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Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy
P.R. Carroll / Urologic Oncology: Seminars and Original Investigations 21 (2003) 480 – 491
487
domain of PSMA [PSMA(ext)]. This article reports on the in vivo behavior and tumor uptake of (131)I- and (111)In-labeled antiPSMA(ext) mAbs (J415, J533, and J591) and their potential utility for radioimmunotherapy. Methods: In nude mice bearing PSMA-positive human LNCaP tumors, the pharmacokinetics, biodistribution, and tumor uptake of these antibodies was compared with (111)In-7E11 mAb, specific to the intracellular domain of PSMA (PSMA(int)). Autoradiographic studies were done to identify intratumoral distribution of radiolabeled mAbs. Results: With (131)I-labeled antibodies, the net tumor retention of radioactivity by day 6 was significantly higher with J415 (15.4% ⫾ 1.1%) and 7E11 (14.5% ⫾ 1.7%) than with J591 (9.58% ⫾ 1.1%). By contrast, the tumor uptake of (111)In-1,4,7,10-tetraazacyclododecaneN,N⬘,N⬘⬘,N⬘⬘⬘-tetraacetic acid-labeled J415 and J591 gradually increased with time and was quite similar to that of 7E11. In addition, the blood clearance of (111)In-labeled J415 and J591 antibodies was relatively faster than that of radiolabeled 7E11. As a consequence, the tumor-to-blood ratios with J415 and J591 were higher than that of 7E11. The localization of radiolabeled anti-PSMA(ext) antibodies in PSMA-positive LNCaP tumors was highly specific because the tumor uptake of (131)I-labeled J415 and J591 was more than twice that of a nonspecific antibody. Furthermore, the tumor uptake of (131)I-J591 was almost 20 times higher in PSMA-positive LNCaP tumors than in PSMA-negative PC3 and DU145 tumor xenografts. Autoradiographic studies suggested that 7E11 (anti-PSMA(int)) distinctly favors localization to areas of necrosis whereas J415 and J591 (anti-PSMA(ext)) demonstrated a distinct preferential accumulation in areas of viable tumor. Conclusion: These results clearly demonstrate that PSMA-specific internalizing antibodies such as J415 and J591 may be the ideal mAbs for the development of novel therapeutic methods to target the delivery of beta-emitting radionuclides [(131)I, (90)Y, and (177)Lu] for the treatment of PSMA-positive tumors. In addition, because J591 and J415 mAbs are specific to PSMA(ext), thus targeting viable tumor, these immunoconjugates are better candidates for targeted radioimmunotherapy than are antibodies targeting PSMA(int).
Commentary Prostate specific membrane antigen (PSMA) is highly expressed by prostate cancers. PSMA is a membrane protein and therefore is potentially very useful as a diagnostic and therapeutic target for monoclonal antibodies. The 7E11/CYT 356 monoclonal antibody binds to an intracellular domain of PSMA. 111In-labeled 7E mAb (Prostascint, Cytogen Corp., Princeton, NJ) has been used for the diagnostic imaging of prostate cancer in lymph nodes or in those patients who have failed biochemically after primary therapy in an attempt to select the most appropriate form of salvage therapy. In contrast to several previous reports, Thomas and colleagues demonstrated that such imaging did not predict the response to salvage radiation therapy in those who failed after surgery. Dr. Smith-Jones et al. have developed monoclonal antibodies that recognize and bind with high affinity to the extracellular domain of PSMA. Such antibodies are likely to be more clinically useful not only as diagnostic agents, but also potentially as targeted radioimmunotherapy. In contrast to 7E11, the antibodies described accumulate in viable tumors. doi:10.1016/S1078-1439(03)00151-0 Peter R. Carroll, M.D.
LABORATORY RESEARCH Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. D’Aimco AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen M-H, Department of Radiation Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA. J Natl Cancer Inst 2003;95:1376 –1383. Background: The relationship between prostate-specific antigen (PSA)-defined recurrence and prostate cancer-specific mortality remains unclear. Therefore, we evaluated the hypothesis that a short post-treatment PSA doubling time (PSA-DT) after radiation therapy is a surrogate end point for prostate cancer-specific mortality by analyzing two multi-institutional databases. Methods: Baseline, treatment, and follow-up information was compiled on a cohort of 8669 patients with prostate cancer treated with surgery (5918 men) or radiation (2751 men) from January 1, 1988, through January 1, 2002, for localized or locally advanced, non-metastatic prostate cancer. We used a Cox regression analysis to test whether the post-treatment PSA-DT was a prognostic factor that was independent of treatment received. All statistical tests were two-sided. Results: The post-treatment PSA-DT was statistically significantly associated with time to prostate cancer-specific mortality and with time to all-cause mortality (all P(Cox) ⬍ .001). However, the treatment received was not statistically significantly associated with time to prostate cancer-specific mortality after PSA-defined disease recurrence for patients with a PSA-DT of less than 3 months (P(Cox) ⫽ .90) and for patients with a PSA-DT of 3 months or more (P(Cox) ⫽ .28) when controlling for the specific value of the PSA-DT. Furthermore, after a PSA-defined recurrence, a PSA-DT of less than 3 months was statistically significantly associated with time to prostate cancerspecific mortality (median time ⫽ 6 years; hazard ratio ⫽ 19.6, 95% confidence interval ⫽ 12.5 to 30.9). Conclusion: A post-treatment PSA-DT of less than 3 months and the specific value of the post-treatment PSA-DT when it is 3 months or more appear to be surrogate end points for prostate cancer-specific mortality after surgery or radiation therapy. We recommend that consideration be given to initiating androgen suppression therapy at the time of a PSA-defined recurrence when the PSA-DT is less than 3 months to delay the imminent onset of metastatic bone disease.
488
G. Chatta / Urologic Oncology: Seminars and Original Investigations 21 (2003) 480 – 491
Commentary Serologic failures, following definitive therapy, constitute the largest sub-population of patients with prostate cancer in the U.S.—50,000 patients per year. Most existing pre-treatment, as well as post-treatment normograms, do not reliably predict disease progression in this group of men. Hence, currently there is no standard therapy for men who experience PSA-defined disease recurrence after initial therapy with either surgery or irradiation. In the above paper, the authors analyze PSA-defined disease recurrence in over 8000 men from two large multi-institutional databases of patients who have undergone local therapy for prostate cancer. They validate the hypothesis that in men with PSA-only recurrences, both a PSA-DT of less than 3 months and the absolute value of the PSA-DT when it is more than 3 months, represent surrogate end points for prostate cancer-specific mortality after surgery or radiation therapy. In the former subset, i.e., men with a PSA-DT of less than 3 months, the median time to prostate-specific mortality was only 6 years. This paper further validates the growing body of literature, emphasizing the importance of the PSA-DT in biochemical failures following definitive therapy. Furthermore, these findings are bound to positively influence prostate cancer care by both helping us define the subset of men with PSA-only disease who are candidates for early systemic therapy and providing a reliable surrogate end-point, i.e., the PSA-DT to rapidly test newer therapies in rationally designed clinical trials. doi:10.1016/S1078-1439(03)00231-X Gurkamal Chatta, M.D.
Multiplex biomarker approach for determining risk of prostate-specific antigen-defined recurrence of prostate cancer. Rhodes DR, Sanda MG, Otte AP, Chinnaiyan AM, Rubin MA, Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI. J Natl Cancer Inst 2003;95:661– 668. Background: Molecular signatures in cancer tissue may be useful for diagnosis and are associated with survival. We used results from high-density tissue microarrays (TMAs) to define combinations of candidate biomarkers associated with the rate of prostate cancer progression after radical prostatectomy that could identify patients at high risk for recurrence. Methods: Fourteen candidate biomarkers for prostate cancer for which antibodies are available included hepsin, pim-1 kinase, E-cadherin (ECAD; cell adhesion molecule), alpha-methylacyl-coenzyme A racemase, and EZH2 (enhancer of zeste homolog 2, a transcriptional repressor). TMAs containing more than 2000 tumor samples from 259 patients who underwent radical prostatectomy for localized prostate cancer were studied with these antibodies. Immunohistochemistry results were evaluated in conjunction with clinical parameters associated with prostate cancer progression, including tumor stage, Gleason score, and prostate-specific antigen (PSA) level. Recurrence was defined as a postsurgery PSA level of more than 0.2 ng/mL. All statistical tests were two-sided. Results: Moderate or strong expression of EZH2 coupled with at most moderate expression of ECAD (i.e., a positive EZH2:ECAD status) was the biomarker combination that was most strongly associated with the recurrence of prostate cancer. EZH2:ECAD status was statistically significantly associated with prostate cancer recurrence in a training set of 103 patients (relative risk [RR] ⫽ 2.52, 95% confidence interval [CI] ⫽ 1.09 to 5.81; P ⫽ .021), in a validation set of 80 patients (RR ⫽ 3.72, 95% CI ⫽ 1.27 to 10.91; P ⫽ .009), and in the combined set of 183 patients (RR ⫽ 2.96, 95% CI ⫽ 1.56 to 5.61; P ⬍ .001). EZH2:ECAD status was statistically significantly associated with disease recurrence even after adjusting for clinical parameters, such as tumor stage, Gleason score, and PSA level (hazard ratio ⫽ 3.19, 95% CI ⫽ 1.50 to 6.77; P ⫽ .003). Conclusion: EZH2:ECAD status was statistically significantly associated with prostate cancer recurrence after radical prostatectomy and may be useful in defining a cohort of high-risk patients.
Commentary Genomic- and proteomic-based studies have led to the identification of a large number of candidate biomarkers, as well as signature patterns of multiple markers for prostate cancer diagnosis, disease progression and prediction of survival. While these candidates include the usual suspects, including oncogenes, proliferation markers and cytoskeletal proteins, there are many additional unexpected molecules such as those involved in processes such as transcriptional repression and fatty acid metabolism. Patterns of expression serving as useful biomarkers are a new and, as yet, clinically untested concept. However, it is likely that different subsets of prostate cancer have their specific molecular signatures. Ultimately, the hope is that individual molecular patterns will help separate indolent (requires no treatment) from aggressive disease, sub-stratify high risk disease, accurately predict recurrent disease, and aid in planning targeted therapy. Exciting as these developments are, clinical application will have to await careful validation of these markers by independent biochemical approaches over large and diverse samples. The above paper is one of several recent contributions by a premier Pathology Informatics group. doi:10.1016/S1078-1439(03)00232-1 Gurkamal Chatta, M.D.
487
domain of PSMA [PSMA(ext)]. This article reports on the in vivo behavior and tumor uptake of (131)I- and (111)In-labeled antiPSMA(ext) mAbs (J415, J533, and J591) and their potential utility for radioimmunotherapy. Methods: In nude mice bearing PSMA-positive human LNCaP tumors, the pharmacokinetics, biodistribution, and tumor uptake of these antibodies was compared with (111)In-7E11 mAb, specific to the intracellular domain of PSMA (PSMA(int)). Autoradiographic studies were done to identify intratumoral distribution of radiolabeled mAbs. Results: With (131)I-labeled antibodies, the net tumor retention of radioactivity by day 6 was significantly higher with J415 (15.4% ⫾ 1.1%) and 7E11 (14.5% ⫾ 1.7%) than with J591 (9.58% ⫾ 1.1%). By contrast, the tumor uptake of (111)In-1,4,7,10-tetraazacyclododecaneN,N⬘,N⬘⬘,N⬘⬘⬘-tetraacetic acid-labeled J415 and J591 gradually increased with time and was quite similar to that of 7E11. In addition, the blood clearance of (111)In-labeled J415 and J591 antibodies was relatively faster than that of radiolabeled 7E11. As a consequence, the tumor-to-blood ratios with J415 and J591 were higher than that of 7E11. The localization of radiolabeled anti-PSMA(ext) antibodies in PSMA-positive LNCaP tumors was highly specific because the tumor uptake of (131)I-labeled J415 and J591 was more than twice that of a nonspecific antibody. Furthermore, the tumor uptake of (131)I-J591 was almost 20 times higher in PSMA-positive LNCaP tumors than in PSMA-negative PC3 and DU145 tumor xenografts. Autoradiographic studies suggested that 7E11 (anti-PSMA(int)) distinctly favors localization to areas of necrosis whereas J415 and J591 (anti-PSMA(ext)) demonstrated a distinct preferential accumulation in areas of viable tumor. Conclusion: These results clearly demonstrate that PSMA-specific internalizing antibodies such as J415 and J591 may be the ideal mAbs for the development of novel therapeutic methods to target the delivery of beta-emitting radionuclides [(131)I, (90)Y, and (177)Lu] for the treatment of PSMA-positive tumors. In addition, because J591 and J415 mAbs are specific to PSMA(ext), thus targeting viable tumor, these immunoconjugates are better candidates for targeted radioimmunotherapy than are antibodies targeting PSMA(int).
Commentary Prostate specific membrane antigen (PSMA) is highly expressed by prostate cancers. PSMA is a membrane protein and therefore is potentially very useful as a diagnostic and therapeutic target for monoclonal antibodies. The 7E11/CYT 356 monoclonal antibody binds to an intracellular domain of PSMA. 111In-labeled 7E mAb (Prostascint, Cytogen Corp., Princeton, NJ) has been used for the diagnostic imaging of prostate cancer in lymph nodes or in those patients who have failed biochemically after primary therapy in an attempt to select the most appropriate form of salvage therapy. In contrast to several previous reports, Thomas and colleagues demonstrated that such imaging did not predict the response to salvage radiation therapy in those who failed after surgery. Dr. Smith-Jones et al. have developed monoclonal antibodies that recognize and bind with high affinity to the extracellular domain of PSMA. Such antibodies are likely to be more clinically useful not only as diagnostic agents, but also potentially as targeted radioimmunotherapy. In contrast to 7E11, the antibodies described accumulate in viable tumors. doi:10.1016/S1078-1439(03)00151-0 Peter R. Carroll, M.D.
LABORATORY RESEARCH Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. D’Aimco AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen M-H, Department of Radiation Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA. J Natl Cancer Inst 2003;95:1376 –1383. Background: The relationship between prostate-specific antigen (PSA)-defined recurrence and prostate cancer-specific mortality remains unclear. Therefore, we evaluated the hypothesis that a short post-treatment PSA doubling time (PSA-DT) after radiation therapy is a surrogate end point for prostate cancer-specific mortality by analyzing two multi-institutional databases. Methods: Baseline, treatment, and follow-up information was compiled on a cohort of 8669 patients with prostate cancer treated with surgery (5918 men) or radiation (2751 men) from January 1, 1988, through January 1, 2002, for localized or locally advanced, non-metastatic prostate cancer. We used a Cox regression analysis to test whether the post-treatment PSA-DT was a prognostic factor that was independent of treatment received. All statistical tests were two-sided. Results: The post-treatment PSA-DT was statistically significantly associated with time to prostate cancer-specific mortality and with time to all-cause mortality (all P(Cox) ⬍ .001). However, the treatment received was not statistically significantly associated with time to prostate cancer-specific mortality after PSA-defined disease recurrence for patients with a PSA-DT of less than 3 months (P(Cox) ⫽ .90) and for patients with a PSA-DT of 3 months or more (P(Cox) ⫽ .28) when controlling for the specific value of the PSA-DT. Furthermore, after a PSA-defined recurrence, a PSA-DT of less than 3 months was statistically significantly associated with time to prostate cancerspecific mortality (median time ⫽ 6 years; hazard ratio ⫽ 19.6, 95% confidence interval ⫽ 12.5 to 30.9). Conclusion: A post-treatment PSA-DT of less than 3 months and the specific value of the post-treatment PSA-DT when it is 3 months or more appear to be surrogate end points for prostate cancer-specific mortality after surgery or radiation therapy. We recommend that consideration be given to initiating androgen suppression therapy at the time of a PSA-defined recurrence when the PSA-DT is less than 3 months to delay the imminent onset of metastatic bone disease.
488
G. Chatta / Urologic Oncology: Seminars and Original Investigations 21 (2003) 480 – 491
Commentary Serologic failures, following definitive therapy, constitute the largest sub-population of patients with prostate cancer in the U.S.—50,000 patients per year. Most existing pre-treatment, as well as post-treatment normograms, do not reliably predict disease progression in this group of men. Hence, currently there is no standard therapy for men who experience PSA-defined disease recurrence after initial therapy with either surgery or irradiation. In the above paper, the authors analyze PSA-defined disease recurrence in over 8000 men from two large multi-institutional databases of patients who have undergone local therapy for prostate cancer. They validate the hypothesis that in men with PSA-only recurrences, both a PSA-DT of less than 3 months and the absolute value of the PSA-DT when it is more than 3 months, represent surrogate end points for prostate cancer-specific mortality after surgery or radiation therapy. In the former subset, i.e., men with a PSA-DT of less than 3 months, the median time to prostate-specific mortality was only 6 years. This paper further validates the growing body of literature, emphasizing the importance of the PSA-DT in biochemical failures following definitive therapy. Furthermore, these findings are bound to positively influence prostate cancer care by both helping us define the subset of men with PSA-only disease who are candidates for early systemic therapy and providing a reliable surrogate end-point, i.e., the PSA-DT to rapidly test newer therapies in rationally designed clinical trials. doi:10.1016/S1078-1439(03)00231-X Gurkamal Chatta, M.D.
Multiplex biomarker approach for determining risk of prostate-specific antigen-defined recurrence of prostate cancer. Rhodes DR, Sanda MG, Otte AP, Chinnaiyan AM, Rubin MA, Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI. J Natl Cancer Inst 2003;95:661– 668. Background: Molecular signatures in cancer tissue may be useful for diagnosis and are associated with survival. We used results from high-density tissue microarrays (TMAs) to define combinations of candidate biomarkers associated with the rate of prostate cancer progression after radical prostatectomy that could identify patients at high risk for recurrence. Methods: Fourteen candidate biomarkers for prostate cancer for which antibodies are available included hepsin, pim-1 kinase, E-cadherin (ECAD; cell adhesion molecule), alpha-methylacyl-coenzyme A racemase, and EZH2 (enhancer of zeste homolog 2, a transcriptional repressor). TMAs containing more than 2000 tumor samples from 259 patients who underwent radical prostatectomy for localized prostate cancer were studied with these antibodies. Immunohistochemistry results were evaluated in conjunction with clinical parameters associated with prostate cancer progression, including tumor stage, Gleason score, and prostate-specific antigen (PSA) level. Recurrence was defined as a postsurgery PSA level of more than 0.2 ng/mL. All statistical tests were two-sided. Results: Moderate or strong expression of EZH2 coupled with at most moderate expression of ECAD (i.e., a positive EZH2:ECAD status) was the biomarker combination that was most strongly associated with the recurrence of prostate cancer. EZH2:ECAD status was statistically significantly associated with prostate cancer recurrence in a training set of 103 patients (relative risk [RR] ⫽ 2.52, 95% confidence interval [CI] ⫽ 1.09 to 5.81; P ⫽ .021), in a validation set of 80 patients (RR ⫽ 3.72, 95% CI ⫽ 1.27 to 10.91; P ⫽ .009), and in the combined set of 183 patients (RR ⫽ 2.96, 95% CI ⫽ 1.56 to 5.61; P ⬍ .001). EZH2:ECAD status was statistically significantly associated with disease recurrence even after adjusting for clinical parameters, such as tumor stage, Gleason score, and PSA level (hazard ratio ⫽ 3.19, 95% CI ⫽ 1.50 to 6.77; P ⫽ .003). Conclusion: EZH2:ECAD status was statistically significantly associated with prostate cancer recurrence after radical prostatectomy and may be useful in defining a cohort of high-risk patients.
Commentary Genomic- and proteomic-based studies have led to the identification of a large number of candidate biomarkers, as well as signature patterns of multiple markers for prostate cancer diagnosis, disease progression and prediction of survival. While these candidates include the usual suspects, including oncogenes, proliferation markers and cytoskeletal proteins, there are many additional unexpected molecules such as those involved in processes such as transcriptional repression and fatty acid metabolism. Patterns of expression serving as useful biomarkers are a new and, as yet, clinically untested concept. However, it is likely that different subsets of prostate cancer have their specific molecular signatures. Ultimately, the hope is that individual molecular patterns will help separate indolent (requires no treatment) from aggressive disease, sub-stratify high risk disease, accurately predict recurrent disease, and aid in planning targeted therapy. Exciting as these developments are, clinical application will have to await careful validation of these markers by independent biochemical approaches over large and diverse samples. The above paper is one of several recent contributions by a premier Pathology Informatics group. doi:10.1016/S1078-1439(03)00232-1 Gurkamal Chatta, M.D.