CXCR4-A Prognostic and Clinicopathological Biomarker for Pancreatic Ductal Adenocarcinoma: A Meta-Analysis

<div><p>Adenocarcinomas of the pancreatic duct (PDAC) are characteristically aggressive tumors that are extremely challenging to treat as curative surgical resection, the definitive treatment, is seldom possible. Regretably, most patients are diagnosed with metastatic disease at the time of initial presentation. In addition, current chemotherapeutic concepts that are used for advanced disease stages show frustrating results. Thus, there is an urgent need to identify novel therapeutic molecular targets that are associated with PDAC disease. Recently, the chemokine receptor CXCR4 has been demonstrated to be highly expressed in metastatic PDAC. However, the results of the published data on CXCR4 and its association with clinicopathological variables and prognosis in PDAC seem to be heterogeneous. Consequently, to clarify the relevance of CXCR4 as a biomarker in PDAC we performed a comprehensive literature search by using PubMed and Web of Science databases to identify articles that focused on the expression of CXCR4 in PDAC by using immunohistochemistry. Subsequently, data from nine relevant studies, encompassing 1183 patients were extracted, qualitatively assessed, and entered into a meta-analysis. By using a random effects model, the pooled hazard ratio of the seven studies that reported on patients overall survival revealed a correlation between expression of CXCR4 and poor prognosis (HR 1.49; 95% CI: 1.04-2.14; <i>P</i> = 0.03; I² = 74%). Although heterogeneity became evident, subgroup analyses confirmed the prognostic value of CXCR4 in PDAC, especially in high-quality studies that performed multivariate analysis. In addition, meta-analysis revealed a strong association of CXCR4 expression with the UICC stage (OR: 3.40; 95% CI: 1.67-6.92; <i>P</i> = 0.0007; I² = 0%) and metastatic disease (N-status: OR: 2.55; 95% CI: 1.56-4.15; <i>P</i> = 0.0002; I² = 26%; recurrence to the liver: OR: 2.80; 95% CI: 1.48-5.29; <i>P</i> = 0.001; I² = 0%). Taken together, our meta-analysis suggests that CXCR4 represents a useful prognostic biomarker in PDAC and might therefore be evaluated as a potential therapeutic target in the treatment of metastatic cancer disease of the pancreas.</p></div

Clinical and methodological characteristics of included studies.

<p>Abbreviation: PMID, PubMed Id; G, gender; D, differentiation; S, UICC stage; Du, Dukès classification; T, depth of invasion; N; lymph node metastasis; Lvi; lymphatic vessel invasion; Vi, blood vessel invasion; NA, not available; IHC, immunohistochemistry, TMA, tissue microarray; PCR, polymerase chain reaction.</p

Association between survivin and lymph node metastasis or blood vessel invasion.

<p>Forest blot reflects the individual summarized OR with CI for the relationship between expression of survivin and (<b>A</b>) lymph node metastasis or (<b>B</b>) blood vessel invasion. Heterogeneity was verified by the Cochrane Q test (Chi-squared test; Chi²) and inconsistency (I²).</p

Subgroup analyses evaluating methodological and demographic effects on the association between CXCR4 and overall survival in patients with PDAC.

<p>Subgroup analyses evaluating methodological and demographic effects on the association between CXCR4 and overall survival in patients with PDAC.</p

Study quality assessment according to the ELCWP Scale.

<p>Abbreviation: NA, not assessed</p><p>^# p-value not calculated because of low study number</p><p>*included 2 studies without survival analysis</p><p>Study quality assessment according to the ELCWP Scale.</p

Analysis for potential publication bias.

<p>Funnel plots were prepared to assess publication bias with respect to the analyzed variable <b>(A)</b> sex, <b>(B)</b> depth of invasion (T-stage), <b>(C)</b> lymph node metastasis (N-status), <b>(D)</b> UICC tumor stage and <b>(E)</b> grade of differentiation. Y-axis represents the standard error (SE), x-axis represents the study's result.</p

Flow chart summarising the literature search and study selection.

<p>Flow chart summarising the literature search and study selection.</p

Meta-analysis assessing the relationship between survivin expression and clinicopathological variables.

<p>Meta-analysis assessing the relationship between survivin expression and clinicopathological variables.</p

Association between CXCR4 and hepatic metastasis during follow up.

<p>Forest plot reflects the individual and pooled OR with CI to assess the association between CXCR4 and hepatic metastasis during follow up. Heterogeneity was quantified by the Cochrane Q test (Chi-squared test; Chi²) and inconsistency (I²).</p

Clinical and methodological characteristics of included studies.

<p>Abbreviation: A, age; D, differentiation; Lvi, lymphovascular invasion; Le, lymphatic embolus; M, distant metastasis; N, lymph node metastasis; Pn, perineural invasion; S, sex; T, depth of invasion; U, UICC stage; Ve, vascular embolus; NS, not specified</p><p>* liver metastasis specified as recurrence</p><p>^$, distant recurrence without organ specification</p><p>^# 428 patients in multivariate analysis</p><p>^§ 249 patients evaluable</p><p>UV, univariate; MV, multivariate</p><p>^Ф, only for 17 patients without recurrence or dead.</p><p>Clinical and methodological characteristics of included studies.</p