Coverage Indications, Limitations, and/or Medical Necessity

Noridian will provide limited coverage for the Prolaris™ prostate cancer assay (Myriad, Salt Lake City, UT) to help determine which patients with early stage, needle biopsy proven prostate cancer, can be conservatively managed rather than treated with definitive surgery or radiation therapy.

Background

In 2014, nearly 233,000 men in the US will be diagnosed with prostate cancer, which accounts for 14% of all new cancer diagnosis. More than 29,000 men will die from this disease representing 5% of all cancer deaths. Gratefully 98.9% of men are surviving at 5 years.

Many individuals do not need treatment for their prostate cancer in as much as their prognosis is excellent even without treatment. However, physicians and patients struggle to know who can safely be observed versus the subgroup that needs more aggressive treatment to achieve cure, and recognize that definitive treatment for localized prostate cancer can have lifelong morbidities.

Traditionally, clinicopathologic characteristics are utilized to determine risk and subsequent treatment. Several nomograms have been introduced to try to determine who is at risk of developing metastatic disease and who, if treated early, could avoid this outcome. A representative one taken from the NCCN (and AUA), divides early prostate cancer into several groups based initially on life expectancy, with a second stratification using clinical exam, reassessment of life expectancy, biopsy (Gleason score), PSA and imaging.

These groups are detailed below:

Risk Category

Very Low Low Intermediate High
Clinicopathologic Findings
T1c AND
Gleason score = 6 AND
PSA = 10 ng/mL AND
< 3 prostate cores with tumor AND
= 50% tumor in any core AND
PSA density of < 0.15 ng/mL/g
T1-T2a AND
Gleason score = 6 AND
PSA = 10 ng/mL
T2b-T2c OR
Gleason score = 7 OR
PSA 10-20 ng/mL
T3a OR
Gleason Score 8-10 OR

PSA > 20 ng/mL
Treatment Options
= 20 y life expectancy
Active Surveillance
RT or Brachy
RP (± LND)
= 10 y life expectancy
Active Surveillance
Active Surveillance
RT or Brachy
RP (± LND
RP (± LND)
RT or Brachy ± Adj Horm
RT + Adj Horm
RT + Brachy
RP + LND ± RT, ADT
< 10 y life expectancy
Observation
Observation
RT or Brachy ± Adj Horm
Observation
N/A

Table 1: NCCN 2014 V2 – Localized Prostate Cancer Risk Stratification and Treatment (PSA – Prostate Specific Antigen; RT – Radiation Therapy; RP – Radical Prostatectomy; LND – lymph node dissection; Adj Horm – Adjuvant Androgen Deprivation)

Use of these stratification and treatment approaches has led to high cure rates for early stage prostate cancer. Yet it is widely accepted that many men are over-treated to achieve the cure rate. In the PIVOT trial men with early prostate cancer, initially randomized to radical prostectomy or observation, showed that over 12 years there was no difference in absolute mortality between the groups. However, this study was hampered by several problems including:
Only 731 of 5023 eligible patients chose to participate in the study based on randomization criteria.

In the group randomized to RP: only 85% of the men received definitively therapy (79% surgery; 6% other).

In the observational group: 10% of the observation group received RP initially and additional 20% eventual received definitive treatment.

Despite broad inclusion criteria, > 50% of patients had a PSA of <10 30="" 40="" 7="" a="" although="" and="" as="" being="" biopsy="" classified="" disease.="" gleason="" had="" initially="" intermediate.="" low="" median="" men="" number="" of="" p="" patients="" proven="" psa="" risk="" score="7" significant="" t1c="" there="" were="" with="">

Although subgroups were small, it appears that high-risk groups (including those with PSA > 10) benefitted from RP. Furthermore, there was a trend for the intermediate risk patients to benefit from RP as well. The small number of patients willing to enter the study, and the high rate of crossover (both initially and subsequently) demonstrates the difficulty of doing observation trials in the United States.

Prolaris™ Prostate Cancer Assay

Test Description

Prolaris™ is an RNA based assay measuring the expression of 31 cell cycle progression (CCP) genes and 15 “housekeeping” genes that act as internal controls and normalization standards in each patient sample. The assay is performed on formalin fixed paraffin-embedded (FFPE) prostate cancer blocks. The assay results are reported as a numerical score along with accompanying interpretive information.

Test Performance

The clinical performance of this assay was assessed in several retrospective validation studies. These include two British cohorts of men diagnosed with prostate cancer on biopsy and then treated conservatively; and an additional cohort of men diagnosed by TURP and conservatively managed. Further validation was performed in various other cohorts including men who underwent radical prostatectomy, and men treated with definitive radiotherapy. The Prolaris™ cell cycle progression score (CCP) was found to be an independent and more robust prognostic factor for disease related death than traditional clinicopathologic factors although disease stage and Gleason score consistently portended a more negative prognostic picture.

Due to the difficulty in obtaining prospective data in early prostate cancer (outcomes take decades to develop, hard to accrue patients to a conservatively managed arm in the US), and given the unmet need, clinical utility can be extrapolated from this retrospective data. Doing so is not without shortcomings. It is unclear how the British cohorts were followed or who went on to receive definitive therapy inside the observation groups. The U.K. standard of care for treating these prostate cancer patients is different. In the U.S. conservatively managed patients is not the common occurrence. Furthermore, the long time period to determine outcomes and the lack of tissue specimens make review of a U.S. cohort unlikely if not impossible for many years.

In several of the published cohorts including the conservatively managed patients, multivariate analysis identified CCP score and Gleason score as the only values that consistently identify increased risk of death from prostate cancer. It also should be noted that the cancer related death rate in these retrospective studies of conservatively managed patients was much greater than would be expected in the United States with 19.3% of the patients with the lowest CCP succumbing to disease. Subset analysis suggests that if the patients with higher risk disease (Gleason score > 7; higher stage) had received definitive treatment (like the current standard in the US) the rate succumbing to disease would likely be substantially better.

The potential usefulness of this test is that it allows physicians to determine which patients with early prostate cancer are candidates for active surveillance or observation and are more likely to have a good outcome without needing to receive definitive treatment.

Criteria for Coverage

The Prolaris™ assay is covered only when the following clinical conditions are met:
Needle biopsy with localized adenocarcinoma of prostate (no clinical evidence of metastasis or lymph node involvement), and
FFPE prostate biopsy specimen with at least 0.5 mm of cancer length, and
Patient Stage as defined by the one of the following:
Very Low Risk Disease (T1c AND Gleason Score = 6 AND PSA = 10 ng/mL AND <3 0.15="" and="" any="" cancer="" core="" cores="" density="" g="" in="" ml="" ng="" of="" or="" p="" prostate="" psa="" tumor="" with="">Low Risk Disease (T1-T2a AND Gleason Score = 6 AND PSA = 10 ng/mL), and

Patient has an estimated life expectancy of greater than or equal to 10 years, and
Patient is a candidate for and is considering conservative therapy and yet and would be eligible for definitive therapy (radical prostectomy, radiation therapy or brachytherapy), and
Result will be used to determine treatment between definitive therapy and conservative management, and
Patient has not received pelvic radiation or androgen deprivation therapy prior to the biopsy, and
Test is ordered by a physician certified in the Myriad Prolaris™ Certification and Training Registry (CTR), and
Patient is monitored for disease progression according to established standard of care, and
Physician must report the development of prostate cancer metastasis or prostate cancer deaths in patients not treated definitively who were deemed low risk by the assay.

Certification and Training Registry (CTR) Program

Because of the complicated nature of management decisions utilizing the Prolaris™ assay and the potential for adverse harm to patients if the test is not used appropriately, testing must be furnished only by physicians who are enrolled in a MolDx approved Myriad Prolaris™ CTR program. This serves to assure the appropriate selection of patients, compliance with management decisions and stringent follow up to ensure the benefits of the test outweigh its risks. As part of this requirement Myriad will provide to the MolDX Contractor reports every 6 months in a mutually agreed upon format.

The goals of the Myriad Prolaris™ CTR program are as follows:
To ensure that physicians understand the limitations of the test based on its validation through retrospective and non-U.S. standards of care studies, and
To inform prescribers and patients on the safe-use conditions for Prolaris™, and
Make a good faith effort to identify any safety concerns from the use of the test

Noridian expects Myriad to:
Establish and maintain the Prolaris™ Certification and Training Registry (CTR);

Ensure that healthcare providers who order the Prolaris™ score are registered and certified in the Prolaris™ CTR program and that the Prolaris™ assay is available only through these providers;

Maintain a secure registry database of Myriad Prolaris™ CTR providers;

Report utilization data by clinicopathologic staging;

Immediately report any prostate cancer metastases or prostate cancer related deaths in patients who did not receive definitive therapy and were Prolaris™ low risk;

Share all required data and reports in a HIPAA complaint fashion

Changes/Expectations for Coverage

Expanded coverage to higher risk cohorts (intermediate or high) would require inclusion of the Prolaris™ assay in a widely accepted treatment guideline (such as AUA, NCCN or ASCO), or through successful development of outcome data through published prospective or prospective-retrospective trials showing a favorable clinical outcome (i.e. non-inferiority of non-definitively treated patients).

Group 1 Codes:
81479 UNLISTED MOLECULAR PATHOLOGY PROCEDURE

Coverage Indications, Limitations, and/or Medical Necessity

Noridian will provide limited coverage for the Oncotype DX® Prostate Cancer Assay (Genomic Health™) to help determine which patients with early stage, needle biopsy proven prostate cancer, can be conservatively managed rather than treated with definitive surgery or radiation therapy.

Background

In 2014, nearly 233,000 men in the US will be diagnosed with prostate cancer, which accounts for 14% of all new cancer diagnosis. More than 29,000 men will die from this disease representing 5% of all cancer deaths. Gratefully 98.9% of men are surviving at 5 years (SEER).

Many individuals do not need treatment for their prostate cancer in as much as their prognosis is excellent even without treatment. However, physicians and patients struggle to know who can safely be observed versus the subgroup that needs more aggressive treatment to achieve cure, and recognize that definitive treatment for localized prostate cancer can have lifelong morbidities (Resnick 2013).

Traditionally, clinicopathologic characteristics are utilized to determine risk and subsequent treatment. Several nomograms have been introduced to try to determine who is at risk of developing metastatic disease and who, if treated early, could avoid this outcome. A representative nomogram taken from the NCCN (and AUA), divides early prostate cancer into several groups based initially on life expectancy, with a second stratification using clinical exam, reassessment of life expectancy, biopsy (Gleason score), PSA and imaging after 5 years.

These groups are detailed below:

Risk Category

Very Low Low Intermediate High
Clinicopathologic Findings
T1c AND
Gleason score = 6 AND
PSA = 10 ng/mL AND
< 3 prostate cores with tumor AND
= 50% tumor in any core AND
PSA density of < 0.15 ng/mL/g
T1-T2a AND
Gleason score = 6 AND
PSA = 10 ng/mL
T2b-T2c OR
Gleason score = 7 OR
PSA 10-20 ng/mL
T3a OR
Gleason Score 8-10 OR

PSA > 20 ng/mL
Treatment Options
= 20 y life expectancy
Active Surveillance
RT or Brachy
RP (± LND)
= 10 y life expectancy
Active Surveillance
Active Surveillance
RT or Brachy
RP (± LND
RP (± LND)
RT or Brachy ± Adj Horm
RT + Adj Horm
RT + Brachy
RP + LND ± RT, ADT
< 10 y life expectancy
Observation
Observation
RT or Brachy ± Adj Horm
Observation
N/A

Table 1: NCCN 2015 V1 – Localized Prostate Cancer Risk Stratification and Treatment (PSA – Prostate Specific Antigen; RT – Radiation Therapy; RP – Radical Prostatectomy; LND – lymph node dissection; Adj Horm – Adjuvant Androgen Deprivation) (PSA – Prostate Specific Antigen; RT – Radiation Therapy; RP – Radical Prostatecomty; LND – lymph node dissection; Adj Horm – Adjuvant Androgren Deprivation)

Use of these stratification and treatment approaches has led to high cure rates for early stage prostate cancer, yet it is widely accepted that many men are over-treated to achieve this cure rate. In the PIVOT trial (Wilt 2012) men with early prostate cancer, initially randomized to radical prostatectomy or observation, showed that over 12 years there was no difference in absolute mortality between the groups. However, this study was hampered by several factors including:
Only 731 of 5023 eligible patients chose to participate in the study based on randomization criteria.
In the group randomized to RP: only 85% of the men received definitively therapy (79% surgery; 6% other).
In the observational group: 10% of the observation group received RP initially and additional 20% eventual received definitive treatment.
Despite broad inclusion criteria, >50% of patients had a PSA of <10 7="" a="" although="" and="" biopsy="" disease.="" gleason="" had="" median="" number="" of="" patients="" proven="" psa="" score="" significant="" t1c="" there="" were="" with="">= 7 (25%), 40% of men were classified initially as being low risk; and 30% were intermediate.

Although subgroups were small, it appears that high-risk groups (including those with PSA > 10) benefitted from RP. Furthermore, there was a trend for the intermediate risk patients to benefit from RP as well. The small number of participants to eligible study patients, and the high rate of crossover (both initially and subsequently) demonstrate the difficulty of doing observation trials in the United States.

Although there is early data that may suggest that some patients with intermediate risk prostate cancer could potentially be considered for active surveillance (AS) (Gleason Score 3+4 = 7, PSA < 10), the NCCN and other mainstream groups still do not recommend this approach, with the NCCN stating, “Active surveillance of intermediate and high-risk clinically localized cancers is not recommended in patients with life expectancy = 10 years as a category 1 recommendation.

Oncotype DX® Prostate Cancer Assay Prostate Cancer Assay


Test Description

Oncotype DX® Prostate Cancer Assay is prostate biopsy-based 17-gene RT-PCR assay, representing four molecular pathways (androgen signaling, cellular organization, stromal response and proliferation), that provides a biologic measure of cancer aggressiveness. The assay is indicated for men who are considered candidates for active surveillance (AS) (those with NCCN® very low- and low-risk prostate cancer). The assay is designed to inform decisions between AS and immediate treatment.

Test Performance

The clinical performance of this assay was assessed in several validation studies. The first was a prospective-retrospective study conducted in a contemporary fit-for-purpose cohort of 395 prostate cancer patient with NCCN very low-, low- and intermediate-risk disease who were considered candidates for AS but who had opted to have radical prostatectomy at a university center from 1997-2011. The objectives were to validate the Genomic Prostate Score (GPS) as a predictor of adverse pathology (AP) at radical prostatectomy, a hallmark of aggressive disease, and to determine whether the GPS added independent predictive information beyond standard clinical and pathologic data. The assay was successfully performed in 96% of needle biopsy specimens. Ninety-nine point five percent (99.5%) of samples with =10 ng/m; RNA yielded a GPS result. Per the pre-specified primary analysis, the GPS was a significant predictor of AP (p=0.002). While conventional clinical risk assessment tools stratified risk, the incorporation of the GPS identified the wide range of biologic risk within each conventional (NCCN and CAPRA) risk group. In multivariable analysis, the GPS was found to predict AP at radical prostatectomy (RP), even after accounting for several standard clinical risk factors (biopsy GS, clinical T-stage, baseline PSA and age). Further analyses showed that by incorporating the GPS results with previously defined clinical risk assessment tools (NCCN, CAPRA), more patient were identified with very low- and low-risk biologic potential and as appropriate candidates for AS. Together, the GPS and the NCCN risk group provide a more accurate prediction of AP.

For the second clinical validation study, a large cohort with a high proportion of African-American men (20%) in the Center for Prostate Disease Research (CPDR) multi-center longitudinal study was identified to test the association of GPS with tumor aggressiveness. Three endpoints for tumor aggressiveness were measured: AP at surgery (actionable); biochemical recurrence (BCR), longer-term; and metastasis (longer-term). This prospective-retrospective study included 402 men with NCCN very low-, low- and intermediate-risk prostate cancer treated with RP at two US military medical centers between 2007-2011. In pre-planned, univariate analyses, GPS was validated as a significant predictor of BCR (primary objective) and confirmed as a significant predictor of AP (first secondary objective) after adjustment for biopsy GS. In addition, while there were very few metastatic events in this low- to intermediate-risk population (n=5 events), there was a strong association of GPS with metastatic recurrence. In multivariable analyses, GPS continued to be strongly associated with BCR and AP after adjustment for NCCN risk group, indicating that GPS adds value beyond standard clinico-pathologic features. A broad and overlapping range of GPS values was observed within each NCCN risk group, age quartile, and racial group. Importantly, GPS distribution, median values, and association of GPS with aggressive prostate cancer outcomes were similar between African-American and Caucasian men.

The incorporation of GPS into risk assessment for AP improved the AUC from 0.63 (NCCN alone) to 0.72 (GPS and NCCN) within the subset with biopsy GS 3+3 and low-volume 3+4 disease, and the AUC for NCCN alone was 0.60 compared with 0.69 by adding GPS (p=0.001). For BCR, the risk profile curve demonstrates a wide range of five-year risk of BCR as GPS increases. The incorporation of GPS improved the c-statistic for NCCN from 0.59 (NCCN alone) to 0.68. The AUC with the use of NCCN risk stratification alone ranges between 0.09 and 0.13. The additional improvement in AUC when GPS is used together with NCCN is 0.09 in all of the above comparisons. Thus, when GPS is combined with NCCN, the AUC, or c-statistics, are improved by a comparable amount to the improvement observed with NCCN alone.

The potential usefulness of this test is that it allows physicians to determine which patients with early prostate cancer are candidates for active surveillance and are more likely to have a good outcome without needing to receive definitive treatment.

Criteria for Coverage

The Oncotype DX® Prostate Cancer Assay is covered only when the following clinical conditions are met:
Needle biopsy with localized adenocarcinoma of prostate (no clinical evidence of metastasis or lymph node involvement), and
Patient stage as defined by the one of the following:
Very Low Risk Disease (T1c AND Gleason Score = 6 AND PSA = 10 ng/mL AND <3 0.15="" and="" any="" cancer="" core="" cores="" density="" g="" in="" ml="" ng="" of="" or="" p="" prostate="" psa="" tumor="" with="">Low Risk Disease (T1-T2a AND Gleason Score = 6 AND PSA = 10 ng/mL),Patient has an estimated life expectancy of = 10 years, and
Patient has a life expectancy of 10-20 years,
Patient is a candidate for and is considering conservative therapy and yet and would be eligible for definitive therapy (radical prostatectomy, radiation therapy or brachytherapy), and
Patient has not received pelvic radiation or androgen deprivation therapy prior to the biopsy, and
Test is ordered by a physician certified in the Genomic Health™ Oncotype DX® Prostate Cancer Assay Certification and Training Registry (CTR), and
Patient is monitored for disease progression according to active surveillance guidelines as recorded in NNCN guidelines, and
Physician must report the development of metastasis or prostate cancer deaths in patients not treated definitively who were deemed low risk by the assay.

Certification and Training Registry (CTR) Program

Because of the complicated nature of management decisions utilizing the Oncotype DX® Prostate Cancer Assay and the potential for adverse harm to patients if the test is not used appropriately, testing must be furnished only by physicians who are enrolled in a MolDX approved Genomic Health™ Oncotype DX® Prostate Cancer Assay CTR program. This serves to assure the appropriate selection of patients, compliance with management decisions and stringent follow up to ensure the benefits of the test outweigh its risks. As part of this requirement Genomic Health™ will provide to Palmetto GBA reports every 6 months in a mutually agreed upon format.

The goals of the Genomic Health™ Oncotype DX® Prostate Cancer Assay CTR program are as follows:
To ensure that physicians understand the limitation of the test based on its validation , , and
To inform prescribers and patients on the safe-use conditions for Oncotype DX® Prostate Cancer Assay™, and
Make a good faith effort to identify any safety concerns from the use of the test, and
Facilitate understanding of the incremental clinical utility of the test versus adherence to current NCCN guidelines.

Noridian expects Genomic Health™ to:
Establish and maintain the Oncotype DX® Prostate Cancer Assay Certification and Training Registry (CTR);
Ensure that healthcare providers who order the Oncotype DX® Prostate Cancer Assay score are registered and certified in the Oncotype DX® Prostate Cancer Assay CTR program and that the Oncotype DX Prostate Cancer Assay is available only through these providers;
Maintain a secure registry database of Genomic Health™ Oncotype DX® Prostate Cancer Assay CTR providers and obtain from referring physicians;
NCCN risk group and treatment recommendation based on current NCCN guidelines prior to receipt of test result;
Test result (i.e., GPS + NCCN risk group), and
Treatment recommendation based on test results, and
Physician-patient treatment decision, and
Report utilization data by clinico-pathologic staging;
Any subsequent change in patient or physician treatment decision, even if the patient has not progressed, and
Immediately report (for patients not treated definitively who were deemed very low or low risk by the assay:
Progression as defined by current NCCN guidelines for patients on AS, or
Development of metastases, or
Prostate cancer deaths.
Share all required data and reports in a HIPAA complaint fashion.