RAMB - JULHO 2017

rinary

EN-2

predict

prostate

cancer

: S

ystematic

review

and

meta

analysis

ssoc

ras

2017; 63(7):656-661

657

Recently, engrailed-2 (EN2), a protein found in the

urine of patients with PCa, proved to be a potential bio-

marker for the diagnosis of PCa compared to ELISA.

The identification of cancer biomarkers that can be

measured in a noninvasive way should improve the spec-

ificity of PSA in the detection of PCa. Thus, we performed

a systematic review and meta-analysis to verify the ac-

curacy of EN2 as a potential biomarker of PCa.

ethod

Data sources and searches

The study protocol was registered at PROSPERO 35417

and included a systematic review according to protocol and

PRISMA-statement guidelines.

We searched the Medline (PubMed), Embase, Co-

chrane Central Register of Controlled Trials, Ibecs, Bio-

sis, Web of Science, Scopus, Conference Abstracts and

Grey Literature (Google Scholar; British Library) data-

bases from January 2005 to July 2016. We used the fol-

lowing terms, both as text words, Medical Subjects Head-

ing (MeSH) or equivalent subject heading/thesaurus

terms: “Prostate cancer” and “prostatic neoplasms.” These

terms were combined with “engrailed-2.” The search had

no language restrictions. The reference list of all available

primary studies was reviewed to identify additional rel-

evant studies. A copy of the complete search strategy is

available on request.

For this review, we used the definitions: Index test –

The diagnostic test consisted of the urine EN2 analysis

and Reference standard

–

The diagnostic reference was

the result of the histological analysis of standard paraffin-

-embedded sections.

The inclusion criteria for this systematic review were:

studies measuring EN2 levels in at least two histological

diagnoses comparing with PCa, benign or normal pros-

tate tissue.

Study selection

The abstracts/titles identified from the search were

screened by two reviewers (E.R.D. and M.C.M.A.). Dis-

agreements about the inclusion or exclusion of studies

were resolved by consensus, and, if consensus was not

possible, disagreements were resolved by a third reviewer

(M.I.R). The final inclusion or exclusion of a study was

made with a standard checklist. We included case-control

and cohort studies, both prospective and retrospective.

Data extraction and quality assessment

We extracted data in duplicate (E.R.D. and M.C.M.A) with

a standard form. We extracted information about study

design, participants’ description, index test description,

reference test description, and total number of participants.

A 2x2 table was created for each study comparing EN2

levels and the histologic diagnosis.

The eligibility criteria of all articles were assessed us-

ing Quality Assessment of Diagnostic Accuracy Studies

(Quadas-2). This tool comprises four domains: patient

selection, index test, reference standard, and flow and

timing. Each domain is assessed in terms of the risk of

bias, and the first three domains are also assessed in terms

of concerns regarding applicability. Signaling questions

are included to help judge the risk of bias.

The quality

assessment of the studies was independently performed

by two authors (E.R.D. and M.C.M.A). Any disagreement

was resolved by consensus.

Data synthesis and statistical analysis

For each study, 2x2 contingency tables were constructed

so that all cases were classified as PCa or benign lesions

We calculated the true-positive rate (TPR; sensitivity),

specificity, and false-positive rate (FPR; 1 – specificity).

Bivariate analysis was used to calculate the pooled esti-

mates of sensitivity, and specificity with 95% confidence

intervals (95CI) for the summary estimates.

The diag-

nostic odds ratio (DOR) can relate to different combina-

tions of sensitivity and specificity. The DOR describes the

odds of positive test results in participants with disease

compared with the odds of positive test results in those

without disease.

Statistical analysis was performed using Meta-DiSc®

(Clinical Biostatistics Unit, Ramón y Cajal Hospital, Madrid,

Spain) (version 1.4) and RevMan 5.3 software.

11,12

esults

The searches identified a total of 248 studies, of which

17 were potentially relevant after initial assessment. Of

these, 15 full-text studies were excluded. Two primary

studies (Morgan et al. and Killick et al.)

7,13

involving 597

participants met the criteria for inclusion and were

analyzed (Figure 1).

The main characteristics of the included studies are

shown in Table 1. Both were conducted in the UK and

used ELISA assay for diagnosis.

Methodological quality of included studies

The risk of bias for patient selection, index test, reference

standard, flow and timing, as well as the concerns for

applicability related to the first three domains, are shown

in Figure 2. The Quadas-2 items for Morgan study had

low risk of bias in all domains. The second study by