Prostate cancer is clinically and molecularly heterogeneous. We sought to determine the prognosis of men with ERG-ETS fusions and SPINK1 overexpression.

Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy prior to metastasis. A case-cohort design sampled two cohorts; one (n=262) enriched with metastasis from the entire cohort and one (n=213) enriched with metastasis from patients with biochemical recurrence (BCR). We analyzed transcriptomic profiles and subtyped tumors as m-ERG(+), m-ETS(+), m-SPINK1(+) or Triple Negative (m-ERG(─)/m-ETS(─)/m-SPINK1(─)). and multivariable logistic regression analyses, Kaplan Meier, and multivariable Cox models were used to evaluate subtypes as predictors of clinical outcomes.

36%, 13%, 11% and 40% of PCa were classified as m-ERG(+), m-ETS(+), m-SPINK1(+), and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1(+) tumors were more common in African-Americans (OR: 5, 95% CI 1.6 - 16) but less commonly associated with positive surgical margins (OR: 0.16, 95% CI 0.03 - 0.69) when compared to m-ERG(+) patients. Compared to the Triple Negative group, m-SPINK1(+) showed similar associations with race and surgical margins in univariable and multivariable analyses across the entire cohort. Survival analyses did not show significant differences between m-ERG(+), m-ETS(+) and Triple Negative patients. m-SPINK1(+) independently predicted prostate cancer specific mortality after metastasis (HR:2.48, 95%CI 0.96-6.4) and biochemical recurrence (HR:3, 95% CI 1.1-8).

SPINK1 overexpression is associated with prostate cancer specific mortality in at-risk men with biochemical and clinical recurrence following prostatectomy. ERG-ETS alterations are not prognostic for outcome.