptor positivity and lower grade tumors together with less widespread histopathologic malignancy.41,42
The retrospective design of our study and the fact that most of the patients belonged to the pre-immunotherapy period are important limitations. The results need to be viewed with caution because the HER2-positive group is small and the physician has a preference in treatment selection. Several additional limitations should be acknowledged. First, PD-L1 expression status was not systematically assessed across all patients; patients with positive PD-L1 status were excluded from the study, which may limit the generalizability of findings to the broader population of metastatic gastric cancer patients. Second, HER2 testing was performed on biopsy specimens in most cases and on resection specimens in patients with prior surgery; interobserver variability and intratumoral heterogeneity in HER2 immunohistochemical scoring across the 11 participating centers may have influenced group classification. Whether all sites used fully standardized protocols (including antibody clones, fixation times and scoring training) could not be confirmed retrospectively. Third, center-level and year-of-treatment adjustments were not performed in our analyses. Temporal changes in treatment patterns and center-specific practice variations may have introduced unmeasured confounding. Sensitivity analyses adjusting for these factors would strengthen the findings and should be addressed in future studies. Finally, the limited number of HER2-positive patients (n = 70) may affect the statistical power of subgroup analyses. However, the large number of patients, comprehensive clinical data collection and long follow-up period are the strengths of the study. Future studies should prospectively examine the efficacy of new treatment options in HER2-low patients and the association of HER2 status with molecular subclassifications. In addition, the clinical implications of heterogeneity in HER2 scoring and the potential use of new agents such as T-DXd in the HER2-low group are priorities to be investigated.
Conclusions
The research established HER2 status as a significant predictive factor for patients with metastatic gastric cancer. The survival benefits observed in HER2-positive patients receiving trastuzumab-based therapies may suggest that targeted therapies remain crucial in this setting. The survival benefit observed in the HER2-low group may indicate that this patient population needs evaluation for alternative treatment approaches. The results suggest that HER2 status assessment should become a standard practice in clinical settings to guide treatment decisions through molecular classification. The HER2 classification system may serve as a critical element for creating individualized treatment plans.
Footnotes
Acknowledgements
Not applicable
Ethical Considerations
This multicenter retrospective study was approved by the Kartal Dr. Lütfi Kırdar City Hospital Scientific Research Ethics Committee (approval no: 2025/010.99/12/14, date: January 24, 2025). Permissions for data use were obtained under the primary ethical approval covering all participating centers involved in this national multicenter study. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki (1975), as revised in 2024.
Author Contributions
Conceptualization, Sedat Yildirim, Ozkan Alan, Tugba Basoglu and Seval Ay Ersoy; methodology, Sedat Yildirim, Ezgi Turkoglu, Nisanur Sariyar Busery, and Akif Dogan; software, Sedat Yildirim; validation, Sedat Yıldırım; formal analysis, Sedat Yildirim, Ezgi Turkoglu. and Alper Topal; investigation, Sedat Yildirim and Ezgi Turkoglu; resources, Sedat Yildirim, Alper Topal, Tuba Baydas, Ahmet Ziya Bayhan, Mehmet Uzun, Kubra Canaslan, Sinem Akbas, Nadiye Sever, Elif Sahin, Aysel Oguz, Ömer Faruk Elcicek, Fariz Emrah Ozkan, Pervin Can Sanci and Teoman Sakalar; data curation, Sedat Yildirim, Ezgi Turkoglu, Nisanur Sariyar Busery, Akif Dogan, Tuba Baydas, Abdullah Sakin, Ahmet Ziya Bayhan, Mehmet Uzun, Kubra Canaslan, Sinem Akbas, Nadiye Sever, Elif Sahin, Aysel Oguz, Ömer Faruk Elcicek, Fariz Emrah Ozkan, Pervin Can Sanci, Teoman Sakalar, Heves Surmeli and Deniz Isik; writing—original draft preparation, Sedat Yildirim, Ozlem Nuray Sever and Hatice Odabas; writing—review and editing, Sedat Yildirim, Ozlem Nuray Sever, Goncagül Akdag Topal, İlkay Tugba Unek, Hacer Demir, Kazim Uygun, Hatice Odabas, Mehmet Artac, Nedim Turan and Mahmut Gumus; visualization, Sedat Yildirim; supervision, Sedat Yildirim and Seval Ay Ersoy; project administration, Sedat Yildirim and Ozlem Nuray Sever; funding acquisition, none. All authors have read and agreed to the published version of the manuscript.
Funding
The authors received no financial support for the research, authorship and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Data Availability Statement
The data generated or analyzed in this study can be obtained from the corresponding author upon reasonable request.
Informed Consent Statement
Due to the retrospective design of the study and the use of anonymized patient data, the requirement for obtaining informed consent was waived by the Ethics Committee.