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Clinical Policy Bulletin:
Prostate Saturation Biopsy
Number: 0698


Policy

Aetna considers a transperineal stereotactic template-guided saturation prostate biopsy medically necessary for the following indications in men with 2 prior extended transrectal prostate biopsies negative for invasive cancer: 

  • Men with an elevated prostate specific antigen (PSA) that is persistently rising; or
  • Men with histologic evidence of atypia on prior prostate biopsy; or
  • Men with histologic findings of high-grade prostatic intraepithelial neoplasia (PIN) on prior biopsy.

Aetna considers prostate saturation biopsy experimental and investigational for all other indications (e.g., surveillance of persons with a positive prostate biopsy) because there is insufficient evidence on the clinical utility of this procedure for indications other than the ones listed above in the peer-reviewed medical literature.

Aetna considers ConfirmMDx (an epigenetic assay to for individuals with a previous negative biopsy and persistent risk factors, leading to consideration of a repeat biopsy) experimental and investigational because its clinical value has not been established.

Note: The know error® DNA Specimen Provenance Assay, a forensic assay to confirm that a surgical specimen belongs to the patient evaluated for treatment, is considered to be part of the laboratory's quality control for specimens. Use of this test is considered an integral part of the biopsy and is not separately reimbursed.

See also CPB 0001 - Transrectal UltrasoundCPB 0168 - Tumor ScintigraphyCPB 0521 - Prostate Cancer Screening.  



Background

Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.  It accounts for 33 % of all male cancers and 10 % of male cancer-related deaths.  The disease is histologically evident in as many as 34 % of men during their fifth decade of life and in up to 70 % of men aged 80 years old and older.  

Transperineal template-guided stereotactic saturation prostate biopsy, typically using 30 to 80 cores, is being proposed as a method to detect prostate cancer in high-risk men with multiple negative extended prostate biopsies, including men with an elevated prostate-specific antigen (PSA) that is persistently rising, men with histologic evidence of atypia on prior prostate biopsy, or men with histologic findings of high-grade prostate intraepithelial neoplasia (PIN) on prior biopsy. 

Digital rectal exam (DRE) and PSA tests detect prostate abnormalities, but they can not determine whether these abnormalities are cancer or benign; only a biopsy can confirm a diagnosis of prostate cancer.  Prostate cancer risk factors include persistent elevated PSA, atypia, or high grade prostatic intraepithelial neoplasia (PIN) on prior biopsy. 

A core needle biopsy of the prostate under transrectal ultrasound guidance is the main method used to diagnose prostate cancer.  A narrow needle is placed through the wall of the rectum into the prostate gland.  The needle removes a cylinder of tissue, usually about 1/2-inch long and 1/16-inch across.  A pathologist assigns a Gleason primary and secondary grade to the biopsy specimen.  Usually 6 to 18 cores are removed to get a good sample and tell how much of the gland (if any) is affected by cancer; however, 10 to 12 tissue cores are considered the standard of care (Wilson and Crawford, 2004). 

It has been reported that 38 % of prostate cancers are missed by prostate biopsy (Patel et al, 2004).  There is some evidence that the sensitivity of needle biopsy could improve by 30 % to 35 % by increasing the number of biopsy cores beyond 6 (e.g., 14 to 45 cores) (Stewart et al, 2001).  Some investigators have proposed even more extensive sampling (30 to 80 cores).  This improvement in sensitivity, however, has been at the cost of doubling the rate of cancer detection of less than 0.5 cm3 in volume identified.  The extent to which an increase in detection rate would reduce morbidity and mortality from prostate cancer or increase the percentage of men treated unnecessarily is unknown.  

Epstein et al (2005) reported the results of prostate saturation biopsy on 103 men who were predicted to have insignificant cancer in their radical prostatectomy (RP) specimen.  All had limited cancer on routine needle biopsy (no core with more than 50 % involvement; Gleason score less than 7, and fewer than 3 cores involved) with a serum PSA density of 0.15 or less.  Insignificant tumor at RP was considered organ-confined tumor, no Gleason pattern 4 or 5, and a tumor volume of less than 0.5 cm3.  Saturation biopsy (average 44 cores) versus an alternate biopsy saturation protocol with half the number of cores was performed on RP specimens.  Of the tumors examined, 97 % were organ confined.  The RP Gleason score was less than 7 in 84 % of the cases.  The RP tumor volume was 0.01 to 2.39 cm3 (median 0.14).  Overall, 71 % of cancers were insignificant; however, 29 % had been incorrectly classified before surgery using a standard biopsy protocol.  The authors calculated that with the saturation biopsy method, the false-positive rate for significant disease was 11.5 %.  Similarly, the false-negative rate for insignificant tumors was 11.5 % (sensitivity 71.9 % and specificity 95.8 %).  Using the alternate biopsy protocol, with half the number of cores, the false-positive rate was 8 % and the false-negative rate was 11.4 % (sensitivity 71.9 % and specificity 97.1 %).  The authors stated that in comparison, using a 12-core biopsy protocol, a false-negative rate of 11.7 % would have been achieved with a false-positive rate of 41.9 %, and lowering the false-positive rate to 28.65 % increased the false-negative rate to 16.0 %. 

A systematic review of the diagnostic value of systematic prostate biopsy methods in the investigation for prostate cancer, prepared by the Centre for Reviews and Dissemination (2005) found that "[s]chemes with 18 and more cores of the 5-region pattern showed the highest cancer yield (RPR 1.48; 95 % confidence interval [CI]: 1.32 to 1.66).  However, the difference in the cancer yield of this scheme to the yield of the 12-core scheme from pattern mid-lobar peripheral zone + lateral peripheral zone (RPR 1.31; 95 % CI: 1.25 to 1.37) and the 10-core scheme of the 5-region pattern (RPR 1.38; 95 % CI: 1.08 to 1.76) was not statistically significant."  The assessment concluded that "[i]t still has to be demonstrated that extended biopsy schemes with a higher cancer yield do lead to a survival benefit due to early cancer detection."

An update to this systematic evidence review on the diagnostic value of biopsy methods in the investigation of prostate cancer reached similar conclusions. Eichler et al (2006) searched 13 electronic databases, screened relevant urological journals and the reference lists of included studies, and contacted experts.  These researchers included studies that compared different systematic prostate biopsy methods using sequential sampling or a randomized design in men scheduled for biopsy due to suspected prostate cancer.  They pooled data using a random effects model when appropriate; and analyzed 87 studies with a total of 20,698 patients.  These investigators pooled data from 68 studies comparing a total of 94 extended schemes with the standard sextant scheme.  An increasing number of cores were significantly associated with the cancer yield.  Laterally directed cores increased the yield significantly (p = 0.003), whereas centrally directed cores did not.  Schemes with 12 cores that took additional laterally directed cores detected 31 % more cancers (95 % CI: 25 to 37) than the sextant scheme.  Schemes with 18 to 24 cores did not detect significantly more cancers.  Adverse events for schemes up to 12 cores were similar to those for the sextant pattern.  Adverse event reporting was poor for schemes with 18 to 24 cores.  The authors concluded that prostate biopsy schemes consisting of 12 cores that add laterally directed cores to the standard sextant scheme strike the balance between the cancer detection rate and adverse events.  Taking more than 12 cores added no significant benefit.

Prostate saturation biopsy may provide increased accuracy in the predictability of prostate tumor volume and grade to select suitable candidates for watchful waiting therapy; however, it is not clear whether early detection and subsequent earlier treatment leads to any change in the natural history and outcome of individuals with prostate cancer.  Randomized controlled trials are needed to determine the clinical utility of prostate saturation biopsy.

Jones et al (2006) reported on the results of a sequential cohort study comparing office-based saturation prostate biopsy to traditional 10-core sampling as an initial biopsy.  Based on improved cancer detection of office-based saturation prostate biopsy repeat biopsy, the authors adopted the technique as an initial biopsy strategy to improve cancer detection.  Two surgeons performed 24-core saturation prostate biopsies in 139 patients undergoing initial biopsy under peri-prostatic local anesthesia.  Indication for biopsy was an increased PSA of 2.5 ng/dl or greater in all patients.  Results were compared to those of 87 patients who had previously undergone 10-core initial biopsies.  Cancer was detected in 62 of 139 patients (44.6 %) who underwent saturation biopsy and in 45 of 87 patients (51.7 %) who underwent 10-core biopsy (p > 0.9).  Breakdown by PSA level failed to show benefit to the saturation technique for any degree PSA increase.  Men with PSA 2.5 to 9.9 ng/dl were found to have cancer in 53 of 122 (43.4 %) saturation biopsies and 26 of 58 (44.8 %) 10-core biopsies.  Complications included 3 cases of prostatitis in each group.  Rectal bleeding was troublesome enough to require evaluation only in 3 men in the saturation group and 1 in the 10-core group.  These investigators concluded that although saturation prostate biopsy improves cancer detection in men with suspicion of cancer following a negative biopsy, it does not appear to offer benefit as an initial biopsy technique.  These findings suggest that further efforts at extended biopsy strategies beyond 10 to 12 cores are not appropriate as an initial biopsy strategy.

In an accompanying editorial, Moon and Theodorescue (2006) reported that the literature shows average cancer detection rates on first repeat biopsy using standard techniques of 22 %, compared with detection rates ranging from 14 to 34 % on first repeat biopsy using saturation techniques.

Merrick et al (2007) ascertained the prostate cancer incidence, anatomical distribution, Gleason score profile, and tumor burden in patients diagnosed by transperineal template-guided saturation biopsy (TTSB).  A total of 102 patients underwent TTSB; all but 1 patient had undergone at least 1 prior negative transrectal ultrasound (TRUS) biopsy.  Criteria for inclusion included an elevated PSA and/or the diagnosis of atypical small acinar proliferation or high-grade PIN on prior biopsy.  The prostate gland was divided into 24 regional biopsy locations.  The median number of biopsy cores was 50.  Multiple clinical parameters were assessed as predictors for prostate cancer diagnosis.  The mean patient age was 64.8 years with a mean PSA of 9.1 ng/ml and a prostate volume of 78.6 cm(3).  On average, patients had undergone 2.1 prior negative TRUS biopsies with a mean of 22.4 core biopsies.  Prostate cancer was diagnosed in 43 patients (42.2 %) with a Gleason score distribution of 6 to 9.  No anatomical region of the prostate gland was spared of cancer.  In patients with prostate cancer, an average of 9.9 cores were involved.  In multi-variate analysis, prostate volume was the best predictor for prostate cancer diagnosis.  The authors concluded that TTBS diagnosed prostate cancer in 42.2 % of patients.  Considerable anatomical variability in prostate cancer distribution was documented.  They also noted that TTBS “results in promising diagnostic yields for patients with prior negative TRUS biopsies.  However, ideal patient selection, optimal transperineal saturation biopsy technique, number of biopsy cores, and regions to be sampled remains to be clarified”.

Stav et al (2008) evaluated the diagnostic value of saturation prostate biopsy in patients with PSA greater than 10 ng/ml, PSA velocity greater than 0.75 ng/ml/year, free PSA ratio less than 0.2, and at least 3 sets of negative biopsy specimens.  A total of 27 patients underwent the procedure with the use of a transrectal approach under general or regional anesthesia.  A systematic coverage of the peripheral zone (PZ) was accomplished by maintaining a fixed distance between punctures (5 mm).  In addition, multiple cores were obtained from the transition zone bilaterally, bladder neck, and midline according to a strict pre-planned template.  The mean number of cores obtained per patient was 61.7 +/- 9.5 (range of 41 to 76).  Average PSA was 19.4 +/- 8.5 ng/ml (range of 10.1 to 49).  Prostate cancer (Gleason score 3+3) was found in 3 patients (11.1 %).  All 3 patients who received a diagnosis of cancer had minimal disease affecting less than 1 % of a single core sampled from the PZ.  Two patients were designated for watchful waiting and 1 patient chose radical prostatectomy.  His pathologic specimen contained carcinoma of prostate (Gleason 3+3) in less than 1 % of the total prostate volume.  All patients were discharged within 24 hours after the procedure.  Asymptomatic bacteremia was documented in 1 patient.  Two patients had epididymitis develop and were treated conservatively.  The authors concluded that according to their findings, saturation prostate biopsy has low diagnostic yield in patients who previously had at least 3 sets of negative traditional biopsy specimens.  In all the cases that prostate cancer was found, it had histologic features consistent with biologically insignificant disease.

Lane et al (2008) stated that it has been reported that the prostate cancer detection rate in men with PSA 2.5 ng/ml or greater undergoing saturation (20 cores or greater) prostate biopsy as an initial strategy is not higher than that in men who undergo 10 to 12 core prostate biopsy.  At a median follow-up of 3.2 years, these investigators reported the cancer detection rate on subsequent prostate biopsy in men who underwent initial saturation prostate biopsy.  Saturation prostate biopsy was used as an initial biopsy strategy in 257 men between January 2002 and April 2006.  Cancer was initially detected in 43 % of the patients who underwent saturation prostate biopsy.  In the 147 men with negative initial saturation prostate biopsy follow-up including DRE and repeat PSA measurement was recommended at least annually.  Persistently increased PSA or an increase in PSA was seen as an indication for repeat saturation prostate biopsy.  During the median follow-up of 3.2 years after negative initial saturation prostate biopsy 121 men (82 %) underwent subsequent evaluation with PSA and DRE.  Median PSA remained 4.0 ng/ml or greater in 57 % of the men and it increased by 1 ng/ml or greater in 23 %.  Cancer was detected in 14 of 59 men (24 %) undergoing repeat prostate biopsy for persistent clinical suspicion of prostate cancer.  No significant association was demonstrated between cancer detection and initial or follow-up PSA, or findings of atypia and high grade prostatic intra-epithelial neoplasia on initial saturation prostate biopsy.  Cancers detected on repeat prostate biopsy were more likely to be Gleason 6 and organ confined at prostatectomy than were those diagnosed on initial saturation prostate biopsy.  The authors concluded that previous experience suggested that while office-based saturation prostate biopsy improves cancer detection in men who have previously undergone a negative prostate biopsy, it does not improve cancer detection as an initial biopsy technique.  Moreover, false-negative rate on subsequent prostate biopsy after initial saturation prostate biopsy is equivalent to that following traditional prostate biopsy.  These data provide further evidence against saturation prostate biopsy as an initial strategy.

Simon et al (2008) reported the findings of using an extensive saturation biopsy in men with negative prostate biopsies but in whom there is still a clinical suspicion for carcinoma.  A total of 40 patients (median age of 63 years) were offered an extensive saturation biopsy if there was clinical suspicion of prostate cancer after previous negative prostate biopsies.  The median (range) number of cores taken was 64 (39 to 139) and was adjusted to the size of the prostate.  All patients received general or spinal anesthesia.  Of the 40 patients, 18 (45 %) had carcinoma in at least 1 core; 16 had a radical prostatectomy, which showed pT2a, pT2b, pT2c, pT3a and pT3b adenocarcinoma of the prostate in 3, 4, 6, 2 and 1 patients, respectively.  Brachytherapy and external radiation were the therapies of choice in the other patients.  A total of 16 patients had marked hematuria after the biopsy procedure.  The authors concluded that there is no significant increase in the cancer detection rate in an extensive saturation-biopsy regimen compared to published series with fewer cores, but the morbidity increased.

Delongchamps and colleagues (2009) assessed a 36-core saturation biopsy scheme on autopsied prostate glands to estimate the detection rate based on the true cancer prevalence, and compared the cancer features on biopsy with whole-mount pathological analysis, as saturation biopsies have been proposed as a tool to increase the prostate cancer detection rate, and as a staging tool to identify potentially insignificant cancers before surgery.  These investigators took 36-core needle biopsies in 48 autopsied prostates from men who had no history of prostate cancer.  The first 18 cores corresponded to an extended biopsy protocol including 6 cores each in the mid peripheral zone (PZ), lateral PZ and central zone.  An additional 6 cores were then taken in each of these three locations.  They compared the histological characteristics of step-sectioned prostates with the biopsy findings.  Tumors were considered clinically insignificant if they were organ-confined with an index tumor volume of less than 0.5 ml and Gleason score of less than or equal to 6.  The pathological evaluation identified 12 (25 %) cases of prostate cancer and 22 tumor foci; 7 prostate cancers were significant.  Of the 22 tumor foci, 16 (73 %) were in the PZ.  The first 18 cores detected 7 cancers (58 %), of which 5 were clinically significant.  The last 18 cores detected 4 cancers, all of which were already detected by the first 18 cores.  Of the 5 cancers remaining undetected by biopsies, 2 were clinically significant and 3 were insignificant.  Comparison of the histological characteristics between biopsies and step-sectioned prostates showed an over-estimation of Gleason score by saturation biopsies in 3 of 7 cases.  The authors concluded that the evaluation of saturation biopsies based on the true prevalence of prostate cancer showed no increase in detection rate over a less extensive 18-core biopsy.  Also, saturation biopsies might over-estimate the final Gleason score on whole-mount analysis.

Guidelines from the National Comprehensive Cancer Network (NCCN, 2009) state that for men at high risk for prostate cancer and multiple negative biopsies, consideration may be given to a saturation biopsy strategy.  NCCN guidelines recommend, in men with 2 negative extended biopsies, but persistently rising PSA values, a saturation biopsy may be considered.  The NCCN Guidelines cited a study by Stewart et al (2001) that found a prostate cancer detection rate of 34 % in a cohort of patients with an average of 2 previous negative sextant prostate biopsies.

Presti (2009) stated that repeat biopsies should include a minimum of 14 cores, the 12 cores recommended for an initial biopsy and 2 additional cores obtained form the right and left anterior apex.  In patients for whom repeat biopsies fail to identify cancer, yet the clinical suspicion remains high, consideration for a saturation biopsy approach seems warranted.

Scattoni and colleagues (2010) noted that prostate biopsy techniques have significantly changed since the original Hodge's "sextant scheme", which should now be considered obsolete.  The feasibility of performing a biopsy scheme with a high number of cores in an out-patient setting is a result of the great improvement and effectiveness of local anesthesia.  Peri-prostatic nerve block with lidocaine injection should be considered the "gold standard" because it provides the best pain relief to patients undergoing prostate biopsy.  The optimal extended protocol should now include the sextant template with an additional 4 to 6 cores directed laterally (anterior horn) to the base and medially to the apex.  Saturation biopsies (i.e., template with greater than or equal to 20 cores, including transition zone) should be carried out only when biopsies are repeated in patients where there is a high suspicion of prostate cancer.  Complementary imaging methods (e.g., color-Doppler and power-Doppler imaging, with or without contrast enhancement, and elastography) could be used in order to increase the accuracy of biopsy and reduce the number of unnecessary procedures.  However, the routine use of these methods is still under evaluation.

Guidance from the National Instutute for Clinical Excellence (NICE, 2010) states that current evidence on the efficacy of transperineal template biopsy of the prostate shows an increase in diagnostic yield in patients with suspected prostate cancer who have had negative or equivocal results from other biopsy methods.  The guidance states that there are no major safety concerns.  Therefore, this procedure may be used for this indication provided that normal arrangements are in place for clinical governance, consent and audit.

NICE (2010) states that evidence was not found to support the use of transperineal template biopsy of the prostate as a mapping technique to determine the exact location and extent of prostate cancer in order to guide focal therapy, nor as part of an active surveillance regime.  Therefore, the procedure should be used with these intentions only with special arrangements for clinical governance, consent and audit or research.

NCCN guidelines on prostate cancer early detection (2012) state that prostate saturation biospy should be considered for high-risk men with multiple negative biopsies. The guidelines state that, in patients with two negative extended prostate biopsies, yet persistently rising PSA values, a saturation biopsy may be considered.

The know error® DNA Specimen Provenance Assay is a forensic assay to confirm that a surgical specimen belongs to the patient evaluated for treatment.  According to the manufacturer, the know error system features a DNA verification test that is intended to eliminate diagnostic mistakes due to specimen provenance complications. This testing incorporates three steps: 1) before a biopsy procedure, a reference sample of the patient's DNA is taken by swabbing the inside of the patient's cheek; the swab is sent to an independent forensic DNA lab; 2) the patient’s biopsy tissue samples are placed in bar coded specimen containers from the biopsy kit and sent to the pathology lab for evaluation; 3) if the biopsy results come back positive, the forensics lab performs a DNA specimen provenance assignment using genetic microsatellite analysis. This test compares the short tandem repeat profile of the patient's biopsy tissue to the patient's reference sample. The manufacturer explained that concurrence of these short tandem repeat profiles allows the practitioner to rule out specimen provenance complications. Once a DNA test is complete, the forensics lab issues an electronic report. If specimen provenance complications are indicated, the appropriate parties are notified to address the error via a defined protocol. Aetna considers the know error system to be part of the laboratory's quality control for specimens, and is not separately reimbursed.

ConfirmMDx (MDxHealth, Irvine, CA) is an epigenetic assay using multiplex polymerase chain reaction (PCR) to measure DNA methylation of gene regions that are associated with cancer.  It is designed to distinguish patients with prostate cancer who have a true-negative biopsy from those who may have occult cancer.  The test supposedly helps urologists rule-out prostate cancer-free men from undergoing unnecessary repeat biopsies and, helps rule-in high-risk patients who may require repeat biopsies and potential treatment.  However, there is inadequate evidence to support the clinical value of ConfirmMDx in patients with prostate cancer.

Stewart, et al. (2013) reported that ConfirmMDx, a multiplex quantitative methylation specific polymerase chain reaction assay determining the methylation status of GSTP1, APC and RASSF1, was strongly associated with repeat biopsy outcome up to 30 months after initial negative biopsy in men with suspicion of prostate cancer. The investigators blindly tested archived prostate biopsy needle core tissue samples of 498 subjects from the United Kingdom and Belgium with histopathologically negative prostate biopsies, followed by positive (cases) or negative (controls) repeat biopsy within 30 months. Clinical performance of the epigenetic marker panel, emphasizing negative predictive value, was assessed and cross-validated. Multivariate logistic regression was used to evaluate all risk factors. The epigenetic assay performed on the first negative biopsies of this retrospective review cohort resulted in a negative predictive value of 90% (95% CI 87-93). In a multivariate model correcting for patient age, prostate specific antigen, digital rectal examination and first biopsy histopathological characteristics the epigenetic assay was a significant independent predictor of patient outcome (OR 3.17, 95% CI 1.81-5.53). The investigators stated that adding this epigenetic assay could improve the prostate cancer diagnostic process and decrease unnecessary repeat biopsies.

Partin, et al., (2014) reported that the ConfirmMDx epigenetic assay was a significant, independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result. The investigators evaluated the archived, cancer negative prostate biopsy core tissue samples of 350 subjects from a total of 5 urological centers in the United States. All subjects underwent repeat biopsy within 24 months with a negative (controls) or positive (cases) histopathological result. Centralized blinded pathology evaluation of the 2 biopsy series was performed in all available subjects from each site. Biopsies were epigenetically profiled for GSTP1, APC and RASSF1 relative to the ACTB reference gene using quantitative methylation specific polymerase chain reaction. Predetermined analytical marker cutoffs were used to determine assay performance. Multivariate logistic regression was used to evaluate all risk factors. The epigenetic assay resulted in a negative predictive value of 88% (95% CI 85-91). In multivariate models correcting for age, prostate specific antigen, digital rectal examination, first biopsy histopathological characteristics and race the test proved to be the most significant independent predictor of patient outcome (OR 2.69, 95% CI 1.60-4.51). The investigators stated  that adding this epigenetic assay to other known risk factors may help decrease unnecessary repeat prostate biopsies.

Wu and colleagues (2011) noted that PSA screening has low specificity.  Assessment of methylation status in body fluids may complement PSA screening if the test has high specificity.  The purpose of this study was to conduct a meta-analysis of the sensitivity and specificity for prostate cancer detection of glutathione-s-transferase-π (GSTP1) methylation in body fluids (plasma, serum, whole blood, urine, ejaculate, and prostatic secretions).  These researchers conducted a comprehensive literature search on Medline (PubMed).  They included studies if they met all 4 of the following criteria: (i) measurement of DNA methylation in body fluids; (ii) a case-control or case-only design; (iii) publication in an English journal; and (iv) adult subjects.  Reviewers conducted data extraction independently using a standardized protocol.  A total of 22 studies were finally included in this paper.  Primer sequences and methylation method in each study were summarized and evaluated using meta-analyses.  This paper represented a unique cross-disciplinary approach to molecular epidemiology.  The pooled specificity of GSTP1 promoter methylation measured in plasma, serum, and urine samples from negative-biopsy controls was 0.89 (95 % CI: 0.80 to 0.95).  Stratified analyses consistently showed a high specificity across different sample types and methylation methods (include both primer sequences and location).  The pooled sensitivity was 0.52 (95 % CI: 0.40 to 0.64).  The authors concluded that the pooled specificity of GSTP1 promoter methylation measures in plasma, serum, and urine was excellent and much higher than the specificity of PSA.  The sensitivity of GSTP1 was modest, no higher than that of PSA.  They stated that these findings suggested that measurement of GSTP1 promoter methylation in plasma, serum, or urine samples may complement PSA screening for prostate cancer diagnosis.

Van Neste et al (2012a) from the MDxHealth stated that PSA-directed prostate cancer screening leads to a high rate of false-positive identifications and an unnecessary biopsy burden.  Epigenetic biomarkers have proven useful, exhibiting frequent and abundant inactivation of tumor suppressor genes through such mechanisms.  An epigenetic, multiplex PCR test for prostate cancer diagnosis could provide physicians with better tools to help their patients.  Biomarkers like GSTP1, APC and RASSF1 have demonstrated involvement with prostate cancer, with the latter 2 genes playing prominent roles in the field effect.  The epigenetic states of these genes can be used to assess the likelihood of cancer presence or absence.  An initial test cohort of 30 prostate cancer-positive samples and 12 cancer-negative samples was used as basis for the development and optimization of an epigenetic multiplex assay based on the GSTP1, APC and RASSF1 genes, using methylation specific PCR (MSP).  The effect of prostate needle core biopsy sample volume and age of formalin-fixed paraffin-embedded (FFPE) samples was evaluated on an independent follow-up cohort of 51 cancer-positive patients.  Multiplexing affects copy number calculations in a consistent way per assay.  Methylation ratios are therefore altered compared to the respective singleplex assays, but the correlation with patient outcome remains equivalent.  In addition, tissue-biopsy samples as small as 20 μm can be used to detect methylation in a reliable manner.  The age of FFPE-samples does have a negative impact on DNA quality and quantity.  The authors concluded that the developed multiplex assay appears functionally similar to individual singleplex assays, with the benefit of lower tissue requirements, lower cost and decreased signal variation.  This assay can be applied to small biopsy specimens, down to 20 microns, widening clinical applicability.  Increasing the sample volume can compensate the loss of DNA quality and quantity in older samples.

Van Neste et al (2012b) noted that prostate cancer is the most common cancer diagnosis in men and a leading cause of death.  Improvements in disease management would have a significant impact and could be facilitated by the development of biomarkers, whether for diagnostic, prognostic, or predictive purposes.  The blood-based prostate biomarker PSA has been part of clinical practice for over 2 decades, although it is surrounded by controversy.  While debates of usefulness are ongoing, alternatives should be explored.  Particularly with recent recommendations against routine PSA-testing, the time is ripe to explore promising biomarkers to yield a more efficient and accurate screening for detection and management of prostate cancer.  Epigenetic changes, more specifically DNA methylation, are among the most common alterations in human cancer.  These changes are associated with transcriptional silencing of genes, leading to an altered cellular biology.  One gene in particular, GSTP1, has been widely studied in prostate cancer.  Thus, a meta-analysis has been conducted to examine the role of this and other genes and the potential contribution to prostate cancer management and screening refinement.  More than 30 independent, peer-reviewed studies have reported a consistently high sensitivity and specificity of GSTP1 hyper-methylation in prostatectomy or biopsy tissue.  The meta-analysis combined and compared these results.  The authors concluded that GSTP1 methylation detection can serve an important role in prostate cancer management.  The meta-analysis clearly confirmed a link between tissue DNA hyper-methylation of this and other genes and prostate cancer.  They stated that detection of DNA methylation in genes, including GSTP1, could serve an important role in clinical practice.

Andres et al (2013) synthesized the principal advances in the field of the study of epigenetics and specifically DNA methylation regarding the diagnosis of urological neoplasms.  Review of the literature (PubMed, MEDLINE y COCHRANE) on the study of DNA methylation in urological neoplasms (prostate cancer, bladder cancer, renal cancer and testicular cancer), considering all the studies published up to January 2013 was carried out.  It was possible to determine the state of methylation of many genes in tumor samples.  When these were compared with healthy tissue samples, it was possible to define the specific aberrant methylation patterns for each type of tumor.  The study and definition of specific abnormal methylation patterns of each type of tumor is a tool having potential utility for diagnosis, evaluation, prediction of prognosis and treatment of the different forms of genito-urinary cancer.  The analysis of gene methylation in urine after micturition or post-prostatic massage urine, semen, in the wash plasma or fluid from prostatic biopsies may allow early detection of bladder, prostate, renal and testicular cancer.  In each of the neoplasms, an epigenetic signature that may be detected in the DNA has been identified, obtained from very scarce or not at all invasive specimens, with potential in the diagnosis and evaluation of prognosis.  Validation of these studies will confirm the accuracy, effectiveness, and reproducibility of the results available up to now.  Criteria have still not been developed that determine if a gene panel provides sufficient information in the health care practice to guide an unequivocal diagnosis or therapeutic conduct.  More studies are needed to compare sensitivity, specificity, positive- and negative-predictive values of the test in each case.  Multi-center studies analyzing the real reproducibility of these results in a clinical setting also do not exist.  The authors concluded that the study of aberrant DNA methylation in biological specimens of patients has an enormous potential for the early diagnosis and screening of genitourinary neoplasms.  They stated that more studies are needed to define the series of genes that would mean unequivocal signatures of malignancy.  This methodology also has potential when defining prognostic groups and potential of response to different therapies

Lin et al (2013) prostate cancer is the second leading cause of cancer death among men worldwide, and not all men diagnosed with prostate cancer will die from the disease.  A critical challenge, therefore, is to distinguish indolent prostate cancer from more advanced forms to guide appropriate treatment decisions.  These investigators used Enhanced Reduced Representation Bisulfite Sequencing, a genome-wide high-coverage single-base resolution DNA methylation method to profile seven localized prostate cancer samples, 7 matched benign prostate tissues, and 6 aggressive castration-resistant prostate cancer (CRPC) samples.  They integrated these data with RNA-seq and whole-genome DNA-seq data to comprehensively characterize the prostate cancer methylome, detect changes associated with disease progression, and identify novel candidate prognostic biomarkers.  The analyses revealed the correlation of cytosine guanine dinucleotide island (CGI)-specific hyper-methylation with disease severity and association of certain breakpoints (deletion, tandem duplications, and inter-chromosomal translocations) with DNA methylation.  Furthermore, integrative analysis of methylation and single-nucleotide polymorphisms (SNPs) uncovered widespread allele-specific methylation (ASM) for the first time in prostate cancer.  These researchers found that most DNA methylation changes occurred in the context of ASM, suggesting that variations in tumor epigenetic landscape of individuals are partly mediated by genetic differences, which may affect prostate cancer disease progression.  They further selected a panel of 13 CGIs demonstrating increased DNA methylation with disease progression and validated this panel in an independent cohort of 20 benign prostate tissues, 16 prostate cancer a, and 8 aggressive CRPCs.  The authors concluded that these results warrant clinical evaluation in larger cohorts to help distinguish indolent prostate cancer from advanced disease.

Wojno and colleagues (2014) reported on an observational study that suggests that the ConfirmMDx may reduce biopsy rates in persons suspected of having prostate cancer. The investigators noted that the diagnosis of PCa is dependent on histologic confirmation in biopsy core tissues. The biopsy procedure is invasive, puts the patient at risk for complications, and is subject to significant sampling errors. The authors stated that an epigenetic test that uses methylation-specific PCR to determine the epigenetic status of the PCa-associated genes GSTP1, APC, and RASSF1 has been clinically validated and is used in clinical practice to increase the negative predictive value (NPV) in men with no history of PCa compared with standard histopathology. The investigators stated that such information can help to avoid unnecessary repeat biopsies.  The investigators posited that the repeat biopsy rate may provide preliminary clinical utility evidence in relation to this assay's potential impact on the number of unnecessary repeat prostate biopsies performed in U.S. urology practices.  The investigators stated that the purpose of this preliminary study was to quantify the number of repeat prostate biopsy procedures to demonstrate a low repeat biopsy rate for men with a history of negative histopathology who received a negative epigenetic assay result on testing of the residual prostate tissue.  In this field observation study, practicing urologists used the ConfirmMDx for PCa to evaluate cancer-negative men considered at risk for PCa. The authors stated that his test has been previously validated in 2 blinded multi-center studies that showed the superior NPV of the epigenetic test over standard histopathology for cancer detection in prostate biopsies. A total of 5 clinical urology practices that had ordered a minimum of 40 commercial epigenetic test requisitions for patients with previous, cancer-negative biopsies over the course of the previous 18 months were contacted to assess their interest to participate in the study.  Select demographic and prostate-screening parameter information, as well as the incidence of repeat biopsy, specifically for patients with a negative test result, was collected and merged into 1 collective database.  All men from each of the 5 sites who had negative assay results were included in the analysis.  A total of 138 patients were identified in these urology practices and were included in the analysis.  The median age of the men was 63 years, and the current median serum PSA level was 4.7 ng/ml.  Repeat biopsies had been performed in 6 of the 138 (4.3 %) men with a negative epigenetic assay result, in whom no evidence of cancer was found on histopathology.  The authors concluded that in this study, a low rate of repeat prostatic biopsies was observed in the group of men with previous histopathologically negative biopsies who were considered to be at risk for harboring cancer.  The data suggested that patients managed using the ConfirmMDx for PCa negative results had a low rate of repeat prostate biopsies.  Moreover, they stated that these results warrant a large, controlled, prospective study to further evaluate the clinical utility of the epigenetic test to lower the unnecessary repeat biopsy rate.

An UpToDate review on “Prostate biopsy” (Benway and Andriole, 2013) as well as the NCCN’ clinical practice guideline on “Prostate cancer” (Version 3.2013) do not mention the use of ConfirmMDx/epigenetic assay.

Nelson et al (2013) stated that there is no consensus on how to investigate men with negative transrectal ultrasound guided prostate biopsy (TRUS-B) but ongoing suspicion of cancer.  Three strategies used are (i) transperineal (TP-B), (ii) transrectal saturation (TS-B) and (iii) MRI-guided biopsy (MRI-B).  These researchers compared cancer yields of these strategies.  Papers were identified by search of PubMed, Embase and Ovid Medline.  Included studies investigated biopsy diagnostic yield in men with at least 1 negative TRUS-B and ongoing suspicion of prostate cancer (PCa).  Data including age, PSA, number of previous biopsy episodes, number of cores at re-biopsy, cancer yield, and Gleason score of detected cancers were extracted.  Meta-regression analyses were used to analyze the data.  A total of 46 studies were included; 12 of TS-B, 14 of TP-B, and 20 of MRI-B, representing 4,657 patients.  Mean patient age, PSA and number of previous biopsy episodes were similar between the strategies.  The mean number of biopsy cores obtained by TP-B and TS-B were greater than MRI-B.  Cancer detection rates were 30.0 %, 36.8 %, and 37.6 % for TS-B, TP-B, and MRI-B, respectively.  Meta-regression analysis showed that MRI-B had significantly higher cancer detection than TS-B.  There were no significant differences however between MRI-B and TP-B, or TP-B and TS-B.  In a sensitivity analysis incorporating number of previous biopsy episodes (36 studies) the difference between MRI-B and TP-B was not maintained resulting in no significant difference in cancer detection between the groups.  There were no significant differences in median Gleason scores detected comparing the 3 strategies.  The authors concluded that in the re-biopsy setting, it is unclear which strategy offers the highest cancer detection rate.  MRI-B may potentially detect more prostate cancers than other modalities and can achieve this with fewer biopsy cores.  However, they stated that well-designed prospective studies with standardized outcome measures are needed to accurately compare modalities and define an optimum re-biopsy approach.

Li and associates (2014) identified the ability of transrectal saturation prostate biopsy (SPBx) as the initial diagnostic approach to reduce the likelihood of finding previously unrecognized PCa during repeat prostate biopsy.  These investigators reviewed PCa detection in 561 men who underwent 1st repeat SPBx after initial negative biopsy between March 2002 and April 2012.  They divided the patients on the basis of the number of cores retrieved on initial biopsy (group 1, initial negative SPBx [n = 81] and group 2, initial negative extended prostate biopsy [n = 480]).  The yield of repeat SPBx was compared between the 2 groups.  Insignificant PCa and low-risk PCa were defined according to Epstein criteria and D'Amico risk criteria, respectively.  Prostate cancer detection on 1st repeat SPBx was 43.1 % lower in group 1 (19.8 % versus 34.8 %; p = 0.008).  Moreover, lower rate of significant PCa (31.3 % versus 74.3 %; p < 0.001) and intermediate- and/or high-risk PCa (25.0 % versus 50.9 %; p = 0.048) in group 1.  Multi-variate analysis confirmed that initial negative SPBx decreased PCa detection on 1st repeat SPBx (odds ratio [OR] = 0.41, 95 % CI: 0.22 to 0.78).  The authors concluded that men whose initial biopsy was per transrectal saturation technique were less likely to have cancer identified during repeat biopsy.  Furthermore, PCa diagnosed after negative initial SPBx was much more likely to be clinically insignificant.  These findings suggested that SPBx may be less likely to miss clinically significant cancer during initial prostate biopsy.  They stated that if confirmed in other studies, this suggests that initial biopsy by saturation technique may eliminate the need for most men to undergo repeat biopsy.

Thompson et al (2014) examined if saturation or transperineal biopsy altered medium-term oncologic outcomes compared with standard transrectal biopsy in active surveillance (AS) for low-risk PCa.  These researchers performed a retrospective analysis of prospectively collected data from 2 cohorts with localized PCa (1998 to 2012) undergoing AS.  Prostate cancer-specific, metastasis-free and treatment-free survival, unfavorable disease and significant cancer at RP were compared for standard (6 to 12 core, median of 10) versus saturation (greater than 12 core, median of 16), and transrectal versus transperineal biopsy, using multi-variate analysis.  A total of 650 men were analyzed; median (mean) follow-up of 55 (67) months.  Prostate cancer-specific, metastasis-free and BCR-free survival were 100 %, 100 % and 99 %, respectively.  Radical treatment-free survival at 5 and 10 years were 57 % and 45 % respectively (median time to treatment of 7.5 years).  On KM analysis, saturation biopsy was associated with increased objective biopsy progression requiring treatment (log rank x2 = 5.87, p = 0.01).  On multi-variate pH analysis, saturation biopsy (HR = 1.68, p < 0.01) but not transperineal approach (p = 0.89) was associated with increased objective biopsy progression requiring treatment.  On logistic regression analysis of 179 men who underwent RP for objective progression, transperineal biopsy was associated with lower likelihood of unfavorable RP pathology (OR = 0.42, p = 0.03) but saturation biopsy did not alter the likelihood (p = 0.25).  Neither transperineal nor saturation biopsy altered the likelihood of significant versus insignificant cancer at RP (p = 0.19 and p = 0.41, respectively).  The authors concluded that active surveillance achieved satisfactory oncologic outcomes.  They stated that saturation biopsy increased progression to treatment on AS; longer follow-up is needed to determine if this represents beneficial earlier detection of significant disease or over-treatment.  Transperineal biopsy reduced the likelihood of unfavorable disease at RP, possibly due to earlier detection of anterior tumors.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
55706
CPT Codes not covered for indications listed in the CPB:
88237
88275
Other CPT codes related to the CPB:
55700
84152
84153
84154
HCPCS codes covered if selection criteria are met:
G0416 - G0419 Surgical pathology, gross and microscopic examinations, for prostate needle biopsy, any method
Other HCPCS codes related to the CPB:
G0102 Prostate cancer screening; digital rectal examination
G0103 Prostate cancer screening; prostate specific antigen test (PSA)
ICD-9 codes covered if selection criteria are met:
233.4 Carcinoma in situ of prostate [PIN III]
602.3 Dysplasia of prostate [PIN I or II]
Other ICD-9 codes related to the CPB:
185 Malignant neoplasm of prostate [ConfirmMDx]
198.82 Secondary malignant neoplasm of genital organs
222.2 Benign neoplasm of prostate
236.5 Neoplasm of uncertain behavior of prostate
600.00 - 602.2 Hyperplasia of prostate, inflammatory diseases of prostate, or other disorders of prostate
602.8-602.9 Other specified and unspecified disorders of the prostate
788.20 - 788.29 Retention of urine
788.41 - 788.43 Frequency of urination and polyuria
788.62 Slowing of urinary stream
788.63 Urgency of urination
790.93 Elevate prostate specific antigen, [PSA] [ConfirmMDx]
V10.46 Personal history of malignant neoplasm of prostate
V16.42 Family history of malignant neoplasm of prostate
V76.44 Special screening for malignant neoplasm of prostate
V84.03 Genetic susceptibility to malignant neoplasm of prostate


The above policy is based on the following references:
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