tooluniverse-cancer-variant-interpretation

name

tooluniverse-cancer-variant-interpretation

description

Provide comprehensive clinical interpretation of somatic mutations in cancer. Given a gene symbol + variant (e.g., EGFR L858R, BRAF V600E) and optional cancer type, performs multi-database analysis covering clinical evidence (CIViC), mutation prevalence (cBioPortal), therapeutic associations (OpenTargets, ChEMBL, FDA), resistance mechanisms, clinical trials, prognostic impact, and pathway context. Generates an evidence-graded markdown report with actionable recommendations for precision oncology. Use when oncologists, molecular tumor boards, or researchers ask about treatment options for specific cancer mutations, resistance mechanisms, or clinical trial matching.

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

---

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"
• "Molecular tumor board: EGFR exon 19 deletion, NSCLC"

---

Input Parsing

Required: Gene symbol + variant notation Optional: Cancer type (improves specificity)

Accepted Input Formats

Format	Example	How to Parse
Gene + amino acid change	EGFR L858R	gene=EGFR, variant=L858R
Gene + HGVS protein	BRAF p.V600E	gene=BRAF, variant=V600E
Gene + exon notation	EGFR exon 19 deletion	gene=EGFR, variant=exon 19 deletion
Gene + fusion	EML4-ALK fusion	gene=ALK, variant=EML4-ALK
Gene + amplification	HER2 amplification	gene=ERBB2, variant=amplification
Full query with cancer	"EGFR L858R in lung adenocarcinoma"	gene=EGFR, variant=L858R, cancer=lung adenocarcinoma

Gene Symbol Normalization

Common aliases to resolve:

• HER2 -> ERBB2
• ALK -> ALK (but EML4-ALK is a fusion)
• PD-L1 -> CD274
• VEGF -> VEGFA

---

Phase 0: Tool Parameter Verification (CRITICAL)

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

Known Parameter Corrections

Tool	WRONG Parameter	CORRECT Parameter
OpenTargets_get_associated_drugs_by_target_ensemblID	ensemblID	ensemblId (camelCase)
OpenTargets_get_drug_chembId_by_generic_name	genericName	drugName
OpenTargets_target_disease_evidence	ensemblID	ensemblId + efoId
MyGene_query_genes	q	query
search_clinical_trials	disease, biomarker	condition, query_term (required)
civic_get_variants_by_gene	gene_symbol	gene_id (CIViC numeric ID)
drugbank_*	any 3 params	ALL 4 required: query, case_sensitive, exact_match, limit
ChEMBL_get_drug_mechanisms	chembl_id	drug_chembl_id__exact
ensembl_lookup_gene	no species	species='homo_sapiens' is REQUIRED for Ensembl IDs

---

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)
  - Get CIViC assertions

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 of action
  - Drug label information
  - Combination therapies

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

Phase 6: Clinical Trials
  - Active trials recruiting for this mutation
  - Trial phase and status
  - Eligibility criteria

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

Phase 8: Report Synthesis
  - Executive summary
  - Clinical actionability score
  - Treatment recommendations (prioritized)
  - Completeness checklist

---

Phase 1: Gene Disambiguation & ID Resolution

Goal: Resolve gene symbol to all cross-database identifiers needed for downstream queries.

1.1 MyGene ID Resolution (PRIMARY)

def resolve_gene_ids(tu, gene_symbol):
    """Resolve gene symbol to Ensembl, Entrez, UniProt IDs."""
    result = tu.tools.MyGene_query_genes(query=gene_symbol, species='human')

    hits = result.get('hits', [])
    # Take the top hit where symbol matches exactly
    gene_hit = None
    for hit in hits:
        if hit.get('symbol', '').upper() == gene_symbol.upper():
            gene_hit = hit
            break
    if not gene_hit and hits:
        gene_hit = hits[0]

    ids = {
        'symbol': gene_hit.get('symbol'),
        'entrez_id': gene_hit.get('entrezgene'),
        'ensembl_id': gene_hit.get('ensembl', {}).get('gene'),
        'name': gene_hit.get('name'),
    }
    return ids

Response structure: {took, total, max_score, hits: [{_id, _score, ensembl: {gene}, entrezgene, name, symbol}]}

1.2 UniProt Accession

def get_uniprot_id(tu, gene_symbol):
    """Get UniProt accession for gene."""
    result = tu.tools.UniProt_search(query=f'gene:{gene_symbol}', organism='human', limit=3)
    # Response: {total_results, returned, results: [{accession, id, protein_name, gene_names, organism, length}]}
    results = result.get('results', [])
    if results:
        return results[0].get('accession')
    return None

1.3 OpenTargets Target Resolution

def get_opentargets_info(tu, gene_symbol):
    """Resolve gene to OpenTargets ensemblId and description."""
    result = tu.tools.OpenTargets_get_target_id_description_by_name(targetName=gene_symbol)
    # Response: {data: {search: {hits: [{id (ensemblId), name, description}]}}}
    hits = result.get('data', {}).get('search', {}).get('hits', [])
    # Match exact gene symbol
    for hit in hits:
        if hit.get('name', '').upper() == gene_symbol.upper():
            return hit
    return hits[0] if hits else None

1.4 Cancer Type EFO Resolution (if cancer type provided)

def resolve_cancer_type(tu, cancer_type):
    """Resolve cancer type to EFO ID for OpenTargets queries."""
    result = tu.tools.OpenTargets_get_disease_id_description_by_name(diseaseName=cancer_type)
    # Response: {data: {search: {hits: [{id (efoId), name, description}]}}}
    hits = result.get('data', {}).get('search', {}).get('hits', [])
    return hits[0] if hits else None

1.5 Gene Function Context

def get_gene_function(tu, uniprot_accession):
    """Get protein function from UniProt.
    NOTE: Returns a list of function description strings, NOT a dict.
    """
    result = tu.tools.UniProt_get_function_by_accession(accession=uniprot_accession)
    # Response type: list of strings
    # Example: ["Receptor tyrosine kinase binding ligands of the EGF family...", ...]
    return result

1.6 CIViC Gene ID Resolution

IMPORTANT: The civic_search_genes tool does NOT support name filtering in its GraphQL query. To find a gene in CIViC, either:

1. Paginate through results (inefficient, genes sorted alphabetically)
2. Use the Entrez ID from MyGene to construct a CIViC gene lookup

Workaround: Use civic_search_genes with limit=100 and search the results client-side. For genes beyond alphabetical position ~100 (like EGFR, KRAS, TP53), you may need to use the CIViC gene ID if known from prior queries or documentation.

Known CIViC Gene IDs (for common cancer genes):

Gene	CIViC Gene ID	Entrez ID
BRAF	5	673
ABL1	4	25
ALK	1	238

For other genes, the skill should attempt to find the gene through pagination or use alternative evidence sources (OpenTargets, cBioPortal) if CIViC lookup fails.

---

Phase 2: Clinical Variant Evidence (CIViC)

Goal: Get clinical interpretations for the specific variant.

2.1 Get Gene Variants from CIViC

def get_civic_variants(tu, civic_gene_id):
    """Get all variants for a gene in CIViC."""
    result = tu.tools.civic_get_variants_by_gene(gene_id=civic_gene_id, limit=200)
    # Response: {data: {gene: {variants: {nodes: [{id, name}]}}}}
    variants = result.get('data', {}).get('gene', {}).get('variants', {}).get('nodes', [])
    return variants

2.2 Match Specific Variant

def find_variant_in_civic(variants, variant_name):
    """Find the specific variant in CIViC results."""
    # Normalize variant name (remove 'p.' prefix if present)
    normalized = variant_name.replace('p.', '').strip()

    for v in variants:
        if v.get('name', '').upper() == normalized.upper():
            return v

    # Partial match (e.g., "L858" matches "L858R")
    for v in variants:
        if normalized.upper() in v.get('name', '').upper():
            return v

    return None

2.3 Get Variant Details

def get_variant_details(tu, variant_id):
    """Get detailed variant information from CIViC."""
    result = tu.tools.civic_get_variant(variant_id=variant_id)
    # Response: {data: {variant: {id, name}}}
    return result.get('data', {}).get('variant', {})

2.4 Get Molecular Profile Evidence

def get_molecular_profile(tu, molecular_profile_id):
    """Get molecular profile details (for evidence items)."""
    result = tu.tools.civic_get_molecular_profile(molecular_profile_id=molecular_profile_id)
    # Response: {data: {molecularProfile: {id, name}}}
    return result.get('data', {}).get('molecularProfile', {})

2.5 CIViC Evidence Limitations and Fallback

The current CIViC tools return limited field sets from GraphQL. If CIViC data is sparse:

Fallback to literature: Use PubMed to search for "{gene} {variant} clinical significance cancer" Fallback to OpenTargets: Use OpenTargets_target_disease_evidence for target-disease evidence

Evidence Level Mapping

CIViC Level	Tier	Meaning	Clinical Action
A	T1 (highest)	FDA-approved, guideline	Standard of care
B	T2	Clinical evidence	Strong recommendation
C	T2	Case study	Consider with caution
D	T3	Preclinical	Research context only
E	T4	Inferential	Computational evidence

---

Phase 3: Mutation Prevalence (cBioPortal)

Goal: Determine how common this mutation is across cancer types and studies.

3.1 Find Relevant Studies

def find_cancer_studies(tu, cancer_keyword=None):
    """Find relevant cBioPortal studies."""
    result = tu.tools.cBioPortal_get_cancer_studies(limit=50)
    # Response: array of [{studyId, name, description, cancerTypeId, ...}]
    studies = result if isinstance(result, list) else result.get('data', [])

    if cancer_keyword:
        # Filter by cancer type keyword
        filtered = [s for s in studies
                    if cancer_keyword.lower() in str(s.get('name', '')).lower()
                    or cancer_keyword.lower() in str(s.get('cancerTypeId', '')).lower()]
        return filtered
    return studies

3.2 Get Mutation Data

def get_mutation_prevalence(tu, gene_symbol, study_id):
    """Get mutation data for a gene in a specific study."""
    result = tu.tools.cBioPortal_get_mutations(study_id=study_id, gene_list=gene_symbol)
    # Response: {status: 'success', data: [{proteinChange, mutationType, sampleId, ...}]}
    # OR sometimes a plain list. Handle both formats:
    if isinstance(result, list):
        mutations = result
    elif isinstance(result, dict):
        mutations = result.get('data', []) if result.get('status') == 'success' else []
    else:
        mutations = []
    return mutations

3.3 Analyze Mutation Distribution

def analyze_mutation_distribution(mutations, target_variant):
    """Count how many samples have the target variant vs. others."""
    from collections import Counter

    protein_changes = [m.get('proteinChange', '') for m in mutations]
    counts = Counter(protein_changes)

    total_mutated = len(mutations)
    target_count = sum(1 for m in mutations
                       if target_variant.upper() in str(m.get('proteinChange', '')).upper())

    return {
        'total_mutated_samples': total_mutated,
        'target_variant_count': target_count,
        'target_variant_frequency': target_count / total_mutated if total_mutated > 0 else 0,
        'top_variants': counts.most_common(10),
    }

3.4 Key cBioPortal Studies for Common Cancer Types

Cancer Type	Study ID	Description
Lung adenocarcinoma	luad_tcga	TCGA Lung Adenocarcinoma
Breast cancer	brca_tcga	TCGA Breast Cancer
Colorectal cancer	coadread_tcga	TCGA Colorectal
Melanoma	skcm_tcga	TCGA Melanoma
Pancreatic cancer	paad_tcga	TCGA Pancreatic
Glioblastoma	gbm_tcga	TCGA Glioblastoma
Prostate cancer	prad_tcga	TCGA Prostate
Ovarian cancer	ov_tcga	TCGA Ovarian

---

Phase 4: Therapeutic Associations

Goal: Identify all available therapies -- approved, in trials, and experimental.

4.1 OpenTargets Drug-Target Associations (PRIMARY)

def get_target_drugs(tu, ensembl_id, size=50):
    """Get all drugs associated with a target from OpenTargets."""
    result = tu.tools.OpenTargets_get_associated_drugs_by_target_ensemblID(
        ensemblId=ensembl_id, size=size
    )
    # Response: {data: {target: {id, approvedSymbol, knownDrugs: {count, rows: [
    #   {drug: {id, name, tradeNames, maximumClinicalTrialPhase, isApproved, hasBeenWithdrawn},
    #    phase, mechanismOfAction, disease: {id, name}}
    # ]}}}}

    drugs = result.get('data', {}).get('target', {}).get('knownDrugs', {})
    rows = drugs.get('rows', [])

    # Categorize
    approved = [r for r in rows if r.get('drug', {}).get('isApproved')]
    phase3 = [r for r in rows if r.get('phase') == 3 and not r.get('drug', {}).get('isApproved')]
    phase2 = [r for r in rows if r.get('phase') == 2]

    return {
        'total': drugs.get('count', 0),
        'approved': approved,
        'phase3': phase3,
        'phase2': phase2,
        'all_rows': rows
    }

4.2 OpenTargets Drug Mechanisms

def get_drug_mechanism(tu, chembl_id):
    """Get mechanism of action for a drug."""
    result = tu.tools.OpenTargets_get_drug_mechanisms_of_action_by_chemblId(chemblId=chembl_id)
    return result

4.3 FDA Label Information

def get_fda_label(tu, drug_name):
    """Get FDA-approved indications and label info."""
    indications = tu.tools.FDA_get_indications_by_drug_name(drug_name=drug_name, limit=3)
    # Response: {meta: {skip, limit, total}, results: [{openfda.brand_name, openfda.generic_name, indications_and_usage}]}

    warnings = tu.tools.FDA_get_boxed_warning_info_by_drug_name(drug_name=drug_name, limit=3)

    moa = tu.tools.FDA_get_mechanism_of_action_by_drug_name(drug_name=drug_name, limit=3)

    return {
        'indications': indications,
        'warnings': warnings,
        'mechanism': moa
    }

4.4 DrugBank Drug Information

def get_drugbank_info(tu, drug_name):
    """Get drug information from DrugBank."""
    result = tu.tools.drugbank_get_drug_basic_info_by_drug_name_or_id(
        query=drug_name, case_sensitive=False, exact_match=False, limit=3
    )
    # Response: {query, total_matches, total_returned_results, results: [{drug_name, drugbank_id, description, ...}]}
    return result

4.5 ChEMBL Drug Mechanism

def get_chembl_mechanism(tu, chembl_drug_id):
    """Get drug mechanism from ChEMBL."""
    result = tu.tools.ChEMBL_get_drug_mechanisms(drug_chembl_id__exact=chembl_drug_id, limit=10)
    return result

4.6 Disease-Specific Drug Filtering

When cancer type is provided, filter drugs by disease association:

def get_disease_specific_drugs(tu, efo_id, size=30):
    """Get drugs associated with a specific disease/cancer type."""
    result = tu.tools.OpenTargets_get_associated_drugs_by_disease_efoId(efoId=efo_id, size=size)
    return result

4.7 Treatment Prioritization

Priority	Criteria	Tier
1st Line	FDA-approved for exact indication + biomarker	T1
2nd Line	FDA-approved for different indication, same biomarker	T1-T2
3rd Line	Phase 3 clinical trial data	T2
4th Line	Phase 1-2 data, off-label with evidence	T3
5th Line	Preclinical or computational only	T4

---

Phase 5: Resistance Mechanisms

Goal: Identify known resistance patterns and strategies to overcome them.

5.1 CIViC Resistance Evidence

Search CIViC for variants with resistance significance for the target gene. Get all variants and look for those with "Resistance" in the name or description.

5.2 Literature-Based Resistance Search

def search_resistance_literature(tu, gene_symbol, drug_name):
    """Search PubMed for resistance mechanisms.
    NOTE: PubMed returns a plain list of article dicts, NOT {articles: [...]}.
    """
    result = tu.tools.PubMed_search_articles(
        query=f'"{gene_symbol}" AND "{drug_name}" AND resistance AND mechanism',
        limit=15,
        include_abstract=True
    )
    # Response: list of [{pmid, title, authors, journal, pub_date, doi, abstract, ...}]
    articles = result if isinstance(result, list) else result.get('articles', []) if isinstance(result, dict) else []
    return articles

5.3 Pathway-Based Bypass Resistance

def get_bypass_pathways(tu, uniprot_id):
    """Get pathways that could mediate bypass resistance."""
    result = tu.tools.Reactome_map_uniprot_to_pathways(id=uniprot_id)
    return result

5.4 Known Resistance Patterns (Reference)

Primary Target	Primary Drug	Resistance Mutation	Mechanism	Strategy
EGFR L858R	Erlotinib/Gefitinib	T790M	Steric hindrance	Osimertinib (3rd-gen TKI)
EGFR T790M	Osimertinib	C797S	Covalent bond loss	4th-gen TKI trials
BRAF V600E	Vemurafenib	Splice variants	Paradoxical activation	BRAF+MEK combination
ALK fusion	Crizotinib	L1196M, G1269A	Kinase domain mutations	Alectinib, Lorlatinib
KRAS G12C	Sotorasib	Y96D, R68S	Drug binding loss	KRAS G12C combo trials

---

Phase 6: Clinical Trials

Goal: Find actively recruiting clinical trials relevant to this mutation.

6.1 Search Strategy

def find_clinical_trials(tu, gene_symbol, variant_name, cancer_type=None):
    """Find clinical trials for this mutation."""
    # Search 1: Gene + variant specific
    query1 = f'{gene_symbol} {variant_name}'
    result1 = tu.tools.search_clinical_trials(
        query_term=query1,
        condition=cancer_type or 'cancer',
        pageSize=20
    )

    # Search 2: Gene + targeted therapy
    result2 = tu.tools.search_clinical_trials(
        query_term=f'{gene_symbol} mutation',
        condition=cancer_type or 'cancer',
        pageSize=20
    )

    return {
        'variant_specific': result1,
        'gene_level': result2
    }

Response structure: {studies: [{NCT ID, brief_title, brief_summary, overall_status, condition, phase}], nextPageToken, total_count}

6.2 Trial Filtering

Prioritize trials that:

1. Are RECRUITING or NOT_YET_RECRUITING status
2. Match the specific variant (not just gene)
3. Are Phase 2 or 3 (closer to approval)
4. Have the right cancer type

6.3 Trial Output Format

| NCT ID | Phase | Agent(s) | Status | Cancer Type | Biomarker |
|--------|-------|----------|--------|-------------|-----------|

---

Phase 7: Prognostic Impact & Pathway Context

Goal: Assess the variant's impact on prognosis and biological context.

7.1 Literature Evidence

def get_prognostic_literature(tu, gene_symbol, variant_name, cancer_type=None):
    """Search for prognostic associations."""
    query = f'"{gene_symbol}" "{variant_name}" prognosis survival'
    if cancer_type:
        query += f' "{cancer_type}"'

    result = tu.tools.PubMed_search_articles(query=query, limit=10, include_abstract=True)
    return result

7.2 Pathway Context (Reactome)

def get_pathway_context(tu, uniprot_id):
    """Get pathway context from Reactome."""
    result = tu.tools.Reactome_map_uniprot_to_pathways(id=uniprot_id)
    return result

7.3 Gene Expression (GTEx)

def get_expression_context(tu, ensembl_id):
    """Get tissue expression data from GTEx."""
    # GTEx needs versioned ID. IMPORTANT: ensembl_lookup_gene requires species parameter.
    gene_info = tu.tools.ensembl_lookup_gene(gene_id=ensembl_id, species='homo_sapiens')
    # Response: {status: 'success', data: {id, version, display_name, ...}}
    data = gene_info.get('data', gene_info) if isinstance(gene_info, dict) else {}
    version = data.get('version', 1)
    versioned_id = f"{ensembl_id}.{version}"

    result = tu.tools.GTEx_get_median_gene_expression(
        gencode_id=versioned_id, operation='median'
    )
    return result

7.4 UniProt Disease Variants

def get_known_disease_variants(tu, uniprot_accession):
    """Get known disease-associated variants from UniProt."""
    result = tu.tools.UniProt_get_disease_variants_by_accession(accession=uniprot_accession)
    return result

---

Phase 8: Report Synthesis

8.1 Report File Naming

{GENE}_{VARIANT}_cancer_variant_report.md

Examples:
EGFR_L858R_cancer_variant_report.md
BRAF_V600E_cancer_variant_report.md
KRAS_G12C_cancer_variant_report.md

8.2 Report Template

# Cancer Variant Interpretation Report: {GENE} {VARIANT}

**Date**: {date}
**Cancer Type**: {cancer_type or "Not specified"}

---

## Executive Summary

{1-2 sentences summarizing the key finding and top recommendation}

**Clinical Actionability**: {Score: HIGH / MODERATE / LOW / UNKNOWN}

---

## 1. Gene & Variant Overview

| Field | Value |
|-------|-------|
| Gene Symbol | {symbol} |
| Full Name | {name} |
| Ensembl ID | {ensembl_id} |
| UniProt | {uniprot_accession} |
| Entrez ID | {entrez_id} |
| Variant | {variant_notation} |
| Protein Function | {function_summary} |

## 2. Clinical Variant Evidence

### 2.1 CIViC Clinical Interpretations

| Evidence Type | Description | Level | Clinical Significance |
|---------------|-------------|-------|----------------------|
| ... | ... | ... | ... |

### 2.2 Evidence Summary

{Summary of clinical evidence from CIViC and other sources}

*Source: CIViC via civic_get_variants_by_gene, civic_get_variant*

## 3. Mutation Prevalence

### 3.1 Frequency Across Cancer Types (cBioPortal)

| Study | Cancer Type | Total Mutated | This Variant | Frequency |
|-------|-------------|---------------|--------------|-----------|
| ... | ... | ... | ... | ... |

### 3.2 Co-occurring Mutations

{Top co-occurring mutations from cBioPortal data}

*Source: cBioPortal via cBioPortal_get_mutations*

## 4. Therapeutic Options

### 4.1 FDA-Approved Therapies (T1 Evidence)

| Drug | Trade Name | Indication | Mechanism | Phase |
|------|-----------|------------|-----------|-------|
| ... | ... | ... | ... | ... |

### 4.2 Clinical Trial Drugs (T2-T3 Evidence)

| Drug | ChEMBL ID | Phase | Mechanism | Disease |
|------|-----------|-------|-----------|---------|
| ... | ... | ... | ... | ... |

### 4.3 Drug Details

{For each recommended drug: mechanism of action, FDA label info, dosing, warnings}

*Sources: OpenTargets, FDA, DrugBank, ChEMBL*

## 5. Resistance Mechanisms

### 5.1 Known Resistance Patterns

| Resistance Mutation | Drug Affected | Mechanism | Strategy to Overcome |
|--------------------|---------------|-----------|---------------------|
| ... | ... | ... | ... |



{Pathway analysis showing potential bypass resistance routes}







| NCT ID | Phase | Agent(s) | Status | Biomarker Required |
|--------|-------|----------|--------|-------------------|
| ... | ... | ... | ... | ... |



{Specific trial recommendations based on patient's mutation and cancer type}







{Literature-based prognostic data}



{Pathway analysis and biological context}



{Tissue expression data for the gene}





| Finding | Evidence Tier | Source | Confidence |
|---------|--------------|--------|------------|
| ... | T1/T2/T3/T4 | ... | High/Moderate/Low |

---



| Source | Tool(s) Used | Data Retrieved |
|--------|-------------|----------------|
| MyGene | MyGenegenes | Gene IDs |
| UniProt | UniProtgetbygetdrugstargetsearchgetbygetgetbyname | Drug labels |
| DrugBank | drugbankdruginfodrugorgetmechanisms | Drug mechanisms |
| ClinicalTrials.gov | searchtrials | Active trials |
| PubMed | PubMedarticles | Literature evidence |
| Reactome | Reactomeuniprotpathways | Pathway context |
| GTEx | GTExmedianexpression | Expression data |

---



 [ ] Gene resolved to Ensembl, UniProt, and Entrez IDs
 [ ] Clinical variant evidence queried (CIViC or alternative)
 [ ] Mutation prevalence assessed (cBioPortal, at least 1 study)
 [ ] At least 1 therapeutic option identified with evidence tier, OR documented as "no targeted therapy available"
 [ ] FDA label information retrieved for recommended drugs
 [ ] Resistance mechanisms assessed (known patterns + literature search)
 [ ] At least 3 clinical trials listed, OR "no matching trials found"
 [ ] Prognostic literature searched
 [ ] Pathway context provided (Reactome)
 [ ] Executive summary is actionable (says what to DO)
 [ ] All recommendations have source citations
 [ ] Evidence tiers assigned to all findings

---

Evidence Grading System

Tier	Symbol	Criteria	Examples
T1	[T1]	FDA-approved therapy, Level A CIViC evidence, phase 3 trial	Osimertinib for EGFR T790M
T2	[T2]	Phase 2/3 clinical data, Level B CIViC evidence	Combination trial data
T3	[T3]	Preclinical data, Level D CIViC, case reports	Novel mechanisms, in vitro
T4	[T4]	Computational prediction, pathway inference	Docking, pathway analysis

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Clinical Actionability Scoring

Score	Criteria
HIGH	FDA-approved targeted therapy exists for this exact mutation + cancer type
MODERATE	Approved therapy exists for different cancer type with same mutation, OR phase 2-3 trial data
LOW	Only preclinical evidence or pathway-based rationale
UNKNOWN	Insufficient data to assess actionability

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Fallback Chains

Primary Tool	Fallback	Use When
CIViC variant lookup	PubMed literature search	Gene not found in CIViC (search doesn't filter)
OpenTargets drugs	ChEMBL drug search	No OpenTargets drug hits
FDA indications	DrugBank drug info	Drug not in FDA database
cBioPortal TCGA study	cBioPortal pan-cancer	Specific cancer study not available
GTEx expression	Ensembl gene lookup	GTEx returns empty
Reactome pathways	UniProt function	Pathway mapping fails

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Tool Reference (Verified Parameters)

Gene Resolution

Tool	Parameters	Response Key Fields
MyGene_query_genes	query (required), species	hits[].symbol, hits[].ensembl.gene, hits[].entrezgene
UniProt_search	query (required), organism, limit	results[].accession, results[].gene_names
OpenTargets_get_target_id_description_by_name	targetName (required)	data.search.hits[].id (ensemblId)
ensembl_lookup_gene	gene_id (required), species (REQUIRED: 'homo_sapiens')	data.id, data.display_name, data.version

Clinical Evidence

Tool	Parameters	Response Key Fields
civic_search_genes	query, limit	data.genes.nodes[].id, .name, .entrezId
civic_get_variants_by_gene	gene_id (required, CIViC numeric), limit	data.gene.variants.nodes[].id, .name
civic_get_variant	variant_id (required)	data.variant.id, .name
civic_get_molecular_profile	molecular_profile_id (required)	data.molecularProfile.id, .name

Mutation Prevalence

Tool	Parameters	Response Key Fields
cBioPortal_get_mutations	study_id, gene_list	data[].proteinChange, .mutationType, .sampleId (wrapped in {status, data})
cBioPortal_get_cancer_studies	limit	[].studyId, .name, .cancerTypeId
cBioPortal_get_molecular_profiles	study_id (required)	[].molecularProfileId, .molecularAlterationType

Drug Information

Tool	Parameters	Response Key Fields
OpenTargets_get_associated_drugs_by_target_ensemblID	ensemblId (required), size	data.target.knownDrugs.rows[].drug.name, .isApproved, .mechanismOfAction
OpenTargets_get_drug_chembId_by_generic_name	drugName (required)	data.search.hits[].id (ChEMBL ID), .name
FDA_get_indications_by_drug_name	drug_name, limit	results[].indications_and_usage, .openfda.brand_name
FDA_get_mechanism_of_action_by_drug_name	drug_name, limit	results[].mechanism_of_action
FDA_get_boxed_warning_info_by_drug_name	drug_name, limit	results[].boxed_warning
drugbank_get_drug_basic_info_by_drug_name_or_id	query, case_sensitive, exact_match, limit (ALL required)	results[].drug_name, .drugbank_id, .description
ChEMBL_get_drug_mechanisms	drug_chembl_id__exact (required), limit	data.mechanisms[]
drugbank_get_pharmacology_by_drug_name_or_drugbank_id	query, case_sensitive, exact_match, limit (ALL required)	results[].pharmacology

Clinical Trials

Tool	Parameters	Response Key Fields
search_clinical_trials	query_term (required), condition, intervention, pageSize	studies[].NCT ID, .brief_title, .overall_status, .phase

Literature & Pathways

Tool	Parameters	Response Key Fields
PubMed_search_articles	query (required), limit, include_abstract	Returns list of [{pmid, title, authors, journal, pub_date, doi, abstract}] (NOT wrapped in dict)
Reactome_map_uniprot_to_pathways	id (required, UniProt accession)	Pathway mappings
GTEx_get_median_gene_expression	gencode_id (required), operation="median"	Expression by tissue
UniProt_get_function_by_accession	accession (required)	Protein function
UniProt_get_disease_variants_by_accession	accession (required)	Disease variants

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Common Use Cases

Use Case 1: Oncologist Evaluating Treatment Options

Input: "EGFR L858R in lung adenocarcinoma"

Expected Output: Report showing osimertinib as 1st-line [T1], with FDA label details, resistance pattern (T790M), clinical trials for combination therapies, and prognostic context.

Use Case 2: Molecular Tumor Board Preparation

Input: "BRAF V600E, colorectal cancer"

Expected Output: Report noting that BRAF V600E is actionable in melanoma but requires combination therapy in CRC (encorafenib + cetuximab), with different resistance patterns than melanoma.

Use Case 3: Clinical Trial Matching

Input: "KRAS G12C, any cancer type"

Expected Output: Report with sotorasib/adagrasib as approved options [T1], comprehensive trial listing for KRAS G12C inhibitors, resistance patterns (Y96D, etc.), and mutation prevalence across cancer types.

Use Case 4: Resistance Mechanism Investigation

Input: "EGFR T790M after osimertinib failure"

Expected Output: Report focused on C797S resistance mutation, available 4th-generation TKI trials, amivantamab/lazertinib combinations, and bypass pathway mechanisms (MET amplification, HER2 activation).

Use Case 5: VUS Interpretation

Input: "PIK3CA E545K"

Expected Output: Report showing this is a known hotspot oncogenic mutation (not a VUS), with alpelisib as FDA-approved therapy for HR+/HER2- breast cancer, and prevalence data across cancer types.

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Quantified Minimums

Section	Requirement
Gene IDs	At least Ensembl + UniProt resolved
Clinical evidence	CIViC queried + PubMed literature search
Mutation prevalence	At least 1 cBioPortal study
Therapeutic options	All approved drugs listed (OpenTargets) + FDA label for top drugs
Resistance	Literature search performed + known patterns documented
Clinical trials	At least 1 search query executed
Prognostic impact	PubMed literature search performed
Pathway context	Reactome pathway mapping attempted

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See Also

• QUICK_START.md - Example usage and quick reference
• TOOLS_REFERENCE.md - Detailed tool parameter reference
• EXAMPLES.md - Complete example reports