Advertisement
You are prohibited from using or uploading content you accessed through this website into external applications, bots, software, or websites, including those using artificial intelligence technologies and infrastructure, including deep learning, machine learning and large language models and generative AI.
No AccessJournal of UrologyAdult Urology1 Nov 2016

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

    View All Author Information

    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.

    References

    • 1 SEER Stat Fact Sheet: Prostate Cancer. Available at http://seer.cancer.gov/statfacts/html/prost.html. Accessed August 1, 2015. Google Scholar
    • 2 : The CAPRA-S score: a straightforward tool for improved prediction of outcomes after radical prostatectomy. Cancer2011; 117: 5039. Google Scholar
    • 3 : Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One2013; 8: e66855. Google Scholar
    • 4 : A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol2014; 66: 550. Google Scholar
    • 5 : mRNA expression signature of Gleason grade predicts lethal prostate cancer. J Clin Oncol2011; 29: 2391. Google Scholar
    • 6 : Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer2015; 113: 382. Google Scholar
    • 7 : Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol2015; 33: 944. Google Scholar
    • 8 : Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol2013; 190: 2047. LinkGoogle Scholar
    • 9 : Characterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypes. Eur Urol2015; 68: 555. Google Scholar
    • 10 : The role of SPINK1 in ETS rearrangement-negative prostate cancers. Cancer Cell2008; 13: 519. Google Scholar
    • 11 : ETS rearrangements in prostate cancer. Asian J Androl2012; 14: 393. Google Scholar
    • 12 : Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate. Cancer2004; 100: 2362. Google Scholar
    • 13 : Tissue-based genomics augments post-prostatectomy risk stratification in a natural history cohort of intermediate- and high-risk men. Eur Urol2016; 69: 157. Google Scholar
    • 14 : A single-sample microarray normalization method to facilitate personalized-medicine workflows. Genomics2012; 100: 337. Google Scholar
    • 15 : Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med2016; 22: 369. Google Scholar
    • 16 : Testing mutual exclusivity of ETS rearranged prostate cancer. Lab Invest2011; 91: 404. Google Scholar
    • 17 : Therapeutic targeting of SPINK1-positive prostate cancer. Sci Transl Med2011; 3: 72ra17. Google Scholar
    • 18 : SPINK1 protein expression and prostate cancer progression. Clin Cancer Res2014; 20: 4904. Google Scholar
    • 19 : SPOP mutations in prostate cancer across demographically diverse patient cohorts. Neoplasia2014; 16: 14. Google Scholar
    • 20 : ERG protein expression in diagnostic specimens is associated with increased risk of progression during active surveillance for prostate cancer. Eur Urol2014; 66: 851. Google Scholar
    • 21 : ERG induces taxane resistance in castration-resistant prostate cancer. Nat Commun2014; 5: 5548. Google Scholar
    • 22 : Molecular profiling of ETS gene rearrangements in patients with prostate cancer registered in REDEEM clinical trial. Urol Oncol2015; 33: 108. Google Scholar
    • 23 : Natural history of progression after PSA elevation following radical prostatectomy. JAMA1999; 281: 1591. Crossref, MedlineGoogle Scholar
    Advertisement