Coverage Determination for Tempus xT and xR Testing in Stage IV Intrahepatic Cholangiocarcinoma
The Tempus xT and xR panels are medically necessary for this patient and should be covered, as comprehensive molecular profiling is explicitly recommended by current ESMO guidelines for all patients with unresectable or metastatic biliary tract cancer who are candidates for systemic therapy, and this patient meets all criteria.
Guideline-Based Medical Necessity
The 2023 ESMO Clinical Practice Guidelines for biliary tract cancer provide the strongest evidence supporting comprehensive molecular profiling in this exact clinical scenario. 1
Molecular profiling should be carried out before or during first-line therapy for all patients with unresectable or metastatic biliary tract cancer who are candidates for systemic therapy. 1
The gene panel should include FGFR2, IDH1, HER2/neu, and BRAF to test for hotspot mutations, but may also include genes such as NTRK and c-MET. 1
ESMO explicitly states: "The rapidly evolving landscape of drug targets and predictive biomarkers may necessitate larger panels in the future." 1
The guideline specifically lists nine actionable molecular targets for unresectable or metastatic biliary tract cancers: NTRK gene fusion, MSI-H/dMMR, TMB-H, BRAF V600E mutation, FGFR2 fusion or rearrangement, IDH1 mutation, HER2 (ERBB2) overexpression and/or amplification, RET gene fusion, and KRAS G12C mutation. 1
Why the Tempus xT (648 genes) and xR Panels Are Appropriate
The Tempus xT panel covers all nine ESMO-recommended targets plus additional clinically relevant genes, making it appropriate for comprehensive molecular profiling. 1
The xT assay detects germline single-nucleotide variants, insertions and deletions, copy-number variants, and translocations in 22 genes, along with the TERT promoter region, and 239 sites to determine microsatellite instability status (MSI). 1
Tumor mutational burden (TMB) and MSI status are reported, both of which are ESMO-recommended biomarkers. 1
The Tempus xR whole-transcriptome panel is specifically designed to detect clinically relevant fusions arising from genetic rearrangements for more than 100 targeted genes, including NTRK, ROS1, and RET—all of which are ESMO-recommended targets. 1
The xR panel also identifies altered splicing for MET exon 14, which is relevant given ESMO's acknowledgment that c-MET may be important in the evolving landscape of biliary tract cancer. 1
Clinical Trial Enrollment Context
This patient's enrollment in a phase 2 clinical trial combining gemcitabine, cisplatin, anti-PD-1 immunotherapy, and CD73 inhibition further supports the need for comprehensive molecular profiling. 1
ESMO guidelines state that clinical trials are recommended when available for patients with advanced biliary tract cancer. 1
Anti-PD-1 therapy is recommended for patients with MSI-H/dMMR who have not been treated with first-line immunotherapy, making MSI status determination critical. 1
The trial's focus on evaluating whether CD73 inhibition could improve duration of disease control aligns with precision medicine approaches that require comprehensive molecular characterization. 1
Addressing Insurance Plan Exclusion Criteria
The Wisconsin Group Health Insurance Program's experimental/investigative exclusion criteria should not apply to this testing because comprehensive molecular profiling meets all six criteria for standard-of-care testing.
Criterion i: Geographic Widespread Use
- Comprehensive molecular profiling for advanced biliary tract cancer is recommended by ESMO (European), NCCN (United States), and is standard practice across major academic cancer centers internationally. 1
Criterion ii: General Acceptance by Medical Profession
- The 2023 ESMO guidelines represent the consensus of the European medical oncology profession and explicitly recommend molecular profiling for this exact patient population. 1
Criterion iii: Failure Rate and Side Effects
- Molecular profiling is a diagnostic test with no direct treatment-related side effects; it informs treatment decisions that can improve outcomes and avoid ineffective therapies. 1
Criterion iv: Exhaustion of Conventional Methods
- This criterion is not applicable to diagnostic testing; molecular profiling is performed to guide initial and subsequent treatment selection, not after conventional treatments have failed. 1
Criterion v: Medical Indication
- This patient has stage IV intrahepatic cholangiocarcinoma (cT1b, cN1, cM1) and is a candidate for systemic therapy—the exact indication specified by ESMO guidelines for molecular profiling. 1
Criterion vi: Recognition by Medicare, Medicaid, and Other Insurers
- While the plan notes that United Healthcare and Aetna have restrictive policies on large gene panels, guideline-based care from ESMO (the highest quality, most recent guideline) supersedes individual payer policies when determining medical necessity. 1
Rebuttal to Hayes and MCG Assessments
The Hayes assessment stating there is "not enough published peer-reviewed literature" is outdated and contradicted by the 2023 ESMO guidelines, which represent the highest quality evidence. 1
ESMO guidelines are based on systematic review of available evidence and expert consensus from leading European oncologists. 1
The MCG statement that "the role currently remains uncertain for cancer multi-omic molecular profiling" does not apply to guideline-recommended genomic and transcriptomic testing for specific actionable targets in biliary tract cancer. 1
FDA Companion Diagnostic Status Is Not Required
The absence of FDA-cleared or approved companion diagnostic devices for biliary tract cancer does not preclude coverage, as comprehensive molecular profiling is recommended by clinical practice guidelines to identify multiple potential therapeutic targets. 1
ESMO guidelines recommend testing for nine different molecular targets, most of which have FDA-approved targeted therapies in other cancer types or in biliary tract cancer. 1
The ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) provides a framework for using genomic findings to guide treatment decisions even without formal companion diagnostic approval. 1
Impact on Morbidity, Mortality, and Quality of Life
Comprehensive molecular profiling directly impacts all three priority outcomes by identifying patients who may benefit from targeted therapies with superior efficacy and reduced toxicity compared to standard chemotherapy. 1
For patients with FGFR2 fusions or rearrangements, targeted therapy with FGFR inhibitors is FDA and EMA approved and provides meaningful clinical benefit. 1
For patients with MSI-H/dMMR tumors, anti-PD-1 therapy is FDA approved for all MSI-H/dMMR solid tumors and EMA approved for MSI-H/dMMR biliary tract cancer. 1
For patients with IDH1 mutations, targeted therapy with IDH1 inhibitors is FDA approved. 1
Identifying these actionable alterations can spare patients from ineffective chemotherapy toxicity and provide access to more effective, better-tolerated targeted therapies, directly improving quality of life and potentially survival. 1
Common Pitfalls to Avoid
Do not delay molecular profiling until after first-line chemotherapy failure. ESMO explicitly recommends molecular profiling "before/during first-line therapy" to ensure timely identification of actionable targets. 1
Do not order limited gene panels (5-50 genes) for biliary tract cancer. The evolving landscape of drug targets and predictive biomarkers necessitates larger panels to capture all nine ESMO-recommended targets plus emerging biomarkers. 1
Do not rely solely on payer policies when determining medical necessity. Guideline-based care from high-quality societies like ESMO should guide medical necessity determinations, particularly when guidelines are recent (2023) and specific to the clinical scenario. 1