prior authorization review panel mco policy s …...family history of prostate cancer represent...

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Prior Authorization Review Panel MCO Policy S ubmission

A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review.

Plan: Aetna Better H ealth Submission Date:05/01/2019

Policy Number:0521 Effective Date: Revision Date: 02/14/2019

Policy Name: Prostate Cancer Screening

Type of Submission – Check all that apply: New Policy Revised Policy* Annual Review – No Revisions

*All revisions to the policy must be highlighted using track changes throughout the document. Please provide any clarifying information for the policy

below: CPB 0521 Prostate Cancer Screening

This CPB has been revised to state that (i) prostate-specific antigen (PSA) screening is considered a medically necessary preventive service for men 45 years of age and older who are considered average-risk for prostate cancer, and for men 40 years of age and older who are considered at high-risk for prostate cancer; and (ii) routine prostate cancer screening for members 75 years of age or older is considered not medically necessary unless life expectancy is greater than or equal to 10 years. (Previous version included medical necessity for PSA screening for men aged 40 years and older, and for men under 40 years of age who are at high-risk for prostate cancer).

Name of Authorized Individual (Please type or print):

Dr. Bernard Lewin, M.D.

Signature of Authorized Individual:

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(https://www.aetna.com/)

Prostate Cancer Screening

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Policy History

Last Re

view

02/14/2019

Effective: 02/12/2002

Next

Review: 05/23/2019

Review

Histor

y

Definitions

Additional Information

Number: 0521

Policy *Please see amendment for Pennsylvania Medicaid at the end of this

CPB.

I. Aetna considers prostate-specific antigen (PSA) screening a medically

necessary preventive service for men 45 years of age and older who are

considered average-risk for prostate cancer, and for men 40 years of age and

older who are considered at high-risk for prostate cancer. Risk groups

include African-American men and men with a family history of prostate

cancer. Note: Routine prostate cancer screening for members 75 years of

age or older is considered not medically necessary unless life expectancy is

greater than or equal to 10 years.

II. When used for routine screening, annual PSA screening is considered

medically necessary, but additional PSA tests may be considered medically

necessary in men with previously elevated PSAs or signs or symptoms of

disease.

III. Aetna considers diagnostic PSA testing medically necessary for men of all

ages with signs or symptoms of prostate cancer, and for follow-up of men

with prostate cancer.

http://www.aetna.com/cpb/medical/data/500_599/0521.html

https://www.aetna.com/

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IV. Aetna considers annual digital rectal examination (DRE) a medically

necessary preventive service.

V. Aetna considers measurement of selenium in the blood or in tissues (such

as toenail clippings) experimental and investigational to assess the risk of

developing prostate cancer because it has no proven value for this

indication.

VI. Aetna considers the following experimental and investigational for prostate

cancer screening because they have no proven value for this indication (not

an all-inclusive list):

• Alpha-methylacyl coenzyme A racemase (AMACR)

• Analysis of prostatic fluid electrolyte composition (e.g., citrate, zinc; not

an all-inclusive list)

• Apifiny non-PSA blood test (Armune BioScience)

• BRAF mutations

• Early prostate cancer antigenE

• Endoglin

• E twenty-six (ETS) gene fusions

• Genetic-based screening

• Human glandular kallikrein 2 (hK2) (also known as kallikrein-related

peptidase 2 [KLK2])

• Interleukin-6

• MicroRNAs in prostatic fluid/tissue

• Neutrophil gelatinase-associated lipocalin (NGAL)

• Prostate cancer gene 3 (PCA3)

• TMPRSS2: ERG gene fusion

• Transforming growth factor-beta 1

See also CPB 0001 - Transrectal Ultrasound (../1_99/0001.html)

and CPB 0352 - Tumor Markers (../300_399/0352.html).

Note: Some plans exclude coverage of preventive services. Please check benefit

plan descriptions for details. Medically necessary diagnostic PSA testing is

covered regardless of whether the member has preventive service benefits.


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Background

The decision to perform routine prostate cancer screening with digital rectal

examination (DRE) or prostate-specific antigen (PSA) is left to the discretion of the

clinician. Patients who request screening should be given objective information

about the potential benefits and harms of early detection and treatment.

The American Cancer Society (ACS) recommends PSA screening for all men over

age 50 and at age 45 for men at higher risk (e.g., men with a family history of

prostate cancer and African-American men). Similar recommendations have been

issued by the American Urological Association (AUA) and the American College of

Radiology. The ACS, however, acknowledges that currently there is no clinical trial

evidence that screening for prostate cancer is associated with a reduction in

mortality.

The updated ACS guideline for the early detection of prostate cancer (Wolf et al,

2010) recommends both the PSA blood test and DRE should be offered annually,

beginning at age 50, to men who have at least a 10-year life expectancy. Men at

high-risk (African-American men and men with a strong family of 1 or more first-

degree relatives (father, brothers) diagnosed at an early age) should begin testing

at age 45. Men at even higher risk, due to multiple first-degree relatives affected at

an early age, could begin testing at age 40. Depending on the results of this initial

test, no further testing might be needed until age 45. The ACS states that information

should be provided to all men about what is known and what is uncertain about the

benefits and limitations of early detection and treatment of prostate cancer so that

they can make an informed decision about testing. Men who ask their doctor to

make the decision on their behalf should be tested.

The ACS states that discouraging testing is inappropriate. Furthermore, not

offering testing is also inappropriate.

In a review on prostate cancer screening, Ilic and colleagues (2011) concluded that

prostate cancer screening did not significantly decrease all-cause or prostate cancer-

specific mortality in a combined meta-analysis of 5 randomized controlled trials. Any

benefits from prostate cancer screening may take greater than 10 years to accrue;

therefore, men who have a life expectancy of less than 10 to 15 years should be

informed that screening for prostate cancer is not beneficial and has harms.


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The American Urological Association (AUA, 2013) recommends against PSA

screening in men under age 40 years (Grade C) and does not recommend routine

screening in men between ages 40 to 54 years at average risk (Grade C). AUA

state that the greatest benefit of screening appears to be in men ages 55 to 69

years. "For men younger than age 55 years at higher risk, decisions regarding

prostate cancer screening should be individualized. Those at higher risk may

include men of African American race; and those with a family history of metastatic

or lethal adenocarcinomas (e.g., prostate, male and female breast cancer, ovarian,

pancreatic) spanning multiple generations, affecting multiple first-degree relatives,

and that developed at younger ages."

The National Comprehensive Cancer Network (NCCN, v.2.2018) recommends

baseline screening beginning at age 45. "African-American men and men with a

family history of prostate cancer represent high-risk groups. However, the panel

believes that current data are insufficient to definitively inform the best strategy for

prostate cancer screening in these populations, and also notes that a baseline PSA

value is a stronger predictive factor than a positive family history or race. Overall,

the panel believes that it is reasonable for African-American men and those with a

strong family history to begin discussing PSA screening with their providers earlier

than those without such risk factors and to consider screening at annual rather than

less frequent screening intervals." Panelists uniformly agreed that PSA testing

should only be offered to men with a 10 or more year life expectancy. The panel

supports screening in men until age 75. The panel recommends that PSA testing to

be considered only in very healthy patients older than 75 years (category 2B);

however, the panel uniformly discourage PSA testing in men unlikely to benefit from

prostate cancer diagnosis based on age and/or comorbidity. The panel

recommends that frequency of testing be 2 to 4 years for men aged 45 to 75 years

with serum PSA values below 1 ng/mL, and at 1 to 2 year intervals for men with

PSA of 1 to 3 ng/mL.


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Most professional societies do not recommend routine screening for prostate

cancer with DRE or serum tumor markers (e.g., PSA). These include the American

Academy of Family Physicians, the U.S. Preventive Services Task Force

(USPSTF), the Institute for Clinical Systems Improvement, the Canadian Task

Force on the Periodic Health Examination, the American College of Preventive

Medicine, the U.S. Office of Technology Assessment, the American Society for

Internal Medicine and American College of Physicians, the National Cancer

Institute, the Centers for Disease Control and Prevention, and the technology

assessment agencies of Canada, England, Sweden, and Australia.

The USPSTF (2018) recommends individualized decision-making about prostate

cancer screening for men aged 55 to 69, thus providing a grade C recommendation

for prostate cancer screening for men in that age group. The USPSTF

systematically reviewed evidence on prostate-specific antigen (PSA)-based

prostate cancer screening, treatments for localized prostate cancer, and prebiopsy

risk calculators, concluding that although screening offers a small potential benefit

of reducing chance of death from prostate cancer in some men, many men will

experience potential harms of screening (i.e., false-positives results that require

additional testing and possible prostate biopsy, overdiagnosis, overtreatment, and

treatment complications such as erectile dysfunction and urinary difficulties). In

regard to age and the effectiveness of PSA-based screening and prostate cancer

mortality, outcomes from randomized clinical trials showed that randomization to

screening was not associated with statistically significant reductions in prostate

cancer mortality among men aged 65 to 74 years at baseline in the Prostate, Lung,

Colorectal, and Ovarian (PLCO) trial (RR, 1.02 [95% CI, 0.77-1.37]) or among men

aged 70 to 74 years at baseline in the European Randomized Study of Screening

for Prostate Cancer (ERSPC) trial (RR, 1.17 [95% CI, 0.82-1.66]). The systematic

review revealed that across all studies, relatively few men older than 70 years were


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enrolled, and there is limited evidence about the differential benefits or harms of

screening for men at higher risk. The USPSTF concluded that the evidence is

limited on the benefit of screening among men older than 70 years, thus, providing

a grade D recommendation against PSA-based screening for prostate cancer in

men 70 years and older. The USPSTF further concluded that the evidence was

insufficient to make a specific recommendation regarding screening discussions for

higher-risk groups: African-American men and those with a family history of

prostate cancer.

The American Academy of Family Physicians (AAFP, 2018) makes the

recommendation against routine screening (i.e., PSA test or DRE) for prostate

cancer. For men who desire PSA screening, it should only be performed after

engaging in shared decision making. Furthermore, PSA-based prostate cancer

screening should not be performed in men over 70 years of age.

An UpToDate review on "Screening for prostate cancer" (Hoffman, 2018)

recommend prostate cancer screening beginning at age 40 to 45 years for men at

high risk (e.g., black men, men with family history of prostate cancer, particularly in

relatives younger than age 65, and men who are known or likely to have the

BRCA1 or BRCA2 mutations) and have a life expectancy greater than or equal to

10 years (Grade 2C). For men at "average risk", the authors recommend prostate

screening discussions with their healthcare provider starting at the age of 50, and

who also have a life expectancy greater than or equal to 10 years. The authors

recommend discontinuing the screening after age 69, or earlier when comorbidities

limit life expectancy to less than 10 years, or patient decides against screening

(Grade 2B). The authors further note that stopping screening at age 65 may be

appropriate if the PSA level is less than 1 ng/mL.

If screening is to be performed, the generally accepted approach is to screen with

DRE and PSA and to limit screening to men with a life expectancy of greater than

10 years. There is currently insufficient evidence to determine the need and

optimal interval for repeat screening or whether PSA thresholds must be adjusted

for density, velocity, or age.

Schenk-Braat and Bangma (2006) noted that PSA is currently the most important

biochemical marker for the diagnosis of prostate cancer. Because of the limited

specificity of PSA, clinically irrelevant tumors and benign abnormalities are also

detected that can potentially lead to over-treatment and the associated physical as


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well as emotional burden for the patient. Furthermore, PSA is used as an indicator

of progression or clinical response following prostate cancer therapy, but the

prognostic value of this marker is limited. Ongoing research is examining several

alternative markers (e.g., osteoprotegerin, human kallikrein 2, and the gene DD3

(PCA3)) that may improve the specificity of current PSA-based diagnostics and the

prognostic value of PSA.

Prostate-specific antigen velocity, the yearly rate of increase of PSA, has not been

proven to improve the test characteristics of PSA, Schroder and colleagues (2006)

stated that PSA-driven screening has been applied to a large part of the male

population in many countries. An elevated PSA in secondary screens may indicate

benign enlargement of the prostate rather than prostate cancer. In such cases the

yearly rate of increase of PSA (PSA velocity [PSAV]) may improve the test

characteristics of PSA. These investigators examined if PSAV predict prostate

cancer in pre-screened populations. Data from the European Randomized Study of

Screening for Prostate Cancer Rotterdam were used to study the issue. Relative

sensitivity, relative specificity, and positive predictive value (PPV) were calculated.

Logistic regression analysis was used to compare odds ratios for positive biopsies.

The relationship between PSAV and parameters of tumor aggressiveness was

investigated. A total of 588 consecutive participants were identified who presented

at their first screening with PSA values less than 4.0 and who progressed to PSA

values greater than 4.0 ng/ml 4 years later were included in this study. None was

biopsied in round-1, all were biopsied in round-2. Relative sensitivity and specificity

depend strongly on PSAV cut-offs of 0.25 to 1.0 ng/ml/year. The use of PSAV cut-

offs did not improve the PPV of the PSA cut-off of 4.0 ng/ml, nor did any of the

PSAV cut-offs improve the odds ratio (OR) for identifying prostate cancer with

respect to the cut-off value of 4.0 ng/ml. The rate of aggressive cancers seems to

increase with increasing PSAV. The authors concluded that PSAV did not improve

the detection characteristics of a PSA cut-off of 4.0 ng/ml in secondary screening

after 4 years.

Wolters et al (2009) evaluated the value of PSAV in screening for prostate cancer.

Specifically, the role of PSAV in lowering the number of unnecessary biopsies and

reducing the detection rate of indolent prostate cancer was evaluated. All men

included in the study cohort were subjects in the European Randomized Study of

Screening for Prostate Cancer (ERSPC), Rotterdam section. During the first and

second screening round, a PSA test was performed on 2,217 men, and all

underwent a biopsy during the second screening round 4 years later. Prostate


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specific antigen velocity was calculated, and biopsy outcome was classified as

benign, possibly indolent prostate cancer, or clinically significant prostate cancer. A

total of 441 cases of prostate cancer were detected, 333 were classified as clinically

significant and 108 as possibly indolent. The use of PSAV cut-offs reduced the

number of biopsies but led to important numbers of missed (indolent and significant)

prostate cancer; PSAV was predictive for prostate ancer (OR: 1.28, p < 0.001) and

specifically for significant prostate cancer (OR: 1.46, p < 0.001) in uni-variate

analyses. However, multi-variate analyses using age, PSA, prostate volume, DRE

and transrectal ultrasonography outcome, and previous biopsy (yes/no) showed that

PSAV was not an independent predictor of prostate

cancer (OR: 1.01, p = 0.91) or significant prostate cancer (OR: 0.87, p = 0.30). The

authors concluded that the use of PSAV as a biopsy indicator would miss a large

number of clinically significant cases of prostate cancer with increasing PSAV cut-

offs. In this study, PSAV was not an independent predictor of a positive biopsy in

general or significant prostate cancer on biopsy. Thus, PSAV does not improve the

ERSPC screening algorithm.

The role of selenium in cancer prevention has been the subject of recent study and

debate. Population studies suggest that people with cancer are more likely to have

low selenium levels (measured in the blood or in tissues such as toenail clippings)

than healthy matched individuals. However, in most cases it is not clear if low

selenium levels are a cause or merely a consequence of disease. Initial evidence

from the Nutritional Prevention of Cancer (NPC) trial suggests that selenium

supplementation reduces the risk of prostate cancer among men with normal

baseline PSA levels and low selenium blood levels. The ongoing Selenium and

Vitamin E Cancer Prevention Trial (SELECT) aims to definitively address the role of

selenium in prostate cancer prevention. The study, which spans from 2001 to 2013,

will include 32,400 men. Currently, it is unclear if selenium is beneficial in the

treatment of prostate cancer or any type of cancer. Measurement of body selenium

(e.g., in serum, toenail clippings) has no proven value in the prevention of prostate

cancer.

Costello and Franklin (2009) proposed that changes in prostatic fluid composition

could provide accurate and reliable biomarkers for the screening of prostate

cancer. Most notable is the consistent and significant decrease in citrate and zinc

that is associated with the development and progression of prostate cancer. These

researchers provided the clinical and physiological basis and the evidence in

support of the utility of prostatic fluid analysis as an effective approach for


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screening/detection of prostate cancer, especially early stage and "at-risk"

subjects. The problem of interference from benign prostatic

hypertrophy that hampers PSA testing is eliminated in the potential prostatic fluid

biomarkers. The potential development of rapid, simple, direct, accurate clinical

tests would provide additional advantageous conditions. The authors stated that

further exploration and development of citrate, zinc and other electrolytes as

prostatic fluid biomarkers are needed to address this critical prostate cancer issue.

A long-term randomized controlled clinical trial found prostate cancer screening had

no effect on mortality (Andriole et al, 2009). From 1993 through 2001, investigators

randomly assigned 76,693 men at 10 U.S. study centers to receive either annual

screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in

the screening group were offered annual PSA testing for 6 years and DRE for 4

years. The subjects and health care providers received the results and decided on

the type of follow-up evaluation. Usual care sometimes included screening, as

some organizations have recommended. The numbers of all cancers and deaths

and causes of death were ascertained. In the screening group, rates of compliance

were 85 % for PSA testing and 86 % for DRE. Rates of screening in the control

group increased from 40 % in the first year to 52 % in the sixth year for PSA testing

and ranged from 41 to 46 % for DRE. After 7 years of follow-up, the incidence of

prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening

group and 95 (2,322 cancers) in the control group (rate ratio, 1.22; 95 % confidence

interval [CI]: 1.16 to 1.29). The incidence of death per 10,000 person-years was

2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate

ratio, 1.13; 95 % CI: 0.75 to 1.70). The data at 10 years were 67 % complete and

consistent with these overall findings. An important limitation of this study is that

subjects in the control group underwent considerable screening outside of the

clinical trial. An accompanying editorial (Barry, 2009) commented that serial

PSA screening has at best a modest effect on prostate cancer mortality during the

first decade of follow-up, and that this benefit comes at the cost of substantial over-

diagnosis and over-treatment.

Available evidence shows that the majority of men with low-risk prostate

tumors receive aggressive treatment, despite the risk of complications. Shao and

colleagues (2010) used the Surveillance, Epidemiology and End Results (SEER)

database to study the records of 123,934 men over the age of 25 who had newly

diagnosed prostate cancer from 2004 to 2006. About 14 % of the men had PSA

values lower than 4, generally younger men. In that group, 54 % had low-risk


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disease that could be safely monitored for progression with little risk. Nonetheless,

75 % of them received aggressive treatment, including a radical prostatectomy and

radiation therapy. Among men in that group over the age of 65, in which "watchful

waiting" is generally advised for low-risk disease, 66 % had aggressive therapy. In

both cases, the percentages were similar to those in the group with PSA levels

between 4 and 20.

Mazzola et al (2011) stated that the introduction and widespread adoption of PSA has

revolutionized the way prostate cancer is diagnosed and treated. However, the use of

PSA has also led to over-diagnosis and over-treatment of prostate cancer resulting in

controversy about its use for screening. Prostate specific antigen also has limited

predictive accuracy for predicting outcomes after treatment and for making clinical

decisions about adjuvant and salvage therapies. Thus, there is an urgent need for

novel biomarkers to supplement PSA for detection and management of prostate

cancer. A plethora of promising blood- and urine-based biomarkers have shown

promise in early studies and are at various stages of development (human kallikrein

2, early prostate cancer antigen, transforming growth factor-beta 1, interleukin-6,

endoglin, prostate cancer gene 3 (PCA3), alpha- methylacyl coenzyme A racemase

(AMACR) and E twenty-six (ETS) gene fusions).

Pettersson et al (2012) stated that whether the genomic re-arrangement trans-

membrane protease, serine 2 (TMPRSS2): v-ets erythroblastosis virus E26 oncogene

homolog (ERG) has prognostic value in prostate cancer is unclear. Among men with

prostate cancer in the prospective Physicians' Health and Health Professionals

Follow-Up Studies, these researchers identified re-arrangement status by

immunohistochemical assessment of ERG protein expression. They used Cox

models to examine associations of ERG over-expression with biochemical recurrence

and lethal disease (distant metastases or cancer-specific mortality). In a meta-

analysis including 47 additional studies, these investigators used random- effects

models to estimate associations between re-arrangement status and outcomes. The

cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and

2005. During a median follow-up of 12.6 years, 266 men experienced recurrence and

85 men developed lethal disease. These researchers found no significant association

between ERG over-expression and biochemical recurrence [hazard ratio (HR), 0.99;

95 % CI: 0.78 to 1.26] or lethal disease (HR, 0.93; 95 % CI: 0.61 to 1.43). The meta-

analysis of prostatectomy series included 5,074 men followed for biochemical

recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events).

TMPRSS2: ERG was associated with stage


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at diagnosis [risk ratio (RR)(≥T3 vs. T2), 1.23; 95% CI, 1.16-1.30) but not with

biochemical recurrence (RR, 1.00; 95 % CI: 0.86 to 1.17) or lethal disease (RR,

0.99; 95 % CI: 0.47 to 2.09). The authors concluded that the findings of this meta-

analysis suggested that TMPRSS2: ERG, or ERG over-expression, is associated

with tumor stage but does not strongly predict recurrence or mortality among men

treated with radical prostatectomy.

Salagierski et al (2012) stated that widespread PSA screening together with the

increase in the number of biopsy cores has led to increased prostate cancer

incidence. Standard diagnostic tools still cannot unequivocally predict prostate

cancer progression, which often results in a significant over-treatment rate. These

investigators presented recent findings on PCA3 and TMPRSS: ERG fusion and

described their clinical implications and performance. The PubMed® database was

searched for reports on PCA3 (130 articles), TMPRSS: ERG and ETS fusion (180

publications) since 1999. In recent years advances in genetics and biotechnology

have stimulated the development of non-invasive tests to detect prostate cancer.

Serum and urine molecular biomarkers have been identified, of which PCA3 has

already been introduced clinically. The identification of prostate cancer specific

genomic aberrations, i.e., TMPRSS2: ERG gene fusion, might improve diagnosis

and affect prostate cancer treatment. The authors concluded that although several

recently developed markers are promising, often showing increased specificity for

prostate cancer detection compared to that of PSA, their clinical application is

limited.

Choudhury et al (2012) noted that despite widespread screening for prostate cancer

and major advances in the treatment of metastatic disease, prostate cancer remains

the second most common cause of cancer death for men in the Western world. In

addition, the use of PSA testing has led to the diagnosis of many potentially indolent

cancers, and aggressive treatment of these cancers has caused significant morbidity

without clinical benefit in many cases. The recent discoveries of inherited and

acquired genetic markers associated with prostate cancer initiation and progression

provide an opportunity to apply these findings to guide clinical decision-making. In

this review, these investigators discussed the potential use of genetic markers to

better define groups of men at high risk of developing prostate cancer, to improve

screening techniques, to discriminate indolent versus aggressive disease, and to

improve therapeutic strategies in patients with advanced disease. PubMed-based

literature searches and abstracts through January 2012 provided the basis for this

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examined secondary sources from reference lists of retrieved articles and data

presented at recent congresses. Cited review articles were only from the years 2007

to 2012, favoring more recent discussions because of the rapidly changing field.

Original research articles were curated based on favoring large sample sizes,

independent validation, frequent citations, and basic science directly related to

potentially clinically relevant prognostic or predictive markers. In addition, all authors

on the manuscript evaluated and interpreted the data acquired. These investigators

addressed the use of inherited genetic variants to assess risk of prostate cancer

development, risk of advanced disease, and duration of response to hormonal

therapies. The potential for using urine measurements such as PCA3 RNA and

TMPRSS2-ERG gene fusion to aid screening was discussed. Multiple groups have

developed gene expression signatures from primary prostate tumors correlating with

poor prognosis and attempts to improve and standardize these signatures as

diagnostic tests were presented. Massive sequencing efforts are underway to define

important somatic genetic alterations (amplifications, deletions, point mutations,

translocations) in prostate cancer, and these alterations hold great promise as

prognostic markers and for predicting response to therapy. These researchers

provided a rationale for assessing genetic markers in metastatic disease for guiding

choice of therapy and for stratifying patients in clinical trials and discussed challenges

in clinical trial design incorporating the use of these markers. The authors concluded

that the use of genetic markers has the potential to aid disease screening, improve

prognostic discrimination, and prediction of response to treatment. However, most

markers have not been prospectively validated for providing useful prognostic or

predictive information or improvement upon clinicopathologic parameters already in

use. They stated that significant efforts are underway to develop these research

findings into clinically useful diagnostic tests in order to improve clinical decision

making.

Measurement of MicroRNAs in Prostatic Fluid/Tissue:

Schubert et al (2016) noted that defining reliable biomarkers is still a challenge in

patients with urological tumors. Because short non-coding RNAs known as

microRNAs (miRNAs) regulate diverse important cellular processes, these non-

coding RNAs are putative molecular candidates. These researchers provided a

critical overview about the current state of miRNAs as biomarkers in urological

cancers with respect to prognostic stratification as well as for individual treatment

selection. They performed a comprehensive review of the published literature

focusing at the clinical relevance of miRNAs in tissues and body fluids of prostate,


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bladder and kidney cancer. Using electronic database, a total of 91 articles,

published between 2009 and 2015, were selected and discussed regarding the

robustness of miRNAs as valid biomarkers. A number of miRNAs have been

identified with prognostic and predictive relevance in different urologic tumor types.

However, the inconsistency of the published results and the lack of multivariate

testing in independent cohorts do not allow an introduction into clinical decision

making at present. The authors concluded that miRNA-based biomarkers are a

promising tool for future personalized risk stratification and response prediction in

urological cancers.

Fabris et al (2016) stated that miRNAs control protein expression through the

degradation of RNA or the inhibition of protein translation. The miRNAs influence a

wide range of biologic processes and are often deregulated in cancer. This family of

small RNAs constitutes potentially valuable markers for the diagnosis, prognosis,

and therapeutic choices in prostate cancer (PCa) patients, as well as potential

drugs (miRNA mimics) or drug targets (anti-miRNAs) in PCa management. These

investigators reviewed the currently available data on miRNAs as biomarkers in

PCa and as possible tools for early detection and prognosis. A systematic review

was performed searching the PubMed database for articles in English using a

combination of the following terms: microRNA, miRNA, cancer, prostate cancer,

miRNA profiling, diagnosis, prognosis, therapy response, and predictive marker.

The authors summarized the existing literature regarding the profiling of miRNA in

PCa detection, prognosis, and response to therapy. The articles were reviewed

with the main goal of finding a common recommendation that could be translated

from bench to bedside in future clinical practice. The authors concluded that the

miRNAs are important regulators of biologic processes in PCa progression. A

common expression profile characterizing each tumor subtype and stage has still

not been identified for PCa, probably due to molecular heterogeneity as well as

differences in study design and patient selection. Moreover, they stated that large-

scale studies that should provide additional important information are still missing;

further studies, based on common clinical parameters and guidelines, are needed

to validate the translational potential of miRNAs in PCa clinical management. Such

common signatures are promising in the field and emerge as potential biomarkers.

The authors noted that the literature showed that microRNAs hold potential as

novel biomarkers that could aid prostate cancer management, but additional studies

with larger patient cohorts and common guidelines are needed before clinical

implementation


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Furthermore, an UpToDate review on “Screening for prostate cancer” (Hoffman,

2013) does not mention the use of microRNAs as a screening tool for prostate

cancer.

BRAF Mutations:

Cohn and colleagues (2017) stated that mutations in the BRAF gene have been

implicated in several human cancers. The objective of this screening study was to

identify patients with solid tumors (other than metastatic melanoma or papillary

thyroid cancer) or multiple myeloma harboring activating BRAFV600 mutations for

enrollment in a vemurafenib clinical study. Formalin-fixed, paraffin-embedded tumor

samples were collected and sent to a central laboratory to identify activating

BRAFV600 mutations by bi-directional direct Sanger sequencing. Overall incidence of

BRAFV600E mutation in evaluable patients (n = 548) was 3 % (95 % CI: 1.7 to 4.7):

11 % in colorectal tumors (n = 75), 6 % in biliary tract tumors (n = 16), 3 % in non-

small cell lung cancers (n = 71), 2 % in other types of solid tumors (n = 180), and 3 %

in multiple myeloma (n = 31). There were no BRAFV600 mutations in this cohort of

patients with ovarian tumors (n = 68), breast cancer (n = 86), or PCa (n = 21). The

authors noted that BRAF mutations have been identified in up to 10 % of Asian

patients with PCa but appeared to be rare among Caucasian patients. The finding of

no mutations among 21 patients with PCa is also consistent with data from the

COSMIC database, showing documented BRAF mutations in approximately 1 % of

almost 2,500 sequenced samples.

Neutrophil Gelatinase-Associated Lipocalin:

Muslu and colleagues (2017) noted that PSA with DRE is used for diagnosis of

PCa, where definite diagnosis can only be made by prostate biopsy. Recently

neutrophil gelatinase-associated lipocalin (NGAL), a lipocalin family member

glycoprotein, come into prominence as a cancer biomarker. In a prospective study,

these researchers tested serum NGAL as a diagnostic biomarker for PCa and for

differentiation of PCa from benign prostatic hyperplasia (BPH). A total of 90

patients who underwent trans-rectal ultrasound (TRUS)-guided 12-core prostate

biopsy between May 2015 and September 2015 were evaluated.

Histopathologically diagnosed 45 PCa and 45 BPH patients were enrolled in this

study. Serum NGAL and PSA levels of all participants were measured, then these

data were evaluated by statistical programs. When sensitivity fixed to 80 %

specificity of NGAL was better than PSA (49 % and 31 %, respectively). Receiver


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operating characteristic (ROC) curve analysis showed that NGAL alone or its

combined use with PSA exhibited better area under curve (AUC) results than PSA

alone (0.662, 0.693, and 0.623, respectively). The authors concluded that NGAL

gave promising results such as increased sensitivity and a better AUC values in

order to distinguish PCa from BPH. They stated that NGAL showed a potential to

be a non-invasive biomarker which may decrease the number of unnecessary

biopsies; more studies are needed to define more accurate cut-off values for both

NGAL alone and PSA-NGAL combination; and more accurate results can be

achieved by increasing the number of cases.

Non-PSA Blood Test:

Apifiny (Armune BioScience, Inc., Kalamazoo, MI) is a non-PSA blood test that

measures eight prostate-cancer-specific autoantibodies in human serum (i.e., ARF

6, NKX3-1, 5’-UTR-BMI1, CEP 164, 3’-UTR-Ropporin, Desmocollin, AURKAIP-1,

CSNK2A2) (AMA, 2017; Armune BioScience, 2017). In essence, The Apifiny

measures the body’s immune-system response to cancerous activity in prostate

tissue. Per Armune BioScience, Inc., autoantibodies are produced and replicated

(amplified) by the immune system in response to the presence of prostate-cancer

cells. The autoantibodies are stable and, because of their amplification, are likely to

be abundant and easy to detect, especially during the early stages of cancer. The

methodology involves immunoassay, flow cytometry, and algorithmic analysis to

derive at a score that indicates a potential risk of having prostate cancer. The use of

Apifiny results may supplement other information about prostate-cancer risks and

may therefore aid in earlier diagnosis of prostate cancer and potentially increase

survival rates. It is not known if Apifiny scores are affected by age, race, or other

factors. The Apifiny non-PSA blood test is not FDA approved (Armune BioScience,

2017).

Schipper et al (2016) discuss novel prostate cancer biomarkers derived from

autoantibody signatures. The authors used T7 phage-peptide detection to identify a

panel eight biomarkers for prostate cancer (PCA) on a training set. The estimated

receiver-operating characteristic (ROC) curve had an area under the ROC curve of

0.69 when applied to the validation set. Spearman correlations were high, within 0.7

to 0.9, indicating that the biomarkers have a degree of inter-relatedness. They noted

that the identified biomarkers play a role in processes such as androgen response

regulation and cellular structural integrity and are proteins that are thought to play a

role in prostate tumorigenesis. The authors concluded that


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autoantibodies against PCA can be developed as biomarkers for detecting PCA.

The scores from the algorithm they developed can be used to indicate a relatively

high or low risk of PCA, particularly for patients with intermediate (4.0 to 10 ng/ml)

PSA levels. Since most commercially available assays test for PSA or have a PSA

component, this novel approach has the potential to improve diagnosis of PCA

using a biologic measure independent of PSA.

Wang et al (2005) discussed autoantibody signature biomarkers in prostate cancer.

The authors constructed phage-protein microarrays in which peptides derived from

a prostate-cancer cDNA library were expressed as a prostate-cancer – phage fusion

protein. They used the phage protein microarrays to analyze serum samples from

119 patients with prostate cancer, along with 138 controls. A phage-peptide

detector that was constructed from the training set was evaluated on an

independent validation set of 128 serum samples (60 from patients with prostate

cancer and 68 from controls). The authors note the 22-phage-peptide detector had

88.2 percent specificity (95 percent confidence interval, 0.78 to 0.95) and 81.6

percent sensitivity (95 percent confidence interval, 0.70 to 0.90) in discriminating

between the group with prostate cancer and the control group. This panel of

peptides performed better than did prostate-specific antigen (PSA) in distinguishing

between the group with prostate cancer and the control group (area under the curve

for the autoantibody signature, 0.93; 95 percent confidence interval, 0.88 to 0.97;

area under the curve for PSA, 0.80; 95 percent confidence interval, 0.71 to 0.88).

Logistic-regression analysis revealed that the phage-peptide panel provided

additional discriminative power over PSA (P<0.001). Among the 22 phage peptides

used as a detector, 4 were derived from in-frame, named coding sequences. The

remaining phage peptides were generated from untranslated sequences. The authors

concluded that autoantibodies against peptides derived from prostate- cancer tissue

could be used as the basis for a screening test for prostate cancer. However, they

note that they have not tested the phage-microarray system for screening for prostate

cancer. They state that this would require extension and confirmation in community-

based screening cohorts. Furthermore, the authors state that although promising,

how it will perform in prospective and multi-institutional studies remains to be

determined.

The National Comprehensive Cancer Network Biomarkers Compendium does not

mention Apifiny, non-PSA test, as a diagnostic or screening option.


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Genetic-Based Screening:

Benafif and Eeles (2016) noted that PCa is the commonest non-cutaneous cancer

in men in the United Kingdom. Epidemiological evidence as well as twin studies

points towards a genetic component contributing to etiology. A family history of PCa

doubles the risk of disease development in 1st-degree relatives. Linkage and genetic

sequencing studies identified rare moderate-high-risk gene loci, which predispose to

PCa development when altered by mutation. Genome-wide association studies

(GWAS) have identified common single-nucleotide polypmorphisms (SNPs), which

confer a cumulative risk of PCa development with increasing number of risk alleles.

There are emerging data that castrate-resistant disease is associated with mutations

in DNA repair genes. Linkage studies investigating possible high-risk loci leading to

PCa development identified possible loci on several chromosomes, but most have

not been consistently replicated by subsequent studies. Germline SNPs related to

PSA levels and to normal tissue radio-sensitivity have also been identified though

not all have been validated in subsequent studies. Utilizing germline SNP profiles as

well as identifying high-risk genetic variants could target screening to high-risk

groups, avoiding the drawbacks of PSA screening. The authors concluded that

incorporating genetics into PCa screening is being investigated currently using both

common SNP profiles and higher risk rare variants. Knowledge of germline genetic

defects will allow the development of targeted screening programs, preventive

strategies and the personalized treatment of PCa.

Eeles and Ni Raghallaigh (2018) noted that PCa is the 2nd most common

malignancy affecting men worldwide, and the commonest affecting men of African

descent. Significant diagnostic and therapeutic advances have been made in the

past 10 years. Improvements in the accuracy of PCa diagnosis include the uptake of

multi-parametric MRI and a shift towards targeted biopsy. There are also more life-

prolonging systemic and hormonal therapies for men with advanced disease.

However, the development of robust screening tools and targeted screening

programs has not followed at the same pace. Evidence to support population-

based screening remains unclear, with the use of PSA as a screening test limiting

the ability to discriminate between clinically significant and insignificant disease.

Since PCa has a large heritable component and given that most men without risk

factors have a low lifetime risk of developing lethal PCa, much work is being done

to further the knowledge of how clinicians can best screen men in higher risk

categories, such as those with a family history (FH) of the disease or those of


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African ancestry. These men have been reported to carry upwards of a 2-fold

increased risk of developing the disease at an earlier age, with evidence suggesting

poorer survival outcomes. In men with a FH of PCa, this is felt to be due to rare, high-

penetrance mutations and the presence of multiple, common low penetrance alleles,

with men carrying specific germline mutations in the BRCA and other DNA repair

genes at particularly high risk. To-date, large scale GWAS have led to the discovery

of approximately 170 SNPs associated with PCa risk, allowing over 30 % of PCa risk

to be explained. Genomic tests, utilizing somatic (prostate biopsy) tissue can also

predict the risk of unfavorable pathology, biochemical recurrence and the likelihood

of metastatic disease using gene expression. Targeted screening studies are

currently under way in men with DNA repair mutations, men with a FH and those of

Afro-Caribbean ethnicity that will greater inform the understanding of disease

incidence and behavior in these men, treatment outcomes and developing the most

appropriate screening regime for such men.

Incorporating a patient's genetic mutation status into risk algorithms allows

clinicians an opportunity to develop targeted screening programs for men in whom

early cancer detection and treatment will positively influence survival, and in the

process offer male family members of affected men the chance to be counselled

and screened accordingly. The authors concluded that advances in the field of uro-

oncology such as the diagnostic performance of multi-parametric MRI and genomic

interrogation have led to a position of potentially use these as screening tools in the

right populations.

Furthermore, an UpToDate review on “Screening for prostate cancer” (Hoffman,

2018) does not mention genetic-based screening.

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

CPT codes covered if selection criteria are met:

84152 Prostate specific antigen (PSA); complexed (direct measurement)

84153 total

84154 free

CPT codes not covered for indications listed in the CPB:

Genetic b ased screening for prostate cancer - no specific code:

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0021U Oncology (prostate), detection of 8 autoantibodies (ARF 6, NKX3-1, 5'-

UTR-BMI1, CEP 164, 3'-UTR-Ropporin, Desmocollin, AURKAIP-1,

CSNK2A2), multiplexed immunoassay and flow cytometry serum,

algorithm reported as risk score

84255 Chemistry, Selenium [PCA3]

TMPRSS2: ERG gene fusion, Measurement of microRNAs in prostatic fluid/tissue:

No specific code

CPT codes not covered for indications listed in the CPB:

81210 BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon

cancer, melanoma), gene analysis, V600 variant(s)

81313 PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-

related peptidase 3 [prostate specific antigen]) ratio (eg, prostate

cancer)

81539 Oncology (high-grade prostate cancer), biochemical assay of four

proteins (Total PSA, Free PSA, Intact PSA, and human kallikrein-2

[hK2]), utilizing plasma or serum, prognostic algorithm reported as a

probability score

83520 Immunoassay for analyte other than infectious agent antibody or

infectious agent antigen; quantitative, not otherwise specified [neutrophil

gelatinase-associated lipocalin (NGAL)]

Other CPT codes related to the CPB:

88271 Molecular cytogenics; DNA probe, each (eg, FISH)

88272 chromosomal in situ hybridization, analyze 3-5 cells (eg, for

derivatives and markers)

88273 chromosomal in situ hybridization, analyze 10-30 cells (eg, for

microdeletions)

88274 Interphase in situ hybridization, analyze 25-99 cells

88275 Interphase in situ hybridization, analyze 100-300 cells

88291 Cytogenics and molecular cytogenics, interpretation and report

Modifier 0Z Solid tumor gene, not otherwise specified

HCPCS codes covered if selection criteria are met:

G0102 Prostate cancer screening; digital rectal examination

G0103 Prostate cancer screening; prostate specific antigen test (PSA)

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ICD-10 codes covered if selection criteria are met:

C61 Malignant neoplasm of prostate

D07.5 Carcinoma in situ of prostate

D29.1 Benign neoplasm of prostate

D40.0 Neoplasm of uncertain behavior of prostate

N40.0 - N40.3 Enlarged prostate

N42.30 - N42.39 Dysplasia of prostate

R97.20 - R97.21 Elevated prostate specific antigen [PSA]

Z12.5 Encounter for screening for malignant neoplasm of prostate

Z15.03 Genetic susceptibility to malignant neoplasm of prostate

Z80.42 Family history of malignant neoplasm of prostate

Z85.46 Personal history of malignant neoplasm of prostate

The above policy is based on the following references:

1. U.S. Preventive Services Task Force. Screening for prostate cancer:

Recommendations and rationale. Ann Intern Med. 2002;137(11):915-916.

2. American College of Radiology (ACR). Resolution No. 36. Reston, VA: ACR;

October 1991.

3. Canadian Task Force on the Periodic Health Examination. Canadian Guide to

Clinical Preventive Health Care. Ottawa, ON: Canada Communications Group;

1994.

4. U.S. Congress, Office of Technology Assessment (OTA). Costs and

effectiveness of prostate cancer screening in elderly men. Pub. No. OTA-PB-

H-145. Washington, DC: U.S. Government Printing Office; 1995.

5. Coley CM, Barry MJ, Fleming C, et al. Early detection of prostate cancer. Part

I: Prior probability and effectiveness of tests. Ann Intern Med. 1997;126 (5):394-

406.

6. Coley CM, Barry MJ, Fleming C, et al. Early detection of prostate cancer. Part

II: Estimating the risks, benefits, and costs. American College of

Physicians. Ann Intern Med. 1997;126(6):468-469.


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7. Middleton RG. Prostate cancer: Are we screening and treating too much? Ann

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8. Ferrini R, Woolf SH. Screening for prostate cancer in American

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9. von Eschenbach A, Ho R, Murphy GP, et al. American Cancer Society

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cancer than prostate-specific antigen. Ned Tijdschr Geneeskd. 2006;150

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32. Ilic D, O'Connor D, Green S, Wilt T. Screening for prostate cancer: A

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33. Bryant RJ, Hamdy FC. Screening for prostate cancer: An update. Eur Urol.

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35. Lin K, Lipsitz R, Miller T, Janakiraman S. Benefits and harms of prostate-

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36. U.S. Preventive Services Task Force. Screening for prostate cancer: U.S.

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37. Satia JA, King IB, Morris JS, Stratton K, White E. Toenail and plasma levels

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40. Costello LC, Franklin RB. Prostatic fluid electrolyte composition for the

screening of prostate cancer: A potential solution to a major problem. Prostate

Cancer Prostatic Dis. 2009;12(1):17-24.

41. Schröder FH, Roobol MJ, van der Kwast TH, et al. Does PSA velocity predict

prostate cancer in pre-screened populations? Eur Urol. 2006;49(3):460-465;

discussion 465.

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43. Schröder FH, Hugosson J, Roobol MJ, et al; ERSPC Investigators. Screening

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2009;360(13):1320-1328.

44. Shao YH, Albertsen PC, Roberts CB, et al. Risk profiles and treatment

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1261.

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determinants and outcomes of deferred treatment or watchful waiting among

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47. Zietman A. Evidence-based medicine, conscience-based medicine, and the

management of low-risk prostate cancer. J Clin Oncol. 2009;27(30):4935-

4936.

48. Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer

and prostate cancer. JAMA. 2009;302(15):1685-1692.

49. Andriole GL, Crawford ED, Grubb RL 3rd, et al; PLCO Project Team. Mortality

results from a randomized prostate-cancer screening trial. N Engl J Med.

2009;360(13):1310-1319.

50. Barry MJ. Screening for prostate cancer -- the controversy that refuses to die.

N Engl J Med. 2009;360(13):1351-1354.

51. Greene KL, Albertsen PC, Babaian RJ, et al. Prostate specific antigen best

practice statement: 2009 update. J Urol. 2009;182(5):2232-2241.

52. Shao YH, Albertsen PC, Roberts CB, et al. Risk profiles and treatment

patterns among men diagnosed as having prostate cancer and a prostate-

specific antigen level below 4.0 ng/ml. Arch Intern Med. 2010;170(14):1256-

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53. Wolf AM, Wender RC, Etzioni RB, et al; American Cancer Society Prostate

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55. Ilic D, O'Connor D, Green S, Wilt TJ. Screening for prostate cancer: An

updated Cochrane systematic review. BJU Int. 2011;107(6):882-891.

56. Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer:

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2010;341:c4543.

57. Chou R, Croswell JM, Dana T, et al. Screening for prostate cancer: A review of

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2011;155(11):762-771.

58. U.S. Preventive Services Task Force. Screening for prostate cancer: Current

recommendation. Rockville, MD: Agency for Healthcare Research and

Quality; 2012.

59. Pettersson A, Graff RE, Bauer SR, et al. The TMPRSS2: ERG rearrangement,

ERG expression, and prostate cancer outcomes: A cohort study and meta-

analysis. Cancer Epidemiol Biomarkers Prev. 2012;21(9):1497-1509.

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61. Choudhury AD, Eeles R, Freedland SJ, et al. The role of genetic markers in

the management of prostate cancer. Eur Urol. 2012;62(4):577-587.

62. Qaseem A, Barry MJ, Denberg TD, et al. Screening for prostate cancer: A

guidance statement from the Clinical Guidelines Committee of the American

College of Physicians. Ann Intern Med. 2013;158(10):761-769.

63. Schubert M, Junker K, Heinzelmann J. Prognostic and predictive miRNA

biomarkers in bladder, kidney and prostate cancer: Where do we stand in

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65. Fabris L, Ceder Y, Chinnaiyan AM, et al. The potential of microRNAs as

prostate cancer biomarkers. Eur Urol. 2016;70(2):312-322.

66. Outzen M, Tjønneland A, Larsen EH, et al. Selenium status and risk of

prostate cancer in a Danish population. Br J Nutr. 2016;115(9):1669-1677.

67. Cohn AL, Day BM, Abhyankar S, et al. BRAFV600 mutations in solid tumors,

other than metastatic melanoma and papillary thyroid cancer, or multiple

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in

private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible

for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to

change.

Copyright © 2001-2019 Aetna Inc.

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AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment toAetna Clinical Policy Bulletin Number: 0521 Prostate Cancer

Screening

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania revised 02/14/2019

Proprietary

http://www.aetnabetterhealth.com/pennsylvania

prior authorization review panel mco policy s …...family history of prostate cancer represent...

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