**Coverage Indications**  
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 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]).
  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. And above) in a clearly defined population.
  6. The test successfully completes a Molecular Diagnostic Services 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 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 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. 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 adenomcarcinoma 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 neuroendocrine 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.

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

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. The most common
clinically relevant genetic alterations were cyclin dependent kinase inhibitor
2A (CDKN2A), fibroblast growth factor receptor 3 (FGFR3), phosphatidylinositol
3 kinase catalytic subunit alpha (PIK3CA) and erythroblastic oncogene B2
(ERBB2).14 Importantly, some of these are targetable mutations for therapies.
For example, in advanced bladder cancer, FGFR3 and fibroblast growth factor
receptor 2 (FGFR2) mutations have 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

Currently erdafitinib (Balversa), a tyrosine kinase pan-FGFR inhibitor, has
been FDA approved as a targeted therapy for patients with prespecified FGFR
alterations who had either previously received chemotherapy or were cisplatin-
ineligible and chemotherapy-naive.16 In a study of 99 patients with locally
advanced and unresectable or metastatic urothelial carcinoma, Loriot et al17
demonstrated that after a median of five cycles of erdafitinib the rate of
confirmed response to erdafitinib therapy was 40% (3% with a complete response
and 37% with a partial response). Among the 22 patients who had undergone
previous immunotherapy, the confirmed response rate was 59%. The median
duration of progression-free survival was 5.5 months, and the median duration
of overall survival was 13.8 months. Treatment-related adverse events of grade
3 or higher, which were managed mainly by dose adjustments, were reported in
46% of the patients; 13% of the patients discontinued treatment because of
adverse events. There were no treatment-related deaths.17

The NCCN Bladder Cancer Panel recommends that molecular/genomic testing be
conducted early for Stages IVA and IVB and may be considered for IIIB. These
findings would facilitate treatment decisions and prevent delays in
administering FDA approved therapies or clinical trial eligibility.13

Other molecular classifiers and tests will be considered when there is
evidence of clinical validity and utility or if nationally recognized
treatment guidelines call for their inclusion in the treatment regimen of the
defined population they are to be used.

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.