Abstract
Although ~40% of screen-detected prostate cancers (PCa) are indolent, advanced-stage PCa is a lethal disease with 5-year survival rates around 29%. Identification of biomarkers for early detection of aggressive disease is a key challenge. Starting with 52 candidate biomarkers, selected from existing PCa genomics datasets and known PCa driver genes, we used targeted mass spectrometry to quantify proteins that significantly differed in primary tumors from PCa patients treated with radical prostatectomy (RP) across three study outcomes: (i) metastasis ≥1-year post-RP, (ii) biochemical recurrence ≥1-year post-RP, and (iii) no progression after ≥10 years post-RP. Sixteen proteins that differed significantly in an initial set of 105 samples were evaluated in the entire cohort (n = 338). A five-protein classifier which combined FOLH1, KLK3, TGFB1, SPARC, and CAMKK2 with existing clinical and pathological standard of care variables demonstrated significant improvement in predicting distant metastasis, achieving an area under the receiver-operating characteristic curve of 0.92 (0.86, 0.99, p = 0.001) and a negative predictive value of 92% in the training/testing analysis. This classifier has the potential to stratify patients based on risk of aggressive, metastatic PCa that will require early intervention compared to low risk patients who could be managed through active surveillance.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed cancer in men, except for superficial skin cancer, and the second leading cause of death due to cancer among American men [1,2]
Using synthetic peptides with and without heavy isotope labeling of C-terminal lysine or arginine, highly sensitive, precise, and multiplex PRISM-SRM assays were developed in our laboratory using procedures we previously established
This project focused on identifying robust biomarkers to predict patients at risk for future cancer progression, including biochemical recurrence and distant metastasis, to enhance existing biopsy or pathology factors used for risk stratification and to provide additional support for safe delay of invasive treatment versus early, aggressive therapy
Summary
Prostate cancer (PCa) is the most commonly diagnosed cancer in men, except for superficial skin cancer, and the second leading cause of death due to cancer among American men [1,2]. Prostate cancer has a complex disease spectrum, ranging from clinically indolent to aggressive subtypes with a high degree of molecular and cellular heterogeneity [3,4,5,6,7]. Prostate cancer screening based on serum prostate-specific antigen (PSA) results in many false positives, biopsy complications, and overdiagnosis that leads to overtreatment [8,9]. Conventional primary and repeat biopsies can be inaccurate and pose unnecessary risks.
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