Feasibility of Early Diagnosis of Pancreatic Cancer using reagent for analyzing purine metabolite (Hypoxanthine, Xanthine) in urine

doi:10.21203/rs.3.rs-5011761/v1

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Feasibility of Early Diagnosis of Pancreatic Cancer using reagent for analyzing purine metabolite (Hypoxanthine, Xanthine) in urine

https://doi.org/10.21203/rs.3.rs-5011761/v1

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Introduction: Pancreatic cancer (PC) is a leading cause of cancer-related mortality, and is often diagnosed at an advanced stage. Early detection is crucial for improving patient outcome. Current biomarkers like CA 19-9 have limitations in terms of sensitivity and specificity. This study investigated the potential of the urinary purine metabolites hypoxanthine and xanthine as biomarkers for early PC detection.

Methods: This single-center, non-blinded clinical trial included 120 participants (60 patients with PC and 60 healthy controls). Patients aged 18-85 years, scheduled for curative PC surgery were recruited. Urine samples were collected preoperatively and analyzed using a purine metabolome analysis kit developed by CUBEBIO. The study assessed the concentrations of hypoxanthine and xanthine and compared them with CA 19-9 levels. Statistical analyses were conducted using SPSS, with significance set at p < 0.05.

Results: PC patients had significantly higher mean ages (65.63 ± 10.58 years) and lower BMI (22.55 ± 3.19 kg/m²) than controls (46.62 ± 13.34 years and 24.94 ± 3.56 kg/m², respectively). Urinary hypoxanthine and xanthine levels were significantly lower in patients with PC (0.136 ± 0.0821) than in controls (0.292 ± 0.1208), with a p-value of <0.001. The diagnostic method showed an area under the curve (AUC) of 0.850, with a sensitivity of 87.9% and specificity of 71.1%. Urinary purine metabolites outperformed CA 19-9 for early-stage PC detection.

Conclusion: Urinary hypoxanthine and xanthine are promising biomarkers for early PC detection, offering a noninvasive, cost-effective diagnostic tool with higher sensitivity and specificity than CA 19-9. These findings support further research to validate and refine this diagnostic approach, potentially improving the early detection and patient outcomes in pancreatic cancer.

Pancreatic cancer (PC) is a malignancy with increasing global incidence and is expected to become a leading cause of cancer-related mortality worldwide [1]. Early detection of pancreatic cancer is crucial for improving patient outcomes as the disease is often asymptomatic until it reaches an advanced and often untreatable stage [2]. Currently, only 15–20% are diagnosed at an early stage when curative surgery is viable [3]. Therefore, a more timely diagnosis and more efficient therapy are urgently required. Although various screening modalities for PC are currently under investigation, their efficacy remains controversial. The American Gastroenterology Association (AGA) recommends a combination of magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) as the choice for PC screening modalities [4]. However, criticism has been raised regarding the effectiveness of screening in terms of cost-effectiveness. The biomarker CA 19 − 9 is not recommended by the AGA for PC screening due to its low positive predictive value [5, 6]. Therefore, owing to the lack of effective screening tools for PC, there is a growing need for new approaches to detect this fatal disease at the earliest and most treatable stages.

Given this backdrop, purine metabolism, an essential step in cellular metabolism, presents a new horizon for cancer diagnosis [7]. Hypoxanthine and xanthine are intermediate metabolites involved in the breakdown of purines, which are essential components of DNA and RNA [7, 8]. Under normal conditions, these purine metabolites are further broken down into uric acid, which is excreted in the urine. However, alterations in purine metabolism can lead to altered levels of hypoxanthine and xanthine in urine [9–11] (Fig. 1). Therefore, these metabolites may serve as potential biomarkers for cancer diagnosis and monitoring. However, the specificity and sensitivity of these biomarkers can vary depending on the type and stage of cancer [12].

This study aimed to investigate the potential of urinary hypoxanthine and xanthine levels as early biomarkers of PC. By assessing the sensitivity and specificity of a new diagnostic method for distinguishing patients with PC from healthy controls, we aimed to significantly contribute to the early detection and management of this formidable disease.

Study design

This single-center, non-blinded clinical trial was approved by the Ethics Committee of Seoul National University Bundang Hospital (Approval No. E-2211-792-350) and was conducted in accordance with the Declaration of Helsinki. The trial was registered at ClinicalTrials.gov (NCT 06291779).

The patients were registered as part of the trial between December 2022 and February 2024. All patients indicated that they fully understood the study and provided written informed consent before participation.

Patients Eligibility

All adult patients aged 18–85 years who were diagnosed with PC and scheduled for curative surgery were recruited for this study. Patients were excluded if they met any of the following criteria: a history of malignancy within the past five years; presence of other types of tumor in the final pathological reports, or evidence of distant metastasis. The control group consisted of patients who were admitted for surgery for benign diseases such as gallbladder disease and inguinal hernia. Patients were excluded if they had a recent history of cancer, active inflammatory disease, or postoperative malignancy diagnosis. Each cohort comprised 60 participants.

Variables

Patient demographics and perioperative outcomes were analyzed, including age, sex, Body Mass Index (BMI), American Society of Anesthesiologists (ASA) score, and preoperative diagnosis of diabetes mellitus (DM). PC-specific investigations included lesion location, preoperative CA19-9 levels, neoadjuvant chemotherapy, type of surgery, and final histopathological diagnosis. Pancreatic cancer staging was determined according to the 8th American Joint Committee on Cancer (AJCC) criteria [13].

Sample collection

Urine samples were obtained during admission prior to surgery. Approximately 10 ml of urine was collected in a 50 ml conical tube. All participants were instructed to fast from midnight before sample collection. Urine samples were collected from the first morning urine, with the initial volume discarded and midstream retained. The samples were immediately refrigerated at temperatures ranges from − 20 to -80°C and subsequently utilized for measurement. Routine urinalysis was simultaneously conducted during urine sample collection.

Measurement of hypoxanthine/xanthine concentration in urine using a purine metabolome analysis kit

Ten microliters of urine was mixed with 90 µL of the reaction mixture. The reaction composition consisted of 76 µl of buffer solution (100 mM potassium phosphate buffer pH 7.0 in 0.1% NP-40), 12.5 µl of enzyme solution (75mU xanthine oxidase in 1% polyethylene glycol), and 10.5 µl of probe solution (10% WST-8) (Fig. 2). After thorough mixing, the reaction was carried out at room temperature and shielded from light for 5 min. To determine the concentration of hypoxanthine/xanthine in the purine metabolome of the urine samples, OD (450 nm) values were measured using High-Performance Liquid Chromatography (HPLC), and the results were compared with those from a control group of individuals without pancreatic cancer (Fig. 3). This method was developed by CUBEBIO (Seoul. Korea)

Statistical analysis

All statistical analyses were performed using Statistical Package for the Social Sciences (version 22.0; IBM SPSS, Armonk, NY, USA). All test results showed the mean and standard deviation (mean ± SEM) of each group and used the t-test after ANOVA for the assessment of significance for each group; only cases with a p value of less than 0.05 (p < 0.05) were considered statistically significant. The area under the curve (AUC) was calculated to compare the performance of the kits. Finally, calibration curves were plotted to assess the scoring system together with the Hosmer–Lemeshow (H-L) test. Statistical significance was set at P < 0.05.

Demographics and study populations

The study was conducted prospectively, encompassing 120 urine samples, including 60 samples from the PC group and 60 samples from the non-cancer group (Table 1). The mean age was significantly higher in the PC group (65.63 ± 10.58 years) compared than in the non-cancer group (46.62 ± 13.34 years), with a p-value of < 0.001. Additionally, the mean BMI was significantly lower in the PC group (22.55 ± 3.19 kg/m²) compared to the non-cancer group (24.94 ± 3.56 kg/m²), with a p-value of 0.002. Furthermore, the American Society of Anesthesiologists (ASA) scores differed markedly, with a higher proportion of ASA 1 in the non-cancer group (48.3%) than in the cancer group (3.3%) and a greater prevalence of ASA 3 in the cancer group (36.7%) than in the non-cancer group (10.0%), yielding a p-value of < 0.001. Lastly, the incidence of preoperative diabetes mellitus (DM) was significantly higher in the cancer group (19.7%) than in the non-cancer group (8.3%; p = 0.041).

Measurement of hypoxanthine/xanthine concentration in urine using a purine metabolome analysis kit

Utilizing the developed diagnostic kit, the mean concentration of purine metabolites in urine for the PC group was 0.136 ± 0.0821, whereas that for the non-cancer group was 0.292 ± 0.1208. The disparity between the two groups proved to be statistically significant, with a p-value of < 0.001. The AUC value for the pancreatic cancer group was 0.850 (0.776–0.924), with a cut-off value of 0.209, a sensitivity of 87.9%, and a specificity of 71.1%. These findings were statistically significant, with a p-value of less than 0.001 (Fig. 4).

Perioperative and pathologic finding in PC group

In the PC group, which comprised 60 patients, the mean CA19-9 level was elevated at 531.82 U/mL (± 10.58). The distribution of the primary tumor location was as follows: head of the pancreas in 34 patients (56.7%), body in 14 patients (23.3%), and tail in 12 patients (20.0%). A significant proportion of the cohort received neoadjuvant treatment (NAT), accounting for 36 patients (57.1%). The remaining 26 (43.3%) patients underwent upfront surgery. Pancreaticoduodenectomy (PD) was the most common procedure performed in 34 patients (56.7%), and distal pancreatectomy (DP), performed in 26 patients (43.3%). The T staging was as follows: T1, 21 patients (35.6%), T2 23 patients (39.0%), T3 14 patients (23.7%); and T4, a single patient (1.7%). Nodal involvement was categorized as N0 in 30 patients (50.8%), N1 in 17 patients (28.8%), and N2 in 12 patients (20.3%), highlighting the diverse disease progression within the study sample (Table 2)

Comparing the value of purine metabolome in urine and CA19-9 for pancreatic cancer

Table 3. presents a comparison between the predictive value of urinary purine metabolites and serum CA 19 − 9 levels across different stages of PC in patients undergoing upfront surgery and in those who received neoadjuvant chemotherapy.

In the upfront surgery cohort, out of 23 patients, the urinary purine metabolite test accurately predicted PDAC in 100% (11/11) of Stage I patients and 100% (5/5) of Stage II patients when utilizing a cut-off value of ≤ 0.2089. In Stage III, the purine metabolite test correctly predicted PDAC in 85.7% (6/7) of the cases. CA 19 − 9, with a cut-off value of ≥ 37, was less predictive in Stage I, identifying PDAC in 45.4% (5/11) of patients (p = 0.012), and showed no statistical significance in Stage II and Stage III at 60% (3/5) and 100% (7/7) prediction rates, respectively, with p-values of 0.167 and 1.000.

Among the 36 patients who received neoadjuvant therapy, the urinary purine metabolite test predicted PDAC in 88.2% (15/17) of Stage I patients, 76.9% (10/13) of Stage II patients, and 83.3% (5/6) of Stage III patients using the same metabolite cut-off. CA 19 − 9 levels were predictive in 76.5% (13/17) of Stage I, 69.2% (9/13) of Stage II, and 66.7% (4/6) of Stage III patients, with p values indicating no significant difference from the purine metabolite test results (p = 0.656, p = 1.000, and p = 1.000, respectively).

Early diagnostic methods for PC present substantial challenges in oncology because of the frequent late-stage diagnosis and subsequent poor prognosis [1–3]. Early diagnosis is crucial for improving patient outcomes as it significantly increases the chances of successful treatment. However, current diagnostic methods remain insufficient, often detecting the disease at an advanced stage when curative options are limited. This study aimed to address these issues by exploring urinary purine metabolites, specifically hypoxanthine and xanthine, as potential biomarkers for early detection of PC.

The use of hypoxanthine and xanthine as biomarkers for cancer diagnosis is based on their role as intermediate metabolites in purine metabolism. Purine metabolism is a crucial cellular process that involves the synthesis and degradation of purines, which are vital components of DNA and RNA [14, 15]. In this pathway, hypoxanthine and xanthine are intermediate products. Hypoxanthine is found in various tissues of the human body, particularly in organs with high cellular turnover and active metabolism such as the liver and muscles [16]. It is also present in the bloodstream as a result of cellular metabolism and can be further broken down into xanthine and subsequently into uric acid by xanthine oxidase, with uric acid being excreted in the urine [17, 18]. However, alterations in purine metabolism, often associated with malignancies, can lead to decreased levels of hypoxanthine and xanthine in urine.

Cancer cells can divide infinitely and require a large supply of nucleic acids [19]. This demand leads to increased activity in both the de novo and salvage nucleotide synthesis pathways [20]. The hypoxanthine salvage pathway plays a crucial role in cancer cells by replacing the purine pool necessary for nucleotide synthesis and cell proliferation [20]. Studies have shown that in colorectal cancer (CRC), the levels of hypoxanthine phosphoribosyl transferase (HPRT) and hypoxanthine are significantly elevated, indicating an increased rate of salvage pathway activity at different stages of CRC development [21, 22]. This process reduces the concentration of purine metabolites in urine, as cancer cells utilize these metabolites more efficiently to support rapid proliferation. This principle has been effectively utilized in diagnosing other cancers, such as non-small cell lung cancer and non-Hodgkin lymphoma, where urinary hypoxanthine has shown good performance in distinguishing patients with cancer from healthy controls [23, 24]. However, to date, there have been no studies on the relationship between urine hypoxanthine and xanthine levels and PC.

Among the various methods available for analyzing hypoxanthine and xanthine in urine, High-Performance Liquid Chromatography (HPLC) offers several advantages [25]. HPLC is a powerful analytical technique that provides high sensitivity, specificity, and precision. It allows for the separation, identification, and quantification of hypoxanthine and xanthine in complex biological matrices, such as urine. HPLC can handle a wide range of sample types and volumes, and the use of high-pressure pumps ensures rapid analysis with excellent resolution [26, 27]. These features make HPLC a superior choice for the accurate measurement of the purine metabolites in this study.

The results indicate that urinary hypoxanthine and xanthine offer superior predictive value over CA 19 − 9 across all stages of PC, especially in early stage disease, where diagnosis is most challenging but beneficial. Table 3 shows that although CA 19 − 9 has a low diagnostic value in the early stages of PC, urinary purine metabolites were detected with high accuracy, even in the early stages. The study demonstrated that the urinary purine metabolite test had an AUC value of 0.850 (0.776–0.924) with a sensitivity of 87.9% and specificity of 71.1% compared to CA 19 − 9, which showed lower sensitivity and specificity, particularly in the early stages of PC. CA 19 − 9, a serum biomarker for PC, exhibits low sensitivity and specificity, especially in the early stages of the disease [28]. Studies have shown that CA 19 − 9, when used alone, has a sensitivity of 68% up to 1 year and 53% up to 2 years before diagnosis [29]. Additionally, populations with Lewis⍺-β- genotype may not express CA 19 − 9, leading to low levels of this marker in certain individuals, limiting its diagnostic utility [30]. Therefore, the higher sensitivity of the urine test compared to CA 19 − 9 makes it more valuable for the early diagnosis of PC.

However, the results in the NAT group were less accurate than those in the non-NAT group that did not receive NAT. This is likely because the accuracy of the test is affected by the drugs used in chemotherapy, which can alter the metabolism of the purine metabolites [31]. Despite this, the prediction rate in the NAT group was still relatively higher than that in the CA 19 − 9.

An ideal early cancer screening tool should be minimally invasive, accurate, cost-effective, and capable of simultaneously detecting multiple types of cancer [32]. In addition, simplicity, high sensitivity, and low cost are crucial features for widespread acceptance and accessibility [33]. In this context, the higher sensitivity of hypoxanthine and xanthine in urine compared to serum CA 19 − 9 allows for a noninvasive, cost-effective, and accessible diagnostic approach. This may be most important in resource-limited settings, where advanced imaging techniques are not readily available or where cost-effectiveness is a key concern. Furthermore, the collection of urine samples is simple and non-invasive, making it an easy and comfortable option for patients.

Despite these promising results, this study had limitations. One significant limitation is the relatively low specificity of the urinary purine metabolite testing. This could be due to various factors, including the influence of non-cancerous conditions that affect purine metabolism, such as subclinical inflammation, infection, or other metabolic disorders, which can also alter hypoxanthine and xanthine levels in urine. Additionally, follow-up and close observation are necessary for individuals confirmed to be positive among the control groups to rule out the possibility of hidden malignancies. Furthermore, the sample size, which is sufficient for the initial findings, requires expansion to larger and more diverse populations to validate these results. The metabolic influence of other factors, such as diet, medication, and co-existing metabolic disorders, requires further exploration to fine-tune the specificity of the purine metabolite test.

In conclusion, urinary hypoxanthine and xanthine tests emerged from our study as a promising screening tool for early PC detection. Its integration into clinical practice could lead to a new era in the management of this challenging malignancy. Further studies are needed to refine this diagnostic method and establish its role in the broader spectrum of oncological metabolomics, potentially enhancing early detection strategies and improving patient outcomes.

Acknowledgment

Contributors

The followings are the role of each author to this study; Study conceptualization and design: HH; Data curation, MK, BL, CHK, YY ; Data formal analysis: MK, BL, CHK ; Project administration: HH, BL ; Visualization: MK, BL; Figures and Tables: MK, BL; Writing and editing: MK, BL, JH

Declaration of interests

We declare no competing interests.

Funding

No funding was received

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Feasibility of Early Diagnosis of Pancreatic Cancer using reagent for analyzing purine metabolite (Hypoxanthine, Xanthine) in urine

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Version 1

Abstract

Introduction

Methods

Study design

Patients Eligibility

Variables

Sample collection

Measurement of hypoxanthine/xanthine concentration in urine using a purine metabolome analysis kit

Statistical analysis

Results

Demographics and study populations

Measurement of hypoxanthine/xanthine concentration in urine using a purine metabolome analysis kit

Perioperative and pathologic finding in PC group

Comparing the value of purine metabolome in urine and CA19-9 for pancreatic cancer

Discussion

Declarations

References

Additional Declarations

Status:

Version 1