Systemic and tumor-specific inflammatory markers VCAM-1 and ICAM-1 as indicators of extent of surgery and oncologic outcome in advanced ovarian cancer

Abstract

Background: Cytoreductive surgery in advanced ovarian cancer presents significant challenges and there is a need for an improved patient selection to surgical treatment. Cytokines and adhesion molecules are key regulators of immune responses, playing crucial roles in tumor cell adhesion, metastasis, and immune evasion. They shape the tumor microenvironment and influence systemic immunity, ultimately affecting cancer progression. Despite their recognized significance in cancer biology, the potential of cytokines as predictive biomarkers for surgical complexity and recurrence in ovarian cancer remains insufficiently characterized. This study aimed to elucidate the correlation between inflammatory cytokines and surgical outcomes, to identify reliable liquid or tissue-based biomarkers that could enhance patient stratification and support preoperative decision-making in ovarian cancer management.

Methods: The Concentration of 10 inflammatory cytokines and 2 adhesion molecules concentrations were measured by Luminex based assay in blood, tumor tissue, and ascitic fluid samples from patients with advanced ovarian cancer prior to cytoreductive surgery. Clinical data were prospectively collected. Correlations between cytokines and adhesion molecules levels and surgical complexity, as well as disease/cancer recurrence, were assessed using Pearson two-tail statistical test analyses. The association between adhesion molecules and surgical extent, and recurrence was analysed using logistic regression yielding odds ratios (OR) with 95 % confidence intervals, adjusted for relevant covariates. The diagnostic accuracy of biomarker candidates was evaluated using receiver operating characteristic (ROC) curve analysis RESULTS: In blood, higher VCAM-1 and ICAM-1 levels correlated with lower surgical complexity scores, while ascitic VCAM-1 was linked to longer surgical durations. CXCL-12 in tumor and IL-32 in ascites were positively correlated with increased surgery duration, indicating their role in systemic inflammation. Elevated VCAM-1 and ICAM-1 levels in tumor tissue were strongly associated with increased cancer recurrence risk, suggesting their involvement in metastasis and immune evasion. Traditional preoperative markers, including albumin and CRP, did not correlate significantly with surgical complexity, highlighting the need for novel biomarkers. In the adjusted multivariable regression model, VCAM-1 in blood was associated with recurrence, OR 10.1 (95 % CI, 1.30-77.8; p=0.027). Similarly, VCAM-1 in blood demonstrated exceptional predictive capability, Area Under Curve=0.886 with cutoff point of 0.696.

Conclusions: Inflammatory markers can serve as valuable predictors of surgical complexity and recurrence in advanced ovarian cancer. Particularly the levels of VCAM-1 in blood was identified as a potential predictive marker to be tested in adequately powered clinical studies. Incorporating these markers into preoperative assessments could improve surgical planning and enhance patient stratification. Further validation and mechanistic studies are needed to fully understand their role in ovarian cancer progression.

Trial registration: ClinicalTrials.gov nr: NCT04065009, European Union Clinical Trials Register nr: 2019-003299-38/SE.

Keywords: Advanced ovarian cancer; Biomarker; Cytoreductive surgery; Surgical complexity.

Fig. 1

Prolonged surgery duration correlates with specific inflammatory markers in blood, tumor, and ascitic fluid. Bioplex analysis revealed significant differences of VCAM-1, ICAM-1levels in blood (A), only VCAM1 levels in ascites (A-C) Levels of VCAM-1, CXCL12, and ICAM-1 in tumor tissue showed negative correlations with surgery duration. (D) In ascitic fluid, IL-32 exhibited a strong positive correlation with surgery duration. (E-H) Positive correlations were observed between surgery duration and levels of CCL2 and CXCL12 in blood, while CCL5 was negatively correlated. (I) Comparison of albumin, CRP, fibrinogen, and transthyretin levels in patients with surgery durations above and below the median. (J-L) Inflammatory markers in blood, tumor, and ascitic fluid were stratified by surgery duration, divided into above or below the median of 336 minutes. Statistical significance was determined using Pearson correlation coefficient, with p-values indicated in the panels. Data represent 40 independent samples.

Fig. 2

Higher surgery complexity scores are associated with differential levels of inflammatory markers in blood, tumor, and ascitic fluid. Significant differences were observed in the levels of VCAM-1, ICAM-1 in blood, VCAM1, ICAM1, and VEGF in tumour, only VCAM1 in ascites. (A) Tumor ICAM-1 and (B-C) ascitic IL-8 and CXCL12 levels showed correlations with the surgery complexity score. (D) IL-32 in ascitic fluid exhibited a strong positive correlation with the surgery complexity score (r = 0.6276, p < 0.0001). (E-G) In blood, negative correlations were found between surgery complexity score and CCL5, CXCL1, and VCAM-1 levels. (H Comparison of albumin, CRP, fibrinogen, and transthyretin levels between the two surgery complexity groups. (I-K) Inflammatory marker concentrations were measured in blood, tumor, and ascitic fluid, stratified by surgery complexity scores (low-medium: 0–7, n = 15; high: 8–8+, n = 25). Statistical significance was determined using Pearson correlation coefficient, with p-values indicated in the panels. Data represent 40 independent samples.

Fig. 3

Patients with recurrence exhibit distinct inflammatory marker profiles compared to those without recurrence. (A) Comparison of albumin, CRP, fibrinogen, and transthyretin levels in patients with surgery durations above and below the median. No significant associations were observed between these markers and recurrence (B) In tumor samples, VCAM-1 and ICAM-1 levels were elevated in the recurrence group (*p < 0.05, ****p < 0.0001). (C) Ascitic fluid showed no statistically significant differences between recurrence and no-recurrence groups, although trends in inflammatory marker levels were observed (D) In blood, levels of ICAM-1 were significantly higher in patients with recurrence (n = 28) compared to those without recurrence (n = 11) (****p < 0.0001). Statistical comparisons were made using ANOVA test, and data represent 40 independent samples.

Fig. 4

ROC curve analyses of VCAM-1 and ICAM-1 to predict surgical complexity and recurrence, adjusted for clinical variables. A-E. ROC curves evaluating the performance of VCAM-1 and ICAM-1 levels in tumor, blood and ascites samples for predicting high surgical complexity scores adjusted for preoperative suspected FIGO stage (III vs. IV). (A) Tumor VCAM-1, (B) Tumor ICAM-1, (C) Blood VCAM-1, (D) Blood ICAM-1, (E) Ascites VCAM-1. F–H. ROC curves assessing VCAM-1 and ICAM-1 as biomarkers for disease recurrence adjusted for clinical variables that may be known prior to the surgical procedure: Age (years, continuous), ECOG performance status (0, 1 or 2), BRCA mutation in tumour (yes vs. no) Preoperative suspected FIGO stage (III vs. IV) . (F) Tumor VCAM-1, (G) Tumor ICAM-1, (H) Blood VCAM-1. All values represent adjusted models. The AUC, optimal cut-off, sensitivity, and specificity values are indicated on each plot. Abbreviations: ROC, Receiver operating characteristic; VCAM-1, Vascular Cell Adhesion Molecule 1; ICAM-1, Intercellular Cell Adhesion Molecule 1; AUC, Area Under Curve; PPV, Positive Predictive Value; NPV, Negative Predictive value; TPR; True Positive Rate; FPR, False Positive Rate; FIGO, International Federation of Gynecology and Obstetrics; ECOG, Eastern Cooperative Oncology Group performance status; BRCA, BReast CAncer gene 1 or 2.