Cancer Variant Interpretation for Precision Oncology

Comprehensive clinical interpretation of somatic mutations in cancer. Transforms a gene + variant input into an actionable precision oncology report covering clinical evidence, therapeutic options, resistance mechanisms, clinical trials, and prognostic implications.

KEY PRINCIPLES:

1. Report-first approach - Create report file FIRST, then populate progressively
2. Evidence-graded - Every recommendation has an evidence tier (T1-T4)
3. Actionable output - Prioritized treatment options, not data dumps
4. Clinical focus - Answer "what should we treat with?" not "what databases exist?"
5. Resistance-aware - Always check for known resistance mechanisms
6. Cancer-type specific - Tailor all recommendations to the patient's cancer type when provided
7. Source-referenced - Every statement must cite the tool/database source
8. English-first queries - Always use English terms in tool calls (gene names, drug names, cancer types), even if the user writes in another language. Respond in the user's language

LOOK UP, DON'T GUESS

When uncertain about any scientific fact, SEARCH databases first (PubMed, UniProt, ChEMBL, ClinVar, etc.) rather than reasoning from memory. A database-verified answer is always more reliable than a guess.

COMPUTE, DON'T DESCRIBE

When analysis requires computation (statistics, data processing, scoring, enrichment), write and run Python code via Bash. Don't describe what you would do — execute it and report actual results. Use ToolUniverse tools to retrieve data, then Python (pandas, scipy, statsmodels, matplotlib) to analyze it.

When to Use

Apply when user asks:

• "What treatments exist for EGFR L858R in lung cancer?"
• "Patient has BRAF V600E melanoma - what are the options?"
• "Is KRAS G12C targetable?"
• "Patient progressed on osimertinib - what's next?"
• "What clinical trials are available for PIK3CA E545K?"
• "Interpret this somatic mutation: TP53 R273H"

Input Parsing

Required: Gene symbol + variant notation (e.g., "EGFR L858R", "BRAF p.V600E", "EML4-ALK fusion", "HER2 amplification") Optional: Cancer type (improves specificity)

Parse the gene symbol and variant separately. For fusions, use the kinase partner as the primary gene. For amplifications/deletions, use the gene name directly. Normalize common aliases: HER2 -> ERBB2, PD-L1 -> CD274, VEGF -> VEGFA.

Phase 0: Tool Parameter Verification (CRITICAL)

BEFORE calling ANY tool for the first time, verify its parameters.

Workflow Overview

Input: Gene symbol + Variant notation + Optional cancer type

Phase 1: Gene Disambiguation & ID Resolution
  - Resolve gene to Ensembl ID, UniProt accession, Entrez ID
  - Get gene function, pathways, protein domains
  - Identify cancer type EFO ID (if cancer type provided)

Phase 2: Clinical Variant Evidence (CIViC)
  - Find gene in CIViC (via Entrez ID matching)
  - Get all variants for the gene, match specific variant
  - Retrieve evidence items (predictive, prognostic, diagnostic)

Phase 3: Mutation Prevalence (cBioPortal)
  - Frequency across cancer studies
  - Co-occurring mutations, cancer type distribution

Phase 4: Therapeutic Associations (OpenTargets + ChEMBL + FDA + DrugBank)
  - FDA-approved targeted therapies
  - Clinical trial drugs (phase 2-3), drug mechanisms
  - Combination therapies

Phase 5: Resistance Mechanisms
  - Known resistance variants (CIViC, literature)
  - Bypass pathway analysis (Reactome)

Phase 6: Clinical Trials
  - Active trials recruiting for this mutation
  - Trial phase, status, eligibility

Phase 7: Prognostic Impact & Pathway Context
  - Survival associations (literature)
  - Pathway context (Reactome), Expression data (GTEx)

Phase 8: Report Synthesis
  - Executive summary, clinical actionability score
  - Treatment recommendations (prioritized), completeness checklist

For detailed code snippets and API call patterns for each phase, see ANALYSIS_DETAILS.md.

Clinical Reasoning Strategies

Driver vs Passenger Reasoning

Not every mutation in a tumor is driving the cancer. Before querying databases, form a hypothesis:

• Is this gene a known oncogene or tumor suppressor? Genes like EGFR, BRAF, KRAS, TP53, PIK3CA are well-established cancer drivers. A mutation in one of these warrants deep investigation. A mutation in a gene with no known cancer role is likely a passenger.
• Is this specific mutation recurrent across tumors (hotspot)? Use cBioPortal to check prevalence across specific studies, or GenomeNexus_get_cancer_hotspots for a direct is_hotspot boolean plus tumor counts from the Chang et al. hotspot database (e.g., BRAF V600E: is_hotspot: true, 897 tumors as a single-residue hotspot, 545 as a 3D-cluster hotspot). A mutation seen in hundreds of independent tumors is almost certainly a driver. A unique, never-before-seen missense in the same gene is less certain.
• What is the predicted functional impact? Truncating mutations (nonsense, frameshift) in tumor suppressors are likely loss-of-function drivers. Missense mutations in oncogenes at known hotspot residues are likely gain-of-function drivers.
• For unique (non-hotspot) missense in driver genes, look at mechanism, not just pathogenicity. AlphaMissense gives a score; the ESMC-6B SAE composite ESM_explain_variant_mechanism(sequence=wt_protein_seq, position=..., ref_aa=..., alt_aa=..., top_k_features=5) answers how the substitution disrupts function — catalytic / ligand-binding / PTM / structural-stability loss. A unique missense that disrupts the same SAE feature category as a known driver hotspot in the same gene is more likely a driver than a missense that disrupts unrelated features. Requires ESM_API_KEY; missense only.
• Conclusion pattern: A recurrent mutation in a known driver gene is likely actionable. A unique mutation in a gene not associated with cancer is likely a passenger. State your assessment and the reasoning behind it.

Actionability Reasoning

Actionable means a therapy exists that targets this alteration. Think in tiers based on evidence strength:

• Tier 1: FDA-approved drug for this mutation in this cancer type. The standard of care — recommend confidently. Example reasoning: "CIViC returns Level A evidence, FDA label confirms indication."
• Tier 2: FDA-approved for this mutation in a different cancer type, or strong clinical trial evidence (phase 2-3) in this cancer type. Reasonable to consider, especially under tumor-agnostic approvals or with molecular tumor board discussion.
• Tier 3: Preclinical evidence only — cell line data, animal models, or case reports. May justify clinical trial enrollment but not off-label use.
• Tier 4: Biological rationale but no direct evidence — the mutation is in a druggable pathway, or a structurally similar mutation responds to therapy. Hypothesis-generating only.

When synthesizing, state the tier and explain WHY you assigned it based on the evidence you found, not just which database returned a hit.

Resistance Reasoning

If the patient has already been treated, ask: could this mutation be a resistance mechanism?

• On-target resistance: Mutations in the drug target gene itself that restore signaling despite drug binding. These typically emerge at the drug-binding site (e.g., EGFR T790M after erlotinib, EGFR C797S after osimertinib, ABL T315I after imatinib).
• Bypass pathway activation: Mutations in parallel signaling pathways that render the target irrelevant (e.g., MET amplification bypassing EGFR inhibition, BRAF activation bypassing MEK inhibition).
• Phenotypic transformation: Lineage changes (e.g., small cell transformation in EGFR-mutant lung cancer) that eliminate dependence on the original driver.
• Timing matters: If the mutation was detected AFTER treatment, it is more likely a resistance mechanism than if it was present at diagnosis.

When to Use Which Tool

Form your clinical hypothesis FIRST based on gene function and mutation type, THEN use tools to validate:

• CIViC (civic_search_genes, civic_get_variants_by_gene): Your primary source for clinical evidence. Returns curated evidence items with evidence levels, clinical significance, and associated therapies. Start here for any variant with potential clinical relevance.
• cBioPortal (cBioPortal_get_mutations): Use to assess mutation prevalence — is this a hotspot? How common is it across cancer types? This informs your driver vs passenger assessment.
• OpenTargets (OpenTargets_get_associated_drugs_by_target_ensemblID): Use for actionability — what drugs target this gene? Cross-reference with CIViC evidence to assign tiers.
• PubMed (PubMed_search_articles): Use when CIViC lacks entries for your variant, or to find resistance mechanism reports and recent clinical trial results.
• ClinicalTrials.gov (search_clinical_trials): Use after establishing the variant is potentially actionable, to find enrollment opportunities.

Tool Reference (Verified Parameters)

Gene Resolution

Clinical Evidence

Drug Information

Mutation Prevalence

Clinical Trials & Literature

Variant Annotation & Cancer Hotspots (Genome Nexus)

Complements CIViC/cBioPortal with structured, computed consequence prediction (VEP/SIFT/PolyPhen/AlphaMissense) plus a dedicated cancer-hotspot lookup — use it to establish in silico pathogenicity and hotspot status before or alongside the curated clinical-evidence search, not instead of it. Requires GRCh37/hg19 coordinates (convert first if you only have GRCh38, e.g. via NCBI Variation Services in tooluniverse-variant-analysis).

Cancer Driver Gene Classification (IntOGen)

Genome Nexus's is_hotspot (above) answers "is this exact variant recurrent?" IntOGen answers a different, gene-level question: "is this whole gene a statistically established cancer driver in this cancer type?", derived from applying 7 independent driver-detection methods (dNdScv, OncodriveFML, OncodriveCLUSTL, HotMAPS, smRegions, CBaSE, MutPanning) to thousands of tumors across 271 cohorts (TCGA, ICGC, Hartwig, and others). Use it to establish gene-level driver status BEFORE or ALONGSIDE the hotspot check — a variant in a gene that isn't a driver in this cancer type is far less likely to be actionable regardless of its hotspot status, and a gene that IS a driver but where your specific variant ISN'T a known hotspot may still warrant the mechanism-based reasoning in "Driver vs Passenger Reasoning" above.

Combined workflow: given gene + cancer type, call IntOGen_get_drivers(cancer_type=...) and check whether the gene appears in driver_genes[] — if yes, it's a statistically established driver in this exact cancer type (report mutations/samples/cohorts as supporting evidence). For the inverse question ("which cancer types is this gene a driver in overall?"), use IntOGen_get_gene_info(gene=...) instead, which also reports which of the 7 detection methods flagged it per cancer type — a gene flagged by multiple independent methods is stronger evidence than one flagged by a single method. Operational note: the IntOGen backend is occasionally slow and can time out (~45s) on a cold request — retry once before reporting "no data found."

Somatic Classification Tiers (CancerVar)

Everything above (Genome Nexus, IntOGen, CIViC, cBioPortal) is evidence you assemble and weigh yourself. CancerVar_classify_variant instead runs the full AMP/ASCO/CAP 2017 rubric server-side and returns a ready-made Tier I-IV verdict — use it as a fast, automatable cross-check on your own manual assessment, not as a replacement for citing the underlying evidence above in a report.

Verified live on BRAF V600E (chrom="7", pos=140453136, ref="A", alt="T", build="hg19"): tier="Tier_I_strong", opai=0.99 — matches the FDA-approved-therapy-association tier this variant is known for, and matches the tool's own documented worked example exactly (unlike InterVar below, this example was accurate). Tier I requires CBP_1 or CBP_2 (FDA-approved association) to be active; Tier II is investigational/preclinical evidence without regulatory approval; Tier III is a true VUS-equivalent; Tier IV is benign. Report the tier alongside which specific cbp_criteria were active, the same way you'd cite ACMG criteria for a germline call — a bare tier number without its supporting criteria is not an audit-ready answer.

Fallback Strategy

When a primary tool returns no results, fall back rather than reporting "no data found":

• CIViC empty -> search PubMed for "[gene] [variant] clinical evidence"
• OpenTargets no drugs -> try ChEMBL drug search by target
• cBioPortal specific study empty -> try pan-cancer study (msk_impact_2017 or similar)
• Reactome no pathways -> use UniProt function annotation for pathway context