Abstract
The diagnostic specificity of prostate specific antigen (PSA) is limited. We aimed to characterize eight anti-PSA monoclonal antibodies (mAbs) to assess the prostate cancer (PCa) diagnostic utility of different PSA molecular forms, total (t) and free (f) PSA and PSA complexed to α1-antichymotrypsin (complexed PSA). MAbs were obtained by immunization with PSA and characterized by competition studies, ELISAs and immunoblotting. With them, we developed sensitive and specific ELISAs for these PSA molecular forms and measured them in 301 PCa patients and 764 patients with benign prostate hyperplasia, and analyzed their effectiveness to discriminate both groups using ROC curves. The free-to-total (FPR) and the complexed-to-total PSA (CPR) ratios significantly increased the diagnostic yield of tPSA. Moreover, based on model selection, we constructed a multivariable logistic regression model to predictive PCa that includes tPSA, fPSA, and age as predictors, which reached an optimism-corrected area under the ROC curve (AUC) of 0.86. Our model outperforms the predictive ability of tPSA (AUC 0.71), used in clinical practice. In conclusion, The FPR and CPR showed better diagnostic yield than tPSA. In addition, the PCa predictive model including age, fPSA and complexed PSA, outperformed tPSA detection efficacy. Our model may avoid unnecessary biopsies, preventing harmful side effects and reducing health expenses.
Highlights
The diagnostic specificity of prostate specific antigen (PSA) is limited
High levels of PSA are a useful marker for prostate cancer (PCa) detection[4], for monitoring follow-up and progression after radical prostatectomy[5], and for monitoring local or systemic therapy[6,7], levels of PSA are increased in some patients with benign prostatic hyperplasia, acute prostatitis[8] or prostate manipulations, leading to unnecessary negative biopsies or to over detection of non-significant cancers
We evaluated the clinical usefulness to discriminate between PCa and non-PCa for these molecular forms, using ROC curves as well as combination of several biomarkers in a predictive model that may enhance sensitivity and specificity of PSA alone
Summary
The diagnostic specificity of prostate specific antigen (PSA) is limited. We aimed to characterize eight anti-PSA monoclonal antibodies (mAbs) to assess the prostate cancer (PCa) diagnostic utility of different PSA molecular forms, total (t) and free (f) PSA and PSA complexed to α1-antichymotrypsin (complexed PSA). Novel score tests to provide the risk of PCa derived from a mathematical algorithm for different kallikrein biomarkers as well as other clinical information, have been developed[17,18] They are known as: 4 K Score [total PSA (tPSA), free PSA (fPSA) and intact PSA and human kallikrein 2 hK2)]19,20, Prostate Health Index (PHI) (tPSA, fPSA ratio and [−2]proPSA)[21,22] or Stockholm-3 test[23,24] (tPSA, fPSA and intact PSA, hK2, MSMB, MIC1, genetic polymorphisms, age, family history, previous prostate biopsy, DRE and prostate volume). The presence of different molecular forms of PSA and kK2 in serum, illustrates the need to develop new anti-PSA antibodies that do not cross-react with hK2 and may distinguish between fPSA and PSA-α1ACT more precisely
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