LCD L38586: MolDX: Prognostic and Predictive Molecular Classifiers for Bladder Cancer

This contractor will cover molecular diagnostic tests for use in a beneficiary with bladder cancer when all of the following conditions are met:

• The beneficiary is being actively managed for bladder cancer.

• The beneficiary is within the population and has the indication for which the test was developed and is covered. The laboratory will make available the appropriate indications of the test to the treating/ordering physician.

• At least 1 of the 2 criteria are met:

• The patient is a candidate for multiple potential treatments, which could be considered to have varied or increasing levels of intensity based on a consensus guideline, and the physician and patient must decide among these treatments. OR

• The patient is a candidate for multiple therapies, and the test has shown that it predicts response to a specific therapy among accepted therapy options based on nationally recognized society consensus guidelines (i.e., National Comprehensive Cancer Network [NCCN], American Society of Clinical Oncology [ASCO], Society of Urologic Oncology [SUO], or American Urological Association [AUA]).

• If Next-Generation Sequencing (NGS) methodology is used in testing, the conditions set by NCD 90.2 are fulfilled (summarized: the patient has advanced cancer; plans on being treated for said cancer, and has not been previously tested with the same test for the same genetic content)

• The test demonstrates analytical validity including both analytical and clinical validations. If the test relies on an algorithm (which may range in complexity from a threshold determination of a single numeric value to a complex mathematical or computational function), the algorithm must be validated in a cohort that is not a development cohort for the algorithm.

• The test has demonstrated clinical validity and utility, establishing a clear and significant biological/molecular basis for stratifying patients and subsequently selecting (either positively or negatively) a clinical management decision (in 4. above) in a clearly defined population.

• The test successfully completes a Molecular Diagnostic Services Program (MolDX ® ) technical assessment that ensures the test is reasonable and necessary as described above.

• Only 1 test may be performed prior to the initiation of therapy UNLESS a second test that interrogates different genomic content AND meets all the criteria established herein, is reasonable and necessary.

• The genomic content interrogated by the test must be relevant to the therapy under consideration.

In the United States, the annual incidence of new bladder cancer is 83,730 patients with approximately 17,200 annual deaths. 1 The majority of bladder cancers originate from the urothelium, with the most important initial risk stratification decision made for these cancers based on whether it is invasive or non-invasive, and how deeply it is has invaded if invasive. 2 Variant histology, common at higher grades, may represent risk of progression or different genetic derivation which may determine whether a more aggressive treatment approach should be considered. 15 In patients who do not have evidence of metastasis at the time of diagnosis, guidelines recommend considering a number of possible treatment approaches of varying intensity and invasiveness, often with recommended follow-up and potential escalation of therapy when there is persistent evidence of cancer. For clinical non-invasive papillary urothelial carcinoma potential treatment approaches include intravesical Bacillus Calmette-Guerin (BCG), intravesical chemotherapy, or even observation. 13 For clinical T1 tumors, potential treatment options include either transurethral resection of the bladder tumor (TURBT) or cystectomy. In patients with stage II or stage IIIa disease, potential treatment options include chemotherapy, radiation, chemoradiation, and surgery accompanied possibly by neoadjuvant and/or adjuvant chemotherapy. 13 While guidelines base recommendations for treatment of localized urothelial cancers heavily on risk stratification, within individual risk groups, the guidelines recommend consideration of multiple treatment strategies of varying levels in intensity and known significant side effects within individual strata. 13 Risk stratification for treatment decisions in patients who are not having or have not yet had a cystectomy are based on clinical staging information; evidence has shown that changes in staging based on pathologic information following cystectomy are common, altering disease risk. 3

Among the non-urothelial bladder cancers, squamous cell carcinoma, adenocarcinoma, and neuroendocrine (NE) tumors have been recognized as important for implications concerning treatment. 2 Current recommendations do not suggest chemotherapy for pure squamous or adenocarcinoma of the bladder, with radiotherapy and/or surgical resection being the mainstays of treatment. 2 NE and NE-like tumors and those tumors with small cell features have been recognized to be a poor prognostic subtype for which aggressive treatment (including chemotherapy and possibly cystectomy and radiotherapy) is recommended regardless of stage. 2 The diagnosis of NE and NE-like tumors in the bladder may be challenging, particularly on histology alone, and therefore often requires use of additional diagnostic information, such as special stains to look for NE features. 5,6

With current standards of care, patients diagnosed with bladder cancer have 5-year relative survival rates (compared to peers without bladder cancer) of 95.8% in cases of in-situ carcinoma and 69.5% in cases of localized cancer with absolute survival rates of 51% and 34% for in-situ and local disease respectively. 7

Molecular subtyping has emerged as a potential diagnostic aid in bladder cancer both to help identify the type of bladder cancer and to more accurately assess the risk and benefit profile of various treatment approaches and to aid in the diagnosis of bladder cancer subtype and risk.