Abstract 3165: Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data

Abstract

Abstract Introduction: Although many (~40%) of the screen-detected prostate cancers are indolent (Gleason Score <= 6) and pose minimal risk for progression, advanced stage prostate cancer is a lethal disease with 5-year survival rates around 29%. The challenge is to identify biomarkers for early detection of aggressive disease, when the cancer is still organ confined. Such markers would be also used to better select patients with indolent and low risk cancers for active surveillance. Material and Methods: To identify a panel of protein markers that could predict prostate cancer progression, we developed ultra-sensitive, high-pressure, high-resolution separations coupled with intelligent selection and multiplexing-selected reaction monitoring (PRISM-SRM) assays for 52 protein markers. Candidate protein markers were identified and selected from existing prostate cancer genomics data sets and validated lists of known prostate cancer drivers. The PRISM-SRM assays used heavy isotope-labeled synthetic peptides as internal standards for quantitative proteomics analysis. Study comprised of a prostate cancer patient cohort with organ confined primary tumors (N=338) presenting following post-surgery features: 53 (15.7%) metastatic progression, 124 (36.7%) biochemical recurrence (BCR), and 161 (47.6%) no progression after more than ten years of follow-up after radical prostatectomy. Index tumor region for each case was scraped from representative 10-m sections of formalin-fixed paraffin embedded (FFPE)-whole-mounted prostatectomy specimens and processed for PRISM-SRM analysis. Results: Overall, PRISM-SRM analysis of the FFPE tissue samples enabled the detection of 42 (80.8%) out of 52 biomarker candidates; in comparison regular LC-SRM without the front-end chromatographic enrichment could detect only 21 (40.4%) of these candidates at the protein level. Kruskal-Wallis testing was used for statistical evaluation of the PRISM-SRM results and comparison of relative protein levels between the “no progression”, BCR and “metastatic progression” groups. Several prostate differentiation/androgen receptor signaling related proteins (FOLH1, PSA and NCOA) and tumor progression-related proteins (TGFB1, CCND1 and SPRC) had significantly different expression levels between the three groups, and showed initial promise in predicting progression to invasive cancer, BCR and metastasis. Conclusion: Ultra-sensitive targeted proteomics can be used to select and verify performance of early prognostic markers based on the analysis of prostatectomy specimens. The top performing markers appeared able to predict progression from organ confined cancer to BCR and metastasis. Citation Format: Yuqian Gao, Yi-Ting Wang, Hui Wang, Denise Young, Jennifer Cullen, Yingjie Song, Yongmei Chen, Athena Schepmoes, Gyorgy Petrovics, Thomas Fillmore, Tujin Shi, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, Albert Dobi, Inger Rosner, Karin Rodland, Isabell Sesterhenn, Shiv Srivastava, Tao Liu. Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3165.