The association between SPINK1 and clinical outcomes in patients with prostate cancer: a systematic review and meta-analysis

Figures & data

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of search results.

Table 1 Characteristics of included studies

Studies	Patients	N	Country	Age (years)	PSA (ng/mL)	Gleason score	Follow-up (months)
Tomlins et al^Citation5	RP/TURP	971	USA	NA	NA	NA	NA
Leinonen et al^Citation8	Endocrine Treated	186	Finland	+: 71.6±8.4 −: 73.8±6.8	+: 63±104 −: 105±429	<7: 25.8% 7: 29.0% >7: 41.9%	70 (2–118)
Lippolis et al^Citation14	RP	3,385	Germany	≤49: 2.9% 50–60: 26.0% 60–70: 63.8% >70: 7.3%	>4: 15.3% 4–10: 55.8% 10–20: 21.1% >20: 7.8%	≤3+3: 38.8% 3+4: 46.4% 4+3: 11.6% ≥4+4: 3.2%	65.8 (1–219)
Grupp et al^Citation15	RP	8,260	Germany	<50: 2.9% 50–60: 24.8% 60–70: 58.7% >70: 12.9%	<4: 12.6% 4–10: 60.4% 10–20: 19.4% >20: 6.5%	≤3+3: 25.6% 3+4: 14.0% 4+3: 55.4% ≥4+4: 4.3%	36.8 (1–228)
Wang et al^Citation16	RP	211	China	≤70: 70.6% >70: 29.4%	<4: 10.4% 4–10: 12.8% >10: 76.8%	<7: 21.8% 7: 33.2% >7: 45.0%	NA
Flavin et al^Citation7	RP	854	Ireland	65.4±6.0	7.0±5.6	2–6: 21.0% 3+4: 37.0% 4+3: 24.3% 8–10: 17.6%	13.5±4.6
Brooks et al^Citation17	RP	963	USA	61.7±7.2	8.7±8.8	<7: 94.0% 3+4: 40.2% 4+3: 12.5% >7: 10.1%	NA
Terry et al^Citation6	RP	279	France	64.1 (44.2–75.2)	13.5 (1.3–119)	<7: 43.0% 3+4: 13.7% 4+3: 18.8% >7: 24.6%	50.1 (1–190.5)
Tomlins et al^Citation13	RP	1,577	USA	63 (37.3–83)	<10: 47.2% 10–20: 19.7% >20: 15.6% NA: 20.3%	≤6: 16.2% 7: 56.3% 8: 12.1% ≥9: 17.9% NA: 0.3%	NA
Pan et al^Citation18	mPCa	155	China	72.6±7.9	70.2±35.4	<7: 5.8% 3+4: 8.4% 4+3: 26.5% >7: 59.4%	38.0 (6–63)
Noh et al^Citation19	RP	64	Korea	+: 66.9±5.5 −: 63.9±5.3	+: 8.8±6.9 −: 13.2±10.0	<7: 27.9% 7: 52.9% >7: 19.1%	49.2 (11–111)
Huang et al^Citation20	RP	178	Canada	NA	NA	<7: 31.1% 7: 56.1% >7: 12.7%	42.0 (0–142)
Johnson et al^Citation21	mPCa	60	USA	+: 60 (46–71) −: 59 (40–71)	<10: 56.7% 10–20: 30.2% >20: 12.1%	≤6: 37.4% 7: 46.2% 8: 12.9% ≥9: 4.4%	48.0 (24–84)

Notes: For age and PSA, data were represented as mean ± SD, mean (range), or percentage. Follow-up was presented as median (range) or mean ± SD.

Abbreviations: PSA, prostate specific antigen; mPCa, metastatic prostate cancer; NA, not available; RP, radical prostatectomy; SD, standard deviation; TURP, transurethral resection of prostate; +, SPINK1 positive; −, SPINK1 negative.

Table 2 Risk of bias for included studies

Studies	Year	Selection				Comparability	Outcome			Total
		➀	➁	➂	➃		➄	➅	➆
Tomlins et al^Citation5	2008	★	★	★	★	★★	★	★	✰	8
Leinonen et al^Citation8	2010	★	★	★	★	★★	★	✰	✰	7
Lippolis et al^Citation14	2013	★	★	★	★	★★	★	★	✰	8
Grupp et al^Citation15	2013	★	★	★	★	★★	★	★	✰	8
Wang et al^Citation16	2014	★	★	★	★	★★	★	✰	✰	7
Flavin et al^Citation7	2014	★	★	★	★	★★	★	★	★	9
Brooks et al^Citation17	2015	★	★	★	★	★★	★	✰	✰	7
Terry et al^Citation6	2015	★	★	★	★	★★	★	★	✰	8
Tomlins et al^Citation13	2015	★	★	★	★	★★	★	★	✰	8
Pan et al^Citation18	2016	★	★	★	★	★★	★	★	★	9
Noh et al^Citation19	2016	★	★	★	★	★★	★	★	★	8
Huang et al^Citation20	2016	★	★	★	★	★★	★	★	✰	8
Johnson et al^Citation21	2016	★	★	★	★	★★	★	★	★	8

Notes: ➀ Representativeness of the exposed cohort; ➁ Selection of the nonexposed cohort; ➂ Ascertainment of exposure; ➃ Outcome not present at start; ➄ Assessment of outcome; ➅ Adequate follow-up length; ➆ Adequacy of follow-up. The solid star represented adequate illustration of the corresponding items. The hollow star represented the opposite.

Figure 2 Forest plots of SPINK1 expression and survival outcomes.

Notes: (A) Biochemical recurrence-free survival, (B) prostate cancer-specific mortality-free survival, (C) overall survival, and (D) CRPC-free survival.
Abbreviations: CI, confidence interval; CRPC, castration-resistant PC, ; df, degrees of freedom; SE, standard error; SPINK1, serine peptidase inhibitor Kazal type 1.

Figure 3 Funnel plot created by outcome of biochemical recurrence-free survival.

Abbreviation: SE, standard error.

Table 3 Summary of findings of graded quality of evidence for all outcomes

Quality assessment					No of participants (studies)	Relative effect (95% CI)	Quality	Importance
Risk of bias	Inconsistency	Indirectness	Imprecision	Other
Biochemical recurrence-free survival
Not serious	Serious	Not serious	Not serious	None	16,760 (9 studies)	HR 1.41 (1.01–1.97)	Very low	Critical
PCSM-free survival for radical prostatectomy
Serious	Serious	Not serious	Serious	None	3,630 (4 studies)	HR 0.69 (0.21–2.25)	Very low	Critical
CRPC-free survival
Serious	Serious	Not serious	Serious	None	341 (2 studies)	HR 3.07 (0.98–9.63)	Very low	Critical
Overall survival for radical prostatectomy
Not serious	Not serious	Not serious	Serious	None	1,972 (2 studies)	HR 0.89 (0.58–1.35)	Very low	Critical
Overall survival for metastatic prostate cancer
Serious	Not serious	Not serious	Serious	None	155 (1 study)	HR 2.59 (1.16–5.78)	Very low	Critical

Abbreviations: CI, confidence interval; CRPC, castration-resistant PCa; HR, hazard ratio; PCSM, prostate cancer-specific mortality.

TomlinsSAAlshalalfaMDavicioniECharacterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypesEur Urol201568455556725964175

 PubMed Web of Science ®Google Scholar

LeinonenKATolonenTTBrackenHAssociation of SPINK1 expression and TMPRSS2:ERG fusion with prognosis in endocrine-treated prostate cancerClin Cancer Res201016102845285120442300

 PubMed Web of Science ®Google Scholar

LippolisGEdsjoAStenmanUHBjartellAA high-density tissue microarray from patients with clinically localized prostate cancer reveals ERG and TATI exclusivity in tumor cellsProstate Cancer Prostatic Dis201316214515023459095

 PubMedGoogle Scholar

GruppKDiebelFSirmaHSPINK1 expression is tightly linked to 6q15- and 5q21-deleted ERG-fusion negative prostate cancers but unrelated to PSA recurrenceProstate201373151690169823843146

 PubMedGoogle Scholar

WangCWangLSuBSerine protease inhibitor Kazal type 1 promotes epithelial-mesenchymal transition through EGFR signaling pathway in prostate cancerProstate201474768970124619958

 PubMedGoogle Scholar

FlavinRPetterssonAHendricksonWKSPINK1 protein expression and prostate cancer progressionClin Cancer Res201420184904491124687926

 PubMedGoogle Scholar

BrooksJDWeiWHawleySEvaluation of ERG and SPINK1 by immunohistochemical staining and clinicopathological outcomes in a multi-institutional radical prostatectomy cohort of 1067 patientsPLoS One2015107e013234326172920

 PubMedGoogle Scholar

TerrySNicolaiewNBassetVClinical value of ERG, TFF3, and SPINK1 for molecular subtyping of prostate cancerCancer201512191422143025639219

 PubMedGoogle Scholar

TomlinsSARhodesDRYuJThe role of SPINK1 in ETS rearrange ment-negative prostate cancersCancer Cell200813651952818538735

 PubMed Web of Science ®Google Scholar

PanXZhangXGongJThe expression profile and prognostic value of SPINK1 in initially diagnosed bone metastatic prostate cancerProstate201676982383327159572

 PubMedGoogle Scholar

NohBJSungJYKimYWChangSGParkYKPrognostic value of ERG, PTEN, CRISP3 and SPINK1 in predicting biochemical recurrence in prostate cancerOncol Lett20161163621363027284364

 PubMedGoogle Scholar

HuangKCEvansADonnellyBBismarTASPINK1 overexpression in localized prostate cancer: a rare event inversely associated with ERG expression and exclusive of homozygous PTEN deletionPathol Oncol Res Epub20161013

 Google Scholar

JohnsonMHRossAEAlshalalfaMSPINK1 defines a molecular subtype of prostate cancer in men with more rapid progression in an at risk, natural history radical prostatectomy cohortJ Urol201619651436144427238617

 PubMedGoogle Scholar