Appeal type: Medical necessity
Decision: Upheld

Prostate Cancer
Genetic Testing

The patient is a male who underwent a prostate biopsy for an elevated prostate-specific antigen (PSA). The biopsy showed Gleason 6 adenocarcinoma in 1 out of 12 cores. The clinical stage was T1c. An Oncotype DX test was ordered on the biopsy specimens. 

The subject under review is the medical necessity of the testing.

The health plan's determination is upheld.

The Oncotype DX testing is not medically necessary for this patient.  The Oncotype DX Prostate Cancer Assay is a real time polymerase chain reaction (RT-PCR) assay designed for analysis of prostate core needle biopsies. The assay measures the expression of 17 genes to calculate a Genomic Prostate Score (GPS). A lower GPS score means more favorable biology and less aggressive disease. This test may be utilized to counsel men regarding the best course of therapy (active surveillance vs. treatment) in newly diagnosed low or low-intermediate prostate cancer.

Two recent studies have suggested that Oncotype DX can predict adverse pathology and unfavorable outcomes after radical prostatectomy. In both these studies, multiple authors are either employed by the manufacturer of the test or have a financial interest. These studies are recently published and need continued validation from a widespread clinical use. In addition, it is difficult to ascribe clinical utility of Oncotype DX Prostate in patients planning to undergo active surveillance as all patients in the above studies, regardless of clinical criteria, elected radical prostatectomy within 6 months of diagnostic biopsy. Moreover, the validity of using different degrees of tumor pathology as "markers" to extrapolate the risk of progression of a tumor in vivo is unclear.

National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer 2018 state," Several tissue-based molecular assays have been developed in an effort to improve decision-making in newly diagnosed men considering active surveillance and in treated men considering adjuvant therapy or treatment for recurrence. Retrospective case cohort studies have shown that these assays provide prognostic information independent of NCCN risk groups, which include likelihood of death with conservative management, likelihood of biochemical recurrence after radical prostatectomy or radiotherapy, and likelihood of developing metastasis after operation or salvage radiotherapy. No randomized controlled trials have studied the utility of these tests. These molecular biomarker tests have been developed with extensive industry support, guidance, and involvement, and have been marketed under the less rigorous Food and Drug Administration (FDA) regulatory pathway for biomarkers. Although full assessment of their clinical utility requires prospective randomized clinical trials, which are unlikely to be done, the panel believes that men with clinically localized disease 'may' consider the use of tumor-based molecular assays at this time. Future comparative effectiveness research may allow these tests and others like them to gain additional evidence regarding their utility for better risk stratification of men with prostate cancer."

European Association of Urology (EAU) Guidelines on Prostate cancer, 2018 state the following, "The Prolaris test (Myriad Genetics) measures the expression of 31 cell-cycle associated genes in biopsy derived

Prostate cancer (PCa) tissue and may be of clinical use to determine whether a patient needs curative treatment or may have his treatment deferred. A systematic review (SR) on the topic concluded that cell-cycle-associated gene expression can be helpful in predicting biochemical recurrence (BCR) risk after local treatment and may alter clinical decision-making but the economic impact on healthcare systems remains to be determined. Similarly, Oncotype DX is a ribonucleic acid (RNA)-based test based on 12 carcinoma associated genes and 5 reference genes which can be applied to carcinoma tissue in prostate biopsies to determine the aggressiveness of the carcinoma. Both tests were shown in prospective studies to provide prognostic information in men with clinically localized PCa, additional to conventional clinico-pathological parameters, including Gleason score and PSA level. The results of prospective multicenter studies are awaited before a recommendation can be made regarding their routine application."

American Urological Association (AUA) Guidelines on Clinically Localized Prostate Cancer, 2017 state, "Among most low-risk localized prostate cancer patients, tissue based genomic biomarkers have not shown a clear role in the selection of candidates for active surveillance. Tissue based genomic biomarkers have not shown a clear role in active surveillance for localized prostate cancer and are not necessary for follow up."

A guideline from the American Society for Clinical Oncology on active surveillance of prostate cancer 2016, states "Use of ancillary tests beyond digital rectal exam (DRE), PSA, and biopsy to improve patient selection or as part of monitoring in an active surveillance (AS) regimen remains investigational. Although there is a potential for genomic tests that use biopsy tissue to predict patients who are more rather than less likely to have disease progression and cancer-specific mortality and for multiparametric magnetic resonance imaging (mpMRI) to guide biopsies to find more clinically aggressive disease, prospective validation of these tests is needed to assess their impact on patient outcomes such as survival. Selective use of these ancillary tests in patients with discordant clinical and/or pathologic findings may be appropriate."

An assessment by Adelaide Health Technology Assessment (Ellery, et al., 2014) concluded that "there is uncertainty about the clinical utility" of the Oncotype DX Prostate and the Prolaris tests, "even when taking into account the highest level of evidence available" The assessment stated that it remains to be verified whether genetic expression of the unique gene panels involved are robust to heterogeneous sampling of prostate tissue at the time of biopsy. Also, the need for tissue which has previously been fixed for histological analysis is of some concern. The assessment observed that this is the most obvious reason for the relatively high number of patients for whom a valid test results could not be obtained.

While Oncotype DX may eventually have a role in making treatment decision about patients with prostate cancer, there is limited data on clinical outcomes to currently support routine use. Hence, it is not considered a generally acceptable standard of care for management of patients with a diagnosis of prostate cancer.