Clinical evaluation of a novel method for the measurement of prostate‐specific antigen, AccuPSA^TM, as a predictor of 5‐year biochemical recurrence‐free survival after radical prostatectomy: results of a pilot study

Abstract

Study Type – Diagnostic (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Nadir Ultrasensitive PSA levels has some value for predicting BCR following RD. AccuPSA assays lower limit of PSA quantification of <0.01 pg/ml greatly enhances sensitivity and specificity of nadir PSA to predict BCR following RP. Our pilot study shows an AccuPSA of 3 pg/ml has a sensitory and specificity of 100% and 75% respectively for predicting 5 year BCR following RP. OBJECTIVES To conduct a proof of concept study to evaluate a novel digital single molecule immunoassay (AccuPSATM) that detects prostate‐specific antigen (PSA) a thousandfold more sensitively than current PSA detection methods. To determine the ability of the AccuPSATM assay to predict 5‐year biochemical recurrence (BCR)‐free survival after radical prostatectomy (RP). PATIENTS AND METHODS A total of 31 frozen serum specimens were obtained from specimen logs maintained at New York University Langone Medical Center and the Johns Hopkins University School of Medicine on men who had undergone RP. Those men without evidence of BCR had a minimum of 5 years' PSA follow‐up. In all cases, preoperative and pathological information were available, as was a serum specimen 3–6 months after RP, with a PSA level of <0.1 ng/mL measured by conventional PSA methods at the time of serum collection. Specimens were tested using the AccuPSATM method. A Cox proportional hazard model and Kaplan–Meier analysis were used to determine whether AccuPSATM predicted the risk of BCR. RESULTS Overall, 11/31 (35.5%) men developed BCR. Mean AccuPSATM nadir levels were significantly different (P < 0.001) between the non‐BCR group (2.27 pg/mL) and the BCR group (46.99 pg/mL). Using a multivariate Cox proportional hazard model, AccuPSATM nadir level was a significant predictor of BCR‐free survival (P < 0.01). Kaplan–Meier analysis of up to 5 years follow‐up showed that 100% of men with AccuPSATM nadir values <3 pg/mL did not develop BCR, whereas 62.5% of men with values >3 pg/mL developed BCR (P= 0.00024). The sensitivity, specificity, positive predictive value and negative predictive value of the AccuPSATM method was 100%, 75%, 69% and 100%, respectively. CONCLUSIONS AccuPSATM assay predicts 5‐year BCR‐ free survival after RP. Identifying a reliable predictor of BCR soon after RP has important implications for frequency of PSA testing, selection of candidates for adjuvant therapy, and reassuring a large subset of men that they are not at risk of recurrence. Larger studies are needed to validate these findings.

Do Ultrasensitive Prostate Specific Antigen Measurements Have a Role in Predicting Long-Term Biochemical Recurrence-Free Survival in Men after Radical Prostatectomy?

“…12,13,16 The 44 post-cystoprostatectomy specimens in this study all had detectable PSA concentrations with the AccuPSA assay (>0.035 pg/mL) and confirmed the two ultrasensitive results between 0.01 and 0.1 ng/mL. Using a threshold of 3.0 pg/mL, the AccuPSA assay has been reported to predict 5-year BCR-free survival with a sensitivity and specificity of 100% and 75%, respectively for recurrence.…”

“…Using a threshold of 3.0 pg/mL, the AccuPSA assay has been reported to predict 5-year BCR-free survival with a sensitivity and specificity of 100% and 75%, respectively for recurrence. 16 In the current study, 66% of results from post-cystoprostatectomy specimens were <3.0 pg/mL. In consideration of potential background PSA, further assessment of different generation PSA assays is needed.…”

“…13,14 Finally, the AccuPSA test (Quanterix Corporation) is a fifth generation assay utilizing SiMoA (single molecule array) technology with a LOQ of 0.035 pg/mL (0.000035 ng/mL). 15,16 At present however, none of these fourth or fifth-generation PSA assays are available for clinical use. In addition, the role of ultrasensitive PSA assays for BCR following RP has primarily been assessed in studies with small sample sizes and short-to intermediate term monitoring…”

Advancing the speed, sensitivity and accuracy of biomolecular detection using multi-length-scale engineering

“…The resulting data, when combined with measurements of Abeta42 levels, can predict cognitive outcome after brain hypoxia due to myocardial infarction 75,76 . The strategy has also been employed to detect toxins 77 , to detect early HIV infection 78 , to predict recurrence of prostate cancer 76,79 , and to measure inflammatory markers in patients with Crohn disease 80 . The digital ELISA method has also been used to measure the low (pg ml −1 ) levels of PSA in patients with prostate cancer who have undergone radical prostatectomies — these levels cannot be measured with a conventional ELISA 79 (Fig.…”

Single molecule enzyme-linked immunosorbent assays: Theoretical considerations

“…We have recently developed a method based on counting single enzyme-labeled immunocomplexes of proteins captured on paramagnetic beads in single molecule arrays (SiMoA) that is typically 1000-fold more sensitive than conventional enzyme-linked immunosorbent assay (ELISA) approaches. 6,7 This method—which we call digital ELISA—has been used to detect proteins important in prostate cancer, 6,7,8,9 Crohn’s disease, 10 and neurological disorders 11 at fg/mL concentrations. In this paper, we describe in detail the theoretical aspects of this digital immunoassay, including the binding kinetics of each step of the assay, and present a theoretical model for the generation of signal in the assay as a function of time, concentrations, and binding constants.…”