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Genomic Tests Should be Used to Help Guide Treatment of Prostate Cancer
Opposing Views
Genomic Tests Should be Used to Help Guide Treatment of Prostate Cancer YES PROSTATE cancer is a heterogeneous disease. This heterogeneity exists on many levels encompassing the spectrum from clinical presentation to disease trajectory as well as molecular features to treatment response. Lack of uniformity in these and other facets persistently confounds the most elementary of clinical decisions facing urologists today, which is how to best treat a man diagnosed with clinically localized prostate cancer. While the question may be simple, the answer has proven to be complex. As clinicians who treat men with prostate cancer, we are keenly aware that significant disparity exists with regard to outcome among men within a given risk group (eg Gleason sum). Beyond the glandular architecture that defines Gleason grade there resides intracellular alterations that drive cancer cell behavior. It stands to reason that a better understanding of these molecular changes, with their attendant impact on clinical outcome, could help improve treatment selection. One has only to look at the field of breast cancer to understand the power of robust molecular risk stratification. Today, a clinician treating a woman diagnosed with breast cancer can leverage tumor receptor status (estrogen and progesterone) and disease genomic biomarker data to guide therapy. To be sure, due to compelling randomized clinical trial data, both assays are currently in the NCCNÒ treatment guidelines for breast cancer. Predictive biomarkers (ie biological assays that predict treatment response) are valuable clinical tools. Why have we not experienced similar progress in clinically localized prostate cancer? The answer seems to be related, in varying degrees, to a number of factors. First, the general protracted natural history of localized prostate cancer makes clinical study challenging. Second, difficulty in visualizing the disease with fidelity in vivo makes identifying areas of cancer for evaluation challenging. Third, lack of ready access to post systemic treatment tissues for examination makes an assessment of molecular markers of 0022-5347/17/1982-0001/0 THE JOURNAL OF UROLOGY® Ó 2017 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
treatment response, and drivers of treatment resistance and aggressivity challenging. And, lastly, the multifocal distribution and inter-focal genetic heterogeneity of primary prostate cancer make biology inference from analysis of a single focus challenging. Among these, it is perhaps inter-focal genomic heterogeneity that represents the biggest obstacle to biopsy applied tissue based genomic tests. Recognizing this obstacle, there has been enthusiasm for the development of biofluidic (ie blood and urine) based genomic tests that have the capacity to draw information from the prostate as a whole, ostensibly minimizing the sampling bias that is inherent to tissue based biopsy assays. For example, the SelectMDxÔ assay, a urine assay that measures RNA transcript levels of DLX1 and HOXC6,1 and the MiPSÔ (Michigan Prostate Score), a urine assay that combines urine T2:ERG and PCA3 RNA transcript levels with serum PSA,2 provide the clinician with the probability of finding any cancer as well as high grade cancer on biopsy. Thus, these genomic tests provide data to inform decision making with regard to who should receive a diagnostic prostate biopsy as opposed to what treatment should be selected should a diagnosis of prostate cancer be made. Importantly, neither assay provides validated and impactful information on clinical trajectory, an issue that is rooted in the heterogeneity of outcomes following treatment for localized disease. So, what do we do? Should we just give up? Absolutely not! In the advanced disease space we have recently seen the striking impact of molecular assays to guide the treatment of patients with prostate cancer. For example, the presence of circulating tumor cells possessing mRNA encoding AR-V7 was shown to be an exquisitely strong predictor of response to treatment with second generation antiandrogens (ie enzalutamide and abiraterone),3 and the identification of somatic DNA repair gene mutations (ie BRCA 1/2) was found to be highly predictive of response to therapies that target DNA repair mechanisms (ie olaparib).4 One
http://dx.doi.org/10.1016/j.juro.2017.05.039 Vol. 198, 1-3, August 2017 Printed in U.S.A.
www.jurology.com
j
1
2
OPPOSING VIEWS
should note that as opposed to localized disease, in both of these cases prior treatment failure likely enriched the presence of genomic alterations of clinical consequence. Taken together, it would seem that the future of genomic tests in arbitrating therapeutic decisions in localized prostate cancer will depend on a combination of tissue and biofluidic based assays taken in the context of specific clinicopathological variables and advanced imaging data. Moving forward, one cannot overstate the importance of validating novel biomarkers in randomized clinical trials or with other robust methods prior to widespread adoption. To quote Daniel Hayes, MD, FACP, current
President of the American Society of Clinical Oncology, “a bad tumor biomarker is as bad as a bad drug.”5 The first step towards effectively combatting localized disease is an acknowledgement of the mixed bag that it is. If one believes that biology drives cancer behavior, a more nuanced and sophisticated understanding of the molecular drivers of prostate cancer can only improve the efficacy of our treatments. It is up to us to prove it. Ganesh S. Palapattu Department of Urology University of Michigan Ann Arbor, Michigan
REFERENCES 1. Dijkstra S, Govers TM, Hendriks RJ et al: Costeffectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnosticsda decision analytical model. BJU Int 2017 Mar 29. doi:10.1111/bju. 13861 [Epub ahead of print]. Accessed April 25, 2017.
2. Tomlins SA, Day JR, Lonigro RJ et al: Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol 2016; 70: 45.
4. Mateo J, Carreira S, Sandhu S et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015; 373: 1697.
3. Antonarakis ES, Lu C, Wang H et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028.
5. Mullard A: Daniel Hayes. Nat Rev Drug Discov 2013; 12: 734.
NO GENOMIC profiling brings the promise of personalized risk prediction in men with prostate cancer facing treatment decisions. The 3 commercially available genomic signatures (ProlarisÒ, Oncotype DXÒ and DecipherÒ test) are considered to be useful resources for patients deciding between immediate treatment versus active surveillance as well as for those who require adjuvant radiation after radical prostatectomy (RP).1 Similar markers used for decision making about breast cancer have been subjected to much more rigorous scientific investigation in order to provide the highest level of evidence to justify their use. For example, the 21 gene “recurrence score” from Oncotype DX has been validated in a large prospective study to select women with breast cancer who can safely avoid adjuvant chemotherapy without compromising 5-year disease-free survival.2 In contrast, the level of evidence supporting genomic testing for decision making about prostate cancer is weak, with no Level 1 evidence or even large prospective studies thus far to support its routine use in clinical practice. Appropriate scientific prospective studies are desperately needed, and should be conducted comparing the results of genomic signatures to the results obtained from validated clinical instruments. This may offer the medical community an opportunity to exercise similar decision making
using the clinical information available to them that does not come with a price tag. If a man is diagnosed with a single core of low volume Gleason 6 cancer, is genetic testing really necessary to confirm that he does not require immediate treatment? While numerous studies show a significant reclassification of risk when applying a genomic profiler,1 there is little evidence to guide physicians on what to do with this information, and the potential dangers of making treatment decisions based on these tests warrant attention. Of 2,432 patients undergoing RP 52% of CAPRA-S low risk men were reassigned to intermediate or high risk and 40% of high risk men were reassigned to intermediate or low risk based on the Decipher test results.3 If one were to be influenced by these results, more than half of the low risk patients would be treated with adjuvant radiotherapy despite the lack of high level evidence supporting its need. While this may not be the intended use of these tests, without the appropriate prospective studies with longitudinal followup to inform physicians about how to properly integrate these tests into clinical practice, this may certainly be the unintended consequence. Furthermore, significant challenges exist when generalizing the data validating these tests to men who may not be the same as those involved in the research studies. For example, Oncotype DX and Prolaris are tests intended for men contemplating
OPPOSING VIEWS
active surveillance, although the primary validation studies were performed in patients who underwent RP.1 As a result, these findings may not be reflective of all men considering active surveillance in clinical practice. This finding highlights the severe selection bias and flaws that exist when using these data to establish valid predictive biomarkers to be used globally in this population. There is also a lack of head-to-head comparisons among the different genomic signatures with each test being touted as superior to the other without any evidence to support such claims. Wei et al sequenced 4 consecutive radical prostatectomy specimens and the genes contributing to these 3 signatures showed marked variation in the same tissue core, suggesting that one would obtain different risk assessments from each test.4 Future studies with prospective comparisons of the different tests on the same population will be needed to determine the best performer for each treatment decision. Tumor heterogeneity remains an issue in tests being conducted on biopsy cores. Wei et al also found significant variation in genomic profiles using the same test in different biopsy cores throughout the RP specimen,4 which suggests that the quality of the prostate samples obtained is critical for accurate risk assessment on the clinical
3
and genomic levels. While this study is limited by a small sample size and does not account for the algorithm or specific platform used by each test, it sheds interesting light on the theory that these tests may not overcome the tumor heterogeneity problem that has long plagued prostate cancer risk stratification. We remain optimistic that genomic testing will play a role in decision making for prostate cancer in the future. However, the current evidence behind these biomarkers is clearly not enough to support routine clinical use at such a high cost. Future longterm prospective trials will and should be required to determine which subset of men with prostate cancer will truly benefit from genomic testing and how to best use this technology. These studies have been conducted in breast cancer. Men with prostate cancer merit a similar level of scientific investment to prove that these tests will offer a comparable benefit to treatment decision making, and, ultimately, long-term outcomes.
Sanoj Punnen and Dipen J. Parekh Department of Urology University of Miami Miller School of Medicine Miami, Florida
REFERENCES 1. Moschini M, Spahn M, Mattei A et al: Incorporation of tissue-based genomic biomarkers into localized prostate cancer clinics. BMC Med 2016; 14: 67.
2. Sparano JA, Gray RJ, Makower DF et al: Prospective validation of a 21-gene expression
assay in breast cancer. N Engl J Med 2015; 373: 2005.
patients. Prostate Cancer Prostatic Dis 2016; 19: 374.
3. Den RB, Santiago-Jimenez M, Alter J et al: Decipher correlation patterns post prostatectomy: initial experience from 2 342 prospective
4. Wei L, Wang J, Lampert E et al: Intratumoral and intertumoral genomic heterogeneity of multifocal localized prostate cancer impacts molecular classifications and enomic prognosticators. Eur Urol 2017; 71: 183.
Genomic Tests Should be Used to Help Guide Treatment of Prostate Cancer YES PROSTATE cancer is a heterogeneous disease. This heterogeneity exists on many levels encompassing the spectrum from clinical presentation to disease trajectory as well as molecular features to treatment response. Lack of uniformity in these and other facets persistently confounds the most elementary of clinical decisions facing urologists today, which is how to best treat a man diagnosed with clinically localized prostate cancer. While the question may be simple, the answer has proven to be complex. As clinicians who treat men with prostate cancer, we are keenly aware that significant disparity exists with regard to outcome among men within a given risk group (eg Gleason sum). Beyond the glandular architecture that defines Gleason grade there resides intracellular alterations that drive cancer cell behavior. It stands to reason that a better understanding of these molecular changes, with their attendant impact on clinical outcome, could help improve treatment selection. One has only to look at the field of breast cancer to understand the power of robust molecular risk stratification. Today, a clinician treating a woman diagnosed with breast cancer can leverage tumor receptor status (estrogen and progesterone) and disease genomic biomarker data to guide therapy. To be sure, due to compelling randomized clinical trial data, both assays are currently in the NCCNÒ treatment guidelines for breast cancer. Predictive biomarkers (ie biological assays that predict treatment response) are valuable clinical tools. Why have we not experienced similar progress in clinically localized prostate cancer? The answer seems to be related, in varying degrees, to a number of factors. First, the general protracted natural history of localized prostate cancer makes clinical study challenging. Second, difficulty in visualizing the disease with fidelity in vivo makes identifying areas of cancer for evaluation challenging. Third, lack of ready access to post systemic treatment tissues for examination makes an assessment of molecular markers of 0022-5347/17/1982-0001/0 THE JOURNAL OF UROLOGY® Ó 2017 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
treatment response, and drivers of treatment resistance and aggressivity challenging. And, lastly, the multifocal distribution and inter-focal genetic heterogeneity of primary prostate cancer make biology inference from analysis of a single focus challenging. Among these, it is perhaps inter-focal genomic heterogeneity that represents the biggest obstacle to biopsy applied tissue based genomic tests. Recognizing this obstacle, there has been enthusiasm for the development of biofluidic (ie blood and urine) based genomic tests that have the capacity to draw information from the prostate as a whole, ostensibly minimizing the sampling bias that is inherent to tissue based biopsy assays. For example, the SelectMDxÔ assay, a urine assay that measures RNA transcript levels of DLX1 and HOXC6,1 and the MiPSÔ (Michigan Prostate Score), a urine assay that combines urine T2:ERG and PCA3 RNA transcript levels with serum PSA,2 provide the clinician with the probability of finding any cancer as well as high grade cancer on biopsy. Thus, these genomic tests provide data to inform decision making with regard to who should receive a diagnostic prostate biopsy as opposed to what treatment should be selected should a diagnosis of prostate cancer be made. Importantly, neither assay provides validated and impactful information on clinical trajectory, an issue that is rooted in the heterogeneity of outcomes following treatment for localized disease. So, what do we do? Should we just give up? Absolutely not! In the advanced disease space we have recently seen the striking impact of molecular assays to guide the treatment of patients with prostate cancer. For example, the presence of circulating tumor cells possessing mRNA encoding AR-V7 was shown to be an exquisitely strong predictor of response to treatment with second generation antiandrogens (ie enzalutamide and abiraterone),3 and the identification of somatic DNA repair gene mutations (ie BRCA 1/2) was found to be highly predictive of response to therapies that target DNA repair mechanisms (ie olaparib).4 One
http://dx.doi.org/10.1016/j.juro.2017.05.039 Vol. 198, 1-3, August 2017 Printed in U.S.A.
www.jurology.com
j
1
2
OPPOSING VIEWS
should note that as opposed to localized disease, in both of these cases prior treatment failure likely enriched the presence of genomic alterations of clinical consequence. Taken together, it would seem that the future of genomic tests in arbitrating therapeutic decisions in localized prostate cancer will depend on a combination of tissue and biofluidic based assays taken in the context of specific clinicopathological variables and advanced imaging data. Moving forward, one cannot overstate the importance of validating novel biomarkers in randomized clinical trials or with other robust methods prior to widespread adoption. To quote Daniel Hayes, MD, FACP, current
President of the American Society of Clinical Oncology, “a bad tumor biomarker is as bad as a bad drug.”5 The first step towards effectively combatting localized disease is an acknowledgement of the mixed bag that it is. If one believes that biology drives cancer behavior, a more nuanced and sophisticated understanding of the molecular drivers of prostate cancer can only improve the efficacy of our treatments. It is up to us to prove it. Ganesh S. Palapattu Department of Urology University of Michigan Ann Arbor, Michigan
REFERENCES 1. Dijkstra S, Govers TM, Hendriks RJ et al: Costeffectiveness of a new urinary biomarker-based risk score compared to standard of care in prostate cancer diagnosticsda decision analytical model. BJU Int 2017 Mar 29. doi:10.1111/bju. 13861 [Epub ahead of print]. Accessed April 25, 2017.
2. Tomlins SA, Day JR, Lonigro RJ et al: Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol 2016; 70: 45.
4. Mateo J, Carreira S, Sandhu S et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015; 373: 1697.
3. Antonarakis ES, Lu C, Wang H et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028.
5. Mullard A: Daniel Hayes. Nat Rev Drug Discov 2013; 12: 734.
NO GENOMIC profiling brings the promise of personalized risk prediction in men with prostate cancer facing treatment decisions. The 3 commercially available genomic signatures (ProlarisÒ, Oncotype DXÒ and DecipherÒ test) are considered to be useful resources for patients deciding between immediate treatment versus active surveillance as well as for those who require adjuvant radiation after radical prostatectomy (RP).1 Similar markers used for decision making about breast cancer have been subjected to much more rigorous scientific investigation in order to provide the highest level of evidence to justify their use. For example, the 21 gene “recurrence score” from Oncotype DX has been validated in a large prospective study to select women with breast cancer who can safely avoid adjuvant chemotherapy without compromising 5-year disease-free survival.2 In contrast, the level of evidence supporting genomic testing for decision making about prostate cancer is weak, with no Level 1 evidence or even large prospective studies thus far to support its routine use in clinical practice. Appropriate scientific prospective studies are desperately needed, and should be conducted comparing the results of genomic signatures to the results obtained from validated clinical instruments. This may offer the medical community an opportunity to exercise similar decision making
using the clinical information available to them that does not come with a price tag. If a man is diagnosed with a single core of low volume Gleason 6 cancer, is genetic testing really necessary to confirm that he does not require immediate treatment? While numerous studies show a significant reclassification of risk when applying a genomic profiler,1 there is little evidence to guide physicians on what to do with this information, and the potential dangers of making treatment decisions based on these tests warrant attention. Of 2,432 patients undergoing RP 52% of CAPRA-S low risk men were reassigned to intermediate or high risk and 40% of high risk men were reassigned to intermediate or low risk based on the Decipher test results.3 If one were to be influenced by these results, more than half of the low risk patients would be treated with adjuvant radiotherapy despite the lack of high level evidence supporting its need. While this may not be the intended use of these tests, without the appropriate prospective studies with longitudinal followup to inform physicians about how to properly integrate these tests into clinical practice, this may certainly be the unintended consequence. Furthermore, significant challenges exist when generalizing the data validating these tests to men who may not be the same as those involved in the research studies. For example, Oncotype DX and Prolaris are tests intended for men contemplating
OPPOSING VIEWS
active surveillance, although the primary validation studies were performed in patients who underwent RP.1 As a result, these findings may not be reflective of all men considering active surveillance in clinical practice. This finding highlights the severe selection bias and flaws that exist when using these data to establish valid predictive biomarkers to be used globally in this population. There is also a lack of head-to-head comparisons among the different genomic signatures with each test being touted as superior to the other without any evidence to support such claims. Wei et al sequenced 4 consecutive radical prostatectomy specimens and the genes contributing to these 3 signatures showed marked variation in the same tissue core, suggesting that one would obtain different risk assessments from each test.4 Future studies with prospective comparisons of the different tests on the same population will be needed to determine the best performer for each treatment decision. Tumor heterogeneity remains an issue in tests being conducted on biopsy cores. Wei et al also found significant variation in genomic profiles using the same test in different biopsy cores throughout the RP specimen,4 which suggests that the quality of the prostate samples obtained is critical for accurate risk assessment on the clinical
3
and genomic levels. While this study is limited by a small sample size and does not account for the algorithm or specific platform used by each test, it sheds interesting light on the theory that these tests may not overcome the tumor heterogeneity problem that has long plagued prostate cancer risk stratification. We remain optimistic that genomic testing will play a role in decision making for prostate cancer in the future. However, the current evidence behind these biomarkers is clearly not enough to support routine clinical use at such a high cost. Future longterm prospective trials will and should be required to determine which subset of men with prostate cancer will truly benefit from genomic testing and how to best use this technology. These studies have been conducted in breast cancer. Men with prostate cancer merit a similar level of scientific investment to prove that these tests will offer a comparable benefit to treatment decision making, and, ultimately, long-term outcomes.
Sanoj Punnen and Dipen J. Parekh Department of Urology University of Miami Miller School of Medicine Miami, Florida
REFERENCES 1. Moschini M, Spahn M, Mattei A et al: Incorporation of tissue-based genomic biomarkers into localized prostate cancer clinics. BMC Med 2016; 14: 67.
2. Sparano JA, Gray RJ, Makower DF et al: Prospective validation of a 21-gene expression
assay in breast cancer. N Engl J Med 2015; 373: 2005.
patients. Prostate Cancer Prostatic Dis 2016; 19: 374.
3. Den RB, Santiago-Jimenez M, Alter J et al: Decipher correlation patterns post prostatectomy: initial experience from 2 342 prospective
4. Wei L, Wang J, Lampert E et al: Intratumoral and intertumoral genomic heterogeneity of multifocal localized prostate cancer impacts molecular classifications and enomic prognosticators. Eur Urol 2017; 71: 183.