MolDX: Prognostic and Predictive Molecular Classifiers for Bladder Cancer

Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A), states that no Medicare payment shall be made for items or services that are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

42 Code of Federal Regulations (CFR) §410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Changes

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

1. The beneficiary is being actively managed for bladder cancer.
2. The beneficiary is within the population and has the indication for which the test was developed and is covered. The lab providing the test is responsible for clearly indicating to treating clinicians the population and indication for test use.
3. At least 1 of the 2 criteria are met:
   1. 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
   2. 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 consensus guidelines.
4. 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.
5. 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.
6. The test successfully completes a Molecular Diagnostic Program (MolDX^®) technical assessment that ensures the test is reasonable and necessary as described in 4. and 5. above.

In the United States, the annual incidence of bladder cancer is 81,400 patients with 17,980 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 In patients who do not have evidence of metastasis at the time of diagnosis, these 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. 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 For example, in advanced bladder cancer, fibroblast growth factor receptor 3  (FGFR3) and fibroblast growth factor receptor 2 (FGFR2) mutations have also been found to be associated with response to erdafitinib, which has been Food and Drug Administration (FDA) approved for use in bladder cancer with FGFR3 and FGFR2 mutations.⁴

Among the non-urothelial bladder cancers, squamous cell carcinoma, adenocarcinoma, and neuroendocrine 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 Neuroendocrine and neuroendocrine-like tumors and those tumors with small cell features have been recognized to be a poor prognostic subtype for which aggressive treatment is recommended regardless of stage including chemotherapy and possibly cystectomy and radiotherapy.² The diagnosis of neuroendocrine (NE) and neuroendocrine-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 neuroendocrine 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.

Ross and colleagues looked at a comprehensive genomic profile (CGP) of 295 cases of advanced urothelial carcinoma and were able to demonstrate that over 90% had at least 1 clinically relevant genetic alteration per each separate case. The most common clinically relevant genetic alterations were cyclin dependent kinase inhibitor 2A (CDKN2A), FGFR3, phosphatidylinositol 3 kinase catalytic subunit alpha (PIK3CA) and erythroblastic oncogene B2 (ERBB2).¹⁴

Seiler and colleagues developed and validated an algorithm that predicts outcomes in urothelial carcinoma based on molecular subtyping using an algorithm based on gene expression data.⁸ The algorithm classified bladder cancer into 1 of 4 subtypes: Claudin-low, basal, luminal-infiltrated, and luminal. They found that the algorithm also predicted response to neoadjuvant chemotherapy. Luminal tumors (non-infiltrated) demonstrated a comparatively good prognosis that appeared minimally affected by differences between patients who did and did not receive neoadjuvant therapy. Basal tumors demonstrated a poor prognosis without neoadjuvant therapy. The prognosis was significantly improved with neoadjuvant therapy to be similar to luminal tumors. The same subtyping algorithm was evaluated in bladder cancers pre-cystectomy as a predictor of pathologic upstaging.⁹ Consistent with Seiler’s work showing better prognoses for luminal tumors, it was found that luminal tumors were less likely to be upstaged. Gene expression data has also been found to identify NE-like bladder cancers that histologically appear like urothelial carcinomas. ¹⁰

Numerous prior Medicare coverage decisions have considered the evidence in the hierarchical framework of Fryback and Thornbury¹¹ where Level 2 addresses diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses on whether the information produces change in the physician's diagnostic thinking; Level 4 concerns the effect on the patient management plan and Level 5 measures the effect of the diagnostic information on patient outcomes. To apply this same hierarchical framework to analyze an in vitro diagnostic test, we utilized the ACCE Model Process for Evaluating Genetic Tests.¹² The practical value of a diagnostic test can only be assessed by taking into account subsequent health outcomes. When a proven, well established association or pathway is available, intermediate health outcomes may also be considered. For example, if a particular diagnostic test result can be shown to change patient management and other evidence has demonstrated that those patient management changes improve health outcomes, then those separate sources of evidence may be sufficient to demonstrate positive health outcomes from the diagnostic test.

For patients with bladder cancer, an array of treatment possibilities exist at all stages of disease. Clinicians must consider not only the potential treatment options but must also make an individualized risk to benefit assessment to determine how to treat a specific patient. Diagnostic tests that aid in this assessment are expected to change physician management in a way that improves patient outcomes.

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1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
2. Flaig TW, Spiess PE, Agarwal N, et al. Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020;18(3): 329-354. .
3. Svatek RS, Shariat SF, Novara G, et al. Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort. BJU International. 2011;107(6):898-904.
4. U.S. Food and Drug Administration (FDA). Balversa™ prescribing information. Accessed April 14, 2021. 
5. Helpap B. Morphology and therapeutic strategies for neuroendocrine tumors of the genitourinary tract. Cancer. 2002;95(7):1415-1420.
6. Ali SZ, Reuter VE, Zakowski MF. Small cell neuroendocrine carcinoma of the urinary bladder: a clinicopathologic study with emphasis on cytologic features. Cancer. 1997;79(2):356-361.
7. National Cancer Institute. Cancer Stat Facts: Bladder Cancer. https://seer.cancer.gov/statfacts/html/urinb.html Accessed April 14, 2021.
8. Seiler R, Ashab HAD, Erho N, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol. 2017;72(4):544-554.
9. Lotan Y, Boorjian SA, Zhang J, et al. Molecular subtyping of clinically localized urothelial carcinoma reveals lower rates of pathological upstaging at radical cystectomy among luminal tumors. Eur Urol. 2019;76(2):200-206.
10. Batista da Costa J, Gibb EA, Bivalacqua TJ, et al. Molecular characterization of neuroendocrine-like bladder cancer. Clin Cancer Res. 2019;25(13):3908-3920.
11. Fryback DG, Thornbury JR. The efficacy of diagnostic imaging. Med Decis Making. 1991;11(2):88-94.
12. Centers for Disease Control and Prevention. ACCE Model List of 44 Targeted Questions Aimed at a Comprehensive Review of Genetic Testing. https://www.cdc.gov/genomics/gtesting/acce/acce_proj.htm. Accessed April 14, 2021.
13. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer, Version 2.2021.
14. Ross JS, Wang K, Khaira D, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer. 2016; 122(5):702-711.

• Bladder Cancer