D-dimer predicts the response of patients with gastric cancer to first-line immunotherapy combined with chemotherapy

Introduction

Gastric cancer (GC) is one of the most commonly diagnosed cancers, as well as the fourth leading cause of cancer-related death among malignant tumors. It has a higher incidence in East Asia, followed by Eastern and Central Europe (1). The primary risk factors include Helicobacter pylori (Hp), alcohol and tobacco history, dietary practices, family medical history, and Epstein–Barr virus (EBV) infections (2,3). At the initial diagnosis, more than half of patients are at the stage of locally advanced or metastatic disease, leading to a significantly unfavorable prognosis. Systemic chemotherapy is an important treatment and antibody-targeting human epidermal receptor 2 (HER-2) serves as the main therapy for HER-2-positive patients. In recent years, immunotherapy, particularly programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitor antibodies, have shown significant benefits in solid organ tumors, including melanoma and non-small cell lung cancer. Based on the findings of CheckMate 649, PD-1 inhibitors combined with chemotherapy has been approved as a first-line treatment for advanced and metastatic GC (4). Previous studies have uncovered that microsatellite instability-high (MSI-H), high expression of PD-L1, EBV-positive status, or high tumor mutational burden (TMB) populations with GC may have a significantly better response to immune checkpoint inhibitors (ICIs), but not all patients derive equal benefits from immunotherapy. The key to further improving the prognosis of advanced and metastatic GC is to accurately identify patients who are sensitive to immunotherapy. Thus, there is a need for exploring more effective prognostic and predictive biomarkers in order to select potential populations who will benefit from immunotherapy.

In recent years, studies have revealed a bidirectional effect between cancer and the hemostatic system. D-dimer, a biomarker of activation of hemostasis and fibrinolysis, was associated with tumor progression and metastasis across multiple malignancies, including pancreatic cancer (5,6), lung cancer (7-9), prostate cancer (10), cervical cancer (11), breast cancer (12-14), and colorectal cancer (15). Numerous studies involving patients with GC have consistently confirmed that elevated D-dimer levels were related to more advanced stages of disease (16), hematogenous metastasis (17), tumor recurrence (18), and poor outcomes (16). In esophageal squamous cell carcinoma and lung cancer, D-dimer has been demonstrated to be related to the efficacy of immunotherapy (19,20). However, there have been no relevant studies to investigate the D-dimer level as a prognostic marker for advanced and metastatic GC patients undergoing ICIs treatment. Thus, we performed a retrospective analysis to explore the predictive value of D-dimer in immunotherapy for advanced and metastatic GC patients. We present this article in accordance with the REMARK reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-824/rc).

Methods

General information

We retrospectively and consecutively collected unresectable locally advanced, recurrent, or metastatic GC patients admitted to The First People’s Hospital of Yunnan Province from April 2021 to March 2023. All patients received first-line immunotherapy combined with chemotherapy. The inclusion criteria were as follows: (I) histopathological confirmation of gastric adenocarcinoma; (II) received a minimum of 2 first-line immunotherapy combined with chemotherapy cycles; (III) presence of measurable lesions and at least one evaluation of tumor response to treatment; (IV) Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. The exclusion criteria were as follows: (I) received preoperative neoadjuvant chemotherapy; (II) double primary cancers; (III) recent operation, infectious disease, or clinically significant cardiovascular or peripheral vascular disease; (IV) received anticoagulant, antiplatelet, or thrombolytic therapy; (V) HER-2 positivity. The study was conducted in accordance with the principles of the Declaration of Helsinki and its subsequent amendments, and has been approved by the Ethics Committee of The First People’s Hospital of Yunnan Province (No. KHLL2024-KY210). As a retrospective study, the need for informed consent was waived by the institutional review board.

Treatment method

All patients received the first-line immunotherapy plus chemotherapy. The PD-1/PD-L1 inhibitors included nivolumab, camrelizumab, sintilimab, or tislelizumab. Chemotherapy regimens included capecitabine plus oxaliplatin (XELOX), S-1 and oxaliplatin (SOX), and other combinations, with 21 days constituting 1 cycle.

Evaluation criteria

Each patient’s response was evaluated after every 2 cycles based on the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) (21). The tumor response included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The overall response rate (ORR) was defined as the percentage of patients achieving CR or PR, whereas disease control rate (DCR) was the percentage of patients with a CR, PR, or SD. Follow-up, which was conducted via telephone or hospital information system, continued until the first-line immunotherapy failure, loss to follow-up, death, or the end of follow-up. The final follow-up date for this study was 15 July 2024. Overall survival (OS) was defined as the duration time from the initiation of immunotherapy to death. Progression-free survival (PFS) was defined as the time period from initiation of immunotherapy to PD or death.

Determination of D-dimer level

The baseline D-dimer and tumor marker levels measured 1 week prior to first-line therapy were obtained from the patient records. The optimal cutoff value for D-dimer levels was determined based on the receiver operating characteristic (ROC) curve and Youden index, and patients were divided into low D-dimer levels and high D-dimer levels.

Statistical analysis

All data were analyzed using SPSS 22.0 (IBM Corp., Armonk, NY, USA) and R version 4.1.3 (R Foundation for Statistical Computing, Vienna, Austria). ROC curve analysis was performed to determine the optimal cutoff value for D-dimer, stratifying patients into low- and high-D-dimer level groups. The chi-square test and Fisher’s exact test were utilized for categorical variables. A P value <0.05 indicated statistically significant differences. The reverse Kaplan-Meier (KM) method was used to calculate the median estimated follow-up, whereas the KM method was employed to analyze survival data. Cox univariate and multivariate analyses were conducted to identify independent prognostic factors. Variables with P<0.1 in univariate analysis were included in the multivariate analysis.

Results

Determination of optimal threshold values and patient stratification

The optimal cut-off value for D-dimer was 0.965 µg/mL [sensitivity =85.7%, specificity =78.9%; 95% confidence interval (CI): 0.717–0.975] and the area under the curve (AUC) was 0.846 based on the ROC curve and Youden index (Figure 1). According to this threshold, 22 patients with D-dimer levels >0.965 µg/mL were assigned to the high-D-dimer group, whereas 18 patients with D-dimer ≤0.965 µg/mL were allocated to the low D-dimer group.

Figure 1 Cut-off values for the D-dimer level determined by ROC curve. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic.

Association of clinicopathological characteristics with D-dimer

A total of 40 patients diagnosed with advanced and metastatic GC were enrolled. All patients were treated with immunotherapy combined with chemotherapy. Among them, 31 patients received sintilimab (77.5%), 7 patients received camrelizumab (17.5%), and the remaining patients received nivolumab (2.5%) and tislelizumab (2.5%), respectively. The clinical characteristics are summarized in Table 1. No statistically significant differences were observed between the low and high D-dimer groups in age, sex, history of smoking and drinking, or other variables. Thus, the patients’ clinical characteristics were balanced between the 2 groups.

Association between D-dimer levels and therapy response

The association between D-dimer levels and therapy response are presented in Table 2. Patients with low D-dimer levels showed higher DCR compared to the high D-dimer group (72.2% vs. 22.7%, P=0.002). However, no statistically significant difference in ORR was observed between the 2 groups (P=0.27).

Association between D-dimer and survival

The median follow-up was 13.1 months [interquartile range (IQR), 8.8–17.2 months]. The median PFS in the low D-dimer group was significantly prolonged compared to that in the high-D-dimer group (13.6 vs. 4.4 months; P<0.001) (Figure 2A). The univariate and multivariate analysis identified elevated D-dimer [P=0.002; hazard ratio (HR) 5.194, 95% CI: 1.861–14.496] and carbohydrate antigen 19-9 (CA19-9; P=0.03; HR 2.662, 95% CI: 1.118–6.338) as independent risk factors of PFS (Table 3). The median OS of the high D-dimer group was 8.1 months, whereas the median OS was not reached in the low D-dimer group. The low D-dimer group had significantly longer OS than the high D-dimer group (P=0.003) (Figure 2B). The univariate and multivariate analysis identified elevated D-dimer (P=0.002; HR 7.041, 95% CI: 1.996–24.836) and CA19-9 (P=0.003; HR 4.129, 95% CI: 1.622–10.512) as independent risk factors of OS (Table 4).

Figure 2 The association of baseline D-dimer levels with prognosis of (A) PFS and (B) OS in GC. GC, gastric cancer; OS, overall survival; PFS, progression-free survival.

Discussion

In recent years, immunotherapy has achieved significant success in various solid organ tumors and has become the first-line treatment for advanced and metastatic GC patients (22-24). Notably, tumors with a high risk of venous thromboembolism (VTE), such as glioblastoma and pancreatic ductal adenocarcinomas, have failed to show significant response from ICIs until now (25-28). The potential role of hypercoagulable tumors in shaping the tumor immune microenvironment (TIME) has been discussed in recent years. In gastric carcinoma cells, thrombin-activated protease-activated receptor 1 (PAR1) induces upregulation of the expression of nuclear factor kappa β (NF-κβ), epidermal growth factor receptor (EGFR), and tenascin-C (TN-C), thereby stimulating tumor cell growth and invasion (29). In addition, thrombin-activated PAR1 induces epithelial-mesenchymal transition (EMT) in gastric carcinoma cells, resulting in metastasis (30). These findings demonstrated that hemostasis activation is not just associated with cancer-associated thrombosis but also with tumor progression, angiogenesis, and metastasis in GC. However, the association between systemic hemostatic activation and the efficacy of immunotherapy is unknown in GC. As far as we know, this was the first study evaluating the prognostic value of pretreatment D-dimer levels in advanced and metastatic GC patients receiving immunotherapy plus chemotherapy. The population of our study was divided into high D-dimer and low D-dimer cohorts based on the optimal D-dimer cut-off values. DCR was markedly elevated in the low D-dimer cohort relative to high D-dimer counterparts. Survival analyses disclosed a significantly improved prognosis for the low D-dimer group compared to the high D-dimer group. In the multivariable assessment, D-dimer >0.965 µg/mL served as an independent risk factor of PFS and OS in advanced and metastatic GC patients treated with ICIs combined with chemotherapy. This was consistent with previous findings of esophageal squamous cell carcinoma treated with ICIs (19). Therefore, we speculate that a procoagulant milieu supports immunosuppressive properties mediated by the tumor. In addition, several previous studies have shown that the presence of liver metastases in GC is associated with worse immunotherapy response and prognosis (31,32), but the presence of liver metastasis was not significant for PFS/OS in our study. These inconsistent results might be associated with the small sample size of patients with liver metastasis in our study. However, the association between liver metastases and immunotherapy response for patients with GC remains controversial. In the CheckMate-649, ATTRACTION-2, and ATTRACTION-4 trials, GC patients, regardless of liver metastases, could benefit from immunotherapy (33-35). The predictive value of liver metastasis in immunotherapy of GC patients needs further prospective clinical validation.

In cancer patients, systemic activation of hemostasis is frequently observed; clotting factors are activated, leading to the formation of the fibrin clot. Recent evidence demonstrates that a procoagulant milieu supports tumor immune escape and interferes with immunotherapy. Coagulation factors play a pivotal role in cancer-associated thrombosis (CAT). Emerging studies indicate that tissue factor (TF), factor VIIa (FVIIa), factor Xa (FXa), and thrombin contribute to cancer immune evasion via unique mechanisms. TF initiates the procoagulant cascade and is aberrantly expressed in triple-negative breast cancer (TNBC), pancreatic cancer, glioma, acute lymphoblastic leukemia, and other malignancies (36-39). In mouse breast cancer models, the TF-FVIIa promotes the PD-L1 expression in breast cancer cells by activating PAR2 (40). Ren et al. found that TF aberrant expression was related to poor prognosis and had low immune-effector cell infiltration in TNBC (41). Notably, the mouse TNBC models of TF knockout presented suppressed tumor growth and increased effector T cell infiltration. Factor X, which is mostly generated by macrophages and monocytes, could promote immune evasion via PAR2 signaling (42). In hepatocytes, FXa-PAR2 signaling enhances PD-L1 transcription while suppressing the infiltration of CD8⁺ T cells in tumors and cytokines secretion (43). In addition, thrombin activates resting platelets to inhibit natural killer (NK) cells as well as cleaves glycoprotein A repetitions predominant (GARP) on platelet-bound cells, leading to the release of active transforming growth factor beta 1 (TGF-β1) and subsequent immunosuppression (44-46). Furthermore, the thrombin/PAR-1 signaling pathway suppresses antitumor immunity in pancreatic ductal adenocarcinoma (47). When a primary tumor releases circulating tumor cells (CTCs) into the vasculature, fibrin stabilizes an ecosystem that brings cancer cells, platelets, and red blood cells into close contact with each other. Intravascular coagulation plays a role in preventing the attack of various cytotoxic immune cells by forming polymerized fibrin. Eventually, cancer cells and other non-cancer cells, such as macrophages, mesenchymal, fibroblasts, endothelial, and osteoblast cells, could produce various procoagulant factors as well as other growth factors and cytokines, impairing the cytotoxic response of tumor stroma infiltrating immune cells. The activation of the coagulation cascade might weaken the efficacy of ICIs by the above mechanisms in GC.

Our data provides a possibility for improving the efficacy of advanced and metastatic GC patients with elevated D-dimer through anticoagulation (AC) combined with ICIs. Previous studies have reported that the combination of rivaroxaban, a direct FXa inhibitor, and ICIs induced synergistic antitumor effects in mouse models of fibrosarcoma cancer and hepatocellular carcinoma treatment (42,43). In addition, Rachidi et al. discovered that anti-platelet therapy with aspirin and clopidogrel potentiated adoptive T cell transfer therapy efficacy in mice models of melanoma (48). Furthermore, Metelli et al. reported that anti-PD-1 therapy in combination with dabigatran etexilate had superior efficacy to monotherapy in colorectal and breast preclinical tumor models (49). These preclinical studies suggested that FXa and thrombin may be promising therapeutic targets to improve ICIs efficacy. This synergistic effect between ICIs and FXa inhibitors was also observed in melanoma patients. In a retrospective study, Haist et al. revealed that melanoma patients receiving FXa inhibitors had a higher rate of CR and ORR (26.9% vs. 12.6%, P=0.037; 69.2% vs. 36.4%, P=0.005), and longer PFS and OS during initial ICIs therapy (50). However, AC did not enhance the response or survival in melanoma patients receiving initial immunotherapy. Consistent with the result from Haist et al., Johannet et al. observed that patients who received AC combined with ICIs therapy did not show significantly different treatment response or survival (51). Given the strong heterogeneity across primary tumor localization, the specific types of AC (FXa or thrombin inhibitors) may impact the efficacy of ICIs treatment. With expanding applications of ICIs in various malignancies, further clinical studies are essential to determine synergistic effects between ICIs and AC.

There are limitations to our study: (I) Single-center design with limited sample size. Future multi-center and more patients should be recruited to verify the results of our study. (II) Absence of PD-L1 expression and MSI status. The impact of PD-L1 expression or MSI status on the treatment outcomes could not be investigated. (III) Lack of immunotherapy alone or chemotherapy alone cohorts.

Conclusions

Our study has revealed that pretreatment D-dimer level may be an independent predictive biomarker for efficacy and prognosis in advanced and metastatic GC patients receiving first-line immunotherapy combined with chemotherapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-824/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-824/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-824/prf

Funding: This study was supported by the Top Talent Program for Youth of Yunnan Ten Thousand Program (No. YNWR-QNBJ-2019-147) and Yunnan Province Clinical Research Center for Hematologic Disease (No. 2023YJZX-XY06).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-824/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the principles of the Declaration of Helsinki and its subsequent amendments, and has been approved by the Ethics Committee of The First People’s Hospital of Yunnan Province (No. KHLL2024-KY210). As a retrospective study, the need for informed consent was waived by the Institutional Review Board.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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