Applications of Genetic Prostate Cancer Screening in Clinic
Applications of Genetic Prostate Cancer Screening in Clinic
The limitations of PSA and DRE screening for prostate cancer have prompted much research into genetic-based screenings. This survey of innovations and obstacles in genomic testing will help prepare urologic clinicians for future interventions.
Objectives:
1. Discuss current biomarkers for prostate cancer testing.
2. Explain the use of genetic testing in prostate cancer screening.
3. List limitations of genetic testing in prostate cancer screening.
Prostate Cancer Epidemiology
Prostate cancer is second only to lung cancer as the most common cancer in American men (American Cancer Society [ACS], 2014c). It is estimated that 233,000 new cases will be diagnosed and that 29,480 men will die of prostate cancer in 2014 (ACS, 2014c). About one in every 36 men will die of prostate cancer (ACS, 2014c). The disease is typically a slow-growing tumor that affects older men, with the majority of cases diagnosed in patients over 65 years of age. Prostate cancer poses a burden for older men in general and black men in particular, and it often adversely affects quality of life (Bellizzi, Latini, Cowan, Duchane, & Carroll, 2008; Dandapani & Sanda, 2008).
The purpose of this article is to review the current state of research in genetics-based testing for prostate cancer to more fully inform urologic clinicians about relevant current and future clinical applications and their limitations.
The high incidence of prostate cancer has heightened interest among clinicians, including urologic nurse professionals, in the use of screening to identify those who are at high risk for developing the disease. Research funding for the disease has increased accordingly (Li-Wan-Po, Farndon, Cooley, & Lithgow, 2010). Current screening for prostate cancer involves both a digital rectal examination (DRE) and measurement of the prostate-specific antigen (PSA) level (American Urological Association [AUA], 2013). The American Cancer Society (ACS) (2014a) recommends that prostate screenings should begin at 50 years of age or even younger, at 40 to 45 years, in men at high risk (i.e., having a first-degree relative with prostate cancer).
The PSA blood test has arguably changed the future trajectory of prostate cancer mortality. A decline in prostate cancer mortality has been observed since the Food and Drug Administration approved the use of the PSA test. Additionally, implementing PSA testing has allowed diagnosis of the disease at a much earlier and potentially more curable stage (Gulati et al., 2013; Kash, Lal, Hashmi, & Mubarak, 2014; Pashtan, Chen, & D'Amico, 2014). Some studies, however, have attributed the decline in prostate cancer mortality in the U.S. to improvements in cancer treatment (Etzioni & Feuer, 2008). The PSA test and the DRE may have also resulted in false-positive or false-negative data. Tests on patients without cancer may show abnormal results, and thus, patients may receive unnecessary additional testing. In contrast, clinically significant cancers may be missed in other patients whose PSA tests or DREs return negative results. Falsepositive results may lead to sustained anxiety about prostate cancer risk in some patients. According to "The American Cancer Society Guidelines for the Early Detection of Cancer" (ACS, 2014a), abnormal results from PSA or DRE screening require prostate biopsies to determine whether or not the abnormal findings are cancerous. Biopsies can be painful; can lead to complications, such as infection or bleeding; and can miss clinically significant cancer (ACS, 2014a).
The limitations of PSA and DRE testing advanced the development of new, genetic-based screening measures to improve risk stratification. Urologic clinicians must gain familiarity with the nature of these innovative tests. DNA, RNA, and protein markers all hold potential for innovations in prostate cancer screening. The applications of these markers to prostate cancer screening have been extensively reviewed in many studies (Li-Wan-Po et al., 2010; Lopergolo & Zaffaroni, 2009; Martin, Mucci, Loda, & Depinho, 2011; Ploussard & de la Taille, 2010; Urquidi, Rosser, & Goodison, 2012; Witte, 2009). Of these potential tests, only the Prostate Cancer Gene 3 (PCA3) test is commercially available. PCA3 is a non-coding RNA, which is produced in prostate tissue only. PCA3 specifically over-expresses in the prostate tissue when this tissue becomes cancerous (Grivennikov, Greten, & Karin, 2010; Xie et al., 2011). When researchers applied the PCA3 screening, the rate of prostate cancer detection increased from 0.63 for PSA alone to 0.71 for PSA combined with PCA3 (Wang, Chinnaiyan, Dunn, Wojno, & Wei, 2009). Since PCA3 screening has only been done in men previously screened with PSA, the utility of PCA3 in isolation is unknown. A PCA3 score of less than 25 has been found to be 4.56 times more likely to trigger a negative repeat biopsy than PCA3 scores of 25 or greater (Gittelman et al., 2013). Increased test specificity, as well as more accurate prediction of a repeat biopsy, was achieved when PCA3 testing was combined with PSA screening and consideration of other clinical information, such as age, race, and family history. The PCA3 score has become a standard measure in cases in which repeat biopsies are required (Gittelman et al., 2013). The most recently published paper on this topic advises that patients should not receive a biopsy if the PCA3 score is lower than 20 (Luo, Gou, Huang, & Mou, 2014).
Urologic clinical professionals are often not fully informed about the most recent developments in genetic screenings for prostate cancer. Recent genetics and genomics studies of prostate cancer have helped to clarify the genetic basis of this common but complex disease. Genome-wide studies have detected numerous variants associated with this disease, as well as common gene fusions and expression "signatures" in prostate tumors. On the basis of these results, some clinicians may advocate gene-based individualized screening for prostate cancer, although such testing may distinguish only disease aggressiveness (Witte, 2009). Genetic alterations associated with prostate cancer have also been found (Hao et al., 2011; Zheng et al., 2008). Ongoing research into genetic markers of prostate cancer is needed to improve the effectiveness of diagnosis and treatment. The genetic testing of prostate cancer susceptibility genes has implications for surveillance and treatment of the disease. The identification of causative mutations provides valuable information for patients and their at-risk family members. Genetic counseling of patients and their family members also promotes enhanced understanding of the disease and treatment (Birmingham et al., 2013; Chan-Smutko, 2012).
Abstract and Introduction
Abstract
The limitations of PSA and DRE screening for prostate cancer have prompted much research into genetic-based screenings. This survey of innovations and obstacles in genomic testing will help prepare urologic clinicians for future interventions.
Objectives:
1. Discuss current biomarkers for prostate cancer testing.
2. Explain the use of genetic testing in prostate cancer screening.
3. List limitations of genetic testing in prostate cancer screening.
Introduction
Prostate Cancer Epidemiology
Prostate cancer is second only to lung cancer as the most common cancer in American men (American Cancer Society [ACS], 2014c). It is estimated that 233,000 new cases will be diagnosed and that 29,480 men will die of prostate cancer in 2014 (ACS, 2014c). About one in every 36 men will die of prostate cancer (ACS, 2014c). The disease is typically a slow-growing tumor that affects older men, with the majority of cases diagnosed in patients over 65 years of age. Prostate cancer poses a burden for older men in general and black men in particular, and it often adversely affects quality of life (Bellizzi, Latini, Cowan, Duchane, & Carroll, 2008; Dandapani & Sanda, 2008).
The purpose of this article is to review the current state of research in genetics-based testing for prostate cancer to more fully inform urologic clinicians about relevant current and future clinical applications and their limitations.
Current Biomarkers For Clinical Prostate Cancer Testing
The high incidence of prostate cancer has heightened interest among clinicians, including urologic nurse professionals, in the use of screening to identify those who are at high risk for developing the disease. Research funding for the disease has increased accordingly (Li-Wan-Po, Farndon, Cooley, & Lithgow, 2010). Current screening for prostate cancer involves both a digital rectal examination (DRE) and measurement of the prostate-specific antigen (PSA) level (American Urological Association [AUA], 2013). The American Cancer Society (ACS) (2014a) recommends that prostate screenings should begin at 50 years of age or even younger, at 40 to 45 years, in men at high risk (i.e., having a first-degree relative with prostate cancer).
The PSA blood test has arguably changed the future trajectory of prostate cancer mortality. A decline in prostate cancer mortality has been observed since the Food and Drug Administration approved the use of the PSA test. Additionally, implementing PSA testing has allowed diagnosis of the disease at a much earlier and potentially more curable stage (Gulati et al., 2013; Kash, Lal, Hashmi, & Mubarak, 2014; Pashtan, Chen, & D'Amico, 2014). Some studies, however, have attributed the decline in prostate cancer mortality in the U.S. to improvements in cancer treatment (Etzioni & Feuer, 2008). The PSA test and the DRE may have also resulted in false-positive or false-negative data. Tests on patients without cancer may show abnormal results, and thus, patients may receive unnecessary additional testing. In contrast, clinically significant cancers may be missed in other patients whose PSA tests or DREs return negative results. Falsepositive results may lead to sustained anxiety about prostate cancer risk in some patients. According to "The American Cancer Society Guidelines for the Early Detection of Cancer" (ACS, 2014a), abnormal results from PSA or DRE screening require prostate biopsies to determine whether or not the abnormal findings are cancerous. Biopsies can be painful; can lead to complications, such as infection or bleeding; and can miss clinically significant cancer (ACS, 2014a).
Development of Genetic Testing for Prostate Cancer
The limitations of PSA and DRE testing advanced the development of new, genetic-based screening measures to improve risk stratification. Urologic clinicians must gain familiarity with the nature of these innovative tests. DNA, RNA, and protein markers all hold potential for innovations in prostate cancer screening. The applications of these markers to prostate cancer screening have been extensively reviewed in many studies (Li-Wan-Po et al., 2010; Lopergolo & Zaffaroni, 2009; Martin, Mucci, Loda, & Depinho, 2011; Ploussard & de la Taille, 2010; Urquidi, Rosser, & Goodison, 2012; Witte, 2009). Of these potential tests, only the Prostate Cancer Gene 3 (PCA3) test is commercially available. PCA3 is a non-coding RNA, which is produced in prostate tissue only. PCA3 specifically over-expresses in the prostate tissue when this tissue becomes cancerous (Grivennikov, Greten, & Karin, 2010; Xie et al., 2011). When researchers applied the PCA3 screening, the rate of prostate cancer detection increased from 0.63 for PSA alone to 0.71 for PSA combined with PCA3 (Wang, Chinnaiyan, Dunn, Wojno, & Wei, 2009). Since PCA3 screening has only been done in men previously screened with PSA, the utility of PCA3 in isolation is unknown. A PCA3 score of less than 25 has been found to be 4.56 times more likely to trigger a negative repeat biopsy than PCA3 scores of 25 or greater (Gittelman et al., 2013). Increased test specificity, as well as more accurate prediction of a repeat biopsy, was achieved when PCA3 testing was combined with PSA screening and consideration of other clinical information, such as age, race, and family history. The PCA3 score has become a standard measure in cases in which repeat biopsies are required (Gittelman et al., 2013). The most recently published paper on this topic advises that patients should not receive a biopsy if the PCA3 score is lower than 20 (Luo, Gou, Huang, & Mou, 2014).
Purpose of This Review
Urologic clinical professionals are often not fully informed about the most recent developments in genetic screenings for prostate cancer. Recent genetics and genomics studies of prostate cancer have helped to clarify the genetic basis of this common but complex disease. Genome-wide studies have detected numerous variants associated with this disease, as well as common gene fusions and expression "signatures" in prostate tumors. On the basis of these results, some clinicians may advocate gene-based individualized screening for prostate cancer, although such testing may distinguish only disease aggressiveness (Witte, 2009). Genetic alterations associated with prostate cancer have also been found (Hao et al., 2011; Zheng et al., 2008). Ongoing research into genetic markers of prostate cancer is needed to improve the effectiveness of diagnosis and treatment. The genetic testing of prostate cancer susceptibility genes has implications for surveillance and treatment of the disease. The identification of causative mutations provides valuable information for patients and their at-risk family members. Genetic counseling of patients and their family members also promotes enhanced understanding of the disease and treatment (Birmingham et al., 2013; Chan-Smutko, 2012).
