Medical Disclaimer
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 Content is derived from published guidelines and regulatory sources and may contain errors or outdated information.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.
5 test recommendations across 1 clinical indication
Stage IVA metastatic HR+/HER2−. Comprehensive biomarker panel required at first metastatic presentation.
Required — 3 tests
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 required at first metastatic presentation. Tissue from metastatic site preferred.
Specimen
PIK3CA Mutation Analysis
PIK3CA
Hotspot mutation analysis of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) identifying the 11 most common activating mutations (exon 9: E542K, E545A/D/G/K, Q546E/K; exon 20: H1047L/R/Y). PIK3CA mutations occur in ~40% of HR+/HER2− metastatic breast cancer. FDA-approved companion diagnostic (therascreen PIK3CA RGQ PCR Kit) for alpelisib (Piqray) + fulvestrant per SOLAR-1 trial. OncoKB Level 1.
Ordering Note
For alpelisib (Piqray) + fulvestrant eligibility after CDK4/6 inhibitor failure. Plasma ctDNA acceptable.
Specimen
Evidence
FDA-approved CDx (therascreen PIK3CA) for alpelisib + fulvestrant in PIK3CA-mutated HR+/HER2− mBC.
BRCA1/BRCA2 Germline Testing
BRCA1/2 Germline
Full sequence analysis and large rearrangement detection of BRCA1 and BRCA2 germline DNA in peripheral blood. Germline BRCA1/2 pathogenic variants found in ~5–7% of unselected breast cancer; up to 15–20% in TNBC. Eligibility criterion for PARP inhibitor therapy: olaparib (Lynparza, OLYMPIAD trial, FDA-approved 2018) and talazoparib (Talzenna, EMBRACA trial, FDA-approved 2018) for HER2− metastatic breast cancer. Also establishes hereditary risk for first-degree relatives. NCCN recommends germline testing for all metastatic breast cancer patients.
Ordering Note
NCCN recommends germline BRCA1/2 for all metastatic HER2− breast cancer. Eligibility for olaparib or talazoparib.
Specimen
Evidence
FDA-approved companion diagnostic. Olaparib (OlympiAD) and talazoparib (EMBRACA) both approved for gBRCA1/2+ HER2− mBC.
Recommended — 2 tests
ESR1 Mutation Analysis (Liquid Biopsy)
ESR1 (ctDNA)
ESR1 (estrogen receptor alpha) ligand-binding domain mutation analysis in circulating tumor DNA (ctDNA). Acquired ESR1 mutations (Y537S, D538G, E380Q, L536R, and others) emerge in ~40% of HR+ metastatic breast cancer treated with aromatase inhibitors and confer resistance to AI therapy. Guides therapy escalation to elacestrant (Orserdu), the first oral SERD approved for ESR1-mutated HR+/HER2− mBC (EMERALD trial). Preferred specimen: plasma ctDNA by ddPCR or NGS-based liquid biopsy.
Ordering Note
After aromatase inhibitor therapy to detect ESR1 mutations. Elacestrant (Orserdu) approved for ESR1-mutated HR+ mBC.
Specimen
HER2 Testing (IHC + FISH)
HER2 IHC/FISH
HER2 (ERBB2) status testing by immunohistochemistry (IHC) with reflex to FISH for IHC 2+ equivocal results, per ASCO/CAP 2018 guidelines. IHC 3+ = HER2 positive. FISH amplification ratio ≥2.0 or average HER2 copy number ≥6.0 signals/cell = HER2 positive. IHC 1+ and 2+/FISH non-amplified = HER2 low (eligible for T-DXd). Required for all newly diagnosed invasive breast cancer. FDA-approved companion diagnostic for multiple HER2-targeted therapies.
Ordering Note
Reassess HER2 status on metastatic biopsy. Determine HER2-low (IHC 1+ or 2+/FISH−) for T-DXd eligibility per DESTINY-Breast04.
Specimen
Evidence
T-DXd (DESTINY-Breast04) approved for HER2-low (IHC 1+, 2+/FISH−) HR+/HER2− and TNBC mBC. HER2 IHC reassessment required.
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 |
|---|---|---|---|---|---|---|
| Comprehensive NGS | Covered | Covered | Covered | Prior Auth | Covered | Covered |
| PIK3CA | Covered | Covered | Covered | Unknown | Prior Auth | Covered |
| BRCA1/2 Germline | Covered | Covered | Covered | Covered | Covered | Covered |
| HER2 IHC/FISH | Covered | Covered | Covered | Unknown | Unknown | Unknown |
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.