Point/Counter

Is genetic testing sophisticated enough to make PSA screening viable for mainstream use?

Click here to read the Cover Story, “Active surveillance, physician–patient communication may redefine role of PSA testing.”

POINT

Yes.

Improvements in biomarkers and genetic tests have refined screening methods to reduce unnecessary biopsies and overdetection of indolent disease. The underlying argument from prostate cancer screening critics is that the method in which serum PSA is used causes more harm than good. It is with this context that I will build my argument that the proponents of prostate cancer screening have risen to the challenge during the past decade.

Behfar Ehdaie, MD, MPH
Behfar Ehdaie

One valid argument against PSA screening is the harms associated with the overdetection and subsequent overtreatment of indolent cancer. To reverse this trend, changes in clinician practice patterns are required. Urologists have responded by introducing active surveillance to closely monitor low-risk prostate cancer. Despite successful efforts to incorporate active surveillance in clinical guidelines, fewer than half of patients eligible for active surveillance forego immediate treatment. Fortunately, secondary tests have been introduced during the past 5 years to curb the rates of detecting indolent cancer by reducing prostate needle biopsies.

Several commercially available options beyond serum PSA are available to help aid prostate biopsy decisions. The 4Kscore (Opko; BioReference Laboratories; and GenPath) is based on a prediction model of clinical variables and measured levels of four kallikrein markers: total PSA, free PSA, intact PSA and hK2. Besides predicting higher-grade cancer on biopsy, the 4Kscore predicted 15- to 20-year risk for distant metastasis or death of prostate cancer in a large population-based study. The Prostate Health Index is a blood test that combines total PSA, free PSA and [-2]proPSA in a formula that predicts higher Gleason grade prostate cancer on biopsy.

In addition to serum tests, other genetic tests have been developed. A prospective, multicenter validation trial reported that using a cutoff for urinary PCA3 of 60 in the initial biopsy setting was associated with an 80% positive predictive value of detecting higher Gleason–grade cancer. TMPRSS2-ERG, a gene fusion found in approximately 50% of prostate cancers, has been combined with PCA3 for the new Mi-Prostate score. Studies have shown combining PCA3 and TMPRSS2-ERG improves the prediction of higher Gleason grade on prostate biopsy.

Overall, it is evident that the harms associated with prostate cancer screening can be reduced by changing physician and patient behavior with regard to immediate treatment for low-risk prostate cancer and decreasing overdetection of indolent prostate cancer. The incorporation of biomarkers in decision-making is supported by studies in thousands of men that have demonstrated enhanced prediction of higher Gleason–grade prostate cancer compared with serum PSA alone — a critical endpoint to reduce the harms associated with overdetection. Importantly, studies that have tested these biomarkers in routine clinical practice have shown a 65% reduction in the incidence of prostate biopsy. Therefore, if used appropriately, these tests positively impact physician–patient decision-making.

In the end, we should be advocates and participants in comparative trials to achieve data to provide cost-effective testing combinations and guide recommendations for smarter prostate cancer screening. Population-based scientists should continue to study utilization of these tests in clinical practice and estimate benefits to prostate cancer–specific outcomes in the absence of another large randomized clinical trial in prostate cancer screening.

References:

EA Heijnsdijk, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1201637.

Konety B, et al. Rev Urol. 2015;17:231–240.

Stattin P, et al. Eur Urol. 2015;doi:10.1016/j.eururo.2015.01.009.

Tomlins SA, et al. Eur Urol. 2015;doi:10.1016/j.eururo.2015.04.039.

Vickers AJ. Urology. 2015;doi:10.1016/j.urology.2014.11.003.

Wei JT, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.52.8505.

Behfar Ehdaie, MD, MPH, is a urologic surgeon at Memorial Sloan Kettering Cancer Center. He can be reached at ehdaieb@mskcc.org. Disclosure: Ehdaie reports no relevant financial disclosures.

COUNTER

No.

Although some genetic tests show promise, none has been proven to reduce harms or improve health outcomes. PSA screening for prostate cancer has been an uncontrolled experiment performed annually on millions of older men in the United States since the early 1990s. Only in the past few years have the U.S. Preventive Services Task Force and other medical groups recognized that routine PSA screening does more harm than good, and that targeted testing should occur only after a shared decision-making discussion in which the patient expresses a clear preference to be screened.

Kenneth W. Lin, MD, MPH
Kenneth W. Lin

The search is on to identify more specific biomarkers that can either replace PSA as a screening test, or augment PSA by predicting which men with elevated levels are at the greatest risk for harboring clinically important — and potentially curable — cancers. However, utilizing genetic tests for this purpose outside of clinical trials is premature. The only genetic test for prostate cancer approved by the FDA is the PCA3 urine assay. In 2014, the Evaluation of Genomic Applications in Practice and Prevention Working Group concluded that PCA3 has insufficient supporting evidence to inform decisions to conduct initial or repeat biopsies for prostate cancer in at-risk men.

Other commercial genetic tests or test combinations include urine assays — TMPRSS2-ERG fusion gene, Mi-Prostate score and ExoDx Prostate(Intelliscore) (Exosome Diagnostics) — and multigene prostate tissue assays, such as Oncotype DX (Genomic Health), Prolaris (Myriad Genetics), Decipher Prostate Cancer Classifier (GenomeDx), ProMark (Metamark) and ConfirmMDx (MDxHealth). Obviously, tissue assays are not suitable for determining which men to biopsy, although they may have a role in reducing unnecessary repeat biopsies or treatments.

The Mi-Prostate score — which incorporates serum PSA, urine PCA3 and TMPRSS2-ERG — is limited by the low prognostic value of the fusion gene test and uncertainty regarding cutoff values across populations. ExoDx may predict high-grade prostate tumors, but its prognostic value has not been studied. A 2016 systematic review commissioned by Agency for Healthcare Research and Quality found insufficient evidence to assess analytic validity of 18 commercially — or close to — available multigene panels for prostate cancer risk assessment, evidence of modest clinical validity beyond patient age and family history, and no studies of clinical utility (eg, effects on process of care, health outcomes, harms and economic outcomes).

It is understandable that physicians and patients who are concerned about prostate cancer are impatient for new tests that promise to maximize the benefits and minimize the harms of PSA testing. But we should have learned our lesson from the PSA experience. Now is not the time to perform more uncontrolled experiments on older men by incorporating unproven genetic tests into clinical practice.

References:

EGAPP Working Group. Genet Med. 2014;doi:10.1038/gim.2013.141.

Hatakeyama S, et al. Int J Clin Oncol. 2016;doi:10.1007/s10147-016-1049-y.

Lin KW and Ebell MH. Am Fam Physician. 2016;94:782-784.

Little J, et al. Genet Med. 2016;doi:10.1038/gim.2015.125.

McGrath S, et al. Prostate Int. 2016;doi:10.1016/j.prnil.2016.07.002.

Patel HD, et al. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2016.0170.

Saini S. Cell Oncol. 2016;doi:10.1007/s13402-016-0268-6.

Kenneth W. Lin, MD, MPH, is associate professor of family medicine at Georgetown University Medical Center. He can be reached at kenneth.lin@georgetown.edu. Disclosure: Lin reports no relevant financial disclosures.

Click here to read the Cover Story, “Active surveillance, physician–patient communication may redefine role of PSA testing.”

POINT

Yes.

Improvements in biomarkers and genetic tests have refined screening methods to reduce unnecessary biopsies and overdetection of indolent disease. The underlying argument from prostate cancer screening critics is that the method in which serum PSA is used causes more harm than good. It is with this context that I will build my argument that the proponents of prostate cancer screening have risen to the challenge during the past decade.

Behfar Ehdaie, MD, MPH
Behfar Ehdaie

One valid argument against PSA screening is the harms associated with the overdetection and subsequent overtreatment of indolent cancer. To reverse this trend, changes in clinician practice patterns are required. Urologists have responded by introducing active surveillance to closely monitor low-risk prostate cancer. Despite successful efforts to incorporate active surveillance in clinical guidelines, fewer than half of patients eligible for active surveillance forego immediate treatment. Fortunately, secondary tests have been introduced during the past 5 years to curb the rates of detecting indolent cancer by reducing prostate needle biopsies.

Several commercially available options beyond serum PSA are available to help aid prostate biopsy decisions. The 4Kscore (Opko; BioReference Laboratories; and GenPath) is based on a prediction model of clinical variables and measured levels of four kallikrein markers: total PSA, free PSA, intact PSA and hK2. Besides predicting higher-grade cancer on biopsy, the 4Kscore predicted 15- to 20-year risk for distant metastasis or death of prostate cancer in a large population-based study. The Prostate Health Index is a blood test that combines total PSA, free PSA and [-2]proPSA in a formula that predicts higher Gleason grade prostate cancer on biopsy.

In addition to serum tests, other genetic tests have been developed. A prospective, multicenter validation trial reported that using a cutoff for urinary PCA3 of 60 in the initial biopsy setting was associated with an 80% positive predictive value of detecting higher Gleason–grade cancer. TMPRSS2-ERG, a gene fusion found in approximately 50% of prostate cancers, has been combined with PCA3 for the new Mi-Prostate score. Studies have shown combining PCA3 and TMPRSS2-ERG improves the prediction of higher Gleason grade on prostate biopsy.

Overall, it is evident that the harms associated with prostate cancer screening can be reduced by changing physician and patient behavior with regard to immediate treatment for low-risk prostate cancer and decreasing overdetection of indolent prostate cancer. The incorporation of biomarkers in decision-making is supported by studies in thousands of men that have demonstrated enhanced prediction of higher Gleason–grade prostate cancer compared with serum PSA alone — a critical endpoint to reduce the harms associated with overdetection. Importantly, studies that have tested these biomarkers in routine clinical practice have shown a 65% reduction in the incidence of prostate biopsy. Therefore, if used appropriately, these tests positively impact physician–patient decision-making.

PAGE BREAK

In the end, we should be advocates and participants in comparative trials to achieve data to provide cost-effective testing combinations and guide recommendations for smarter prostate cancer screening. Population-based scientists should continue to study utilization of these tests in clinical practice and estimate benefits to prostate cancer–specific outcomes in the absence of another large randomized clinical trial in prostate cancer screening.

References:

EA Heijnsdijk, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1201637.

Konety B, et al. Rev Urol. 2015;17:231–240.

Stattin P, et al. Eur Urol. 2015;doi:10.1016/j.eururo.2015.01.009.

Tomlins SA, et al. Eur Urol. 2015;doi:10.1016/j.eururo.2015.04.039.

Vickers AJ. Urology. 2015;doi:10.1016/j.urology.2014.11.003.

Wei JT, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.52.8505.

Behfar Ehdaie, MD, MPH, is a urologic surgeon at Memorial Sloan Kettering Cancer Center. He can be reached at ehdaieb@mskcc.org. Disclosure: Ehdaie reports no relevant financial disclosures.

COUNTER

No.

Although some genetic tests show promise, none has been proven to reduce harms or improve health outcomes. PSA screening for prostate cancer has been an uncontrolled experiment performed annually on millions of older men in the United States since the early 1990s. Only in the past few years have the U.S. Preventive Services Task Force and other medical groups recognized that routine PSA screening does more harm than good, and that targeted testing should occur only after a shared decision-making discussion in which the patient expresses a clear preference to be screened.

Kenneth W. Lin, MD, MPH
Kenneth W. Lin

The search is on to identify more specific biomarkers that can either replace PSA as a screening test, or augment PSA by predicting which men with elevated levels are at the greatest risk for harboring clinically important — and potentially curable — cancers. However, utilizing genetic tests for this purpose outside of clinical trials is premature. The only genetic test for prostate cancer approved by the FDA is the PCA3 urine assay. In 2014, the Evaluation of Genomic Applications in Practice and Prevention Working Group concluded that PCA3 has insufficient supporting evidence to inform decisions to conduct initial or repeat biopsies for prostate cancer in at-risk men.

Other commercial genetic tests or test combinations include urine assays — TMPRSS2-ERG fusion gene, Mi-Prostate score and ExoDx Prostate(Intelliscore) (Exosome Diagnostics) — and multigene prostate tissue assays, such as Oncotype DX (Genomic Health), Prolaris (Myriad Genetics), Decipher Prostate Cancer Classifier (GenomeDx), ProMark (Metamark) and ConfirmMDx (MDxHealth). Obviously, tissue assays are not suitable for determining which men to biopsy, although they may have a role in reducing unnecessary repeat biopsies or treatments.

The Mi-Prostate score — which incorporates serum PSA, urine PCA3 and TMPRSS2-ERG — is limited by the low prognostic value of the fusion gene test and uncertainty regarding cutoff values across populations. ExoDx may predict high-grade prostate tumors, but its prognostic value has not been studied. A 2016 systematic review commissioned by Agency for Healthcare Research and Quality found insufficient evidence to assess analytic validity of 18 commercially — or close to — available multigene panels for prostate cancer risk assessment, evidence of modest clinical validity beyond patient age and family history, and no studies of clinical utility (eg, effects on process of care, health outcomes, harms and economic outcomes).

PAGE BREAK

It is understandable that physicians and patients who are concerned about prostate cancer are impatient for new tests that promise to maximize the benefits and minimize the harms of PSA testing. But we should have learned our lesson from the PSA experience. Now is not the time to perform more uncontrolled experiments on older men by incorporating unproven genetic tests into clinical practice.

References:

EGAPP Working Group. Genet Med. 2014;doi:10.1038/gim.2013.141.

Hatakeyama S, et al. Int J Clin Oncol. 2016;doi:10.1007/s10147-016-1049-y.

Lin KW and Ebell MH. Am Fam Physician. 2016;94:782-784.

Little J, et al. Genet Med. 2016;doi:10.1038/gim.2015.125.

McGrath S, et al. Prostate Int. 2016;doi:10.1016/j.prnil.2016.07.002.

Patel HD, et al. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2016.0170.

Saini S. Cell Oncol. 2016;doi:10.1007/s13402-016-0268-6.

Kenneth W. Lin, MD, MPH, is associate professor of family medicine at Georgetown University Medical Center. He can be reached at kenneth.lin@georgetown.edu. Disclosure: Lin reports no relevant financial disclosures.