Potential Utility of Novel Biomarkers in Active Surveillance of Low-Risk Prostate Cancer

Table 2

Studies investigating the prognostic value of novel biomarkers in active surveillance.

Biomarkers	Reference	Year		Predictor variables	Study endpoint(s)	Results
%−2proPSA, PHI	Makarov et al. [27]	2009	71	−2proPSA/%fPSA	Biopsy progression	−2proPSA/%fPSA was significantly associated with unfavorable biopsy in repeat biopsy (Cox HR, 2.53; 95% CI, 1.18–5.41; ).
	Isharwal et al. [28]	2011	71	−2proPSA/%fPSA, PHI, and biopsy tissue DNA content	Biopsy progression	PHI and −2proPSA/%fPSA showed improvement in the predictive accuracy (c-index, 0.6908 and 0.6884, resp.) for unfavorable biopsy conversion in the multivariate models including the biopsy tissue DNA content.
	Tosoian et al. [29]	2012	167	%fPSA, %−2proPSA, −2proPSA/%fPSA, and PHI	Biopsy progression	Baseline and longitudinal measurements of %fPSA, %−2proPSA, −2proPSA/%fPSA, and PHI demonstrated significant associations with biopsy reclassification, and %−2proPSA and PHI provided the greatest predictive accuracy for high-grade cancer.
	Hirama et al. [30]	2014	134	%−2proPSA, PHI	Biopsy progression	Baseline %−2proPSA and PHI were the only independent predictive factors for pathological upgrading in multivariate logistic regression analysis ( and , resp.).
PCA3	Ploussard et al. [41]	2011	106	PCA3 score	Prognostic pathologic findings in RP specimens	The risk of having a cancer ≥0.5 cm^3 and a significant PCa was increased by 3-fold in men with a PCA3 score of ≥25 compared with men with a PCA score of <25. In a multivariate analysis, a high PCA3 score (≥25) was an important predictive factor for tumor volume ≥0.5 cm^3 (OR: 5.4; ) and significant PCa (OR: 12.7; ).
	Tosoian et al. [42]	2010	294	PCA3 score	Biopsy progression	PCA3 alone could not be used to identify men with progression on biopsy (AUC, 0.589; 95% CI, 0.496–0.683; ). After adjustment for age and date of diagnosis, PCA3 was not significantly associated with progression on biopsy ().
	Lin et al. [43]	2013	387	PCA3 score	Biopsy progression	PCA3 score was significantly associated with a higher biopsy Gleason score and tumor volume in subsequent biopsies ( for all comparisons). Using log-transformed biomarker scores as continuous predictors, the OR for a Gleason score of ≥7 versus <7 for PCA3 was 1.67 (95% CI: 1.10–2.52; )
TMPRSS2:ERG	Lin et al. [43]	2013	387	TMPRSS2:ERG	Biopsy progression	TMPRSS2:ERG score was significantly associated with a higher biopsy Gleason score and tumor volume in subsequent biopsies ( for all comparisons). Using log-transformed biomarker scores as continuous predictors, the OR for a Gleason score of ≥7 versus <7 for TMPRSS2:ERG was 1.24 (95% CI: 1.01–1.53; ).
	Whelan et al. [49]	2013	216	TMPRSS2:ERG model; Secretion capacity model (PSA, total EPS RNA, and total EPS volume)	Upgrading Upstaging in RP specimens	The AUCs of the TMPRSS2:ERG model and the secretion capacity models for detecting upstaging in the NCCN AS group were 0.80 and 0.79, respectively. TMPRSS2:ERG model was associated with a reduced risk of upstaging and of both upstaging and Gleason upgrading by 2.4-fold and 2.7-fold, respectively ( and , resp.).
	Berg et al. [50]	2014	265	ERG positivity	Clinical progression; Biopsy progression; PSA progression	The ERG-positive group showed significantly higher incidences of overall AS progression () and of the subgroups PSA progression () and biopsy progression (). ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (HR, 2.45; 95% CI, 1.62–3.72; ).

%−2proPSA: percentage of −2proPSA to free PSA; PHI: Prostate Health Index; %fPSA: percentage of free PSA to total PSA; HR: hazard ratio; CI: confidence interval; RP: radical prostatectomy; PCa: prostate cancer; OR: odds ratio; AUC: area under the curve; PSA: prostate-specific antigen; EPS: expressed prostatic secretion; NCCN: National Comprehensive Cancer Network; AS: active surveillance.