Abstract
Background
Gastroenteropancreatic neuroendocrine neoplasms (GEP‐NENs) account for more than 50% of all NENs. The survival of patients with GEP‐NENs has improved based on early diagnosis and improved treatment strategies. The real‐world data of GEP‐NENs in Taiwan are limited. A multicenter registry study was conducted to obtain real‐world data on GEP‐NENs in Taiwan.
Methods
Patients with pathologically diagnosed GEP‐NENs were enrolled. Data were on the baseline characteristics, treatment strategies, and patient survival. Also evaluated was the expression status of six biomarkers, including SSTR2, SSTR5, PDX‐1, CDX‐2, mASH1, and NeuroD, in tumors. Overall survival (OS) was analyzed and plotted via the Kaplan–Meier method. Cox regression analysis was used to analyze the prognostic factors of OS.
Results
A total of 600 GEP‐NEN patients were enrolled. Pancreatic NENs accounted for 43.0% of all patients. The 5‐year and 10‐year OS rates of all patients were 70.9% and 61.3%, respectively. In the multivariable Cox regression analysis, older age (hazard ratio [HR] = 1.02; 95% CI, 1.01–1.03), higher Eastern Cooperative Oncology Group performance status score, higher tumor grade (World Health Organization classification) and stage 4 disease (HR = 6.22; 95% CI, 3.60–10.76) were associated with poor OS. Positive SSTR2 expression (HR = 0.53; 95% CI, 0.31–0.91) was associated with better OS according to multivariate Cox regression analysis.
Conclusions
This study provides real‐world data on 600 GEP‐NENs in Taiwan and identifies age, Eastern Cooperative Oncology Group performance status score, tumor grade, tumor stage, and SSTR2 expression as prognostic factors for the survival of GEP‐NENs.
Keywords: gastroenteropancreas, neuroendocrine neoplasm, prognostic factor, registry study, survival
Short abstract
This study investigated the demography of 600 GEP‐NENs in Taiwan and revealed that age, tumor grade, stage, ECOG PS score, and SSTR2 expression are prognostic factors for OS in GEP‐NEN patients. This study demonstrated improvements in the treatment of GEP‐NENs in Taiwan.
INTRODUCTION
Neuroendocrine neoplasms (NENs) are tumors with neuroendocrine differentiation that may develop throughout the whole body. 1 Gastroenteropancreatic NENs (GEP‐NENs) account for more than 50% of NENs. 2 , 3 , 4 , 5 , 6 , 7 Previous studies have shown that the survival of NENs depends on many factors, such as sex, age, stage, tumor grade, primary site, diagnosis period, and income quintile. 2 , 3 , 5 , 6 Early‐stage NENs can be completely excised via surgery or endoscopy and exhibit a good prognosis. The survival of patients with advanced‐staged NENs varies. Many systemic treatment strategies, such as somatostatin analogs (SSAs), targeted therapies, chemotherapies, and peptide receptor radionuclide therapy, have been shown to improve the survival of patients with advanced NENs in clinical trials. 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 In addition, liver‐directed therapies, such as transarterial embolization (TAE)/transarterial chemoembolization (TACE), transarterial radioembolization, radiofrequency ablation (RFA), and even surgery, have also been shown to be beneficial for some patients with NEN and liver metastases. 16 , 17 We previously reported the incidence and survival of NENs in Taiwan according to the Taiwan Cancer Registry (TCR) database. 5 , 18 However, some data, such as tumor grade, stage, and treatment patterns, are missing from the TCR database. To obtain more comprehensive information on GEP‐NENs in Taiwan, we conducted a multicenter registry study to investigate the baseline characteristics, treatment patterns, and clinical outcomes of GEP‐NENs in Taiwan (Taiwan Cooperative Oncology Group [TCOG] study, T1214). In this study, we also investigated biomarkers via immunohistochemistry to identify potential biomarkers associated with the prognosis of GEP‐NENs.
PATIENTS AND METHODS
Patients, study design, and data collection
This was a longitudinal multicenter registry study (TCOG T1214). Twelve hospitals participated in this study. Pathologically proven patients with GEP‐NEN were included in this study. A goal of 600 patients was planned to be enrolled. The preenrollment data, including the baseline characteristics and prior treatments of the patients, were collected via chart review. We collected the data periodically after patient enrollment and recorded further treatment and survival status. For tumor grading, we used the World Health Organization (WHO) 2010 classification for GEP‐NENs. Tumors with Ki‐67 ≤2% or a mitosis count <2/10 high‐power fields (HPFs), Ki‐67 between 3% and 20% or a mitosis count between 2 and 20/10 HPFs, and Ki‐67 >20% or a mitosis count >20/10 HPFs were classified as neuroendocrine tumor (NET) grade 1 (G1), NET G2, and neuroendocrine carcinoma (NEC) G3, respectively. The tumors mixed with adenocarcinoma and neuroendocrine carcinoma were classified as mixed adenoneuroendocrine carcinoma (MANEC). Immunohistochemical staining for SSTR2, SSTR5, PDX‐1, CDX‐2, mASH1, and NeuroD was performed for patients whose archived tumors were available. The study protocol was reviewed and approved by the institutional review board of each participating hospital. The eligible patients were enrolled from 2014 to 2020. All patients provided signed informed consent. A few patients’ data were unknown, including clinical stage (2.7%), WHO grade (6.0%), and primary site of GEP‐NENs (3.0%). These data were excluded for survival analysis when performing subgroup analysis for these three factors.
Immunohistochemical staining of archived tumor samples
Immunohistochemical staining was performed on sections (4 μm), which were cut from available archived formalin‐fixed paraffin‐embedded tissues. The antibodies used were as follows: CDX‐2 (1:20, clone AMT28, Novocastra Laboratories Ltd., Newcastle, UK), polyclonal Neuro D antibody (1:200; N‐19; Santa Cruz Biotechnology, Santa Cruz, CA, USA), monoclonal mASH1 antibody (1:50; 24B72D11.1; Becton Dickinson Biosciences, Franklin Lakes, NJ, USA), monoclonal PDX‐1 antibody (amino acids 91 to 283) (MAB2419, clone 267712; R&D Systems, Minneapolis, MN, USA), monoclonal SSTR2 antibody (1:50; clone UMB1, Abcam, Cambridge, UK), and monoclonal SSTR5 antibody (1:100; clone UMB4, Abcam). After high‐temperature antigen retrieval, the samples were stained with labeled streptavidin‐biotin‐peroxidase (125°C for 1 minute). A positive result indicates that the biomarkers were detected under the immunohistochemical stain in the tissue sample regardless of the staining intensity and percentages of positive tumor staining.
Statistical analysis
We used SAS statistical software (Version 9.4, SAS Institute Inc., Cary, NC, USA) to perform the statistical analysis in this study. Descriptive analyses were performed for the baseline characteristics of the patients and summarized data, including the number of patients, medians, minimums, and maximums for continuous variables and the frequencies and percentages for categorical variables. We used Fisher’s exact test to compare the differences in baseline characteristics for categorical variables, whereas we used a t test for continuous variables. Overall survival (OS) was defined as the time from the date of diagnosis of GEP‐NENs to the date of patient death due to any cause or to the last date that the patient was known to be alive. We used the Kaplan‒Meier method to estimate the probabilities of OS, including the 5‐ and 10‐year survival rates. We used univariate and multivariate Cox proportional hazards models to evaluate the risk associated with baseline characteristics and biomarkers for OS and calculate hazard ratios (HRs) and 95% CIs. All tests were two‐tailed. A p value < .05 was considered significant.
RESULTS
Baseline characteristics and treatment strategies for GEP‐NENs
A total of 600 patients diagnosed with GEP‐NENs were enrolled in this registry study. The baseline characteristics of these patients, including sex, age, Eastern Cooperative Oncology Group performance status (ECOG PS) scores, clinical stage, WHO tumor grade, primary site, and functioning tumors, are listed in Table 1. Because more of the enrolled patients with NEN had tumors of the pancreas, rectum, or stomach origin in this study, the baseline characteristics of the patients at these three sites are listed in Supplementary Table 1. The treatment methods for the 600 patients included surgery (51.7%), endoscopic ablation (19.3%), SSAs (34.7%), targeted therapies (24.7%), chemotherapies (28.7%), radiation therapy (10.5%), RFA (3.7%), TAE/TACE (9.0%), Yi‐90 radioembolization (2.8%), and immunotherapy (2.0%).
TABLE 1.
Baseline characteristics of patients with GEP‐NET.
| Variables | N (%) | Variables | N (%) |
|---|---|---|---|
| Age, years | N = 600 | Primary location | N = 600 |
| Median (range) | 55.4 years (16.6‐87.9) | Esophagus | 9 (1.5%) |
| Sex | N = 600 | Stomach | 82 (13.7%) |
| Men | 333 (55.5%) | Pancreas | 258 (43.0%) |
| Women | 267 (44.5%) | Small intestine | 37 (6.2%) |
| ECOG PS | N = 600 | Appendix | 14 (2.3%) |
| 0 | 400 (66.7%) | Colon | 30 (5.0%) |
| 1 | 171 (28.5%) | Rectum | 118 (19.7%) |
| 2 | 25 (4.2%) | Liver | 15 (2.5%) |
| 3 | 4 (0.7%) | Ampulla Vater | 10 (1.7%) |
| Clinical stage | N = 600 | Biliary tract | 6 (1.0%) |
| 1 | 247 (41.2%) | Anus | 2 (0.3%) |
| 2 | 80 (13.3%) | Cecum | 1 (0.2%) |
| 3 | 56 (9.3%) | Unknown primary | 18 (3.0%) |
| 4 | 201 (33.3%) | ||
| Unknown | 16 (2.7%) | Functioning tumors | 78 (13.0%) |
| WHO grade | N = 600 | Gastrinoma | 24 (4.0%) |
| 1 | 275 (45.8%) | Insulinoma | 22 (3.7%) |
| 2 | 174 (29.0%) | Glucagonoma | 7 (1.2%) |
| 3 | 103 (17.7%) | VIPoma | 2 (0.3%) |
| MANEC | 12 (2.0%) | Somatostatinoma | 1 (0.2%) |
| Unknown | 36 (6.0%) | Carcinoid syndrome | 22 (3.7%) |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance score; GEP‐NET, gastroenteropancreatic neuroendocrine tumor; MANEC, mixed adeno‐neuroendocrine carcinoma; WHO, World Health Organization.
Biomarker expression in GEP‐NENs
We assessed the expression of biomarkers, including SSTR2, SSTR5, PDX‐1, CDX‐2, mASH1, and NeuroD, in patients with paraffin‐embedded tumor samples. The percentages of positive SSTR2, SSTR5, PDX‐1, CDX‐2, mASH1, and NeuroD staining among GEP‐NEN tumors are shown in Table 2. The percentages of positive biomarkers in G1/G2 and G3 tumors were different (Table 2). Among these biomarkers, the difference in the percentage of SSTR2‐positive expression was more significant between G1/G2 (89.8%) and G3 (51.0%) tumors (p < .001). A greater percentage of patients with G1/G2 tumors had positive SSTR5 (39.8% vs. 21.6%, p = .012) and NeuroD (79.8% vs. 64.6%, p = .025) staining than patients with G3 tumors. In contrast, patients with G1/G2 tumors had a lower percentage of positive mASH1 staining (53.3% vs. 70.8%, p = .028) than patients with G3 tumors. We divided the patients into pancreatic and nonpancreatic NEN groups to analyze whether there was a difference in the expression status of these biomarkers in GEP‐NENs. No significant difference in the percentage of positive staining for each biomarker, except for PDX‐1, was noted between pancreatic and nonpancreatic NENs (Supplementary Table 2). The percentage of positive PDX‐1 staining was greater in pancreatic (67.9%) NENs than in nonpancreatic (57.2%) NENs.
TABLE 2.
The expression status of biomarkers in GEP‐NET tumors.
| Biomarkers | Grade | Positive | Negative | Total case number | p value |
|---|---|---|---|---|---|
| N (%) | N (%) | ||||
| SSTR2 | All | 307 (82.1%) | 67 (17.9%) | 374 | |
| G1/G2 | 272 (89.8%) | 31 (10.2%) | 303 | <.0001 | |
| G3 | 26 (51.0%) | 25 (49.0%) | 51 | ||
| SSTR5 | All | 131 (35.5%) | 238 (64.5%) | 369 | |
| G1/G2 | 119 (39.8%) | 180 (60.2%) | 299 | .0124 | |
| G3 | 11 (21.6%) | 40 (78.4%) | 51 | ||
| PDX‐1 | All | 223 (61.9%) | 137 (38.1%) | 360 | |
| G1/G2 | 176 (60.3%) | 116 (39.7%) | 292 | .2676 | |
| G3 | 34 (69.4%) | 15 (30.6%) | 49 | ||
| CDX‐2 | All | 97 (27.3%) | 258 (72.7%) | 355 | |
| G1/G2 | 70 (24.3%) | 218 (75.7%) | 288 | .0748 | |
| G3 | 18 (37.5%) | 30 (62.5%) | 48 | ||
| mASH1 | All | 191 (54.1%) | 162 (45.9%) | 353 | |
| G1/G2 | 153 (53.3%) | 134 (46.7%) | 287 | .0277 | |
| G3 | 34 (70.8%) | 14 (29.2%) | 48 | ||
| NeuroD | All | 267 (75.6%) | 86 (24.4%) | 353 | |
| G1/G2 | 229 (79.8%) | 58 (20.2%) | 287 | .0248 | |
| G3 | 31 (64.6%) | 17 (35.4%) | 48 |
Abbreviation: GEP‐NET, gastroenteropancreatic neuroendocrine tumor.
Survival of patients with GEP‐NEN
We analyzed the survival of all patients in this study. The 5‐ and 10‐year survival rates of all patients were 70.9% and 61.3%, respectively. OS was analyzed based on sex, age, ECOG PS score, tumor grade, stage, primary site, and the presence of functional syndrome. No difference in survival was noted according to sex or functional syndrome (Supplementary Figure 1). Longer survival was noted in patients of younger ages, lower ECOG PS scores, earlier stages, and lower tumor grades (Figure 1). The survival of patients differs among patients with NENs of different primary sites. Owing to the limited number of cases in some primary sites, we analyzed the survival differences among different primary sites with more than 20 cases, including gastric, duodenal, colonic, rectal, and pancreatic NENs. The best survival was observed in patients with duodenal and rectal NENs, followed by those with gastric, pancreatic, and colonic NENs (Figure 1). Significantly poor survival was noted in patients with ECOG PS scores >1, stage 4 tumors, G3 tumors, and MANEC. The median OS times of patients with ECOG PS scores of 1 and 2, stage 4, and G3 tumors were 82.4 months (95% CI, 47.3–121.5), 29.1 months (95% CI, 9.8–48.1), 36.0 months (95% CI, 29.1–51.0), and 20.2 months (95% CI, 14.5–26.2), respectively. The median OS of patients with other conditions was not achieved or not analyzable. The 5‐ and 10‐year OS rates of the patients in each condition are listed in Supplementary Table 3. The survival curves of patients with pancreatic NENs were also analyzed. Similar to that noted in all patients with NEN, younger age, lower ECOG PS score, lower tumor grade, and earlier stage were associated with better OS in patients with pancreatic NEN (Figure 2). The survival curves of patients with rectal and gastric NENs according to these factors are shown in Supplementary Figures 2 and 3. In addition to the prognostic factors of pancreatic NENs, sex was also a prognostic factor for the OS of patients with rectal and gastric NENs; women exhibited longer survival than men did. The 5‐ and 10‐year survival rates of patients with pancreatic, rectal, and gastric NENs were 71.5%/58.2%, 81.5%/78.8%, and 68.5%/60.4%, respectively. The 5‐ and 10‐year survival rates of these three types of NENs according to sex, age, ECOG PS score, tumor grade, and stage are listed in Table 3.
FIGURE 1.
Overall survival curves of all patients with GEP‐NEN according to (A) age, (B) ECOG PS score, (C) stage, (D) WHO grade, and (E) primary site. ECOG PS indicates Eastern Cooperative Oncology Group performance score; GEP‐NEN, gastroenteropancreatic neuroendocrine neoplasm; WHO, World Health Organization.
FIGURE 2.
Overall survival curves of patients with pancreatic NEN based on (A) age, (B) ECOG PS score, (C) stage, and (D) WHO grade. ECOG PS indicates Eastern Cooperative Oncology Group performance score; NEN, neuroendocrine neoplasm; WHO, World Health Organization.
TABLE 3.
The median OS, 5‐, and 10‐year survival rate of pancreatic, rectal, and gastric NET patients by sex, age, ECOG PS score, WHO grading, and stage.
| Pancreas | Rectum | Stomach | |||||||
|---|---|---|---|---|---|---|---|---|---|
| N | 5‐year | 10‐year | N | 5‐year | 10‐year | N | 5‐year | 10‐year | |
| All | 258 | 71.5% | 58.2% | 118 | 81.5% | 78.8% | 82 | 68.5% | 60.4% |
| Sex | 258 | 118 | 82 | ||||||
| Men | 141 | 71.3% | 59.8% | 69 | 73.3% | 71.4% | 44 | 51.9% | 46.7% |
| Women | 117 | 71.7% | 55.8% | 49 | 93.6% | 89.3% | 38 | 86.8% | 76.4% |
| Age | 258 | 118 | 82 | ||||||
| <60 | 156 | 76.7% | 66.0% | 83 | 87.8% | 86.1% | 48 | 77.6% | 71.7% |
| ≥60 | 102 | 63.4% | 45.1% | 35 | 67.7% | 62.5% | 34 | 55.9% | 44.7% |
| ECOG PS | 258 | 118 | 82 | ||||||
| 0 | 161 | 79.5% | 64.3% | 91 | 92.3% | 90.8% | 59 | 78.5% | 78.5% |
| 1 | 83 | 62.8% | 52.4% | 24 | 52.8% | 45.2% | 21 | 47.1% | 23.6% |
| >1 | 14 | 28.6% | 19.0% | 3 | ‐ | 2 | ‐ | ||
| WHO grade | 238 | 112 | 79 | ||||||
| G1 | 95 | 90.9% | 85.3% | 81 | 92.9% | 92.9% | 43 | 90.6% | 87.4% |
| G2 | 101 | 67.4% | 42.5% | 22 | 57.8% | 46.3% | 15 | 83.6% | ‐ |
| G3 | 40 | 13.9% | 9.3% | 7 | 66.7% | ‐ | 16 | 12.5% | 6.3% |
| MANEC | 2 | ‐ | 2 | ‐ | 5 | ‐ | |||
| Stage | 253 | 116 | 79 | ||||||
| 1 | 88 | 95.2% | 89.9% | 82 | 93.0% | 93.0% | 36 | 97.1% | 88.3% |
| 2 | 42 | 89.7% | 66.2% | 7 | 100% | 83.3% | 13 | 84.6% | 84.6% |
| 3 | 17 | 62.7% | 53.8% | 8 | 85.7% | 85.7% | 7 | 51.4% | 51.4% |
| 4 | 106 | 43.9% | 29.0% | 19 | 26.3% | 19.7% | 23 | 17.4% | 5.8% |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance score; MANEC, mixed adeno‐neuroendocrine carcinoma; NET, neuroendocrine tumor; OS, overall survival; WHO, World Health Organization.
Univariate and multivariate Cox regression analyses of OS in patients with GEP‐NEN
To evaluate the prognostic value of baseline characteristics for the OS of patients with GEP‐NEN, we performed univariate and multivariate Cox regression analyses for OS according to sex, age, ECOG PS score, tumor grade, stage, presence of functional syndrome, and primary site (pancreas vs nonpancreas) (Table 4). In the univariate analysis, older age, higher ECOG PS score (1, >1 vs. 0), higher tumor grade and MANEC (G2, G3, and MANEC vs. G1), and later stage (stage 2, 3, and 4 vs. 1) were prognostic factors associated with poor OS in patients with GEP‐NEN. In the multivariate analysis, the prognostic role of older age, ECOG PS score (1, >1 vs. 0) and tumor grade (G2, G3, and MANEC vs. G1) in OS prediction persisted. Compared with stage 1 disease, only stage 4 disease was significantly associated with poor OS (HR = 6.22; 95% CI, 3.60–10.76; p < .001).
TABLE 4.
Univariate and multivariate Cox regression analysis of OS.
| Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | |
| Sex, referent: men | ||||||
| Women | 0.88 | 0.66‐1.16 | .352 | 1.05 | 0.78‐1.43 | .740 |
| Age | 1.04 | 1.03‐1.05 | <.001 | 1.02 | 1.01‐1.03 | <.001 |
| ECOG PS score, referent: 0 | ||||||
| 1 | 3.07 | 2.29‐4.11 | <.001 | 1.55 | 1.11‐2.15 | .010 |
| >1 | 6.88 | 4.33‐10.94 | <.001 | 2.85 | 1.69‐4.79 | <.001 |
| WHO grade, referent: G1 | ||||||
| G2 | 4.40 | 2.89‐6.70 | <.001 | 2.02 | 1.26‐3.26 | .004 |
| G3 | 18.00 | 11.77‐27.53 | <.001 | 6.65 | 3.97‐11.15 | <.001 |
| MANEC | 9.93 | 4.56‐21.62 | <.001 | 6.02 | 2.56‐14.15 | <.001 |
| Stage, referent: 1 | ||||||
| 2 | 2.64 | 1.40‐4.95 | .003 | 1.59 | 0.80‐3.19 | .189 |
| 3 | 5.24 | 2.84‐9.67 | <.001 | 1.39 | 0.68‐2.83 | .372 |
| 4 | 13.68 | 8.64‐21.66 | <.001 | 6.22 | 3.60‐10.76 | <.001 |
| Functional syndrome, referent: Yes | ||||||
| No | 1.41 | 0.91‐2.16 | .121 | 0.83 | 0.52‐1.31 | .414 |
| Primary site, referent: nonpancreas | ||||||
| Pancreas | 1.07 | 0.81‐1.41 | .641 | 0.95 | 0.70‐1.28 | .720 |
Abbreviations: HR, hazard ratio; OS, overall survival.
The survival analysis of patients with stage 4 pancreatic NEN undergoing primary tumor resection
Because pancreatic NEN was the largest group of patients in this study, we analyzed the treatment strategies for stage 4 patients. The treatment methods for the 106 patients with pancreatic NEN diagnosed as stage 4 disease included surgery (39.6%), SSAs (60.4%), targeted therapies (69.8%), chemotherapies (57.5%), radiation therapy (11.3%), RFA (1.9%), TAE/TACE (18.9%), Yi‐90 radioembolization (9.4%), and immunotherapy (4.7%). Thirty‐two patients underwent primary tumor resection among 42 patients who received surgical treatment. The median OS of the patients who underwent primary tumor resection (not reached) was longer than the patients did not (26.2 months [95% CI, 17.0–35.4]). The HR of undergoing primary tumor resection versus not undergoing primary tumor resection was 0.309 (95% CI, 0.170–0.561) according to univariate Cox regression analysis. The HR remained significantly lower for OS after multivariate analysis adjusted for sex, age, ECOG PS score, tumor grade, and presence of functional syndrome (HR = 0.353; 95% CI, 0.183–0.681; p = .002).
Associations of biomarkers with survival of patients with GEP‐NENs
We analyzed the associations of SSTR2, SSTR5, PDX‐1, CDX‐2, mASH1, and NeuroD expression with the OS of patients. Among the six biomarkers, the SSTR2 (p < .001), PDX‐1 (p = .042), and CDX‐2 (p = .018) expression was associated with the OS of patients with GEP‐NEN (Figure 3A‐C). We further analyzed the associations of OS with SSTR2, PDX‐1, and CDX‐2 according to sex, age, ECOG PS score, stage, tumor grade, presence of functional syndrome, and primary site of NENs. Patients with tumors positive for SSTR2 staining had longer OS than those without positive SSTR2 staining for tumors. Associations were observed in patients of male and female sex, younger and older age, stage 3/4, ECOG PS score 1 through 3, nonpancreatic NENs, and absence of functional syndrome (Supplementary Figure 4). The survival curves of subgroup patients with tumors stained with PDX‐1 and CDX‐2 are shown in Supplementary Figures 5 and 6. The HRs of SSTR2‐positive versus SSTR2‐negative patients, PDX‐1–positive versus PDX‐1–negative patients, and CDX‐2–positive versus CDX‐2–negative patients were 0.37 (95% CI, 0.24–0.55), 1.53 (95% CI, 1.01–2.32), and 1.63 (95% CI, 1.09–2.46), respectively, according to univariate Cox regression analysis. However, only the SSTR2‐positive status remained a significant prognostic factor for OS after multivariate analysis (HR = 0.53; 95% CI, 0.31–0.91; p = .020). The HRs of PDX‐1–positive versus PDX‐1–negative patients and CDX‐2–positive versus CDX‐2–negative patients were 1.49 (95% CI, 0.92–2.42; p = .102) and 1.38 (95% CI, 0.86–2.22; p = .186), respectively.
FIGURE 3.
Overall survival curves of patients with GEP‐NEN stratified based the expression of (A) SSTR2, (B) PDX‐1, and (C) CDX‐2. GEP‐NEN indicates gastroenteropancreatic neuroendocrine neoplasm.
DISCUSSION
This study enrolled 600 GEP‐NEN patients in Taiwan with longitudinal follow‐up. The 5‐ and 10‐year survival rates of all patients were 70.9% and 61.3%, respectively. Older age, a higher ECOG PS score, a higher tumor grade, and stage 4 disease are poor prognostic factors for OS in GEP‐NENs. Positive SSTR2 staining in GEP‐NEN tumors is an independent good prognostic factor for OS.
In our previous nationwide population‐based studies from the TCR database, information on grade and stage was lacking. We added WHO 2010 classification, stage, and the ECOG PS score to analyze the prognostic value of GEP‐NENs in this study. This information makes the analysis more comprehensive. In the present study, some findings from the TCR database were not identified in our previous studies. 5 , 18 First, the proportion of NEN tumor grade at different primary sites is variable. The percentage of higher grade (G2) NET was greater in the pancreas (39.8%) than that in the rectum (18.6%) and stomach (18.1%). Second, the distributions of the stages of NENs at different primary sites also differ. The percentage of higher stage (stage 4) NENs was greater in pancreas (40.6%) than that in rectum (16.1%) and stomach (28.9%). Third, we demonstrated that SSTR2 and SSTR5, which are expressed in NETs, were shown to be expressed in approximately 50% and 20% of G3 GEP‐NENs, respectively. Fourth, our OS analysis demonstrates consistency with Dasari et al’s study that the increased incidence of G1 and localized stages and the development of novel systemic agents for advanced‐stage patients are possible reasons for the improved survival of GEP‐NEN patients. 2 Age, sex, tumor grade, stage, marital status, tumor size, and primary site were reported to be prognostic factors for the OS of GEP‐NENs in the United States according to an analysis of the Surveillance, Epidemiology, and End Results database. 19 The presence of hormonal syndrome was also reported to be a prognostic factor for GEP‐NENs in Spain by analysis of the National Cancer Registry of Spain (RGETNE). 20 In our current study, although women had a lower HR than men did, this difference was not significant according to multivariate analysis, which was probably because of the smaller sample size of our cohort than the sample sizes in the Surveillance, Epidemiology, and End Results and RGET databases. In terms of the primary site, a difference in the OS of patients was not observed when the primary site was classified based on pancreatic or nonpancreatic origin. Moreover, the presence of functional syndrome was not associated with better OS in patients GEP‐NENs in our current study.
Stage 4 is a poor prognostic factor for OS GEP‐NENs. There has been considerable progress in systemic treatment strategies for metastatic GEP‐NETs in recent decades, including SSAs, targeted therapies, peptide receptor radionuclide therapy, and chemotherapies. 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 21 , 22 , 23 , 24 In Taiwan, octreotide LAR and lanreotide have been reimbursed for treatment of GEP‐NETs since 2013 and 2017, respectively. Sunitinib and everolimus have been reimbursed for the treatment of unresectable or metastatic pancreatic NETs since 2012 and 2013, respectively. In addition, everolimus has been reimbursed for the treatment of unresectable or metastatic nonfunctioning gastrointestinal NETs since 2017. The reimbursement of these drugs has enabled more patients with GEP‐NET to receive SSAs and targeted therapies in the past decade. Our study revealed improvements in survival, particularly for patients with pancreatic (5‐year OS rate: 71.4% vs 30.2%) and gastric (5‐year OS rate: 68.9% vs 46.4%) NENs, compared with our previous studies, which reported the survival of patients with NENs diagnosed earlier (1996–2008) in Taiwan. 18 The 5‐year OS rate of patients with stage 4 pancreatic NENs was 43.9% in the current study, which further demonstrates improvements in the treatment of patients with advanced‐stage disease. In addition, our data show that patients with stage 4 pancreatic NEN who underwent primary tumor resection had longer survival than those who did not. The result suggests the benefit of adding surgery to other systemic therapy for patients with stage 4 pancreatic NEN, which is consistent with the improvement in survival for metastatic GEP‐NET patients underwent primary tumor resection reported by Tierney et al. 25 However, patient selection based on various factors, such as low tumor burden, oligometastasis, and good performance status, may be useful for determining whether patients should undergo primary tumor resection.
In the present study, we evaluated the expression of six biomarkers and identified their potential prognostic role in GEP‐NENs. SSTR2 and SSTR5 are expressed in GEP‐NENs, with higher percentages in G1/G2 tumors than in G3 tumors. 26 , 27 , 28 , 29 SSTR2 has been demonstrated to be a good prognostic factor for GEP‐NENs. 27 , 29 , 30 , 31 , 32 However, the use of SSTR5 expression as a prognostic factor for OS in GEP‐NENs is controversial. 29 , 32 Our data revealed that SSTR2 expression is a good prognostic factor for OS in GEP‐NENs, which is consistent with the findings of previous studies. 27 , 29 , 30 , 31 , 32 However, SSTR5 was not associated with the OS of patients with GEP‐NEN in our current study. PDX‐1, CDX‐2, mASH1, and NeuroD are biomarkers reported to be differentially expressed in GEP‐NENs with different primary sites and/or grades. 33 , 34 , 35 , 36 , 37 However, their prognostic role in GEP‐NENs is not well understood, with high NeuroD expression reported to be associated with better OS for 14 poorly differentiated NECs of GEP origin by Shida et al. 35 However, their case number was smaller. In our current study, NeuroD was not a prognostic factor for OS of 353 patients with GEP‐NENs. Consistent with Shida et al.’s report, the percentage of mASH1 expression was greater in high‐grade NECs than in NETs of GEP origin in our current study, although the percentage of mASH1 expression in GEP‐NETs in our cohort (53.3%) was much greater than that in Shida et al.’s cohort (8.3%). 36 Our study provides information on the percentage and prognostic role of these six biomarkers in GEP‐NENs with a larger sample size. In addition to the analysis of biomarkers for NEN tumors, germline mutational testing is important for the diagnosis of some inherited tumor syndromes associated with NEN, such as multiple endocrine neoplasia type 1, von Hippel Lindau syndrome, tuberous sclerosis, and neurofibromatosis 1.38‐41 Although we did not evaluate the germline mutations for our patients in the current study, it is suggested that performing germline testing for patients with clinically suspected inherited tumor syndromes would be helpful not just for diagnosis but also for treatments targeting genetic alterations. 41 , 42
There are several limitations of this study. First, although the participants in this study included gastroenterologists, surgeons, and medical oncologists, not all doctors taking care of patients with GEP‐NEN at each institution were included. Therefore, the distribution of primary sites in our current study is not consistent with that in the TCR database. For this reason, we had more patients with pancreatic NENs than with rectal NENs, although the rectum was the most common site of NENs in Taiwan. However, the percentage of small intestinal NENs was lower in the current study, which was consistent with the findings of our and other previous studies that the incidence of small intestinal NENs were higher in Caucasian but lower in Asian. 5 , 18 , 43 Second, this study is a registry study that enrolled patients with GEP‐NEN retrospectively and prospectively. Because the enrolled patients had to provide informed consent, dead patients were not included in this study. Therefore, it is possible that the longer OS was for this reason because the patients who died were expected to have a shorter survival time. However, we amended the protocol to include patients with GEP‐NEN diagnosed after 2011 to avoid this bias for survival analysis. Third, there were some differences between WHO 2010 and 2022 classifications, particularly for the G3 NENs. The tumors with Ki‐67 >20% were classified as G3 NEC according to WHO 2010, whereas these tumors were classified into G3 NET or NEC by morphology or molecular markers according to WHO 2022. 44 , 45 The treatment strategy and survival of G3 NET and NEC may differ. 46 According to the NORDIC 2 study, the median progression‐free survival (PFS; 7.4 vs 3.4 months, p ≤ .001) and OS (21.8 vs 7.4 months, p ≤ .001) were significantly longer for 427 G3 NET than 117 NEC patients with advanced disease. 46 For G3 NET patients with Ki‐67 <55%, first‐line platinum‐based chemotherapy (PFS = 3.5 months; OS = 14.3 months) yielded a much worse outcome than first‐line temozolomide‐based treatment (PFS = 10.4 months; OS = 22.5 months). 46 The results suggest the guidance for selection of chemotherapy regimen for patients with NEC and G3 NET. Because our current study started in 2014 and all the enrolled patients were diagnosed before 2020, we used WHO 2010 but not 2022 classification for grading of the tumors. The median OS of our G3 NEN patients with stage 4 disease, including G3 NET and NEC by WHO 2022, was 14.0 (95% CI, 10.1–17.9) months (data not shown). The survival was between 7.4 and 21.8 months for NEC and G3 NET, respectively, in the NORDIC 2 study.
CONCLUSIONS
Our study investigated the demography of 600 GEP‐NENs in Taiwan and revealed that age, tumor grade, stage, ECOG PS score, and SSTR2 expression are prognostic factors for OS in patients with GEP‐NEN. This study demonstrated improvements in the treatment of GEP‐NENs in Taiwan.
AUTHOR CONTRIBUTIONS
Hui‐Jen Tsai: Writing—original draft, writing—review and editing, project administration, resources, data curation, software, formal analysis, methodology, validation, visualization, investigation and conceptualization. Ming‐Huang Chen: Writing—review and editing, visualization and resources. Hsiu‐Po Wang: Writing—review and editing, visualization and resources. Chin‐Fu Hsiao: Investigation, writing—original draft, writing—review and editing, visualization, validation, methodology, software, formal analysis and data curation. Yen‐Yang Chen: Writing—review and editing, visualization and resources. Jen‐Shi Chen: Writing—review and editing, visualization and resources. Mei‐Due Yang: Writing—review and editing, visualization and resources. Chin‐Yuan Tzen: Methodology, writing—review and editing, writing—original draft and visualization. Yan‐Shen Shan: Writing—review and editing, visualization and resources. Li‐Yaun Bai: Writing—review and editing, visualization and resources. De‐Chuan Chan: Writing—review and editing, visualization and resources. Pei‐Yi Chu: Writing—original draft, visualization, writing—review and editing and methodology. Ching‐Liang Ho: Visualization, writing—review and editing and resources. Youngsen Yang: Visualization, writing—review and editing and resources. Johnson Lin: Writing ‐ review and editing, visualization and resources. Hsuan‐Yu Lin: Visualization, writing—review and editing, resources. Cheng‐Shyong Chang: Visualization, writing—review and editing, resources. Chuan‐Cheng Wang: Writing—review and editing, visualization and resources. Tsann‐Long Hwang: Conceptualization, visualization, writing—review and editing, resources, supervision and investigation. Li‐Tzong Chen: Conceptualization, investigation, writing—review and editing, visualization, resources, supervision and funding acquisition.
CONFLICT OF INTEREST STATEMENT
Dr. Li‐Tzong Chen has received research funding from Novartis to the National Health Research Institutes. All the other authors declare that they have no financial conflicts of interest.
CLINICAL TRIAL REGISTRATION
This study was registered at Clinical Trials.gov, NCT02102893.
PATIENT CONSENT STATEMENT
All patients provided signed informed consent.
Supporting information
Supplementary Material
Figure S1
Figure S2
Figure S3
Figure S4
Figure S5
Figure S6
Table S1
Table S2
Table S3
ACKNOWLEDGMENTS
This study was sponsored by Taiwan Cooperative Oncology Group and partially funded by Novartis.
We thank the Taiwan Cooperative Oncology Group for their support of this study (TCOG T1214 study).
Tsai H‐J, Chen M‐H, Wang H‐P, et al. Clinical outcomes of gastroenteropancreatic neuroendocrine neoplasms in Taiwan: A multicenter registry study—TCOG T1214 study. Cancer. 2025;e70019. doi: 10.1002/cncr.70019
Contributor Information
Tsann‐Long Hwang, Email: hwangtl@cgmh.org.tw.
Li‐Tzong Chen, Email: leochen@nhri.org.tw.
DATA AVAILABILITY STATEMENT
All the data generated or analyzed during the current study are included in this published article and its supplementary information files.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material
Figure S1
Figure S2
Figure S3
Figure S4
Figure S5
Figure S6
Table S1
Table S2
Table S3
Data Availability Statement
All the data generated or analyzed during the current study are included in this published article and its supplementary information files.