Appeal type: Experimental/Investigational
Decision: Upheld

Diagnosis: Thymic carcinoma
Treatment: FoundationOne CDx Test (0037U)
The insurer denied the FoundationOne CDx Test (0037U)
The denial is upheld. 

The patient is a male with metastatic squamous cell carcinoma of the thymus.

The patient was diagnosed with a stage IVB (cT3 [growing into nearby tissue] cN0 [not spread to lymph nodes] cM1b [spread into distant organs or lungs]) squamous cell carcinoma of the thymus upon biopsy of a left lower lobe lung nodule. Upon evaluation, he also had an anterior mediastinal mass, and biopsy of this mass was also positive for squamous cell carcinoma of the thymus.

The patient's sites of metastatic disease include bilateral lungs. Comorbidities include hypertension, high cholesterol and sleep apnea. He has a 39 pack-year history of smoking.

A FoundationOne CDx tumor mutation panel test was performed on the tumor.

This was denied as not meeting Excellus Corporate Medical Policy for Molecular Panel Testing of Tumor Tissue to Identify Targeted Therapies for cancers (Excluding NSCLC [non-small cell lung cancer] and CRC [colorectal cancer]) criteria for coverage.

A letter of appeal was submitted by the appealer. This letter failed to provide any references that demonstrate that the use of FoundationOne CDx testing used to select treatment will improve the management of metastatic squamous cell carcinoma of the thymus.

No, the health plan should not cover the FoundationOne CDx Test (0037U). 

The patient had a squamous cell carcinoma of the thymus, and a FoundationOne CDx tumor mutation panel test was performed on the tumor. The services provided by Foundation Medicine were a FoundationOne CDx test. The FoundationOne CDx test ("companion diagnostic test") is a more focused next generation sequencing-based test that analyzes all guideline-recommended genes in solid tumors. It detects substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA (deoxyribonucleic acid) isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens (1). It is a somatic mutation panel test performed on tumors to identify mutations for selecting targeted therapies.

The NCCN (National Comprehensive Cancer Guidelines) Guidelines for the treatment of squamous cell carcinoma of the thymus do not support any tumor mutation testing (2).

There are no clinical studies of the use of the FoundationOne CDx assay to direct therapy of squamous cell carcinoma of the thymus (www.pubmed.gov, 1).

Studies of mutation panel testing of thymic carcinoma only demonstrate that this testing is feasible and not that the use of test results to direct therapy will improve outcomes (3, 4).

The standard of care in the United States does not yet include selecting chemotherapy for tumor based on the somatic mutation profile of the tumor.

The use of somatic mutation panel test results to select targeted therapies for cancer was studied in a randomized clinical trial that compared the outcomes of treating patients with targeted agents based on panel test results vs conventional treatments (5). The conclusions of this phase III study was that, "The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy."

Jones et al. analyzed the requirement for sequencing normal tissue in interpreting mutation panel sequencing of tumors (6). This study suggested that as many of 31% of "actionable" mutations in panels such as the FoundatioOne test might be "false positive."

The use of next-generation sequencing panels for treatment selection for solid tumors was reviewed (7). This review concludes, "Currently, there is little information available on the post-analytic processes unique to next-generation sequencing platforms used by the companies offering these tests. Additionally, evidence of clinical validity showing an association between the genetic markers curated in these tests with treatment response to approved molecularly targeted therapies is lacking across all solid-tumor types. To date, there is no published data of improved outcomes when using the commercially available tests to guide treatment decisions."

The issue with the use of somatic panel mutation testing for selection of therapy for cancer is that the presence of mutation in a cancer of a given type does not imply a response to treatment with an agent that is targeting that mutation. As the efficacy of the testing is unproven, it would not be medically appropriate.

As the testing was not medically appropriate, the health plan should not cover this testing.

No, the the FoundationOne CDx Test (0037U) was not likely to be more beneficial for the enrollee than any available standard therapy.
No mutation panel testing is recommended for squamous cell cacrinoma of the thymus. The testing performed did not benefit the patient.