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genoCDS is a clinical reference tool for qualified healthcare professionals only. Content is derived from published guidelines and regulatory sources and may contain errors or outdated information. It is not a substitute for professional medical judgment, institutional protocols, or individual patient assessment. Always verify recommendations against current primary sources before making clinical decisions. Full disclaimer →
Stage Stage IVA
Single extrathoracic metastatic lesion or contralateral lung nodule or pleural/pericardial involvement. Metastatic but potentially oligometastatic.
7 test recommendations across 1 clinical indication
Stage IVA metastatic colon cancer. Comprehensive biomarker panel required: extended RAS/RAF, MSI-H/dMMR, HER2, NTRK, KRAS G12C. Must complete RAS testing before initiating anti-EGFR therapy.
Required — 3 tests
BRAF V600E Mutation Analysis
BRAF V600E
Detection of BRAF V600E (p.Val600Glu) point mutation. Dabrafenib + trametinib (Tafinlar + Mekinist) is FDA-approved for BRAF V600E-mutant metastatic NSCLC. BRAF V600E occurs in 1.5–4% of NSCLC, more commonly in adenocarcinoma, and is enriched in current/former smokers. Non-V600E BRAF mutations occur more frequently but currently lack approved targeted therapy.
Ordering Note
Required for all mCRC. BRAF V600E qualifies for encorafenib + cetuximab (BEACON-CRC) post first-line; strong negative prognostic marker guiding first-line intensity.
Specimen
Evidence
Microsatellite Instability / Mismatch Repair Status (MSI/MMR)
MSI/MMR
Testing for microsatellite instability (MSI) and/or mismatch repair (MMR) deficiency. Methods: PCR-based MSI testing, IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2), or NGS-based MSI calculation. MSI-H (high instability) / dMMR (deficient MMR) is an FDA-approved pan-tumor biomarker for pembrolizumab and dostarlimab. MSI-H/dMMR is rare in NSCLC (<1%) but justifies routine testing given pan-tumor approval. IHC for MMR proteins can be performed on most tissue specimens.
Ordering Note
Required for all mCRC. MSI-H/dMMR (~4–5%) qualifies for pembrolizumab (KEYNOTE-177) or nivolumab ± ipilimumab first-line.
Specimen
Evidence
Extended RAS/RAF Panel
RAS/RAF Panel
Comprehensive RAS/RAF hotspot panel detecting KRAS exons 2–4 (codons 12, 13, 59, 61, 117, 146), NRAS exons 2–4, and BRAF V600E. Extended RAS testing is mandatory before initiating anti-EGFR therapy (cetuximab, panitumumab) in metastatic CRC — any RAS mutation is a contraindication. BRAF V600E status drives eligibility for encorafenib + cetuximab (BEACON-CRC).
Ordering Note
Mandatory before any anti-EGFR therapy (cetuximab, panitumumab). Must cover KRAS exons 2/3/4 and NRAS exons 2/3/4. Any RAS mutation = absolute contraindication to anti-EGFR. Also detects BRAF V600E.
Specimen
Evidence
Recommended — 4 tests
HER2 (ERBB2) Mutation and Amplification
HER2/ERBB2
Analysis of HER2 (ERBB2) for activating mutations (most commonly exon 20 insertions) and amplification. Trastuzumab deruxtecan (T-DXd; Enhertu) is FDA-approved for HER2-mutant metastatic NSCLC. HER2 alterations occur in 2–4% of NSCLC, predominantly adenocarcinoma in female never-smokers. HER2 mutations and amplifications are distinct — mutations in exon 20 (e.g., YVMA insertion) are most actionable. Note: HER2 amplification without mutation has limited therapeutic implications in NSCLC (unlike breast cancer).
Ordering Note
Recommended for RAS/RAF wild-type mCRC. HER2 amplification (~2–3%) is eligible for tucatinib + trastuzumab (MOUNTAINEER, FDA 2023). HER2 amplification also confers anti-EGFR resistance.
Specimen
Evidence
NTRK1/2/3 Gene Fusion Analysis
NTRK fusion
Pan-tumor detection of NTRK1, NTRK2, and NTRK3 gene fusions encoding TRK (tropomyosin receptor kinase) fusion proteins. Larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) are FDA-approved pan-tumor for TRK fusion-positive cancers regardless of histology. NTRK fusions are rare in NSCLC (<1%) but the high response rate and pan-tumor approval make routine testing appropriate for all NSCLC patients. IHC screening may precede confirmatory molecular testing.
Ordering Note
Recommended for all mCRC. NTRK fusions (~0.2–0.35%) are highly actionable with FDA-approved entrectinib/larotrectinib (tumor-agnostic).
Specimen
Evidence
KRAS G12C Mutation Analysis
KRAS G12C
Detection of KRAS G12C (p.Gly12Cys) mutation. Sotorasib (Lumakras) and adagrasib (Krazati) are FDA-approved for KRAS G12C-mutant metastatic NSCLC after prior platinum-based chemotherapy. KRAS G12C is the most common KRAS mutation in NSCLC (~13% of adenocarcinoma, 5% of squamous) and is associated with tobacco exposure. KRAS mutations overall are the most common oncogenic driver in NSCLC.
Ordering Note
Recommended when comprehensive RAS panel used. KRAS G12C (~3–4% of mCRC) is eligible for sotorasib or adagrasib. Adagrasib + cetuximab shows enhanced response.
Specimen
Evidence
Comprehensive Solid Tumor NGS Panel
Comprehensive NGS
Next-generation sequencing panel covering ≥300 cancer-relevant genes, including all major NSCLC drivers (EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, NTRK, HER2, FGFR), plus tumor mutational burden (TMB) and microsatellite instability (MSI). Examples include FoundationOne CDx, Tempus xT, Caris MI Transcriptome, and equivalent institutional panels. Preferred over single-gene sequential testing for efficiency and cost-effectiveness.
Ordering Note
Comprehensive NGS covers all required biomarkers (RAS/RAF/MSI/HER2/NTRK/KRAS G12C) in a single assay. Preferred approach per NCCN when tissue is available.
Specimen
Evidence
Payer Coverage
Payer Coverage Summary
Coverage status as of last policy review. Prior authorization requirements and coverage criteria may change. Verify directly with each payer before ordering.
| Test | Medicare (CMS) | UnitedHealth | Anthem BCBS | Humana | Cigna | Aetna |
|---|---|---|---|---|---|---|
| MSI/MMR | Covered | Covered | Unknown | Unknown | Unknown | Unknown |
| RAS/RAF Panel | Covered | Covered | Covered | Covered | Covered | Covered |
| HER2/ERBB2 | Covered | Unknown | Unknown | Unknown | Unknown | Unknown |
| NTRK fusion | Covered | Unknown | Unknown | Unknown | Unknown | Unknown |
| KRAS G12C | Covered | Covered | Covered | Covered | Covered | Covered |
| Comprehensive NGS | Covered | Covered | Covered | Prior Auth | Covered | Covered |
Coverage data last verified via automated policy research. Always confirm current policies with each payer.
Recommendations on this page are derived from publicly available guidelines (NCCN, ASCO, ESMO, FDA, OncoKB) and are paraphrased for reference. They do not constitute medical advice. Evidence levels reflect the grading systems of each respective organization and should be interpreted in clinical context. This reference is updated periodically but may not reflect the most recent guideline revisions.