Abstract
Background: Immunotherapy-based regimens are standard first-line treatment for advanced gastroesophageal junction or gastric cancer (GEJ/GC), but their efficacy in alpha-fetoprotein-producing gastric cancer (AFPGC) remains unclear. We investigated the positivity of AFP influenced immunotherapy outcomes in advanced GEJ/GC, and examined whether this role is influenced by the patient’s HER2 status. Secondly, we aim to assess the efficacy of anti-angiogenic agents within advanced AFP-positive GEJ/GC (AFP-GEJ/GC). Methods: This retrospective study analyzed patients with advanced GEJ/GC receiving first-line immunotherapy, stratified by HER2 status. AFP-positive GEJ/GC was defined as a pretreatment serum AFP level ≥ 20 ng/mL or positive immunohistochemistry. Results: In the overall population, the AFP-GEJ/GC group (n = 79) showed similar median progression-free survival (mPFS; 7.30 vs. 8.53 months; P = 0.42) and median overall survival (mOS; 21.80 vs. 19.70 months; P = 0.38) compared with the AFP-negative group (n = 478). In the HER2-negative cohort, 246 patients receiving standard two-drug chemotherapy combined with PD-1 inhibitors, the AFP-GEJ/GC group (n = 16) exhibited shorter mPFS (5.40 vs. 7.0 months; P = 0.02) and numerically worse mOS (11.40 vs. 16.80 months; P = 0.24) compared with the AFP-negative group (n = 230), despite similar objective response rates (ORRs 50.0% vs. 45.2%; P = 0.80) and disease control rates (DCRs 93.8% vs. 90.4%; P > 0.99). In the HER2-positive cohort, 107 patients receiving standard chemotherapy-based regimens, AFP-GEJ/GC (n = 14) showed numerically shorter mPFS (7.67 vs. 12.20 months; P = 0.60) but similar mOS (32.40 vs. 28.30 months; P = 0.38) versus AFP-negative group (n = 93). Notably, anti-angiogenic combination therapy did not statistically improve mPFS and mOS in AFP-GEJ/GC (n = 79). However, in the HER2-negative AFP-GEJ/GC group (n = 47), anti-angiogenic combination therapy (n = 31) was associated with a modestly longer mPFS (6.33 vs. 5.40 months; P = 0.02) and a numerical improved mOS (15.70 vs. 11.40 months; P = 0.15) compared with chemo-immunotherapy (n = 16). Conclusion: AFP positivity may indicate inferior efficacy of first-line chemo-immunotherapy in HER2-negative advanced GEJ/GC, and anti-angiogenic therapy warrants further evaluation as a potential strategy to improve outcomes.
Keywords: Alpha-fetoprotein, immune checkpoint inhibitors, anti-angiogenic inhibitors, gastric cancer
Introduction
Alpha-fetoprotein-producing gastric cancer (AFPGC) is a distinct and clinically aggressive subtype of gastric cancer, with a higher prevalence reported in Asian populations. The reported incidence varies widely, ranging from 0.39% to 15% of all gastric cancers globally [1-3] and is estimated between 2.5% and 6.9% specifically in China [4-6]. A key challenge in the clinical management and investigation of AFPGC is the absence of a universally accepted diagnostic definition. Reported studies have adopted varied criteria, including different serum AFP cutoff values (e.g., 0, 20, or 40 ng/ml) or the use of immunohistochemistry (IHC) staining to define positivity [1-3]. Despite these inconsistencies, aberrant expression of AFP-an oncofetal glycoprotein normally restricted to fetal development-has been suggested to reflect aggressive tumor biology [7,8]. Elevated serum AFP levels have been strongly associated with an increased risk of liver and lymph node metastasis as well as vascular invasion, thereby indicating an unfavorable prognosis.
Clinically, AFPGC demonstrates a marked male predominance (approximately 2:1), with a median age at diagnosis of around 60 years. These tumors most commonly originate in the gastric antrum or body and, on gross examination, frequently present as Bormann type III lesions characterized by ulceration and a tendency to bleed. Histologically, AFPGC represents a heterogeneous entity comprising three major subtypes [8]. The predominant subtype is hepatoid adenocarcinoma of the stomach (HAS), which morphologically resembles hepatocellular carcinoma and accounts for the majority of cases (55.6%-77.8%). Less common variants include tumors with yolk sac differentiation (4.4%-11.1%) and the embryonic gastrointestinal type, thought to arise from intestinal metaplasia (11.1%-26.7%). AFP overexpression has been associated with poor prognosis, with 5-year survival rates often reported below 20% [3,9]. One study observed a marked decline in 3-year OS from 54.3% in patients with serum AFP < 20 ng/mL to 7.7% in those with levels > 300 ng/mL [10]. In additional, evidence suggests that AFPGC may exhibit reduced sensitivity to chemotherapy, with patients showing lower objective response rates (ORR) to standard regimens compared with conventional gastric adenocarcinoma [11].
The therapeutic landscape of advanced gastric cancer is increasingly defined by molecular subtyping, reflecting a paradigm shift driven by advances in next-generation sequencing (NGS) and other profiling technologies [12,13]. Central to this stratified approach is the status of human epidermal growth factor receptor 2 (HER2), a proto-oncogene on chromosome 17 that encodes a receptor tyrosine kinase critical for regulating cell proliferation and survival [14-16]. HER2 overexpression or amplification, observed in approximately 20% of advanced gastroesophageal junction/gastric cancers (GEJ/GC), delineates a distinct therapeutic subgroup [17]. For patients with HER2-positive disease, the current first-line standard of care-particularly in those with programmed death-ligand 1 (PD-L1) expression (Combined Positive Score [CPS] ≥ 1)- is a combination of chemotherapy, trastuzumab, and an immune checkpoint inhibitor such as pembrolizumab, as established by landmark trials [18]. For most patients with HER2-negative disease, immunotherapy has also become an integral component of first-line treatment. A series of pivotal Phase 3 trials [19], including CheckMate-649 [20], ORIENT-16 [21], RATIONALE-305 [22], KEYNOTE-859 [23], and GEMSTONE-303 [24], have consistently demonstrated a survival benefit with the addition of an anti-PD-1/L1 antibody to standard chemotherapy. The therapeutic landscape is further expanding with the development of bispecific antibodies, such as the programmed death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor cadonilimab [25] and PD-L1/TGF-β (transforming growth factor-β) inhibitor SHR-1701 [26], both of which have demonstrated promising efficacy in this setting.
Although immunotherapy-based regimens have become the standard first-line treatment for advanced gastric cancer, their role and efficacy in the aggressive AFPGC subtype are not yet well established. Notably, studies have reported a higher rate of HER2 positivity rate in AFPGC (approximately 20%) compared with conventional gastric cancer [11,27,28], with some NGS-based analyses indicating rates as high as 37.5% [29]. However, it remains unclear whether elevated serum AFP similarly confers resistance in HER2-positive patients receiving immunotherapy-based regimens. This highlights the need to analyze HER2-positve and HER2-negative AFPGC separately, as their biological characteristics and treatment responses may differ. In particular, these tumors are characterized by a pro-angiogenic microenvironment driven by the activation of the vascular endothelial growth factor (VEGF) signaling pathway, providing a strong biological rationale for the incorporation of anti-angiogenic agents [30-36].
Therefore, this study was designed to explore two key questions. First, we investigated the potential predictive and prognostic significance of AFP in patients with advanced GEJ/GC receiving first-line immunotherapy-based regimens, with consideration of HER2 status. Second, we examined the role of anti-angiogenic combination strategies in AFP-positive GEJ/GC (AFP-GEJ/GC).
Materials and methods
Patients
Clinical data of patients with advanced GEJ/GC who received first-line immunotherapy at Peking University Cancer Hospital from January 1, 2009, to October 30, 2024 were retrospectively collected. The clinical data included sex, age, time of diagnosis, tumor location, pathological type, degree of differentiation, Lauren classification, HER2 status, baseline serum AFP level, PD-L1 CPS, liver metastasis, metastatic site, portal vein tumor thrombus, history of gastrectomy, Eastern Cooperative Oncology Group (ECOG) performance status and treatment regimens. HER2-positivity was defined as immunohistochemistry (IHC) 3+ or IHC 2+ combined with fluorescence in situ hybridization (FISH) positivity or NGS showing HER2 amplification in primary or metastatic lesions. AFP-GEJ/GC was defined as GEJ/GC patients with serum AFP level ≥ 20 ng/mL (radioimmunoassay, normal range: < 7 ng/mL) or AFP-positive IHC staining (primary antibodies against AFP, rabbit polyclonal, Zhongshanjinqiao Technologies, Beijing, China). The inclusion criteria were (1) a diagnosis of advanced GEJ/GC according to AJCC/UICC 8th edition; (2) at least 2 cycles of combined immunotherapy administered at our hospital. Exclusion criteria were: (1) presence of other malignancies; (2) history of hepatitis; (3) incomplete survival information. In addition, if patients presented with liver metastases, we differentiated these from hepatocellular carcinoma based on radiological characteristics to ensure that all patients ultimately included in the study had AFP-GEJ/GC. A total of 79 advanced AFP-GEJ/GC cases were identified, primarily through serology (n = 77) with a small number diagnosed by histology (n = 2).
Efficacy evaluation
All patients were followed from the first day of hospitalization. Laboratory tests were conducted every 1 to 2 weeks, and imaging assessments - including contrast-enhanced computed tomography and magnetic resonance imaging-were performed every 6 weeks. Treatment efficacy was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST1.1) [37] and was recorded as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). ORR was defined as the proportion of patients who achieved CR or PR as the best response to treatment among all evaluable cases. The disease control rate (DCR) was defined as the proportion of patients who achieved CR, PR, or SD as the best response to treatment among all evaluable cases. Progression-free survival (PFS) was defined as the time from the first dose of first-line treatment until PD or death. Overall survival (OS) was defined as the time from the first dose of first-line treatment until death or the date the patient was last known to be alive.
Statistical analysis
All statistical analyses were performed using SPSS 26.0 (IBM Corp. Armonk, NY, USA) and R version 4.2.2 (R Foundation for Statistical Computing). Descriptive statistics were used to summarize patient characteristics. Continuous variables were expressed as mean ± standard deviation or median (interquartile range, IQR), as appropriate for their distribution. Categorical variables were presented as frequency and percentage. Group comparisons were performed using Pearson’s chi-square test (for expected frequencies ≥ 5) or Fisher’s exact test (for expected frequencies < 5). Survival outcomes were analyzed using Kaplan-Meier curves with log-rank tests for between-group comparisons. The Cox proportional hazards model was employed to evaluate the associations between covariates and survival outcomes, with results expressed as hazard ratios (HRs) and corresponding 95% CI. All variables first underwent univariate Cox regression screening; those demonstrating a significance level of P < 0.1 were subsequently incorporated into multivariate Cox regression analyses to determine independent prognostic factors for both PFS and OS. Statistical significance was defined as a two-sided P value < 0.05.
Results
Between January 1, 2009, and October 30, 2024, 716 patients were assessed for eligibility. Of these, 29 patients had other malignancies, 35 patients had missing response information, and 95 patients were enrolled in double-blind clinical trials. Therefore, all these patients were excluded. The final cohort included 402 patients who were HER2-negative and 155 patients who were HER2-positive. Among them, we selected 246 HER2-negative patients receiving standard two-drug chemotherapy (SOX, XELOX and FOLFOX) combined with PD-1 inhibitors, and 107 HER2-positive patients receiving standard chemotherapy (SOX, XELOX and FOLFOX)-based regimens for efficacy and prognostic analysis. These patients were further stratified into AFP-positive group (serum AFP ≥ 20 ng/mL or positive AFP IHC) and AFP-negative group. Figure 1 illustrates the complete patient screening flowchart.
Figure 1.
Flowchart of the study process. Abbreviations: RCT, randomized controlled trial; HER2, human epidermal growth factor receptor-2; PD-L1, Programmed death-ligand 1; FOLFOX, Calcium folinate, Fluorouracil and Oxaliplatin; SOX, S-1 and Oxaliplatin; XELOX, Capecitabine and Oxaliplatin; PD-1, Programmed cell death protein 1; AFP, alpha-fetoprotein.
Patient characteristics
A total of 557 patients with advanced GEJ/GC (median age: 61.0 years; 68.8% male) who received first-line immunotherapy regimens were enrolled in this study. The AFP positive rates were similar between the HER2-negative and HER2-positive groups (14.18% and 14.19%, respectively).
Baseline characteristics are detailed in Tables 1 and 2. In HER2-negative cohort, AFP-GEJ/GC patients had higher percentage of intestinal adenocarcinoma according to the Lauren classification (52.6% vs. 34.2%; P = 0.013). Patients with AFP-GEJ/GC (n = 57) displayed significantly elevated rates of liver metastasis (70.2% vs. 31.6%; P < 0.001) and PVTT (19.3% vs. 3.5%; P < 0.001) compared with those of patients with AFP-negative (n = 345). In HER2-positive cohort, patients with AFP-GEJ/GC (n = 22) displayed significantly elevated rates of liver metastasis (77.3% vs. 54.1%; P < 0.001). Compared to HER2-negative GEJ/GC patients, HER2-positive patients demonstrated higher proportions of intestinal adenocarcinoma according to the Lauren classification (67.1% vs. 36.8%), well-differentiated tumors (73.5% vs. 38.3%), and liver metastasis (57.4% vs. 37.1%). The median serum AFP levels in AFP-GEJ/GC patients were 345.0 ng/mL in HER2-positive cases and 916.1 ng/mL in HER2-negative cases.
Table 1.
Baseline characteristics of 402 HER2-negative patients with advanced GEJ/GC receiving combined immunotherapy
| Characteristic | Category | Total (n = 402) | AFP-negative (n = 345) | AFP-positive (n = 57) | p-value |
|---|---|---|---|---|---|
| Sex, n (%) | Female | 133 (33.1%) | 118 (34.2%) | 15 (26.3%) | 0.241 |
| Male | 269 (66.9%) | 227 (65.8%) | 42 (73.7%) | ||
| Age (years) | Mean [SD] | 58.1 (12.4) | 58.1 (12.6) | 58.3 (11.3) | 0.876 |
| < 65 | 256 (63.7%) | 218 (63.2%) | 38 (66.7%) | 0.658 | |
| ≥ 65 | 146 (36.3%) | 127 (36.8%) | 19 (33.3%) | ||
| Primary site, n (%) | GC | 278 (69.0%) | 236 (68.0%) | 42 (74.0%) | 0.424 |
| GEJ | 124 (31.0%) | 109 (32.0%) | 15 (26.0%) | ||
| Gastrectomy, n (%) | Yes | 45 (11.2%) | 36 (10.4%) | 9 (15.8%) | 0.256 |
| No | 357 (88.8%) | 309 (89.6%) | 48 (84.2%) | ||
| ECOG, n (%) | 0 | 193 (48.0%) | 167 (48.4%) | 26 (45.6%) | 0.669 |
| 1 | 204 (50.8%) | 174 (50.4%) | 30 (52.6%) | ||
| 2 | 5 (1.2%) | 4 (1.2%) | 1 (1.8%) | ||
| HER2 status, n (%) | IHC 0 | 205 (51.0%) | 173 (50.2%) | 32 (56.1%) | 0.700 |
| IHC 1+ | 156 (38.8%) | 136 (39.4%) | 20 (35.1%) | ||
| IHC 2+FISH- | 41 (10.2%) | 36 (10.4%) | 5 (8.8%) | ||
| MMR, n (%) | pMMR | 391 (97.3%) | 336 (97.4%) | 55 (96.5%) | > 0.999 |
| dMMR | 5 (1.2%) | 5 (1.4%) | 0 (0.0%) | ||
| Unknown | 6 (1.5%) | 4 (1.2%) | 2 (3.5%) | ||
| PD-L1 CPS, n (%) | < 1 | 102 (25.4%) | 85 (24.6%) | 17 (29.8%) | 0.242 |
| ≥ 1 | 279 (69.4%) | 247 (71.6%) | 32 (56.2%) | ||
| < 5 | 180 (44.8%) | 154 (44.6%) | 26 (45.6%) | 0.471 | |
| ≥ 5 | 201 (50.0%) | 178 (51.6%) | 23 (40.4%) | ||
| < 10 | 261 (64.9%) | 224 (64.9%) | 37 (64.9%) | 0.334 | |
| ≥ 10 | 120 (29.9%) | 108 (31.3%) | 12 (21.1%) | ||
| Unknown | 21 (5.2%) | 13 (3.8%) | 8 (14.0%) | ||
| Lauren type, n (%) | Intestinal | 148 (36.8%) | 118 (34.2%) | 30 (52.6%) | 0.013 |
| Non-intestinal | 236 (58.7%) | 211 (61.2%) | 25 (43.9%) | ||
| Unknown | 18 (4.5%) | 16 (4.6%) | 2 (3.5%) | ||
| Differentiation, n (%) | Poorly | 239 (59.5%) | 207 (60.0%) | 32 (56.1%) | 0.525 |
| Well | 154 (38.3%) | 129 (37.4%) | 25 (43.9%) | ||
| Unknown | 9 (2.2%) | 9 (2.6%) | 0 (0.0%) | ||
| Liver metastasis, n (%) | Present | 149 (37.1%) | 109 (31.6%) | 40 (70.2%) | < 0.001 |
| Absent | 253 (62.9%) | 236 (68.4%) | 17 (29.8%) | ||
| PVTT, n (%) | Present | 23 (5.7%) | 12 (3.5%) | 11 (19.3%) | < 0.001 |
| Absent | 379 (94.3%) | 333 (96.5%) | 46 (80.7%) | ||
| Number of metastatic sites, n (%) | 1 | 122 (30.3%) | 109 (31.6%) | 13 (22.8%) | 0.236 |
| ≥ 2 | 280 (69.7%) | 236 (68.4%) | 44 (77.2%) | ||
| Serum AFP (ng/mL) | Median [IQR] | 916.1 (251.0, 3013.0) |
Abbreviations: AFP, alpha-fetoprotein; IQR, interquartile range; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry; FISH, Fluorescence in situ hybridization; dMMR, mismatch repair deficiency; pMMR, proficient mismatch repair; PD-L1, Programmed death-ligand 1; CPS, combined positive score; GC, gastric cancer; GEJ, gastroesophageal junction; PVTT, portal vein tumor thrombus.
Table 2.
Baseline characteristics of 155 HER2-positive patients with advanced GEJ/GC receiving combined immunotherapy
| Characteristic | Category | Total (n = 155) | AFP-negative (n = 133) | AFP-positive (n = 22) | p-value |
|---|---|---|---|---|---|
| Sex, n (%) | Female | 41 (26.5%) | 36 (27.1%) | 5 (22.7%) | 0.868 |
| Male | 114 (73.5%) | 97 (72.9%) | 17 (77.3%) | ||
| Age (years) | Mean [SD] | 62.8 (11.6) | 63.0 (11.5) | 62.2 (12.8) | 0.494 |
| < 65 | 74 (47.7%) | 62 (26.6%) | 12 (54.6%) | 0.646 | |
| ≥ 65 | 81 (52.3%) | 71 (53.4%) | 10 (45.4%) | ||
| Primary site, n (%) | GC | 98 (63.2%) | 83 (62.4%) | 15 (68.2%) | 0.778 |
| GEJ | 57 (36.8%) | 50 (37.6%) | 7 (31.8%) | ||
| Gastrectomy, n (%) | Yes | 38 (24.5%) | 35 (26.3%) | 3 (13.6%) | 0.311 |
| No | 117 (75.5%) | 98 (73.7%) | 19 (86.7%) | ||
| ECOG, n (%) | 0 | 82 (52.9%) | 68 (51.1%) | 14 (63.6%) | 0.599 |
| 1 | 70 (45.2%) | 62 (46.6%) | 8 (36.4%) | ||
| 2 | 3 (1.9%) | 3 (2.3%) | 0 (0.0%) | ||
| HER2 status, n (%) | 2+/FISH+ | 27 (17.4%) | 20 (15.0%) | 7 (31.8%) | 0.069 |
| 3+ | 128 (82.6%) | 113 (85.0%) | 15 (68.2%) | ||
| MMR, n (%) | pMMR | 147 (94.8%) | 126 (94.7%) | 21 (95.5%) | |
| dMMR | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| Unknown | 8 (5.2%) | 7 (5.3%) | 1 (4.5%) | ||
| PD-L1 CPS, n (%) | < 1 | 36 (23.2%) | 29 (21.8%) | 7 (31.8%) | 0.457 |
| ≥ 1 | 92 (59.4%) | 79 (59.4%) | 13 (59.1%) | ||
| < 5 | 70 (45.2%) | 59 (44.4%) | 11 (50.0%) | 0.976 | |
| ≥ 5 | 58 (37.4%) | 49 (36.8%) | 9 (10.9%) | ||
| < 10 | 97 (62.6%) | 84 (63.2%) | 13 (59.1%) | 0.258 | |
| ≥ 10 | 31 (20.0%) | 24 (18.0%) | 7 (31.8%) | ||
| Unknown | 27 (17.4%) | 25 (18.8%) | 2 (9.1%) | ||
| Lauren type, n (%) | Intestinal | 104 (67.1%) | 92 (69.2%) | 12 (54.5%) | 0.566 |
| Non-intestinal | 37 (23.9%) | 31 (23.3%) | 6 (27.3%) | ||
| Unknown | 14 (9.0%) | 10 (7.5%) | 4 (18.2%) | ||
| Differentiation, n (%) | Poorly | 38 (24.5%) | 34 (25.6%) | 4 (18.2%) | 0.579 |
| Well | 114 (73.5%) | 98 (73.7%) | 16 (72.7%) | ||
| Unknown | 3 (2.0%) | 1 (0.7%) | 2 (9.1%) | ||
| Liver metastasis, n (%) | Present | 89 (57.4%) | 72 (54.1%) | 17 (77.3%) | < 0.001 |
| Absent | 66 (42.6%) | 61 (45.9%) | 5 (22.7%) | ||
| PVTT, n (%) | Present | 16 (10.3%) | 12 (9.0%) | 4 (18.2%) | 0.248 |
| Absent | 139 (89.7%) | 121 (91.0%) | 18 (81.8%) | ||
| Number of metastatic sites, n (%) | 1 | 37 (23.9%) | 34 (25.6%) | 3 (13.6%) | 0.344 |
| ≥ 2 | 118 (76.1%) | 99 (74.4%) | 19 (86.4%) | ||
| Serum AFP (ng/mL) | Median [IQR] | 345.0 (47.0, 1163.0) |
Comparison of the first-line regimens
As shown in Table 3, treatment regimens (chemotherapy, immunotherapy, and anti-HER2 therapy) were balanced between patients with AFP-negative GEJ/GC and AFP-GEJ/GC. Within the HER2-negative cohort (n = 402), the distribution of systemic treatments was comparable between the AFP-negative and AFP-positive subgroups, with most of patients (90.4% and 96.5%) received standard platin-containing two drug regimens, including SOX, XELOX, and FOLFOX. Regarding immunotherapy, 91.9% and 96.5% of patients received PD-1/PD-L1 inhibitors, respectively. For HER2-positive patients (n = 155), 133 patients were AFP-negative, and 22 patients had AFP-GEJ/GC. All patients received first-line anti-HER2 therapy. Since a considerable proportion participated in clinical trials of investigational drugs, the proportion who received standard platin-containing two drug regimens in this study was only 69.6% and 63.6%, respectively. Meanwhile, only 87.2% and 77.3% of patients received a PD-1 inhibitor as their immunotherapy. In terms of anti-angiogenic therapy, the proportions of anti-angiogenic drug administration of the first-line treatments were 61.4% and 3.8% in the AFP-GEJ/GC and AFP-negative GEJ/GC subgroups, respectively (P < 0.001). In the overall cohort, among the 48 patients who received anti-angiogenic therapy, 44 were treated with apatinib, 2 with lenvatinib, 1 with fruquintinib, and 1 with anlotinib.
Table 3.
First-line treatment regimens of 155 patients who were HER2-positive and 402 patients who were HER2-negative
| HER2-positive patients (n = 155) | |||
|
| |||
| Regimen | AFP-negative | AFP-positive | p-value |
|
| |||
| Chemotherapy | 133 | 22 | 0.672 |
| No chemotherapy (%) | 39 (29.3%) | 8 (36.4%) | |
| XELOX/SOX/FOLFOX (%) | 93 (69.9%) | 14 (63.6%) | |
| AOS (%) | 1 (0.8%) | 0 (0.0%) | |
| Immunotherapy | 0.390 | ||
| PD-1 inhibitors (%) | 116 (87.2%) | 17 (77.3%) | |
| PD-1/LAG-3 inhibitors (%) | 2 (1.5%) | 0 (0.0%) | |
| PD-1/CTLA4 inhibitors (%) | 15 (11.3%) | 5 (22.7%) | |
| Anti-HER2 therapy | 0.117 | ||
| HER2 monoclonal antibody (%) | 102 (76.7%) | 16(72.7%) | |
| HER2 bispecific antibody (%) | 18 (13.5%) | 6(27.3%) | |
| HER2-ADC (%) | 13 (9.8%) | 0 (0.0%) | |
|
| |||
| HER2-negative patients (n = 402) | |||
|
| |||
| Regimen | AFP-negative | AFP-positive | p-value |
|
| |||
| Chemotherapy | 345 | 57 | 0.374 |
| Monotherapy (%) | 8 (2.3%) | 0 (0.0%) | |
| XELOX/SOX/FOLFOX (%) | 312 (90.4%) | 55 (96.5%) | |
| Taxane-containing dual drug regimens (%) | 11 (3.2%) | 2 (3.5%) | |
| AOS/POS (%) | 14 (4.1%) | 0 (0.0%) | |
| Immunotherapy | 0.101 | ||
| PD-1/PD-L1 inhibitors (%) | 317 (91.9%) | 55 (96.5%) | |
| PD-1/PD-L1+TIGIT inhibitor (%) | 18 (5.2%) | 0 (0.0%) | |
| PD-1+CTLA-4 inhibitor (%) | 9 (2.6%) | 1 (1.8%) | |
| PD-L1+TGF-β inhibitor (%) | 1 (0.3%) | 1 (1.8%) | |
| Anti-angiogenic therapy | < 0.001 | ||
| Combined (%) | 13 (3.8%) | 35 (61.4%) | |
| Not combined (%) | 332 (96.2%) | 22 (38.6%) | |
Abbreviations: SOX, S-1 and Oxaliplatin; XELOX, Capecitabine and Oxaliplatin; FOLFOX, Calcium folinate, Fluorouracil and Oxaliplatin; AOS, Nab-paclitaxel, Oxaliplatin and S-1; POS, Paclitaxel, Oxaliplatin and S-1; PD-1, Programmed death protein 1; PD-L1, Programmed death-ligand 1; LAG3, Lymphocyte activation gene-3; CTLA-4, Cytotoxic T lymphocyte-associated antigen 4; HER2, Human epidermal growth factor receptor-2; ADC, antibody-drug conjugate; TIGIT, T cell immunoglobulin and ITIM domain; TGF-β, Transforming growth factor beta.
Therapeutic efficacy
The median follow-up duration was 19.97 months (range: 11.50-37.43 months). In the overall population, the AFP-GEJ/GC group (n = 79) showed similar median progression-free survival (mPFS; 7.30 vs. 8.53 months; P = 0.42; Figure 2A) compared with the AFP-negative group (n = 478). In HER2-negative cohort, patients who were HER2-negative and received standard chemotherapy plus PD-1 inhibitors (n = 246, 16 AFP-GEJ/GC cases and 230 AFP-negative cases) were analyzed. Patients with AFP-GEJ/GC exhibited significantly shorter mPFS compared with that of AFP-negative patients (5.40 vs. 7.00 months; P = 0.02; Figure 2C), despite similar ORRs (50.0% vs. 45.2%, P = 0.798; Table 4) and DCRs (93.8% vs. 90.4%; P > 0.999; Table 4). Further analysis of the AFP ≥ 100 ng/mL (5.23 vs. 7.04 months; P < 0.01; Supplementary Figure 1A) and ≥ 400 ng/mL (5.20 vs. 7.01 months; P = 0.05; Supplementary Figure 1B) subgroups revealed a similar trend. Notably, AFP-GEJ/GC showed numerically shortened mPFS trend in PD-L1 CPS<5 subgroup (5.40 vs. 6.57 months; P = 0.18, Supplementary Figure 2A) and in PD-L1 CPS ≥ 5 subgroup ( 5.80 vs. 7.23 months; P = 0.29; Supplementary Figure 2B).
Figure 2.
Kaplan-Meier curves of PFS and OS in advanced GEJ/GC. (A and B): Kaplan-Meier curve of the PFS (A) and OS (B) of 507 patients with advanced GEJ/GC. (C and D): Kaplan-Meier curve of the PFS (C) and OS (D) of 246 patients with HER2-negative advanced GEJ/GC receiving standard chemotherapy plus a PD-1 inhibitor with AFP thresholds of 20 ng/mL. (E and F): Kaplan-Meier curves of PFS (E) and OS (F) in 107 patients with HER2-positive advanced GEJ/GC receiving standard chemotherapy plus immunotherapy plus anti-HER2 therapy with AFP thresholds of 20 ng/mL. Abbreviations: ICI, immune checkpoint inhibitor; HER2, human epidermal growth factor receptor-2; SOX, S-1 and Oxaliplatin; XELOX, Capecitabine and Oxaliplatin; PFS, progression-free survival; GEJ/GC, gastroesophageal junction/gastric cancer; PD-1, programmed cell death protein 1; AFP, alpha-fetoprotein; HER2-GC, HER2-negative gastric cancer; HER2+GC, HER2-positive gastric cancer.
Table 4.
Comparisons of the ORR and DCR between patients who were AFP-positive and AFP-negative
| Group | AFP-negative | AFP-positive | p-value |
|---|---|---|---|
| HER2-negative (n = 402) | 345 | 57 | |
| ORR (CR+PR) | 167 (48.4%) | 34 (59.6%) | 0.152 |
| DCR (CR+PR+SD) | 312 (90.4%) | 53 (93.0%) | 0.804 |
| SOX/XELOX/FOLFOX+PD-1 inhibitor (n = 246) | 230 | 16 | |
| ORR (CR+PR) | 104 (45.2%) | 8 (50.0%) | 0.798 |
| DCR (CR+PR+SD) | 208 (90.4%) | 15 (93.8%) | > 0.999 |
| HER2-positive (n = 155) | 133 | 22 | |
| ORR (CR+PR) | 104 (78.2%) | 15 (68.2%) | 0.076 |
| DCR (CR+PR+SD) | 127 (95.5%) | 20 (90.9%) | 0.317 |
| SOX/XELOX/FOLFOX+ immunotherapy + anti-HER2 (n = 107) | 93 | 14 | |
| ORR (CR+PR) | 72 (77.4%) | 9 (64.3%) | 0.284 |
| DCR (CR+PR+SD) | 93 (100.0%) | 13 (92.9%) | 0.082 |
Abbreviations: SOX, S-1 and Oxaliplatin; XELOX, Capecitabineand Oxaliplatin; FOLFOX, Calcium folinate, Fluorouracil and Oxaliplatin; CR, Complete response; PR, Partial response; SD, Stable disease; PD, Progressive disease; ORR, Objective response rate; DCR, Disease control rate.
In the HER2-positive cohort (n = 107; 14 with AFP-GEJ/GC; 93 AFP-negative GEJ/GC), patients with AFP-GEJ/GC showed a trend toward shorter mPFS (7.67 vs. 12.20 months; P = 0.60; Figure 2E), a trend toward lower ORRs (64.3% vs. 77.4%; P = 0.284; Table 4), and numerically lower DCRs (92.9% vs. 100.0%; P = 0.082; Table 4) compared with those of patients who were AFP-negative. Further analysis of the AFP ≥ 100 ng/mL (7.70 vs. 11.20 months; P = 0.73; Supplementary Figure 1C) and ≥ 400 ng/mL (7.70 vs. 11.90 months; P =0.92; Supplementary Figure 1D) subgroups revealed a similar trend. Notably, the trend toward shortened mPFS was more pronounced in the PD-L1 CPS ≥ 1 subgroup (7.33 vs. 13.10 months; P = 0.17; Supplementary Figure 2D). However, in the PD-L1 CPS<1 subgroup, AFP-GEJ/GC showed similar mPFS versus AFP-negative patients (10.30 vs. 10.50 months; P = 0.66, Supplementary Figure 2C).
Efficacy analysis of combination VEGFR-targeted therapy in AFP-GEJ/GC
Notably, anti-angiogenic combination therapy did not statistically improve mPFS in AFP-GEJ/GC (Figure 3A, 7.93 vs. 7.30 months, P = 0.95, n = 79). Among the 57 patients with HER2-negative AFP-producing GEJ/GC, 47 received standard chemotherapy plus anti-PD-1 inhibitors, either with or without anti-angiogenic therapy. Patients treated with the anti-angiogenic combination regimens (n = 31) demonstrated superior PFS compared with those receiving standard chemoimmunotherapy (n = 16; mPFS: 6.33 vs. 5.40 months, P = 0.02; Figure 3C). The survival analysis also revealed a trend toward improved OS (15.70 vs. 11.40 months, P = 0.15; Figure 3D), suggesting clinically relevant benefits of anti-angiogenic therapy in HER2-negative AFP-GEJ/GC.
Figure 3.
Kaplan Meier curves of the PFS and OS in patients with advanced AFP-GEJ/C according to treatment with or without anti-angiogenic agents. A: Kaplan Meier curves of the PFS of patients who were AFP-GEJ/GC (n = 79); B: Kaplan Meier curves of the OS of patients with AFP-GEJ/GC (n = 79); C: Kaplan Meier curves of the PFS of patients who were HER2-negative AFP-GEJ/GC (n = 47) receiving standard chemotherapy plus PD-1 inhibitor with or without anti-VEGFR therapy; D: Kaplan Meier curves of the OS of patients with HER2-negative AFP-GEJ/GC (n = 47); E: Kaplan Meier curves of the PFS of patients who were HER2-negative and AFP-negative (n = 252); F: Kaplan Meier curves of the OS of patients who were HER2-negative and AFP-negative (n = 252). Abbreviations: PFS, progression-free survival; C+I, standard chemotherapy plus PD-1 inhibitor; C+I+V, standard chemotherapy plus PD-1 inhibitor plus anti-VEGFR therapy; OS, overall survival; HER2, human epidermal growth factor receptor-2; AFP, alpha-fetoprotein.
To validate whether this benefit was specific to AFP-producing GEJ/GC, we further analyzed a control cohort of 345 HER2-negative AFP-negative patients. In this group, anti-angiogenic combination regimens (n = 13) did not confer additional benefit in terms of PFS (6.87 vs. 7.27 months; P = 0.32) or OS (18.40 vs. 17.30 months; P = 0.89) compared with chemoimmunotherapy (n = 239; Figure 3E, 3F).
For HER2-positive AFPGC, the efficacy of anti-angiogenic therapy remains to be determined. Notably, in our study, the potential for a triple-combination strategy (HER2/PD-1/VEFGR blockade) to overcome resistance represents a critical translational direction, as exemplified by a patient achieving long-term survival under this regimen (Supplementary Materials).
Prognostic analysis
In the overall population, the AFP-GEJ/GC group (n = 79) showed similar median overall survival (Figure 2B; mOS: 21.80 vs. 19.70 months; P = 0.38) compared with the AFP-negative group (n = 478). In the HER2-negative cohort, 246 patients receiving standard two-drug chemotherapy combined with PD-1 inhibitors, the AFP-GEJ/GC group (n = 16) exhibited numerically worse mOS (Figure 2D, 11.40 vs. 16.80 months; P = 0.24) compared with the AFP-negative group (n = 230). Further analysis of the AFP ≥ 100 ng/mL (11.10 vs. 16.40 months; P = 0.32; Supplementary Figure 3A) and ≥ 400 ng/mL (9.17 vs. 16.43 months; P = 0.06; Supplementary Figure 3B) subgroups revealed a similar trend. In the HER2-positive cohort, 107 patients receiving standard chemotherapy-based regimens, AFP-GEJ/GC (n = 14) showed similar mOS (Figure 2F, 32.40 vs. 28.30 months; P = 0.38) versus AFP-negative group (n = 93). Further analysis of the AFP ≥ 100 ng/mL (32.50 vs. 28.50 months; P = 0.17; Supplementary Figure 3C) and ≥ 400 ng/mL (32.50 vs. 28.90 months; P = 0.44; Supplementary Figure 3D) subgroups revealed a similar trend. Notably, anti-angiogenic combination therapy did not statistically improve mOS in AFP-GEJ/GC (Figure 3B, n = 79).
In the HER2-negative advanced GEJ/GC cohort receiving standard chemotherapy (SOX, XELOX, or FOLFOX) plus anti-PD-1 inhibitors (n = 246), univariate cox regression analysis revealed no clinicopathological variables significantly associated with OS (all P > 0.05; Supplementary Figure 5A). In contrast, among patients with HER2-positive advanced GEJ/GC treated with standard chemotherapy-based regimens (n = 107), non-intestinal Lauren classification and ECOG performance status of 2 were significantly associated with shorter OS (Supplementary Figure 5B), and multivariate analysis further confirmed ECOG performance status of 2 as an independent adverse prognostic factor (Supplementary Figure 6). Notably, serum AFP levels exhibited opposite trends across subgroups: in HER2-negative patients, elevated AFP (≥ 400 ng/mL) was associated with a tendency toward worse OS (HR 2.037, 95% CI 0.943-4.398, P = 0.070), whereas in HER2-positive patients, higher AFP levels suggested a trend toward better survival (HR 0.632, 95% CI 0.193-2.069, P = 0.448), although neither reached statistical significance (Figure 2D, 2F, Supplementary Figure 3).
Considering the established role of PD-L1 expression in patient selection for immunotherapy in real-world clinical practice, we further evaluated survival outcomes stratified by PD-L1 CPS. In the HER2-negative cohort, patients with PD-L1 CPS ≥ 5 and AFP-GEJ/GC had significantly shorter OS compared with AFP-negative patients (8.50 vs. 17.50 months; P < 0.01; Supplementary Figure 4B), whereas no difference was observed in the CPS < 5 subgroup (14.80 vs. 16.20 months; P = 0.33; Supplementary Figure 4A). In the HER2-positive cohort, further stratification using a CPS cutoff of 1 showed no significant differences in OS between AFP-GEJ/GC and AFP-negative patients across either PD-L1 subgroup (Supplementary Figure 4C, 4D).
Discussion
This study provides a comprehensive evaluation of treatment efficacy and prognosis of AFP-GEJ/GC compared with AFP-negative tumors, stratified by HER2 status, PD-L1 CPS and treatment regimens [38]. In HER2-negative patients, AFP-GEJ/GC was associated with inferior efficacy of chemoimmunotherapy, particularly in the PD-L1 CPS ≥ 5 subgroup. In HER2-positive patients, no significant differences were observed, although a trend toward shorter PFS in AFP-GEJ/GC was noted, especially in the PD-L1 CPS ≥ 1 subgroup. Importantly, the addition of anti-angiogenic therapy conferred a PFS benefit in HER2-negative AFP-GEJ/GC, suggesting a potential therapeutic avenue for this aggressive phenotype.
During the chemotherapy treatment period, AFP ≥ 20 ng/mL predicted both reduced ORR (43% vs. 56.1%; P = 0.024) and inferior OS (10.9 vs. 15.7 months; P = 0.004) in advanced gastric cancer [11]. However, in the era of chemoimmunotherapy, the prognostic and predictive role of AFP in GEJ/GC remains less clearly defined. Our findings underscore that AFP positivity predicted inferior efficacy, with its adverse prognostic impact most evident in the PD-L1 CPS ≥ 5 subgroup. Our findings align with certain aspects of previous research, while also revealing discrepancies that warrant further investigation. Liu et al. observed a substantial improvement in immunotherapy efficacy in AFPGC compared with chemotherapy regimens (ORR: 85.7% vs. 21.4%; P = 0.005; PFS: 22 vs. 4.3 months). Nevertheless, given the relatively small sample size (n = 21), these results should be interpreted with caution, as the potential for selection bias cannot be excluded [39]. In contrast, another study demonstrated that AFP ≥ 20 ng/mL predicted significantly reduced benefit from chemotherapy-ICI combinations compared with AFP < 20 ng/mL (mPFS: 3.93 vs. 13.3 months, P < 0.001; mOS: 10.8 vs. 20.63 months, P = 0.001). It is noteworthy that patients in this cohort predominantly received immunotherapy in the second- or third-line setting, which may partly explain the shorter survival outcomes compared with those observed in our study [40]. Functionally, AFP acts as a potent immunosuppressive factor, attenuating the activity of natural killer (NK) cell, monocytes and dendritic cells (DCs), thereby facilitating tumor immune evasion [41-44]. Such immunosuppressive mechanisms may account for the adverse impact of elevated AFP levels on the efficacy of immunotherapy.
Clinical evidence regarding HER2-positive AFP-GEJ/GC remains limited. A few case reports have described durable responses to chemotherapy plus trastuzumab in this rare subset. In 2012, Amano et al. reported the successful treatment of a 74-year-old patient with metastatic HER2-positive AFP-GEJ/GC using trastuzumab combined with docetaxel and S-1 [45]. Similarly, Hayashi et al. described a recurrent HER2-positive AFP-GEJ/GC case achieving more than three years of survival with chemotherapy plus trastuzumab [46]. However, in the immunotherapy era, systemic studies specifically addressing advanced HER2-positive AFP-GEJ/GC remain scarce due to the disease’s rarity. Compared with HER2-negative AFP-GEJ/GC, our study showed AFP status did not significantly influence PFS or OS. Nonetheless, AFP-positive GEJ/GC cases tended to exhibit shorter PFS compared with AFP-negative cases, a trend that was particularly evident in the PD-L1 CPS ≥ 1 subgroup. However, the sample size was relatively small, and these findings require confirmation in larger, prospective cohorts.
Taken together, our findings suggest that AFP is associated with a similar trend of reduced PFS in both HER2-negative and HER2-positive advanced GEJ/GC, whereas the divergent OS outcomes may be attributed to the broader availability of subsequent treatment options in HER2-positive patients. Prior studies using multiplex immunohistochemistry [47] and single cell RNA sequencing [48] have revealed distinct immune microenvironmental features between HER2-positive and HER2-negative gastric cancers. as well as between HER2-positive patients stratified by PD-L1 CPS ≥ 1 and CPS < 1 [49]. These differences may underlie the divergent impact of AFP on treatment efficacy across subgroups, warranting further mechanistic investigation.
Another important finding of our study is that the incorporation of anti-angiogenic agents may have potential therapeutic implications in HER2-negative AFPGC, as demonstrated through comparative analyses with AFP-negative gastric cancer. In the LEAP-015 study [50], lenvatinib plus pembrolizumab and chemotherapy improved PFS and ORR in patients with PD-L1 CPS ≥ 1, but did not confer a significant OS benefit. Thus, anti-VEGF combined with PD-1 blockade has not yet established a role as standard first-line treatment in advanced gastric cancer. AFPGC is characterized by aggressive biology with high malignant potential, extensive angiogenesis, and markedly elevated VEGF expression and microvessel density compared with non-AFPGC [8,51,52]. In our cohort, AFP-GEJ/GC tumors exhibited more frequent liver metastasis rates (72.2% vs. 37.9%; P < 0.001) and PVTT incidence (19% vs. 5%; P < 0.001), consistent with AFP-mediated hematogenous dissemination and vascular invasion [1,3,9,53]. Taken together, these clinical and molecular features, along with prior evidence of benefit from ramucirumab or apatinib-based therapy [30,32], suggest that integration of anti-angiogenic strategies may represent an effective therapeutic approach specifically for AFPGC.
The prognostic significance of AFP positivity in gastric cancer remains controversial. In our study, AFP was not an independent predictor of OS in patients with advanced GC, irrespective of HER2 status, yet AFP-positive patients within the HER2-negative/PD-L1 CPS ≥ 5 subgroup exhibited significantly shorter survival. These findings partially align with previous studies, where AFP positivity has been reported as an adverse prognostic factor [5,10,40], although other investigations have suggested no significant association with OS [32,54]. Interestingly, favorable outcomes have been described in AFPGC with HER2 overexpression, particularly following surgery or chemotherapy [55], while our earlier work highlighted liver or peritoneal metastases, non-regional lymph node involvement, and PVTT as poor prognostic indicators in advanced AFP-GEJ/GC treated with chemotherapy alone [54]. Notably, in our AFP-positive cohort, PD-L1 CPS did not predict immunotherapy benefit (mOS: 14.8 vs. 8.5 months for CPS < 5 vs. ≥ 5, Supplementary Figure 4A, 4B), suggesting PD-L1 expression alone may be an inadequate biomarker for guiding immunotherapy in AFP-GEJ/GC. Given the limited sample size of patients with available PD-L1 data, further validation in larger, prospective cohorts is warranted to refine patient stratification strategies in this unique subgroup.
Nevertheless, this study has several limitations. Its retrospective design and relatively small sample size inevitably introduced selection bias, and heterogeneity in post-first-line treatments further complicated the interpretation of OS outcomes. Due to the extended time span of the study and missing information on subsequent-line treatments in some patients, the impact of later-line therapies on OS was not analyzed. In addition, the rarity of AFP-GEJ/GC, particularly among HER2-positive patients, restricted the number of cases that could be analyzed. Future studies with larger sample sizes and more diverse cohorts will be essential to better define the therapeutic efficacy and prognostic relevance of AFP positivity advanced GEJ/GC.
Conclusion
AFP positivity may indicate inferior efficacy of first-line chemo-immunotherapy in HER2-negative advanced GEJ/GC. Moreover, our findings provide a basis for future prospective studies to evaluate the potential role of anti-angiogenic combination strategies in AFPGC. Collectively, these results highlight the potential role of AFP in patient risk stratification and in guiding future therapeutic decision-making in advanced gastric cancer.
Acknowledgements
We appreciate the patients, relatives of patients and research team for their participation. We deeply appreciate Beijing Natural Science Foundation (7244292), National Natural Science Foundation of China (National Science Foundation of China, 82272627), Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation, L234003), Capital’s Funds for Health Improvement and Research (2024-1-1021), Beijing Hospitals Authority’s Ascent Plan (DFL20241104) and Noncommunicable Chronic Diseases-National Science, Technology Major Project (2024ZD0520600).
Disclosure of conflict of interest
None.
Supporting Information
References
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