PSA Velocity Is Associated With Gleason Score in Radical Prostatectomy Specimen: Marker for Prostate Cancer Aggressiveness
George Washington University, Washington, Washington, D.C., United States Urology
(Impact Factor: 2.19).
07/2008; 72(5):1116-20; discussion 1120. DOI: 10.1016/j.urology.2008.01.082
Conflicting evidence has been reported on the association of prostate-specific antigen velocity (PSAV) with Gleason score in prostate needle biopsy specimens. The Gleason score is an important prognostic indicator for men with prostate cancer, and, in modern practice, it frequently affects treatment decisions. To our knowledge, the relationship between preoperative PSAV and Gleason score in the radical prostatectomy specimen has not been formally demonstrated.
A total of 1049 men treated with radical prostatectomy had data on PSAV and Gleason score. Statistical analysis was performed to examine the relationship between the preoperative PSAV and the prostatectomy Gleason score and other adverse tumor features.
The median preoperative PSAV was 0.84, 0.97, and 1.39 ng/mL/y in men with a Gleason score of 6, 7, and 8-10, respectively (P = .05). A PSAV greater than 2 ng/mL/y was significantly associated with a prostatectomy Gleason score of 7 or greater on univariate and multivariate analysis. In addition, the preoperative PSAV was significantly lower in men with organ-confined disease (0.82 vs 1.17 ng/mL/y, respectively, P = .002).
Our results have further validated PSAV as a marker for prostate cancer aggressiveness. The preoperative PSAV was a significant independent predictor of the Gleason score and non-organ-confined disease in the radical prostatectomy specimen. Thus, PSAV could be useful in treatment decision-making and in assessing the likelihood of long-term cancer control in men with prostate cancer.
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ABSTRACT: Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer and second leading cause of cancer-related death of men in developed countries. Measurement of prostate specific antigen (PSA) is a very sensitive method for diagnosing and monitoring of prostate cancer (PCa), but the specificity needs improvement. Measurements of different molecular forms of PSA have been shown to improve differentiation between PCa and benign prostatic diseases. However, accurate measurement of some isoforms has not been achieved in previous assays. The aim of the present study was to develop new assays that reliably measure enzymatically active PSA, PSA-α1-chymotryposin (PSA-ACT) and PSA-α1-protease inhibitor (PSA-API), and to evaluate their diagnostic value. Double-label immunofluorometric assays using a novel monoclonal antibody (MAb) and another antibody to either free PSA (fPSA) or total PSA (tPSA) were developed and used to measure PSA-ACT and fPSA or tPSA at the same time. These assays provide enough sensitivity for measurement of PSA-ACT in sera with low PSA levels. The results obtained confirmed that proportion of PSA-ACT to tPSA (%PSA-ACT) was as useful as proportion of fPSA to tPSA (%fPSA) for discrimination between PCa and benign prostatic hyperplasia (BPH). We developed an immunoassay for detection of PSA-API based on proximity ligation, which improved assay sensitivity 10-fold compared with conventional assays. Our results confirmed previous findings that the PSA-API level is somewhat lower in men with than without PCa, and the combination of %fPSA and proportion of PSA-API to tPSA (%PSA-API) provides diagnostic improvement compared with either method alone. Assays based on this principle should be applicable to other immunoassays in which the nonspecific background is a problem. An immunopeptidometric sandwich assay (IPMA) was developed to measure the enzymatically active PSA. This assay showed high specificity, but sensitivity was not good enough for measurement of PSA concentrations in the gray zone, 2-10 µg/L, in which tPSA does not efficiently differentiate between PCa and BPH. We further developed a solid-phase proximity ligation immunoassay, which provided a 10-fold improvement in sensitivity. This proof of concept study shows that peptides reacting with proteins are potentially useful for sensitive and specific measurement of protein variants for which specific MAbs cannot be obtained. Prostataspesifisen antigeenin (PSA) määrittäminen seerumista on herkkä menetelmä eturauhassyövän diagnostiikkaan, mutta se ei sovellu hyvin eturauhassyövän ja eturauhasen hyvänlaatuisen liikakasvun erottamiseen. Spesifisyyttä on pystytty lisäämään erilaisten PSA-muotojen mittaamisella. Kuitenkaan useiden PSA-muotojen luotettava mittaaminen ei ole ollut mahdollista aikaisemmilla menetelmillä. Tutkimukseni tarkoituksena on ollut kehittää uusia määritysmenetelmiä näiden PSA-muotojen määrittämiseksi [entsymaattisesti aktiivinen PSA, sekä PSA-α1-kymotrypsiini (PSA-ACT) ja PSA-α1-proteaasi inhibiittori (PSA-API) kompleksit]. Lisäksi tutkin näiden menetelmien diagnostista merkitystä. Tuotimme uusia vasta-aineita ja pystytin herkkiä määritysmenetelmiä PSA-ACT ja PSA-API kompleksien mittaamiseksi. Kehittämilläni menetelmillä voidaan PSA-ACT:n määrityksen kanssa samanaikaisesti mitata vapaata PSA:ta tai kokonais PSA:ta. Tästä on etua mm. määritettäessä PSA-ACT:n suhdetta kokonais PSA:han, minkä havaittiin myös tässä tutkimuksessa olevan eturauhassyövän diagnostiikassa yhtä hyödyllinen kuin vapaan PSA:n suhde kokonais PSA:han ja huomattavasti parempi kuin pelkkä kokonais PSA:n mittaus. PSA-API kompleksin mittaamiseksi käytettiin ns. läheisyys-ligaatioon perustuvaa immunomääritystä, jossa vasta-aineiden tulee sitoutua toistensa lähelle ja signaali saadaan aikaan DNA:n monistamiseen perustuvalla menetelmällä. Tällä tavoin saavutettiin 10 kertaa parempi herkkyys kuin perinteisillä menetelmillä ja päästiin eroon aiempia menetelmiä vaivanneesta korkeasta taustasta. Kliiniset tuloksemme vahvistavat aikaisemmat löydökset, joiden mukaan PSA-API tasot ovat jonkin verran korkeammat miehillä, joilla on eturauhassyöpä. Menetelmä soveltunee myös muiden immunomääritysten parantamiseksi. Kehitin myös kaksi immunopeptidometristä määritysmenetelmää, joissa PSA:n tunnistamiseen käytettiin aktiiviseen PSA:han sitoutuvaa peptidiä. Ensimmäinen menetelmä oli spesifinen, muttei tarpeeksi herkkä. Parantaakseni herkkyyttä kehitin läheisyys-ligaatio menetelmän, jossa peptidi ja kaksi vasta-ainetta tunnistavat PSA:n. Tämä menetelmä paransi herkkyyttä 10-kertaisesti. Tämä uuteen periaatteeseen perustuva menetelmä osoittaa että peptidejä voidaan käyttää herkkiin ja spesifeihin määritysmenetelmiin, myös mitattaessa sellaisia proteiini-variantteja, joita vastaan on vaikea kehittää vasta-aineita.
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ABSTRACT: The successful management of prostate cancer requires early detection, appropriate risk assessment and optimum treatment. To this end, much research has been conducted over many years with the goal of identifying a reliable and easily measurable tumour marker that could be used on a large scale for the diagnosis, staging and monitoring of the disease. Prostate-specific antigen (PSA) was independently discovered by two groups in the 1960s and 1970s, in semen and prostate tissue, and given different names. It later became evident that these proteins were encoded by the same gene and were the same protein. PSA was then identified as a useful marker for assessing patients with prostate cancer during their follow-up. In 1986, PSA was approved by the United States Food and Drug Administration to monitor prostate cancer, and in 1994 approved as a tool for detecting the disease in men aged > or =50 years. PSA is now the most widely used serum marker for detecting and monitoring prostate cancer, but its use as a diagnostic marker is controversial because it has several limitations, including its low specificity (PSA levels are also increased in benign prostatic hyperplasia, and in general inflammatory responses) and low sensitivity. Furthermore, PSA levels are highly variable over time, and PSA poorly distinguishes indolent from aggressive cancers. As such, the use of PSA level as a diagnostic tool can lead to over-detection of cancers that pose little threat to health and/or life. Moreover, the impact of PSA screening on prostate cancer mortality rates remains controversial, and will do so until the results of currently ongoing randomized controlled studies in Europe and the USA become available. To overcome the limitations of using PSA, research on PSA kinetics has developed considerably in the last decade. We review publications on the added value of PSA kinetics compared with single PSA measurements in the early detection of prostate cancer, and in predicting the outcome of patients with localized and advanced disease.
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ABSTRACT: Pathologic upgrading to Gleason 7 or higher on radical prostatectomy (RP) specimens occurs in many patients with Gleason 6 prostate cancer on preoperative biopsy. We evaluated whether biopsy characteristics and preoperative factors, including preoperative PSA velocity (PSAV), are predictive of pathologic upgrading.
We identified 235 consecutive Gleason 6 prostate cancer patients who underwent biopsies at our institution, had multiple pre-biopsy PSA values, and eventually underwent RP. Preoperative biopsy, clinical characteristics, and PSAV were analyzed to determine the risk of pathologic upgrading or extracapsular extension. These clinical factors were evaluated for association with biochemical recurrence following RP.
Overall, 48% of patients were upgraded to Gleason grade 7 or higher following RP. Median PSAV was 0.61 ng/mL/y, and PSAV was similar between upgraded and non-upgraded patients (1.01 vs. 0.78, P = 0.1). PSA velocity level was not associated with extracapsular disease (P = 0.4). PSA velocity > 1 was associated with biochemical recurrence (HR 3.23, P = 0.01) but this was not statistically significant in a multivariable model. Increasing PSA density (HR 2.18, P < 0.001), bilateral cores positive (HR 1.89, P < 0.05), and any biopsy core involvement > 50% (HR 2.52, P < 0.05) were most associated with pathologic upgrading. On multivariate analysis, only bilateral cancer detection at biopsy (HR 1.90, P < 0.05) significantly predicted upgrading.
PSAV has a limited role in predicting Gleason 6 upgrading. Patients with bilateral cancer detected on transrectal biopsy should be encouraged to have radical local therapy due to high risk of harboring more aggressive disease.
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