Advances In Prostate Cancer Research

SAN DIEGO – Information about prostate tumor biology obtained from a multigene assay helped investigators discriminate low- and intermediate-risk prostate cancers in the context of tumor heterogeneity and limited sampling with needle biopsies, a clinical validation study showed.

Furthermore, the information garnered from the assay might take the place of a second biopsy for identifying appropriate patients for active surveillance.

"I’d like to suggest that we are on the very front wave of a paradigm shift," Dr. Eric A. Klein said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation. "We have learned so much about the biology and genomics of prostate cancer. We’re at the point now where we can exploit that clinically and make precision decisions for our patients."

The test, known as the Oncotype DX Genomic Prostate Score (GPS), is a biopsy-based pretreatment tool of Genomic Health Inc. that can help clinicians predict which men are more likely to harbor an aggressive form of prostate cancer. It became available in May 2013.

For patients with newly diagnosed, low- or intermediate-risk prostate cancer, limited accuracy of pretreatment risk assessment has led to underuse of active surveillance and overtreatment of nonlethal cancers, with all of the accompanying morbidity and cost, said Dr. Klein, who chairs the Glickman Urological and Kidney Institute at the Cleveland Clinic and who led the GPS development studies.

"The real problem for patients in active surveillance [is that] biopsy only samples potentially the low-grade tumor," he said. "So the question that exists is, how well does the Gleason grade predict biologic potential? And how accurately does the biopsy capture the biology of the whole prostate? The answer to the second question is unknown."

He discussed efforts to develop and validate a biopsy-based gene expression profile that predicts aggressive prostate cancer in the context of tumor heterogeneity, multifocality, and biopsy undersampling, which "limit the accuracy, precision, and confidence of current risk assessment. The goal was to explore genomics on biopsy to take decision-making from average risk based on grade, stage, and PSA [prostate-specific antigen], to more precisely define individual biological risk across the spectrum of each clinical risk group."

He and his associates conducted two development studies based on patients treated between 1987 and 2007: one to identify genes predictive of clinical recurrence, prostate cancer death, and adverse pathology at prostatectomy across multiple tumor regions sampled from each patient’s prostate, and a second to confirm the predictive value of these genes in prostate biopsies.

Next, independent researchers conducted a clinical validation study, which tested needle biopsies from patients with low to intermediate clinical risk who were treated during 1997-2011. This study was led by Dr. Peter Carroll, chair of the urology department at the University of California, San Francisco, and Dr. Matthew R. Cooperberg, also of UCSF. They used reverse-transcription polymerase chain reaction testing from prostate tumor tissue to quantitate gene expression, and used Cox proportional hazards or logistic regression to analyze associations with clinical recurrence and adverse pathology.

From a cohort sampling of 441 radical prostatectomy patients in the first development study, Dr. Klein and his associates identified 288 genes that predicted metastasis or death regardless of whether the gene expression was measured in the lowest Gleason pattern present or the highest Gleason pattern present. "This was a surprising finding," he said. "It challenges some of our notions about the biology of prostate cancer. What we’re suggesting is that grade, stage, and PSA only give us so much predictive power. We now have the tools available to unleash something that we can’t see under the microscope – the biology of the tumor – in a way that’s clinically exploitable."

For the second development study, the researchers evaluated 81 predictive genes from needle biopsy tissue in 167 patients, 58 of whom had adverse pathology at prostatectomy. Multivariate analysis of both development studies revealed 17 genes representing four biological pathways (stromal response, cellular organization, androgen signaling, and proliferation) that predicted outcome. Dr. Klein characterized the 17 genes as "a window" into the entire prostate.

"There is data in the literature that suggests the genomic signal that is present in patients with metastatic or advanced disease is almost always present in the primary tumor," he said. "It won’t be true in every case, but for the vast majority of prostate cancers I think this is true. The suggestion is that by measuring gene expression in the biopsy we can capture that signal."

The clinical validation study performed at UCSF included needle biopsy tissue from 395 patients, of whom 123 had adverse pathology at time of prostatectomy. The UCSF researchers reported that the GPS algorithm assessed in biopsies with tumor length as little as 1 mm from patients suitable for active surveillance predicted adverse pathology at prostatectomy, after adjustment for conventional pretreatment factors (P less than .005). In addition, the net reclassification improvement corresponding to at least a 5% change in predicted probability of favorable pathology with the addition of GPS to the CAPRA (Cancer of the Prostate Risk Assessment) score was 0.41 (P less than .001).

The biologic information from GPS "adds to our ability to make a precision decision for the patient," Dr. Klein said. "It doesn’t replace grade stage and PSA. It doesn’t replace clinical judgment. It’s another piece of very powerful information that can influence patient decision-making."

He went on to note that a test like the GPS could reduce the burden of determining eligibility for active surveillance. "Typically, in most practices, if you’re going to be considered for active surveillance after initial biopsy that shows low-grade disease, you have a second biopsy," Dr. Klein said. "I believe that the rationale is established that you could substitute this kind of biomarker for a second biopsy."

Dr. Klein disclosed that he has received research support and/or consulting fees from Genomic Health, GenomeDx Biosciences, and Metamark.

dbrunk@frontlinemedcom.com

SAN DIEGO – Information about prostate tumor biology obtained from a multigene assay helped investigators discriminate low- and intermediate-risk prostate cancers in the context of tumor heterogeneity and limited sampling with needle biopsies, a clinical validation study showed.

Furthermore, the information garnered from the assay might take the place of a second biopsy for identifying appropriate patients for active surveillance.

"I’d like to suggest that we are on the very front wave of a paradigm shift," Dr. Eric A. Klein said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation. "We have learned so much about the biology and genomics of prostate cancer. We’re at the point now where we can exploit that clinically and make precision decisions for our patients."

The test, known as the Oncotype DX Genomic Prostate Score (GPS), is a biopsy-based pretreatment tool of Genomic Health Inc. that can help clinicians predict which men are more likely to harbor an aggressive form of prostate cancer. It became available in May 2013.

For patients with newly diagnosed, low- or intermediate-risk prostate cancer, limited accuracy of pretreatment risk assessment has led to underuse of active surveillance and overtreatment of nonlethal cancers, with all of the accompanying morbidity and cost, said Dr. Klein, who chairs the Glickman Urological and Kidney Institute at the Cleveland Clinic and who led the GPS development studies.

"The real problem for patients in active surveillance [is that] biopsy only samples potentially the low-grade tumor," he said. "So the question that exists is, how well does the Gleason grade predict biologic potential? And how accurately does the biopsy capture the biology of the whole prostate? The answer to the second question is unknown."

He discussed efforts to develop and validate a biopsy-based gene expression profile that predicts aggressive prostate cancer in the context of tumor heterogeneity, multifocality, and biopsy undersampling, which "limit the accuracy, precision, and confidence of current risk assessment. The goal was to explore genomics on biopsy to take decision-making from average risk based on grade, stage, and PSA [prostate-specific antigen], to more precisely define individual biological risk across the spectrum of each clinical risk group."

He and his associates conducted two development studies based on patients treated between 1987 and 2007: one to identify genes predictive of clinical recurrence, prostate cancer death, and adverse pathology at prostatectomy across multiple tumor regions sampled from each patient’s prostate, and a second to confirm the predictive value of these genes in prostate biopsies.

Next, independent researchers conducted a clinical validation study, which tested needle biopsies from patients with low to intermediate clinical risk who were treated during 1997-2011. This study was led by Dr. Peter Carroll, chair of the urology department at the University of California, San Francisco, and Dr. Matthew R. Cooperberg, also of UCSF. They used reverse-transcription polymerase chain reaction testing from prostate tumor tissue to quantitate gene expression, and used Cox proportional hazards or logistic regression to analyze associations with clinical recurrence and adverse pathology.

From a cohort sampling of 441 radical prostatectomy patients in the first development study, Dr. Klein and his associates identified 288 genes that predicted metastasis or death regardless of whether the gene expression was measured in the lowest Gleason pattern present or the highest Gleason pattern present. "This was a surprising finding," he said. "It challenges some of our notions about the biology of prostate cancer. What we’re suggesting is that grade, stage, and PSA only give us so much predictive power. We now have the tools available to unleash something that we can’t see under the microscope – the biology of the tumor – in a way that’s clinically exploitable."

For the second development study, the researchers evaluated 81 predictive genes from needle biopsy tissue in 167 patients, 58 of whom had adverse pathology at prostatectomy. Multivariate analysis of both development studies revealed 17 genes representing four biological pathways (stromal response, cellular organization, androgen signaling, and proliferation) that predicted outcome. Dr. Klein characterized the 17 genes as "a window" into the entire prostate.

"There is data in the literature that suggests the genomic signal that is present in patients with metastatic or advanced disease is almost always present in the primary tumor," he said. "It won’t be true in every case, but for the vast majority of prostate cancers I think this is true. The suggestion is that by measuring gene expression in the biopsy we can capture that signal."

The clinical validation study performed at UCSF included needle biopsy tissue from 395 patients, of whom 123 had adverse pathology at time of prostatectomy. The UCSF researchers reported that the GPS algorithm assessed in biopsies with tumor length as little as 1 mm from patients suitable for active surveillance predicted adverse pathology at prostatectomy, after adjustment for conventional pretreatment factors (P less than .005). In addition, the net reclassification improvement corresponding to at least a 5% change in predicted probability of favorable pathology with the addition of GPS to the CAPRA (Cancer of the Prostate Risk Assessment) score was 0.41 (P less than .001).

The biologic information from GPS "adds to our ability to make a precision decision for the patient," Dr. Klein said. "It doesn’t replace grade stage and PSA. It doesn’t replace clinical judgment. It’s another piece of very powerful information that can influence patient decision-making."

He went on to note that a test like the GPS could reduce the burden of determining eligibility for active surveillance. "Typically, in most practices, if you’re going to be considered for active surveillance after initial biopsy that shows low-grade disease, you have a second biopsy," Dr. Klein said. "I believe that the rationale is established that you could substitute this kind of biomarker for a second biopsy."

Dr. Klein disclosed that he has received research support and/or consulting fees from Genomic Health, GenomeDx Biosciences, and Metamark.

dbrunk@frontlinemedcom.com

SAN DIEGO – Information about prostate tumor biology obtained from a multigene assay helped investigators discriminate low- and intermediate-risk prostate cancers in the context of tumor heterogeneity and limited sampling with needle biopsies, a clinical validation study showed.

Furthermore, the information garnered from the assay might take the place of a second biopsy for identifying appropriate patients for active surveillance.

"I’d like to suggest that we are on the very front wave of a paradigm shift," Dr. Eric A. Klein said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation. "We have learned so much about the biology and genomics of prostate cancer. We’re at the point now where we can exploit that clinically and make precision decisions for our patients."

The test, known as the Oncotype DX Genomic Prostate Score (GPS), is a biopsy-based pretreatment tool of Genomic Health Inc. that can help clinicians predict which men are more likely to harbor an aggressive form of prostate cancer. It became available in May 2013.

For patients with newly diagnosed, low- or intermediate-risk prostate cancer, limited accuracy of pretreatment risk assessment has led to underuse of active surveillance and overtreatment of nonlethal cancers, with all of the accompanying morbidity and cost, said Dr. Klein, who chairs the Glickman Urological and Kidney Institute at the Cleveland Clinic and who led the GPS development studies.

"The real problem for patients in active surveillance [is that] biopsy only samples potentially the low-grade tumor," he said. "So the question that exists is, how well does the Gleason grade predict biologic potential? And how accurately does the biopsy capture the biology of the whole prostate? The answer to the second question is unknown."

He discussed efforts to develop and validate a biopsy-based gene expression profile that predicts aggressive prostate cancer in the context of tumor heterogeneity, multifocality, and biopsy undersampling, which "limit the accuracy, precision, and confidence of current risk assessment. The goal was to explore genomics on biopsy to take decision-making from average risk based on grade, stage, and PSA [prostate-specific antigen], to more precisely define individual biological risk across the spectrum of each clinical risk group."

He and his associates conducted two development studies based on patients treated between 1987 and 2007: one to identify genes predictive of clinical recurrence, prostate cancer death, and adverse pathology at prostatectomy across multiple tumor regions sampled from each patient’s prostate, and a second to confirm the predictive value of these genes in prostate biopsies.

Next, independent researchers conducted a clinical validation study, which tested needle biopsies from patients with low to intermediate clinical risk who were treated during 1997-2011. This study was led by Dr. Peter Carroll, chair of the urology department at the University of California, San Francisco, and Dr. Matthew R. Cooperberg, also of UCSF. They used reverse-transcription polymerase chain reaction testing from prostate tumor tissue to quantitate gene expression, and used Cox proportional hazards or logistic regression to analyze associations with clinical recurrence and adverse pathology.

From a cohort sampling of 441 radical prostatectomy patients in the first development study, Dr. Klein and his associates identified 288 genes that predicted metastasis or death regardless of whether the gene expression was measured in the lowest Gleason pattern present or the highest Gleason pattern present. "This was a surprising finding," he said. "It challenges some of our notions about the biology of prostate cancer. What we’re suggesting is that grade, stage, and PSA only give us so much predictive power. We now have the tools available to unleash something that we can’t see under the microscope – the biology of the tumor – in a way that’s clinically exploitable."

For the second development study, the researchers evaluated 81 predictive genes from needle biopsy tissue in 167 patients, 58 of whom had adverse pathology at prostatectomy. Multivariate analysis of both development studies revealed 17 genes representing four biological pathways (stromal response, cellular organization, androgen signaling, and proliferation) that predicted outcome. Dr. Klein characterized the 17 genes as "a window" into the entire prostate.

"There is data in the literature that suggests the genomic signal that is present in patients with metastatic or advanced disease is almost always present in the primary tumor," he said. "It won’t be true in every case, but for the vast majority of prostate cancers I think this is true. The suggestion is that by measuring gene expression in the biopsy we can capture that signal."

The clinical validation study performed at UCSF included needle biopsy tissue from 395 patients, of whom 123 had adverse pathology at time of prostatectomy. The UCSF researchers reported that the GPS algorithm assessed in biopsies with tumor length as little as 1 mm from patients suitable for active surveillance predicted adverse pathology at prostatectomy, after adjustment for conventional pretreatment factors (P less than .005). In addition, the net reclassification improvement corresponding to at least a 5% change in predicted probability of favorable pathology with the addition of GPS to the CAPRA (Cancer of the Prostate Risk Assessment) score was 0.41 (P less than .001).

The biologic information from GPS "adds to our ability to make a precision decision for the patient," Dr. Klein said. "It doesn’t replace grade stage and PSA. It doesn’t replace clinical judgment. It’s another piece of very powerful information that can influence patient decision-making."

He went on to note that a test like the GPS could reduce the burden of determining eligibility for active surveillance. "Typically, in most practices, if you’re going to be considered for active surveillance after initial biopsy that shows low-grade disease, you have a second biopsy," Dr. Klein said. "I believe that the rationale is established that you could substitute this kind of biomarker for a second biopsy."

Dr. Klein disclosed that he has received research support and/or consulting fees from Genomic Health, GenomeDx Biosciences, and Metamark.

dbrunk@frontlinemedcom.com

SAN DIEGO – Over the past 20 years, death rates from prostate cancer in the United States have declined by 39%, due largely to early detection and/or improved treatment, according to Dr. Peter R. Carroll.

"It’s important to realize that this accounts for 20% of the decrease in cancer-specific deaths in men," said Dr. Carroll, professor and chair of the department of urology at the University of California, San Francisco. "However, the Achilles’ heel of PSA [prostate-specific antigen] testing is that it does so at the risk of overdetection – detecting disease that would not have become clinically apparent over a patient’s lifetime if left untreated. In this country, detection and treatment are too tightly linked."

In addition, widespread use of serum PSA has resulted in a "dramatic stage and grade shift, with most cancers currently being detected of limited cancer grade and stage," he said. Data from his colleagues at UCSF found that between 1990 and 2012, age-adjusted death rates from prostate cancer decreased 3.96% in North America yet increased 41% worldwide. In the United States, men with nonpalpable PSA-driven cancer comprise the largest segment of prostate cancer patients. "We think that we’ve seen a leveling of overdetection, but I think we’ll see another round of overdetection, because of a lowering PSA threshold to prompt biopsy, aggressive rescreening, the use of PSA velocity at low PSA values to prompt biopsy, and the use of saturation biopsies," he said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation.

In 2012 the U.S. Preventive Services Task Force came out against prostate cancer screening, classifying it as a grade D recommendation (Ann. Intern. Med. 2012;157[2]:120-34). The magnitude of overdetection varies with time period, age, comorbidities, region, definition, and screening practices and is thought to range between 2% and 67%, Dr. Carroll said. "I think a good number is somewhere between 35% and 40%." A recently published nomogram for predicting overdiagnosis found that depending on a man’s age, Gleason score, and PSA level, the likelihood that his tumor has been overdiagnosed ranges from 2.9% to 88.1% (J. Natl. Cancer Inst. 2014 [doi:10.1093/jnci.djt367]).

If prostate cancer screening is to be undertaken, "it should only be done recognizing that selective, rather than indiscriminate, treatment should follow," Dr. Carroll said. "Such an approach has been shown to reduce mortality while managing many with active surveillance in lieu of immediate treatment" (Lancet Oncol. 2010;11[8]:725-32). At UCSF, where more than 1,000 men are on active surveillance, the 5-year treatment-free survival is 65%, the 5-year overall survival is 97%, and the 5-year prostate cancer–specific survival is 100%. "The window of opportunity for treatment appears to be open for a long period of time," he said.

Potential solutions Dr. Carroll proposed to decrease the rates of overdetection include:

• Reducing the treatment of low-risk tumors.

• Identifying high-risk populations and targeting prevention and screening efforts to those populations.

• Developing new screening markers.

• Developing clinical and patient tools to support informed decision making about prevention, screening, biopsy, and treatment.

• Changing screening guidelines.

"The single biggest predictor of risk is a baseline PSA. It trumps ethnicity and family history," Dr. Carroll said. "I think there’s a strong rationale for a baseline screening between ages 45 and 55. If you screen beyond age 70, you increase the risk of overdetection. But if you stop screening you also increase the mortality. So beyond age 70 you want to individualize, consider screening only in those with a long life expectancy, and perhaps change the rationale for biopsy. Digital rectal examination in my mind is optional as a primary screening maneuver. Screening can be done at 1- to 2-year intervals. One thing we need to get away from is using PSA velocity at low PSA levels. That drives overdetection quite a bit."

Dr. Carroll disclosed that he has received honoraria, research support, and/or consulting fees from Genomic Health, Intuitive, Janssen, and Myriad.

dbrunk@frontlinemedcom.com

SAN DIEGO – Over the past 20 years, death rates from prostate cancer in the United States have declined by 39%, due largely to early detection and/or improved treatment, according to Dr. Peter R. Carroll.

"It’s important to realize that this accounts for 20% of the decrease in cancer-specific deaths in men," said Dr. Carroll, professor and chair of the department of urology at the University of California, San Francisco. "However, the Achilles’ heel of PSA [prostate-specific antigen] testing is that it does so at the risk of overdetection – detecting disease that would not have become clinically apparent over a patient’s lifetime if left untreated. In this country, detection and treatment are too tightly linked."

In addition, widespread use of serum PSA has resulted in a "dramatic stage and grade shift, with most cancers currently being detected of limited cancer grade and stage," he said. Data from his colleagues at UCSF found that between 1990 and 2012, age-adjusted death rates from prostate cancer decreased 3.96% in North America yet increased 41% worldwide. In the United States, men with nonpalpable PSA-driven cancer comprise the largest segment of prostate cancer patients. "We think that we’ve seen a leveling of overdetection, but I think we’ll see another round of overdetection, because of a lowering PSA threshold to prompt biopsy, aggressive rescreening, the use of PSA velocity at low PSA values to prompt biopsy, and the use of saturation biopsies," he said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation.

In 2012 the U.S. Preventive Services Task Force came out against prostate cancer screening, classifying it as a grade D recommendation (Ann. Intern. Med. 2012;157[2]:120-34). The magnitude of overdetection varies with time period, age, comorbidities, region, definition, and screening practices and is thought to range between 2% and 67%, Dr. Carroll said. "I think a good number is somewhere between 35% and 40%." A recently published nomogram for predicting overdiagnosis found that depending on a man’s age, Gleason score, and PSA level, the likelihood that his tumor has been overdiagnosed ranges from 2.9% to 88.1% (J. Natl. Cancer Inst. 2014 [doi:10.1093/jnci.djt367]).

If prostate cancer screening is to be undertaken, "it should only be done recognizing that selective, rather than indiscriminate, treatment should follow," Dr. Carroll said. "Such an approach has been shown to reduce mortality while managing many with active surveillance in lieu of immediate treatment" (Lancet Oncol. 2010;11[8]:725-32). At UCSF, where more than 1,000 men are on active surveillance, the 5-year treatment-free survival is 65%, the 5-year overall survival is 97%, and the 5-year prostate cancer–specific survival is 100%. "The window of opportunity for treatment appears to be open for a long period of time," he said.

Potential solutions Dr. Carroll proposed to decrease the rates of overdetection include:

• Reducing the treatment of low-risk tumors.

• Identifying high-risk populations and targeting prevention and screening efforts to those populations.

• Developing new screening markers.

• Developing clinical and patient tools to support informed decision making about prevention, screening, biopsy, and treatment.

• Changing screening guidelines.

"The single biggest predictor of risk is a baseline PSA. It trumps ethnicity and family history," Dr. Carroll said. "I think there’s a strong rationale for a baseline screening between ages 45 and 55. If you screen beyond age 70, you increase the risk of overdetection. But if you stop screening you also increase the mortality. So beyond age 70 you want to individualize, consider screening only in those with a long life expectancy, and perhaps change the rationale for biopsy. Digital rectal examination in my mind is optional as a primary screening maneuver. Screening can be done at 1- to 2-year intervals. One thing we need to get away from is using PSA velocity at low PSA levels. That drives overdetection quite a bit."

Dr. Carroll disclosed that he has received honoraria, research support, and/or consulting fees from Genomic Health, Intuitive, Janssen, and Myriad.

dbrunk@frontlinemedcom.com

SAN DIEGO – Over the past 20 years, death rates from prostate cancer in the United States have declined by 39%, due largely to early detection and/or improved treatment, according to Dr. Peter R. Carroll.

"It’s important to realize that this accounts for 20% of the decrease in cancer-specific deaths in men," said Dr. Carroll, professor and chair of the department of urology at the University of California, San Francisco. "However, the Achilles’ heel of PSA [prostate-specific antigen] testing is that it does so at the risk of overdetection – detecting disease that would not have become clinically apparent over a patient’s lifetime if left untreated. In this country, detection and treatment are too tightly linked."

In addition, widespread use of serum PSA has resulted in a "dramatic stage and grade shift, with most cancers currently being detected of limited cancer grade and stage," he said. Data from his colleagues at UCSF found that between 1990 and 2012, age-adjusted death rates from prostate cancer decreased 3.96% in North America yet increased 41% worldwide. In the United States, men with nonpalpable PSA-driven cancer comprise the largest segment of prostate cancer patients. "We think that we’ve seen a leveling of overdetection, but I think we’ll see another round of overdetection, because of a lowering PSA threshold to prompt biopsy, aggressive rescreening, the use of PSA velocity at low PSA values to prompt biopsy, and the use of saturation biopsies," he said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation.

In 2012 the U.S. Preventive Services Task Force came out against prostate cancer screening, classifying it as a grade D recommendation (Ann. Intern. Med. 2012;157[2]:120-34). The magnitude of overdetection varies with time period, age, comorbidities, region, definition, and screening practices and is thought to range between 2% and 67%, Dr. Carroll said. "I think a good number is somewhere between 35% and 40%." A recently published nomogram for predicting overdiagnosis found that depending on a man’s age, Gleason score, and PSA level, the likelihood that his tumor has been overdiagnosed ranges from 2.9% to 88.1% (J. Natl. Cancer Inst. 2014 [doi:10.1093/jnci.djt367]).

If prostate cancer screening is to be undertaken, "it should only be done recognizing that selective, rather than indiscriminate, treatment should follow," Dr. Carroll said. "Such an approach has been shown to reduce mortality while managing many with active surveillance in lieu of immediate treatment" (Lancet Oncol. 2010;11[8]:725-32). At UCSF, where more than 1,000 men are on active surveillance, the 5-year treatment-free survival is 65%, the 5-year overall survival is 97%, and the 5-year prostate cancer–specific survival is 100%. "The window of opportunity for treatment appears to be open for a long period of time," he said.

Potential solutions Dr. Carroll proposed to decrease the rates of overdetection include:

• Reducing the treatment of low-risk tumors.

• Identifying high-risk populations and targeting prevention and screening efforts to those populations.

• Developing new screening markers.

• Developing clinical and patient tools to support informed decision making about prevention, screening, biopsy, and treatment.

• Changing screening guidelines.

"The single biggest predictor of risk is a baseline PSA. It trumps ethnicity and family history," Dr. Carroll said. "I think there’s a strong rationale for a baseline screening between ages 45 and 55. If you screen beyond age 70, you increase the risk of overdetection. But if you stop screening you also increase the mortality. So beyond age 70 you want to individualize, consider screening only in those with a long life expectancy, and perhaps change the rationale for biopsy. Digital rectal examination in my mind is optional as a primary screening maneuver. Screening can be done at 1- to 2-year intervals. One thing we need to get away from is using PSA velocity at low PSA levels. That drives overdetection quite a bit."

Dr. Carroll disclosed that he has received honoraria, research support, and/or consulting fees from Genomic Health, Intuitive, Janssen, and Myriad.

dbrunk@frontlinemedcom.com

SAN DIEGO – Now is the time for researchers and clinicians to examine strategies and interventions for preventing prostate cancer, in the opinion of Dr. Peter H. Gann.

"In the last 12 years or so we have seen a litany of failure with regard to prostate cancer prevention in trials with clinical endpoints," Dr. Gann, professor and director of pathology research at the University of Illinois at Chicago, said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation.

"With vitamin E supplementation, for example, we see a possible increased risk of prostate cancer, no effect with selenium and possibly and increased risk of diabetes, no effect from soy, and the potential impact of green tea polyphenols is unresolved."

Moreover, it’s conceivable that you might need to screen 1,500 average-risk patients to prevent one prostate cancer from occurring. "That means that preventive agents don’t have to be safe; they have to be incredibly safe if they’re going to be used in this way," Dr. Gann said.

He proposed five ways to advance prostate cancer prevention efforts:

• Develop better preclinical models. Canadian investigators have reported success with generating high fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development (Cancer Res. 2013 Dec. 19 [doi:10.1158/0008-5472.CAN-13-2921-T]). "One of the incredible things about this is that the transplantable cells can be obtained from needle biopsies," said Dr. Gann, who was not involved with the study. "Architecture and protein marker expression is preserved in these xenografts, as are other molecular characteristics of the tumor, which is fantastic."

An unrelated Australian study demonstrated that it’s possible to generate xenografts of the earlier low-to-moderate grade, localized tumors (Nat. Protoc. 2013;8:836-48). "Why is this exciting for us in prevention? More and more we’re thinking about not how to prevent things from the initiation stage but rather in terms of progression," Dr. Gann explained. "Being able to have individualized samples that we can study versus agents that may inhibit progression is a major opportunity, I think."

• Improve clinical trial design and infrastructure. The existing networks for prostate cancer prevention trials are largely undeveloped, unlike cooperative group networks available for therapeutic trials, according to Dr. Gann. "Many investigators with promising ideas do not have access to the clinical infrastructure or funding sources they need for translational research," he noted. "Moreover, the pros and cons of various available designs for phase II and III trials have not been adequately debated, amidst a shifting landscape in which some designs become less feasible as others become more feasible."

• Develop better risk stratification and patient targeting. What if clinicians could do a better job of sorting out who is truly at risk for prostate cancer? "Active surveillance cohorts are the most promising opportunity we have for prevention trials involving low-risk interventions," Dr. Gann said. Cumulative results from genome-wide association studies and the expected results from sequencing studies capable of identifying rare genetic variants with high penetrance hold promise for identifying populations for whom preventive strategies would have the most benefit, he added.

• Develop better interventional agents. To date, "I think we’ve taken a haphazard approach to identifying agents for prostate cancer prevention," Dr. Gann said. "With preclinical models lacking, sometimes they’re not vetted very well, either. We’re not going to be able to develop a rational approach to preventing prostate cancer until we have a better idea of how it all comes about. One idea is to do high throughput cell assay based drug screening, which we do for therapeutics but not for chemopreventive agents. The question is, do we have the right libraries of compounds and do we have the right readouts? I suggest that we can start with compounds, especially dietary agents that could inhibit 5-alpha reductase. We also need to think beyond a pharmacologic approach: studying the effects of diet and physical activity, for example."

• Establish better intermediate endpoints for phase II trials. A lack of intermediate endpoint biomarkers (IEBs) for phase II trials is creating a "phase II bottleneck," he said. "There is an ongoing explosion of opportunities provided by new biotechnology and computational methods, but converting these opportunities into validated IEBs for trials will take thought and planning."

Dr. Gann disclosed that he has received grant support from GlaxoSmithKline.

dbrunk@frontlinemedcom.com

SAN DIEGO – Now is the time for researchers and clinicians to examine strategies and interventions for preventing prostate cancer, in the opinion of Dr. Peter H. Gann.

"In the last 12 years or so we have seen a litany of failure with regard to prostate cancer prevention in trials with clinical endpoints," Dr. Gann, professor and director of pathology research at the University of Illinois at Chicago, said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation.

"With vitamin E supplementation, for example, we see a possible increased risk of prostate cancer, no effect with selenium and possibly and increased risk of diabetes, no effect from soy, and the potential impact of green tea polyphenols is unresolved."

Moreover, it’s conceivable that you might need to screen 1,500 average-risk patients to prevent one prostate cancer from occurring. "That means that preventive agents don’t have to be safe; they have to be incredibly safe if they’re going to be used in this way," Dr. Gann said.

He proposed five ways to advance prostate cancer prevention efforts:

• Develop better preclinical models. Canadian investigators have reported success with generating high fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development (Cancer Res. 2013 Dec. 19 [doi:10.1158/0008-5472.CAN-13-2921-T]). "One of the incredible things about this is that the transplantable cells can be obtained from needle biopsies," said Dr. Gann, who was not involved with the study. "Architecture and protein marker expression is preserved in these xenografts, as are other molecular characteristics of the tumor, which is fantastic."

An unrelated Australian study demonstrated that it’s possible to generate xenografts of the earlier low-to-moderate grade, localized tumors (Nat. Protoc. 2013;8:836-48). "Why is this exciting for us in prevention? More and more we’re thinking about not how to prevent things from the initiation stage but rather in terms of progression," Dr. Gann explained. "Being able to have individualized samples that we can study versus agents that may inhibit progression is a major opportunity, I think."

• Improve clinical trial design and infrastructure. The existing networks for prostate cancer prevention trials are largely undeveloped, unlike cooperative group networks available for therapeutic trials, according to Dr. Gann. "Many investigators with promising ideas do not have access to the clinical infrastructure or funding sources they need for translational research," he noted. "Moreover, the pros and cons of various available designs for phase II and III trials have not been adequately debated, amidst a shifting landscape in which some designs become less feasible as others become more feasible."

• Develop better risk stratification and patient targeting. What if clinicians could do a better job of sorting out who is truly at risk for prostate cancer? "Active surveillance cohorts are the most promising opportunity we have for prevention trials involving low-risk interventions," Dr. Gann said. Cumulative results from genome-wide association studies and the expected results from sequencing studies capable of identifying rare genetic variants with high penetrance hold promise for identifying populations for whom preventive strategies would have the most benefit, he added.

• Develop better interventional agents. To date, "I think we’ve taken a haphazard approach to identifying agents for prostate cancer prevention," Dr. Gann said. "With preclinical models lacking, sometimes they’re not vetted very well, either. We’re not going to be able to develop a rational approach to preventing prostate cancer until we have a better idea of how it all comes about. One idea is to do high throughput cell assay based drug screening, which we do for therapeutics but not for chemopreventive agents. The question is, do we have the right libraries of compounds and do we have the right readouts? I suggest that we can start with compounds, especially dietary agents that could inhibit 5-alpha reductase. We also need to think beyond a pharmacologic approach: studying the effects of diet and physical activity, for example."

• Establish better intermediate endpoints for phase II trials. A lack of intermediate endpoint biomarkers (IEBs) for phase II trials is creating a "phase II bottleneck," he said. "There is an ongoing explosion of opportunities provided by new biotechnology and computational methods, but converting these opportunities into validated IEBs for trials will take thought and planning."

Dr. Gann disclosed that he has received grant support from GlaxoSmithKline.

dbrunk@frontlinemedcom.com

SAN DIEGO – Now is the time for researchers and clinicians to examine strategies and interventions for preventing prostate cancer, in the opinion of Dr. Peter H. Gann.

"In the last 12 years or so we have seen a litany of failure with regard to prostate cancer prevention in trials with clinical endpoints," Dr. Gann, professor and director of pathology research at the University of Illinois at Chicago, said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation.

"With vitamin E supplementation, for example, we see a possible increased risk of prostate cancer, no effect with selenium and possibly and increased risk of diabetes, no effect from soy, and the potential impact of green tea polyphenols is unresolved."

Moreover, it’s conceivable that you might need to screen 1,500 average-risk patients to prevent one prostate cancer from occurring. "That means that preventive agents don’t have to be safe; they have to be incredibly safe if they’re going to be used in this way," Dr. Gann said.

He proposed five ways to advance prostate cancer prevention efforts:

• Develop better preclinical models. Canadian investigators have reported success with generating high fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development (Cancer Res. 2013 Dec. 19 [doi:10.1158/0008-5472.CAN-13-2921-T]). "One of the incredible things about this is that the transplantable cells can be obtained from needle biopsies," said Dr. Gann, who was not involved with the study. "Architecture and protein marker expression is preserved in these xenografts, as are other molecular characteristics of the tumor, which is fantastic."

An unrelated Australian study demonstrated that it’s possible to generate xenografts of the earlier low-to-moderate grade, localized tumors (Nat. Protoc. 2013;8:836-48). "Why is this exciting for us in prevention? More and more we’re thinking about not how to prevent things from the initiation stage but rather in terms of progression," Dr. Gann explained. "Being able to have individualized samples that we can study versus agents that may inhibit progression is a major opportunity, I think."

• Improve clinical trial design and infrastructure. The existing networks for prostate cancer prevention trials are largely undeveloped, unlike cooperative group networks available for therapeutic trials, according to Dr. Gann. "Many investigators with promising ideas do not have access to the clinical infrastructure or funding sources they need for translational research," he noted. "Moreover, the pros and cons of various available designs for phase II and III trials have not been adequately debated, amidst a shifting landscape in which some designs become less feasible as others become more feasible."

• Develop better risk stratification and patient targeting. What if clinicians could do a better job of sorting out who is truly at risk for prostate cancer? "Active surveillance cohorts are the most promising opportunity we have for prevention trials involving low-risk interventions," Dr. Gann said. Cumulative results from genome-wide association studies and the expected results from sequencing studies capable of identifying rare genetic variants with high penetrance hold promise for identifying populations for whom preventive strategies would have the most benefit, he added.

• Develop better interventional agents. To date, "I think we’ve taken a haphazard approach to identifying agents for prostate cancer prevention," Dr. Gann said. "With preclinical models lacking, sometimes they’re not vetted very well, either. We’re not going to be able to develop a rational approach to preventing prostate cancer until we have a better idea of how it all comes about. One idea is to do high throughput cell assay based drug screening, which we do for therapeutics but not for chemopreventive agents. The question is, do we have the right libraries of compounds and do we have the right readouts? I suggest that we can start with compounds, especially dietary agents that could inhibit 5-alpha reductase. We also need to think beyond a pharmacologic approach: studying the effects of diet and physical activity, for example."

• Establish better intermediate endpoints for phase II trials. A lack of intermediate endpoint biomarkers (IEBs) for phase II trials is creating a "phase II bottleneck," he said. "There is an ongoing explosion of opportunities provided by new biotechnology and computational methods, but converting these opportunities into validated IEBs for trials will take thought and planning."

Dr. Gann disclosed that he has received grant support from GlaxoSmithKline.

dbrunk@frontlinemedcom.com

SAN DIEGO – Is there a future for prostate cancer chemoprevention?

"Some people think not," Maarten C. Bosland, Ph.D., said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation. "Maybe we should just engage in more exercise and decrease our body weight."

Population studies of people who move from low-risk to high-risk countries indicate that the risk of prostate cancer – including the risk of dying from the disease – could be modified by environmental factors that are not yet understood. However, the 5-alpha reductase inhibitor trials provided proof of principle that the risk of a subset of prostate cancer can be reduced by drugs. Why, then, has the prostate cancer prevention field not moved forward?

Reasons for the current stagnation of progress include failure of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to show preventive activity of selenium and vitamin E; the failure of a high-risk phase III study to show preventive activity of selenized yeast; the refusal of the Food and Drug Administration to approve finasteride for prostate cancer prevention, and uncertainty regarding the long-term effects of treatment with 5-alpha reductase inhibitors, according to Dr. Bosland of the department of pathology at the University of Illinois at Chicago.

Then there’s the issue of clinical or biologic significance.

"Some prostate cancers start early while others start late," he explained. "In each of these categories, some of the cancers can lead to death and others won’t; they’ll remain clinically insignificant. This poses a problem in thinking about how to go about chemoprevention. We want to prevent death from prostate cancer, but the window of opportunity in which we can intervene in a chemoprevention setting is limited, and it encompasses different stages of prostate cancer. This is difficult in terms of how we conduct clinical trials and identify endpoints that are meaningful in terms of preventing death from prostate cancer."

In the case of SELECT, investigators made a direct jump to a phase III study, based on evidence from clinical trials with prostate cancer as a secondary endpoint. "I think we should go back to the traditional approach, with phase I, II, and III trials [of candidate agents for prostate cancer chemoprevention]," Dr. Bosland said.

"There were no phase II studies to support phase III trials when SELECT and other studies with selenium were started." Clinical study "needs to be driven by the biology and mechanisms of prostate cancer," he said.

Speaking in the context of clinical studies, Dr. Bosland said that researchers are challenged by the fact that prostate cancer development is complicated by a range of different pathways and multiple underlying mechanisms. "That is consistent with the enormous heterogeneity of prostate cancer morphologically, genetically, and clinically," he said. "There are several types of prostate cancer with a different frequency, time of onset, and potential to progress. This means that we need a broad spectrum of chemoprevention agents or combination of agents. Multiple preclinical models are needed to represent the different pathways/types of cancer and progression to lethality. We need to focus on the ultimate goal of preventing only aggressive lethal cancer. We don’t want to interfere with clinically insignificant cancer. It’s meaningless."

To accomplish this, Dr. Bosland recommended the development of a valid high-throughput system to identify new candidate agents for prostate cancer chemoprevention. "Markers of fatal/lethal disease need to be identified for application in clinical trials," he continued. "A systematic evaluation of the predictive value of preclinical models, phase II designs, and biomarkers is also needed."

His other recommendations include: Conduct no phase III trials before having data from phase II trials, and conduct no phase II trials before having adequate preclinical data; consider the mechanism and biology of the agent and target before embarking on clinical studies; and develop a rational identification of candidate agents based on biology, mechanism, and results of high-throughput screening. "Only if we do all of this and find the funding for it will there be a future for prostate cancer chemoprevention," Dr.Bosland concluded.

Dr. Bosland said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Is there a future for prostate cancer chemoprevention?

"Some people think not," Maarten C. Bosland, Ph.D., said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation. "Maybe we should just engage in more exercise and decrease our body weight."

Population studies of people who move from low-risk to high-risk countries indicate that the risk of prostate cancer – including the risk of dying from the disease – could be modified by environmental factors that are not yet understood. However, the 5-alpha reductase inhibitor trials provided proof of principle that the risk of a subset of prostate cancer can be reduced by drugs. Why, then, has the prostate cancer prevention field not moved forward?

Reasons for the current stagnation of progress include failure of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to show preventive activity of selenium and vitamin E; the failure of a high-risk phase III study to show preventive activity of selenized yeast; the refusal of the Food and Drug Administration to approve finasteride for prostate cancer prevention, and uncertainty regarding the long-term effects of treatment with 5-alpha reductase inhibitors, according to Dr. Bosland of the department of pathology at the University of Illinois at Chicago.

Then there’s the issue of clinical or biologic significance.

"Some prostate cancers start early while others start late," he explained. "In each of these categories, some of the cancers can lead to death and others won’t; they’ll remain clinically insignificant. This poses a problem in thinking about how to go about chemoprevention. We want to prevent death from prostate cancer, but the window of opportunity in which we can intervene in a chemoprevention setting is limited, and it encompasses different stages of prostate cancer. This is difficult in terms of how we conduct clinical trials and identify endpoints that are meaningful in terms of preventing death from prostate cancer."

In the case of SELECT, investigators made a direct jump to a phase III study, based on evidence from clinical trials with prostate cancer as a secondary endpoint. "I think we should go back to the traditional approach, with phase I, II, and III trials [of candidate agents for prostate cancer chemoprevention]," Dr. Bosland said.

"There were no phase II studies to support phase III trials when SELECT and other studies with selenium were started." Clinical study "needs to be driven by the biology and mechanisms of prostate cancer," he said.

Speaking in the context of clinical studies, Dr. Bosland said that researchers are challenged by the fact that prostate cancer development is complicated by a range of different pathways and multiple underlying mechanisms. "That is consistent with the enormous heterogeneity of prostate cancer morphologically, genetically, and clinically," he said. "There are several types of prostate cancer with a different frequency, time of onset, and potential to progress. This means that we need a broad spectrum of chemoprevention agents or combination of agents. Multiple preclinical models are needed to represent the different pathways/types of cancer and progression to lethality. We need to focus on the ultimate goal of preventing only aggressive lethal cancer. We don’t want to interfere with clinically insignificant cancer. It’s meaningless."

To accomplish this, Dr. Bosland recommended the development of a valid high-throughput system to identify new candidate agents for prostate cancer chemoprevention. "Markers of fatal/lethal disease need to be identified for application in clinical trials," he continued. "A systematic evaluation of the predictive value of preclinical models, phase II designs, and biomarkers is also needed."

His other recommendations include: Conduct no phase III trials before having data from phase II trials, and conduct no phase II trials before having adequate preclinical data; consider the mechanism and biology of the agent and target before embarking on clinical studies; and develop a rational identification of candidate agents based on biology, mechanism, and results of high-throughput screening. "Only if we do all of this and find the funding for it will there be a future for prostate cancer chemoprevention," Dr.Bosland concluded.

Dr. Bosland said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Is there a future for prostate cancer chemoprevention?

"Some people think not," Maarten C. Bosland, Ph.D., said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation. "Maybe we should just engage in more exercise and decrease our body weight."

Population studies of people who move from low-risk to high-risk countries indicate that the risk of prostate cancer – including the risk of dying from the disease – could be modified by environmental factors that are not yet understood. However, the 5-alpha reductase inhibitor trials provided proof of principle that the risk of a subset of prostate cancer can be reduced by drugs. Why, then, has the prostate cancer prevention field not moved forward?

Reasons for the current stagnation of progress include failure of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to show preventive activity of selenium and vitamin E; the failure of a high-risk phase III study to show preventive activity of selenized yeast; the refusal of the Food and Drug Administration to approve finasteride for prostate cancer prevention, and uncertainty regarding the long-term effects of treatment with 5-alpha reductase inhibitors, according to Dr. Bosland of the department of pathology at the University of Illinois at Chicago.

Then there’s the issue of clinical or biologic significance.

"Some prostate cancers start early while others start late," he explained. "In each of these categories, some of the cancers can lead to death and others won’t; they’ll remain clinically insignificant. This poses a problem in thinking about how to go about chemoprevention. We want to prevent death from prostate cancer, but the window of opportunity in which we can intervene in a chemoprevention setting is limited, and it encompasses different stages of prostate cancer. This is difficult in terms of how we conduct clinical trials and identify endpoints that are meaningful in terms of preventing death from prostate cancer."

In the case of SELECT, investigators made a direct jump to a phase III study, based on evidence from clinical trials with prostate cancer as a secondary endpoint. "I think we should go back to the traditional approach, with phase I, II, and III trials [of candidate agents for prostate cancer chemoprevention]," Dr. Bosland said.

"There were no phase II studies to support phase III trials when SELECT and other studies with selenium were started." Clinical study "needs to be driven by the biology and mechanisms of prostate cancer," he said.

Speaking in the context of clinical studies, Dr. Bosland said that researchers are challenged by the fact that prostate cancer development is complicated by a range of different pathways and multiple underlying mechanisms. "That is consistent with the enormous heterogeneity of prostate cancer morphologically, genetically, and clinically," he said. "There are several types of prostate cancer with a different frequency, time of onset, and potential to progress. This means that we need a broad spectrum of chemoprevention agents or combination of agents. Multiple preclinical models are needed to represent the different pathways/types of cancer and progression to lethality. We need to focus on the ultimate goal of preventing only aggressive lethal cancer. We don’t want to interfere with clinically insignificant cancer. It’s meaningless."

To accomplish this, Dr. Bosland recommended the development of a valid high-throughput system to identify new candidate agents for prostate cancer chemoprevention. "Markers of fatal/lethal disease need to be identified for application in clinical trials," he continued. "A systematic evaluation of the predictive value of preclinical models, phase II designs, and biomarkers is also needed."

His other recommendations include: Conduct no phase III trials before having data from phase II trials, and conduct no phase II trials before having adequate preclinical data; consider the mechanism and biology of the agent and target before embarking on clinical studies; and develop a rational identification of candidate agents based on biology, mechanism, and results of high-throughput screening. "Only if we do all of this and find the funding for it will there be a future for prostate cancer chemoprevention," Dr.Bosland concluded.

Dr. Bosland said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com