Effect of androgen blockade on HER-2 and matrix metalloproteinase-2 expression on bone marrow micrometastasis and stromal cells in men with prostate cancer.

INTRODUCTION: HER-2 has been associated with castrate resistant prostate cancer and matrix metalloproteinase-2 (MMP-2) in the dissemination and invasion of tumor cells as well as activating angiogenesis. We present an immunocytochemical study of the effect of androgen blockade on the expression of HER-2 and MMP-2 in bone marrow micrometastasis and the surrounding stromal cells in men with prostate cancer. METHODS AND PATIENTS: A cross-sectional study of men with prostate cancer. Touch preps were obtained from bone marrow biopsies of men with prostate cancer, before and after radical prostatectomy and during androgen blockade. Micrometastasis detected with anti-PSA immunocytochemistry underwent processing with anti-HER-2 and anti-MMP-2 immunocytochemistry. Patients were defined as HER-2 positive or negative, MMP-2 negative or an MMP-2 pattern described as border or central and stromal MMP-2 defined as positive or negative. The expression of the biomarkers was compared before and after primary treatment and during androgen blockade in relation to the serum PSA at the time of sampling and duration of androgen blockade. RESULTS: 191 men participated, 35 men before surgery and 43 after surgery; there were no significant differences in HER-2 expression between groups, there was no MMP-2 expression centrally or stromal expression of MMP-2. In men with androgen blockade, HER-2 expression was significantly higher; there was a trend for increasing HER-2 expression up to 5 years; central MMP-2 expression significantly increased after 3 years, while stromal MMP-2 significantly increased after 6 years. MMP-2 expression both in micrometastasis and stroma was significantly associated with HER-2 expression. Expression of MMP-2 at the border of the micrometastasis was not associated with HER-2 expression and occurred in the absence of androgen blockade. CONCLUSIONS: Androgen blockade decreases serum PSA by eliminating HER-2 negative prostate cancer cells. However, there is early selection of HER-2 positive cancer cells which leads to androgen independence and to increased expression of MMP-2 activity in the micrometastasis. The increased MMP-2 activity in the micrometastasis increases the expression of MMP-2 in the surrounding stromal cells and thus could promote angiogenesis and tumor growth resulting in macrometastatic androgen independent disease.

A performance analysis of the presence of malignant circulating prostate cells as a predictive factor for the detection of prostate cancer in the first, second and third prostate biopsy.

OBJECTIVES: Serum prostate specific antigen and digital rectal examination are the tests used as screening tests to detect prostate cancer. However, only approximately 30% of men with suspicion of cancer have it confirmed on prostate biopsy, and not all of these need treatment. Detection of circulating tumor cells in localized prostate cancer has given variable results, but it could be a useful complementary screening tool to detect prostate cancer in men with abnormal screening tests before the evaluation with prostate biopsy. This may be more so in subsequent biopsies where serum PSA has a decreased diagnostic yield. To evaluate the diagnostic yield of the detection of CPCs as a complementary PC screening test in a population fulfilling criteria for an initial, second and third prostate biopsy for suspicion of PC. METHODS: A prospective screening study of consecutive patients aged 45-80 years presenting to the urologist for PC screening. Inclusion criteria were PSA >4.0 ng/ml, PSA velocity >0.35 ng/ml/year and/or DRE suspicious for cancer. Patients fulfilling inclusion criteria had blood taken for CPC detection and then underwent 12-core transrectal prostate biopsy. Double immune-his-tochemical staining with anti-PSA and anti-P504S was used to detect CPCs. Both cytologist and pathologist were blinded to the results of the biopsy, CPC results and clinical details. The diagnostic yield of the presence or absence of CPC was evaluated; the prostate biopsy was classified as cancer or no-cancer. RESULTS: 282 men participated, 83 undergoing of these undergoing a second and 38 a third biopsy, with a mean age of 66.2 ± 8.9 years and a median serum PSA of 5.10 ng/ml, 5.45 ng/ml and 6.45 ng/ml for first, second and third biopsies. Cancer was detected in 33,6%, 10.8% and 29.0% of first, second and third biopsies respectively, CPCs were detected in 36.9%, 21.7% and 36.8% of the patients. Sensibility, specificity and negative predictive value were 86% ,91% and 94% for the first biopsy, 89%, 87% and 99% for the second and 100% , 89% and 100% for third biopsy respectively. All the CPC determinations were interpretable. There were 11 false negative cases, all with small low grade tumors. Of the 29 men with a false positive CPC, 8/10 had cancer detected in the subsequent biopsy. CONCLUSIONS: The use of CPC detection could be useful as a complementary prostate cancer screening test, especially for excluding cancer, and including patients with indications for repeat biopsies. Men with a false positive CPC detection had a high risk of detecting cancer in the succeeding biopsy.

Análisis del desempeño de la presencia de células prostáticas malignas circulantes como factor predictivo para la detección de cáncer de próstata en la primera, segunda y tercera biopsia prostática / A performance analysis of the presence of malignant circulating prostate cells as a predictive factor for the detection of prostate cancer in the first, second and third prostate biopsy

OBJETIVO: El PSA en conjunto con el tacto rectal son los exámenes más utilizados para el cribado de cáncer de próstata (CP), sin embargo, en solo el 30% de estos pacientes se confirma el diagnóstico. En el presente estudio evaluamos el rendimiento diagnóstico de la detección de células prostáticas circulantes malignas (mCPC) para la detección precoz del CP en pacientes que cumplen con los criterios para realización de una o más biopsias prostáticas. MÉTODO: Estudio prospectivo, ciego, con reclutamiento consecutivo de pacientes entre 45-80 años, con sospecha de CP. Criterios de inclusión: PSA sérico >4,0 ng/ml, elevación >0,75 ng/ml/año, tacto rectal sospechoso de cáncer. La detección de mCPC fue realizada por inmunohistoquímica con doble marcación hacia el PSA y P504S. Se evalúo el rendimiento diagnóstico de la presencia o ausencia de mCPC comparándolos con los resultados de la biopsia prostática, la cual se clasificó como cáncer o no cáncer. RESULTADOS: Participaron 282 hombres; 83 de los cuales fueron sometidos a una segunda biopsia y 38 a una tercera. La edad media fue 66.2 ± 8.9 años; una media de PSA de 5,10, 5,45 y 6,45 ng/dl para la primera, segunda y tercera biopsia respectivamente. Se diagnosticó CP en 33.6%, 10,8% y 29,0% y las mCPC se detectaron en 36,9%, 21,7% y 36,8% de la primera, segunda y tercera biopsia respectivamente. Con una sensibilidad, especificidad y valor predictivo negativo de 86.2%, 90.8% y 94.3% para la primera biopsia; 89%, 87% y 99% para la segunda y 100%, 89% y 100% para la tercera biopsia respectivamente. Ocurrieron 11 casos de falsos negativos, con un CP pequeño y de bajo grado. De los 29 pacientes con un falso positivo para CPC, 8/10 tuvieron un cáncer detectado en la siguiente biopsia. CONCLUSIÓN: El uso de la detección de mCPC puede ser un método útil como examen complementario a los actualmente en uso para la detección de cáncer prostático, y durante el seguimiento de pacientes con PSA persistentemente elevado para determinar la necesidad de una re biopsia. Las mCPCs tienen un especial valor por su alto valor predictivo negativo en pacientes con un PSA ≥4.0ng/ml (AU)

OBJECTIVES: Serum prostate specific antigen and digital rectal examination are the tests used as screening tests to detect prostate cancer. However, only approximately 30% of men with suspicion of cancer have it confirmed on prostate biopsy, and not all of these need treatment. Detection of circulating tumor cells in localized prostate cancer has given variable results, but it could be a useful complementary screening tool to detect prostate cancer in men with abnormal screening tests before the evaluation with prostate biopsy. This may be more so in subsequent biopsies where serum PSA has a decreased diagnostic yield. To evaluate the diagnostic yield of the detection of CPCs as a complementary PC screening test in a population fulfilling criteria for an initial, second and third prostate biopsy for suspicion of PC. METHODS: A prospective screening study of consecutive patients aged 45-80 years presenting to the urologist for PC screening. Inclusion criteria were PSA >4.0ng/ml, PSA velocity >0.35ng/ml/year and/or DRE suspicious for cancer. Patients fulfilling inclusion criteria had blood taken for CPC detection and then underwent 12-core transrectal prostate biopsy. Double immune-his-to chemical staining with anti-PSA and anti-P504S was used to detect CPCs. Both cytologist and pathologist were blinded to the results of the biopsy, CPC results and clinical details. The diagnostic yield of the presence or absence of CPC was evaluated; the prostate biopsy was classified as cancer or no-cancer. RESULTS: 282 men participated, 83 undergoing of these undergoing a second and 38 a third biopsy, with a mean age of 66.2 ± 8.9 years and a median serum PSA of 5.10ng/ml, 5.45ng/ml and 6.45ng/ml for first, second and third biopsies. Cancer was detected in 33,6%, 10.8% and 29.0% of first, second and third biopsies respectively, CPCs were detected in 36.9%, 21.7% and 36.8% of the patients. Sensibility, specificity and negative predictive value were 86%, 91% and 94% for the first biopsy, 89%, 87% and 99% for the second and 100%, 89% and 100% for third biopsy respectively. All the CPC determinations were interpretable. There were 11 false negative cases, all with small low grade tumors. Of the 29 men with a false positive CPC, 8/10 had cancer detected in the subsequent biopsy. CONCLUSIONS: The use of CPC detection could be useful as a complementary prostate cancer screening test, especially for excluding cancer, and including patients with indications for repeat biopsies. Men with a false positive CPC detection had a high risk of detecting cancer in the succeeding biopsy (AU)

Redefining micrometastasis in prostate cancer - a comparison of circulating prostate cells, bone marrow disseminated tumor cells and micrometastasis: Implications in determining local or systemic treatment for biochemical failure after radical prostatectomy.

The presence of cells positive for cytokeratins or prostate-specific antigen (PSA) in bone marrow aspirates (BMAs) has been used to indicate the presence of micrometastasis. The aim of this prospective study of prostate cancer patients was to determine the presence of prostate cells in blood and BMAs and to compare them with bone marrow biopsy touch prep samples. The results indicated that there was a satisfactory concordance between circulating prostate cells (CPCs) in blood and disseminated tumor cells (DTCs) in BMAs for all Gleason scores (κ>0.50). However, neither were concordant with the presence of prostate cells in bone marrow biopsies except for high-grade tumors, Gleason 8 and 9. Phenotypic characteristics of CPCs and DTCs were identical (κ>0.9) but were different than cells detected in bone marrow biopsies (κ<0.2). The expression of matrix metalloproteinase-2 (MMP-2) in bone marrow biopsies was positively associated with the Gleason score (trend Chi-squared <0.05) and may explain the differences between the presence of DTCs and the presence of prostate cells in bone marrow biopsies. If the presence of DTCs was used to indicate micrometastatic disease, 20% of patients would be misclassified compared to micrometastasis defined as patients with a positive biopsy. This may have clinical implications for patients with low-grade tumors.

Rendimiento diagnóstico de la detección de células prostáticas malignas en la circulación sanguínea para la detección précoz del cáncer prostático: una comparación con la biopsia prostática / Diagnostic performance of malignant prostatic cells detection in blood for early detection of prostate cancer: comparison to prostatic biopsy

OBJETIVO: El PSA y el tacto rectal son los exámenes utilizados para el tamizaje de cáncer prostático (CP), pero solo en el 30% de los pacientes con sospecha de cáncer prostático se confirma el diagnóstico. La detección de células prostáticas circulantes en sangre puede ser una herramienta útil para la detección de cáncer prostático en estos pacientes.Evaluar el rendimiento diagnóstico de la detección de CPCm para la detección precoz del CP, en una población que cumple los criterios para la realización de una biopsia prostática por sospecha de CP.MÉTODO: Estudio prospectivo, con reclutamiento consecutivo de pacientes entre 45-80 años, con sospecho de CP. Criterios de inclusión: PSA sérico >4,0 ng/ml, elevación >0,35 ng/ml/año, tacto rectal sospechoso de cáncer. Pacientes con alguno de estos criterios fue sometido a una biopsia prostática transrectal y a la determinación de CPCm en sangre. La detección de CPCm fue realizada por inmunohistoquímica con doble marcación hacia el PSA y P504S. Tanto el citólogo como el patólogo fueron ciegos al resultado de las CPCm y la BP, así como a los datos clínicos. Se evalúo el rendimiento diagnóstico de la presencia o ausencia de CPCm. La biopsia se clasificó como cáncer o no cáncer. Los pacientes fueron divididos entre 1) PSA ≥4,0ng/ml y 2) PSA <4,0ng/ml y cumple con otro criterio para una BP.RESULTADOS: Participaron 228 hombres; edad media de 66.8 ± 8.8 años; PSA mediana de 5.15 ng/dl. Se diagnosticó CP en 28.6% de los casos mediante la BP y las CPCm se detectaron en 31% de todos los pacientes. Con una sensibilidad, especificidad y valor predictivo negativo de 86.2%, 90.8% y 94.3%, respectivamente. Razón de verosimilitud negativa y positiva de 0,15 y 9,36. En hombres con un PSA <4,0ng/ml, hubo 13,3% con CP, una sensibilidad y especificidad de 83,3% y 84,6% y valor predictivo negativo de 97,1%. Ocurrieron 9 casos de falsos negativos, con un CP pequeño y de bajo grado(AU)

CONCLUSIÓN: La detección de CPCm podría ser útil como examen complementario en la detección de cáncer prostático, en especial para su exclusión, incluido pacientes con PSA < de 4 ng/ml(AU)

OBJECTIVES: Serum prostate specific an-tigen and digital rectal examination are the tests used as screening tests to detect prostate cancer. However, only approximately 30% of men with suspicion of can-cer have it confirmed on prostate biopsy, and not all of these need treatment. Detection of circulating tumor cells in localized prostate cancer has given variable re-sults, but it could be a useful complementa-ry screening tool to detect prostate cancer in men with abnormal screening tests before the evaluation with prostate biopsy.To evaluate the diagnostic yield of the detection of mCPC as a complementary PC screening test in a po-pulation fulfilling criteria for a prostate biopsy for sus-picion of PC.METHODS: A prospective screening study of consecuti-ve patients aged 45-80 years presenting to the urologist for PC screening. Inclusion criteria were PSA >4.0ng/ml, PSA velocity >0.35ng/ml/year and/or DRE suspi-cious for cancer. Patients fulfilling inclusion criteria had blood taken for mCPC detection and then underwent 12-core transrectal prostate biopsy. Double immune-histochemical staining with anti-PSA and anti-P504S was used to detect mCPC. Both cytologist and pathologist were blinded to the results of the biopsy, mCPC results and clinical de-tails. The diagnostic yield of the presence or absence of mCPC was evaluated; the prostate biopsy was classi-fied as cancer or no-cancer(AU)

RESULTS: 228 men participated, with a mean age of 66.8 ± 8.8 years and a median serum PSA of 5.15ng/ml. 28.6% of the biopsies were positive for PC, and mCPC were detected in 31.0% of all cases. Sensibility, specifici-ty and negative predictive value were 86.2%, 90.8% and 94.3% respectively. The negative and positive like-lihood ratios were 9.36 and 0.15. In men with a PSA <4.0ngml, 13.3% had cancer detected on biopsy, with a sensibility and specificity for mCPC detection of 83.3% and 84.6% and negative predictive value of 97.1%. All the mCPC determinations were interpretable. There were 9 false negative cases, all with small low grade tumors.CONCLUSIONS: The use of mCPC detection could be useful as a complementary prostate cancer screening test, especially for excluding cancer, including patients with a serum PSA <4.0ng/ml(AU)

Diagnostic performance of malignant prostatic cells detection in blood for early detection of prostate cancer: comparison to prostatic biopsy.

OBJECTIVES: Serum prostate specific antigen and digital rectal examination are the tests used as screening tests to detect prostate cancer. However, only approximately 30% of men with suspicion of cancer have it confirmed on prostate biopsy, and not all of these need treatment. Detection of circulating tumor cells in localized prostate cancer has given variable results, but it could be a useful complementary screening tool to detect prostate cancer in men with abnormal screening tests before the evaluation with prostate biopsy. To evaluate the diagnostic yield of the detection of mCPC as a complementary PC screening test in a population fulfilling criteria for a prostate biopsy for suspicion of PC. METHODS: A prospective screening study of consecutive patients aged 45-80 years presenting to the urologist for PC screening. Inclusion criteria were PSA >4.0 ng/ml, PSA velocity >0.35 ng/ml/year and/or DRE suspicious for cancer. Patients fulfilling inclusion criteria had blood taken for mCPC detection and then underwent 12-core transrectal prostate biopsy. Double immune-histochemical staining with anti-PSA and anti-P504S was used to detect mCPC. Both cytologist and pathologist were blinded to the results of the biopsy, mCPC results and clinical details. The diagnostic yield of the presence or absence of mCPC was evaluated; the prostate biopsy was classified as cancer or no -cancer. RESULTS: 228 men participated, with a mean age of 66.8 ± 8.8 years and a median serum PSA of 5.15 ng/ml. 28.6% of the biopsies were positive for PC, and mCPC were detected in 31.0%of all cases. Sensibility, specificity and negative predictive value were 86.2%, 90.8% and 94.3% respectively. The negative and positive like-lihood ratios were 9.36 and 0.15. In men with a PSA <4.0ngml, 13.3% had cancer detected on biopsy, with a sensibility and specificity for mCPC detection of 83.3% and 84.6% and negative predictive value of 97.1%. All the mCPC determinations were interpretable. There were 9 false negative cases, all with small low grade tumors. CONCLUSIONS: The use of mCPC detection could be useful as a complementary prostate cancer screening test, especially for excluding cancer, including patients with a serum PSA <4.0 ng/ml.

Presence of prostate cells in bone marrow biopsies as a sign of micrometastasis in cancer patients.

The presence of prostate cancer cells in bone marrow of patients with clinically localized disease is associated with increased chance of disease recurrence. The presence of prostate specific antigen (PSA) in bone marrow aspirates has been used to indicate the presence of micrometastasis. The aim of this study was to present a prospective study of prostate cancer patients to determine the presence of cells that express PSA in aspirates taken from bone marrow and to compare with bone marrow biopsy samples. Results indicated a significant difference between the frequency of cells detected in bone marrow aspirate and biopsy samples (P<0.0002) when all patients were considered. There was no difference between the frequencies of cells detected in bone marrow aspirate and biopsy of patients analyzed before treatment. However, there was a significant (P<0.003) difference between them after treatment. There was also a significant difference in the frequency of PSA positive cells detected (P<0.005) in Stages I to IV as well as in the frequency of cells detected (P<0.0002) when analyzed according to Gleason score. The present results explain the lack of correlation between positive aspirates and prognosis in numerous clinical cases.