Potential biomarkers for the prognosis of gastrointestinal stromal tumors

Abstract

In this editorial we comment on the article published in the recent issue of World Journal of Gastrointestinal Oncology. This study aims to explore the relationship between preoperative inflammation markers and the recurrence of gastrointestinal stromal tumors (GIST) after surgery. It is well known that the best-documented prognostic parameters for GIST are mitotic activity, tumor size and anatomical site. Besides, mutation status represents a prognostic as well as predictive factor. This study provides a new tool for postoperative recurrence risk assessment of GIST patients by establishing a line chart prediction model, which is certificated by previous research that high platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio correlated with increased tumour sizes, more advanced tumour stages and mitotic index. However, as a retrospective study, inevitable bias exists in the results; furthermore, the sample size of this study is relatively small, influencing the universality of the results. Moreover, when assessing risk rating and prognosis of GIST, some novel inflammatory makers could be taken into consideration, such as proenkephalin and SLITRK3. Overall, this study can offer an additional model for GIST prognosis and recurrence risk assessment, independent of the traditional prognostic factors of GIST.

Key Words: Gastrointestinal stromal tumors; Prognostic parameters; Inflammatory markers; Recurrence risk; Personalized therapy

Core Tip: The importance of predicting prognosis in the management of gastrointestinal stromal tumors (GIST) is well known, with a particular focus on mitotic activity, tumor size, anatomical location, and KIT and platelet-derived growth factor receptor alpha mutation status. It underscores the emerging significance of inflammatory markers such as the neutrophil-to-lymphocyte ratio, systemic immune-to-inflammation index, platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in predicting GIST prognosis and recurrence risk. This study identified the MLR and PLR as independent risk factors, thereby providing a predictive model for recurrence-free survival. However, it is important to note that the study has limitations, including its retrospective design, small sample size, and lack of external validation.

INTRODUCTION

Gastrointestinal stromal tumors (GIST) are mesenchymal tumor with variable behavior, with an incidence ranging from 1.1 cases per 100000 person/years to 1.5 cases per 100000 person/years[1]. In contrast, microGIST are relatively common. Prognostic parameters play a crucial role in the management of GIST, helping to estimate the risk of recurrence after surgery, which is essential for establishing adjuvant therapy schemes. The best-documented prognostic parameters for GIST are mitotic activity, tumor size and anatomical site. Besides, mutation status of KIT and platelet-derived growth factor receptor alpha serves as a prognostic and predictive parameter[2,3]. These elements are incorporated into the National Institutes of Health risk classification system, which categorizes GIST cases into low-risk, intermediate-risk, and high-risk groups for recurrence[4,5]. This classification facilitates establish the strategy of adjuvant therapy, highlighting the importance of prognostic indicators. It is recommended that patients with high-risk GSIT may get privileged form a standard three-years adjuvant treatment. Many clinical trials have recommended imatinib as the first-line treatment for GIST, with sunitinib, regorafenib, and ripretinib identified as subsequent therapeutic options for advanced cases[3]. Additionally, various tyrosine kinase inhibitors are utilized in different treatment settings[6].

EXPANDING INFLAMMATORY INDICATORS FOR GIST

In recent years, inflammatory markers, such as the neutrophil-to-lymphocyte ratio, systemic immune-to-inflammation index, platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), have demonstrated potential value for the prognosis of various cancers, including GIST[7-10]. Compared with classical prognostic parameters, inflammatory markers are readily accessible and cost effective to examine, and they provide additional prognostic information that allows clinicians to conduct more comprehensive assessments[8,9]. In patients with GIST, inflammatory markers are associated with the risk of disease recurrence. These markers not only reflect the systemic antitumour inflammatory response but are also closely associated with tumour progression, invasion, and prognosis. Elevated levels of certain markers may indicate a more aggressive disease phenotype and poorer prognosis in patients with GIST. Additionally, inflammatory markers have also been explored for their ability to predict neoadjuvant and immunotherapy efficacy in advanced tumour patients[11,12]. Additionally, in GIST, inflammatory markers are related to angiogenesis and the immune response within the tumour microenvironment. These markers provide insights into the host immune status, which can be useful for making personalized treatment decisions. Furthermore, certain inflammatory markers may serve as predictors of adjuvant treatment efficacy, indicating promising prognostic value for recurrence-free survival (RFS) in patients (Table 1)[3,13-21].

Table 1 Relationship between systemic inflammatory markers and the prognosis of gastrointestinal stromal tumors.

Inflammatory markers	Impact	Mechanism	Threshold value	Ref.
NLR	High preoperative NLR is associated with decreased DFS and is an independent prognostic factor	Higher NLR may reflect the inflammatory state and immunosuppressive state of the body, which may be related to tumor progression and response to treatment	1.92-6	Kumarasamy et al[14], Bigot et al[20], Malietzis et al[21]
SII	A promising predictor for RFS and effect of neoadjuvant therapy	A high level of SII indicates an enhanced systemic inflammatory state and a weakened immune response, while a high level of SII may indicate that the inflammatory microenvironment promotes tumor invasion and metastasis	544.6-820.0	Goh et al[16], Lu et al[17]
PLR	High PLR is an independent prognostic factor for RFS in patients with GIST	High PLR may indicate the immune surveillance ability is decreased, which may be related to tumor progression	275
PENK	High expression of PENK was associated with superior OS and RFS in patients with GIST	PENK is a neuropeptide precursor, which may affect the proliferation and apoptosis of tumor cells through its interaction with opioid receptors. The high expression of PENK may be related to the tumor inhibition pathway	IHC score ≥ 4: PENK positive. IHC score < 4: PENK negative
GNRI	A promising predictor for RFS	GNRI is an objective nutritional assessment method based on serum albumin levels and body weight ratios, reflecting the nutritional status of patients to influence prognosis	98.3	Lu et al[17]
PNI	A promising predictor for effect of neoadjuvant therapy	PNI reflects the nutritional status and immune function of patients. Low PNI may indicate decreased immune function and poor nutritional status, further promoting the formation of an inflammatory microenvironment	47.2
MLR	As a prognostic indicator for the recurrence of GIST, with elevated MLR correlating with an increased risk of postoperative recurrence	Monocytes and lymphocytes play crucial roles in the immune modulation within the tumor microenvironment. A high MLR may signify underlying chronic inflammation, which could facilitate tumor progression and recurrence. Furthermore, an elevated MLR might reflect compromised immune surveillance capabilities	/
SLITRK3	SLITRK3 expression is closely associated with OS and DFS in GIST patients	Elevated levels of SLITRK3 may be linked to the aggressiveness and unfavorable prognosis of GIST; however, the precise mechanisms underlying its action and the critical pathways involved in GIST remain to be elucidated	IHC score ≥ 4: SLITRK3 positive. IHC score < 4: SLITRK3 negative

DFS: Disease-free survival; GNRI: Geriatric nutritional risk index; IHC: Immunohistochemical; MLR: Monocyte-to-lymphocyte ratio; NLR: Neutrophil-to-lymphocyte ratio; OS: Overall survival; PENK: Proenkephalin; PLR: Platelet-to-lymphocyte ratio; PNI: Prognostic nutritional index; RFS: Recurrence-free survival; SII: Systemic immune-to-inflammation index.

However, these results may be influenced by various factors, including infection status, nutritional status, and other conditions unrelated to cancer. This could result in false-positive outcomes during prognostic assessments. Therefore, ensuring the consistency and reproducibility of inflammatory markers is essential for their clinical application. Further validation of their prognostic value calls for larger, multicenter studies. Standardized thresholds should be established for these markers[3,14]. It is highly important to establish standardized thresholds and interpretations for these markers to increase their reliability across different studies and clinical settings.

In this study, which identified the MLR and PLR as independent risk factors among four inflammatory biomarkers derived from neutrophils, platelets, monocytes, and lymphocytes (Figure 1), the authors established a line chart prediction model correlating inflammatory markers with RFS and offered a novel clinical tool for assessing postoperative recurrence risk in GIST patients. This study also emphasized the ongoing sensitivity of inflammatory markers in patients receiving postoperative targeted therapy.

Figure 1  The effect of four inflammatory biomarkers derived from neutrophils, platelets, monocytes, and lymphocytes.

Nevertheless, as a relatively small-sample retrospective study, there was inevitable bias in the results. Second, the study only conducted internal validation without external or multicenter data verification. Third, the impact of postoperative targeted therapy on prognostic data may not fully reflect the operative situation. A larger sample size, external validation of the prediction model, deeper exploration of novel biomarkers, better handling of confounding factors, and improved practical application of findings for this study are highly important. We suggest that future studies create a user-friendly online platform where clinicians can input patient data, obtain prognostic predictions on the basis of the model and validate standardized thresholds for the inflammatory markers used in the model.

NOVEL PROGNOSTIC PARAMETERS FOR GIST

Research into novel prognostic parameters for GIST is thriving. New markers such as cytokines and chemokines are being explored for their potential role in GIST prognosis. Recent studies identified SLITRK3 as a significant predictor for the recurrence and metastasis of GIST, with higher expression levels correlating with poorer patient outcomes[18]. On the other hand, another study found that high proenkephalin (PENK) expression in GIST is associated with better overall survival and RFS[19]. On the molecular front, next-generation sequencing of liquid biopsy detecting circulating tumor DNA offers a non-invasive approach to detect mutation status and monitor progression and response to treatment in real-time[22].

CONCLUSION

In conclusion, integration both classical and novel prognostic parameters-including inflammatory markers-into the clinical management of GIST, is essential for personalized treatment strategies. These markers hold promising value for enhancing risk stratification, guiding adjuvant therapy decisions, and improving our ability to predict and manage disease recurrence among GIST patients. Further research is warranted to fully elucidate the mechanisms underlying the association between inflammation and GIST progression and to translate these findings into clinical practice.