SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy Cohort.

Purpose: Prostate cancer is clinically and molecularly heterogeneous. We determined the prognosis of men with ERG-ETS fusions and SPINK1 over expression.

Materials And Methods: Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy before metastasis. A case-cohort design sampled a cohort (262) enriched with metastasis from the entire cohort and a cohort (213) enriched with metastasis from patients with biochemical recurrence. 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.

Results: Overall 36%, 13%, 11% and 40% of prostate cancer was classified as m-ERG, m-ETS, m-SPINK1 and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1 tumors were more common in African-American men (OR 5, 95% CI 1.6-16) but less commonly associated with positive surgical margins (OR 0.16, 95% CI 0.03-0.69) compared to the m-ERG group. 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 among m-ERG, m-ETS and Triple Negative cases. 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).

Conclusions: SPINK1 over expression is associated with prostate cancer specific mortality in at risk men with biochemical and clinical recurrence after prostatectomy. ERG-ETS alterations are not prognostic for outcome.