@erosolaraijs/cure 2.3.1 → 2.4.0

package/dist/capabilities/precisionMedicineModule.js

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+/**
+ * Precision Medicine and Genomic Interpretation Module
+ *
+ * ╔═══════════════════════════════════════════════════════════════════════════════╗
+ * ║  PRECISION ONCOLOGY - BIOMARKER-DRIVEN TREATMENT SELECTION                  ║
+ * ╠═══════════════════════════════════════════════════════════════════════════════╣
+ * ║  This module provides:                                                        ║
+ * ║  - Comprehensive genomic interpretation                                      ║
+ * ║  - Actionable mutation databases                                             ║
+ * ║  - Pharmacogenomics for toxicity prediction                                  ║
+ * ║  - Tumor microenvironment analysis                                           ║
+ * ║  - ctDNA/liquid biopsy interpretation                                        ║
+ * ║  - Variant actionability scoring                                             ║
+ * ╚═══════════════════════════════════════════════════════════════════════════════╝
+ */
+// ═══════════════════════════════════════════════════════════════════════════════
+// ACTIONABLE GENOMIC DATABASE
+// ═══════════════════════════════════════════════════════════════════════════════
+export const ACTIONABLE_GENOMIC_DATABASE = [
+    // EGFR Mutations
+    {
+        gene: 'EGFR',
+        alteration: 'Exon 19 deletion',
+        alterationType: 'In-frame Deletion',
+        frequency: '45% of EGFR mutations',
+        cancerTypes: ['NSCLC Adenocarcinoma'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB, NCCN'
+        },
+        therapies: [
+            {
+                drug: 'Osimertinib',
+                class: 'Third-generation EGFR TKI',
+                approvalStatus: 'FDA-Approved',
+                indication: 'First-line metastatic NSCLC',
+                responseRate: '80%',
+                medianPFS: '18.9 months',
+                keyTrial: 'FLAURA'
+            },
+            {
+                drug: 'Erlotinib',
+                class: 'First-generation EGFR TKI',
+                approvalStatus: 'FDA-Approved',
+                indication: 'First-line (less preferred)',
+                responseRate: '65%',
+                medianPFS: '10.4 months',
+                keyTrial: 'EURTAC'
+            }
+        ],
+        clinicalTrials: ['Amivantamab combinations', 'EGFR-MET bispecifics'],
+        resistance: [
+            { mutation: 'T790M', frequency: '50-60%', overcomingStrategy: ['Osimertinib'] },
+            { mutation: 'C797S', frequency: '10-25%', overcomingStrategy: ['Amivantamab', 'BLU-945 (investigational)'] },
+            { mutation: 'MET amplification', frequency: '5-20%', overcomingStrategy: ['EGFR TKI + MET inhibitor'] }
+        ],
+        prognosticValue: { impact: 'Favorable', description: 'Better outcomes with TKI therapy' }
+    },
+    {
+        gene: 'EGFR',
+        alteration: 'L858R',
+        alterationType: 'Missense Mutation',
+        frequency: '40% of EGFR mutations',
+        cancerTypes: ['NSCLC Adenocarcinoma'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB, NCCN'
+        },
+        therapies: [
+            {
+                drug: 'Osimertinib',
+                class: 'Third-generation EGFR TKI',
+                approvalStatus: 'FDA-Approved',
+                indication: 'First-line metastatic NSCLC',
+                responseRate: '77%',
+                medianPFS: '18.9 months',
+                keyTrial: 'FLAURA'
+            }
+        ],
+        clinicalTrials: ['Same as exon 19 del'],
+        resistance: [
+            { mutation: 'T790M', frequency: '50-60%', overcomingStrategy: ['Osimertinib'] },
+            { mutation: 'C797S', frequency: '10-25%', overcomingStrategy: ['Amivantamab'] }
+        ],
+        prognosticValue: { impact: 'Favorable', description: 'Response to EGFR TKI, slightly less favorable than exon 19 del' }
+    },
+    {
+        gene: 'EGFR',
+        alteration: 'Exon 20 insertion',
+        alterationType: 'In-frame Insertion',
+        frequency: '10% of EGFR mutations',
+        cancerTypes: ['NSCLC Adenocarcinoma'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Amivantamab',
+                class: 'EGFR-MET bispecific antibody',
+                approvalStatus: 'FDA-Approved',
+                indication: 'After platinum-based chemo',
+                responseRate: '40%',
+                medianPFS: '8.3 months',
+                keyTrial: 'CHRYSALIS'
+            },
+            {
+                drug: 'Mobocertinib',
+                class: 'EGFR exon 20-specific TKI',
+                approvalStatus: 'FDA-Approved',
+                indication: 'After platinum-based chemo',
+                responseRate: '28%',
+                medianPFS: '7.3 months',
+                keyTrial: 'EXCLAIM'
+            }
+        ],
+        clinicalTrials: ['First-line amivantamab + lazertinib'],
+        resistance: [],
+        prognosticValue: { impact: 'Unfavorable', description: 'Resistant to standard EGFR TKIs, less favorable outcomes' }
+    },
+    // ALK Fusions
+    {
+        gene: 'ALK',
+        alteration: 'EML4-ALK fusion',
+        alterationType: 'Fusion',
+        frequency: '3-5% of NSCLC',
+        cancerTypes: ['NSCLC Adenocarcinoma'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB, NCCN'
+        },
+        therapies: [
+            {
+                drug: 'Lorlatinib',
+                class: 'Third-generation ALK TKI',
+                approvalStatus: 'FDA-Approved',
+                indication: 'First-line',
+                responseRate: '76%',
+                medianPFS: 'NR (60% at 3 years)',
+                keyTrial: 'CROWN'
+            },
+            {
+                drug: 'Alectinib',
+                class: 'Second-generation ALK TKI',
+                approvalStatus: 'FDA-Approved',
+                indication: 'First-line',
+                responseRate: '83%',
+                medianPFS: '34.8 months',
+                keyTrial: 'ALEX'
+            },
+            {
+                drug: 'Brigatinib',
+                class: 'Second-generation ALK TKI',
+                approvalStatus: 'FDA-Approved',
+                indication: 'First-line',
+                responseRate: '74%',
+                medianPFS: '24 months',
+                keyTrial: 'ALTA-1L'
+            }
+        ],
+        clinicalTrials: ['Next-gen ALK inhibitors'],
+        resistance: [
+            { mutation: 'G1202R', frequency: '20-30%', overcomingStrategy: ['Lorlatinib'] },
+            { mutation: 'L1196M', frequency: '10%', overcomingStrategy: ['Lorlatinib', 'Brigatinib'] },
+            { mutation: 'Compound mutations', frequency: '10-15%', overcomingStrategy: ['Lorlatinib (partial)', 'Clinical trial'] }
+        ],
+        prognosticValue: { impact: 'Favorable', description: 'Excellent response to ALK TKIs, long-term survival possible' }
+    },
+    // KRAS G12C
+    {
+        gene: 'KRAS',
+        alteration: 'G12C',
+        alterationType: 'Missense Mutation',
+        frequency: '13% of NSCLC, 3% of CRC',
+        cancerTypes: ['NSCLC Adenocarcinoma', 'Colorectal Cancer'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Sotorasib',
+                class: 'KRAS G12C inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'NSCLC after prior therapy',
+                responseRate: '37%',
+                medianPFS: '6.8 months',
+                keyTrial: 'CodeBreaK 100'
+            },
+            {
+                drug: 'Adagrasib',
+                class: 'KRAS G12C inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'NSCLC after prior therapy',
+                responseRate: '43%',
+                medianPFS: '6.5 months',
+                keyTrial: 'KRYSTAL-1'
+            }
+        ],
+        clinicalTrials: ['Combinations with SHP2 inhibitors', 'First-line combinations'],
+        resistance: [
+            { mutation: 'Multiple mechanisms', frequency: '50%+ at progression', overcomingStrategy: ['Combination strategies', 'SHP2 inhibitors'] }
+        ],
+        prognosticValue: { impact: 'Unfavorable', description: 'Historically poor prognosis, now improving with targeted therapy' }
+    },
+    // BRAF V600E
+    {
+        gene: 'BRAF',
+        alteration: 'V600E',
+        alterationType: 'Missense Mutation',
+        frequency: '50% melanoma, 8% CRC, 2% NSCLC',
+        cancerTypes: ['Melanoma', 'Colorectal Cancer', 'NSCLC', 'Thyroid Cancer'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Dabrafenib + Trametinib',
+                class: 'BRAF + MEK inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'Melanoma, NSCLC, Anaplastic thyroid',
+                responseRate: '64-68%',
+                medianPFS: '11-14 months',
+                keyTrial: 'COMBI-d/v, BRF113928'
+            },
+            {
+                drug: 'Encorafenib + Binimetinib',
+                class: 'BRAF + MEK inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'Melanoma',
+                responseRate: '63%',
+                medianPFS: '14.9 months',
+                keyTrial: 'COLUMBUS'
+            },
+            {
+                drug: 'Encorafenib + Cetuximab',
+                class: 'BRAF + EGFR inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'CRC after prior therapy',
+                responseRate: '20%',
+                medianPFS: '4.3 months',
+                keyTrial: 'BEACON'
+            }
+        ],
+        clinicalTrials: ['Triplet combinations', 'Immunotherapy combinations'],
+        resistance: [
+            { mutation: 'MAPK reactivation', frequency: 'Common', overcomingStrategy: ['Add MEK inhibitor', 'Immunotherapy switch'] }
+        ],
+        prognosticValue: { impact: 'Unfavorable', description: 'Poor prognosis especially in CRC; targetable' }
+    },
+    // HER2 Amplification/Mutation
+    {
+        gene: 'HER2/ERBB2',
+        alteration: 'Amplification',
+        alterationType: 'Amplification',
+        frequency: '15-20% breast, 10-15% gastric',
+        cancerTypes: ['Breast Cancer', 'Gastric Cancer', 'Esophageal Cancer'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Trastuzumab + Pertuzumab',
+                class: 'Anti-HER2 antibodies',
+                approvalStatus: 'FDA-Approved',
+                indication: 'HER2+ breast (first-line)',
+                responseRate: '80%',
+                medianPFS: '18.7 months',
+                keyTrial: 'CLEOPATRA'
+            },
+            {
+                drug: 'Trastuzumab Deruxtecan (T-DXd)',
+                class: 'HER2-directed ADC',
+                approvalStatus: 'FDA-Approved',
+                indication: 'HER2+ breast (second-line), HER2-low, gastric',
+                responseRate: '52-79%',
+                medianPFS: '10-29 months',
+                keyTrial: 'DESTINY-Breast01/03/04'
+            }
+        ],
+        clinicalTrials: ['T-DXd combinations', 'Novel ADCs'],
+        resistance: [
+            { mutation: 'Bypass pathways', frequency: 'Variable', overcomingStrategy: ['ADC therapy', 'TKI combinations'] }
+        ],
+        prognosticValue: { impact: 'Context-Dependent', description: 'Historically poor prognosis, now favorable with anti-HER2 therapy' }
+    },
+    // PIK3CA Mutations
+    {
+        gene: 'PIK3CA',
+        alteration: 'H1047R/E545K/E542K',
+        alterationType: 'Missense Mutation',
+        frequency: '40% HR+ breast cancer',
+        cancerTypes: ['Breast Cancer'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Alpelisib',
+                class: 'PI3K alpha inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'HR+/HER2- with PIK3CA mutation after prior ET',
+                responseRate: '26%',
+                medianPFS: '11 months',
+                keyTrial: 'SOLAR-1'
+            }
+        ],
+        clinicalTrials: ['Next-gen PI3K inhibitors'],
+        resistance: [],
+        prognosticValue: { impact: 'Neutral', description: 'Predictive of response to PI3K inhibitor' }
+    },
+    // ROS1 Fusion
+    {
+        gene: 'ROS1',
+        alteration: 'Various fusions',
+        alterationType: 'Fusion',
+        frequency: '1-2% of NSCLC',
+        cancerTypes: ['NSCLC Adenocarcinoma'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Entrectinib',
+                class: 'ROS1/TRK inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'First-line ROS1+ NSCLC',
+                responseRate: '77%',
+                medianPFS: '19 months',
+                keyTrial: 'STARTRK-2, ALKA-372-001'
+            },
+            {
+                drug: 'Crizotinib',
+                class: 'ROS1/ALK/MET inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'First-line ROS1+ NSCLC',
+                responseRate: '72%',
+                medianPFS: '19.3 months',
+                keyTrial: 'PROFILE 1001'
+            }
+        ],
+        clinicalTrials: ['Repotrectinib', 'Next-gen ROS1 TKIs'],
+        resistance: [
+            { mutation: 'G2032R', frequency: '30-40%', overcomingStrategy: ['Repotrectinib (investigational)', 'Lorlatinib'] }
+        ],
+        prognosticValue: { impact: 'Favorable', description: 'Excellent response to ROS1 inhibitors' }
+    },
+    // NTRK Fusions (Tissue-agnostic)
+    {
+        gene: 'NTRK1/2/3',
+        alteration: 'Various fusions',
+        alterationType: 'Fusion',
+        frequency: '<1% of common cancers, higher in rare cancers',
+        cancerTypes: ['Tissue-agnostic', 'Infantile Fibrosarcoma', 'Secretory Breast', 'Thyroid'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA tissue-agnostic approval',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Larotrectinib',
+                class: 'TRK inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'NTRK fusion-positive solid tumors',
+                responseRate: '75%',
+                medianPFS: '28.3 months',
+                keyTrial: 'NAVIGATE, SCOUT, LOXO-TRK-14001'
+            },
+            {
+                drug: 'Entrectinib',
+                class: 'TRK/ROS1 inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'NTRK fusion-positive solid tumors',
+                responseRate: '57%',
+                medianPFS: '11.2 months',
+                keyTrial: 'STARTRK-1/2, ALKA-372-001'
+            }
+        ],
+        clinicalTrials: ['Next-gen TRK inhibitors for resistance'],
+        resistance: [
+            { mutation: 'Solvent front mutations', frequency: '10-20%', overcomingStrategy: ['Selitrectinib', 'Repotrectinib'] }
+        ],
+        prognosticValue: { impact: 'Favorable', description: 'Excellent durable responses across tumor types' }
+    },
+    // RET Alterations
+    {
+        gene: 'RET',
+        alteration: 'Fusion or Mutation',
+        alterationType: 'Fusion',
+        frequency: '1-2% NSCLC, 10-20% thyroid',
+        cancerTypes: ['NSCLC', 'Thyroid Cancer (MTC, PTC)'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA-approved therapy exists',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Selpercatinib',
+                class: 'Selective RET inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'RET-altered NSCLC and thyroid',
+                responseRate: '64-85%',
+                medianPFS: '16.5-24.9 months',
+                keyTrial: 'LIBRETTO-001'
+            },
+            {
+                drug: 'Pralsetinib',
+                class: 'Selective RET inhibitor',
+                approvalStatus: 'FDA-Approved',
+                indication: 'RET-altered NSCLC and thyroid',
+                responseRate: '57-72%',
+                medianPFS: '13-17 months',
+                keyTrial: 'ARROW'
+            }
+        ],
+        clinicalTrials: ['Resistance mutation-targeting agents'],
+        resistance: [
+            { mutation: 'G810X solvent front', frequency: '10-20%', overcomingStrategy: ['Investigational agents'] }
+        ],
+        prognosticValue: { impact: 'Favorable', description: 'Excellent response to selective RET inhibitors' }
+    },
+    // MSI-H/dMMR (Tissue-agnostic)
+    {
+        gene: 'MSI-H/dMMR',
+        alteration: 'Microsatellite Instability High',
+        alterationType: 'Frameshift',
+        frequency: '15% CRC, 20-30% endometrial, variable others',
+        cancerTypes: ['Tissue-agnostic'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA tissue-agnostic approval',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Pembrolizumab',
+                class: 'Anti-PD-1',
+                approvalStatus: 'FDA-Approved',
+                indication: 'MSI-H/dMMR solid tumors',
+                responseRate: '39-45%',
+                medianPFS: '16.5 months (CRC)',
+                keyTrial: 'KEYNOTE-158, KEYNOTE-177'
+            },
+            {
+                drug: 'Dostarlimab',
+                class: 'Anti-PD-1',
+                approvalStatus: 'FDA-Approved',
+                indication: 'dMMR solid tumors',
+                responseRate: '42%',
+                medianPFS: 'Not reached',
+                keyTrial: 'GARNET'
+            }
+        ],
+        clinicalTrials: ['Neoadjuvant immunotherapy'],
+        resistance: [
+            { mutation: 'Beta-2-microglobulin loss', frequency: '5-10%', overcomingStrategy: ['Combination immunotherapy'] }
+        ],
+        prognosticValue: { impact: 'Favorable', description: 'Excellent response to immunotherapy' }
+    },
+    // TMB-High
+    {
+        gene: 'TMB-High',
+        alteration: 'Tumor Mutational Burden ≥10 mut/Mb',
+        alterationType: 'Missense Mutation',
+        frequency: 'Variable by cancer type',
+        cancerTypes: ['Tissue-agnostic'],
+        actionability: {
+            level: 'Level 1',
+            description: 'FDA tissue-agnostic approval',
+            source: 'OncoKB'
+        },
+        therapies: [
+            {
+                drug: 'Pembrolizumab',
+                class: 'Anti-PD-1',
+                approvalStatus: 'FDA-Approved',
+                indication: 'TMB-H (≥10 mut/Mb) solid tumors',
+                responseRate: '29%',
+                medianPFS: 'Variable',
+                keyTrial: 'KEYNOTE-158'
+            }
+        ],
+        clinicalTrials: ['Combination strategies'],
+        resistance: [],
+        prognosticValue: { impact: 'Context-Dependent', description: 'Predictive of immunotherapy response' }
+    }
+];
+export const PHARMACOGENOMIC_MARKERS = [
+    {
+        gene: 'DPYD',
+        variant: 'DPYD*2A, *13, c.2846A>T, HapB3',
+        affectedDrugs: [
+            {
+                drug: '5-Fluorouracil (5-FU)',
+                effect: 'Reduced DPD enzyme activity, increased toxicity risk',
+                recommendation: 'Test before initiating fluoropyrimidines',
+                doseAdjustment: '*2A/*2A: Avoid; Heterozygous: 50% dose reduction'
+            },
+            {
+                drug: 'Capecitabine',
+                effect: 'Same as 5-FU',
+                recommendation: 'Same as 5-FU',
+                doseAdjustment: 'Same as 5-FU'
+            }
+        ],
+        testingRecommendation: 'Strongly Recommended',
+        guidelineSource: 'CPIC, EMA'
+    },
+    {
+        gene: 'UGT1A1',
+        variant: 'UGT1A1*28, *6',
+        affectedDrugs: [
+            {
+                drug: 'Irinotecan',
+                effect: 'Reduced glucuronidation, increased SN-38 toxicity',
+                recommendation: 'Consider testing for high-dose irinotecan',
+                doseAdjustment: '*28/*28: Reduce dose 30%; *28/*6 or *6/*6: Reduce dose'
+            },
+            {
+                drug: 'Sacituzumab govitecan',
+                effect: 'Contains SN-38, similar toxicity risk',
+                recommendation: 'Consider testing',
+                doseAdjustment: '*28/*28: Monitor closely, consider dose reduction'
+            }
+        ],
+        testingRecommendation: 'Consider',
+        guidelineSource: 'CPIC, FDA label'
+    },
+    {
+        gene: 'TPMT/NUDT15',
+        variant: 'TPMT*2, *3A, *3B, *3C; NUDT15*3',
+        affectedDrugs: [
+            {
+                drug: '6-Mercaptopurine',
+                effect: 'Reduced thiopurine metabolism, severe myelosuppression',
+                recommendation: 'Test before initiating thiopurines',
+                doseAdjustment: 'Poor metabolizer: 10% of normal dose'
+            },
+            {
+                drug: 'Azathioprine',
+                effect: 'Same as 6-MP',
+                recommendation: 'Same',
+                doseAdjustment: 'Same'
+            }
+        ],
+        testingRecommendation: 'Required',
+        guidelineSource: 'CPIC, FDA label'
+    },
+    {
+        gene: 'G6PD',
+        variant: 'G6PD deficiency',
+        affectedDrugs: [
+            {
+                drug: 'Rasburicase',
+                effect: 'Hemolytic anemia, methemoglobinemia',
+                recommendation: 'Screen before use',
+                doseAdjustment: 'Contraindicated in G6PD deficiency'
+            }
+        ],
+        testingRecommendation: 'Required',
+        guidelineSource: 'FDA label'
+    },
+    {
+        gene: 'CYP2D6',
+        variant: 'Poor metabolizer',
+        affectedDrugs: [
+            {
+                drug: 'Tamoxifen',
+                effect: 'Reduced conversion to active metabolite endoxifen',
+                recommendation: 'Consider testing, especially if concurrent CYP2D6 inhibitors',
+                doseAdjustment: 'PM: Consider alternative (aromatase inhibitor if postmenopausal)'
+            }
+        ],
+        testingRecommendation: 'Consider',
+        guidelineSource: 'CPIC'
+    },
+    {
+        gene: 'HLA-B*57:01',
+        variant: 'Presence of allele',
+        affectedDrugs: [
+            {
+                drug: 'Abacavir',
+                effect: 'Hypersensitivity reaction',
+                recommendation: 'Test before initiating',
+                doseAdjustment: 'Do not use if positive'
+            }
+        ],
+        testingRecommendation: 'Required',
+        guidelineSource: 'FDA label, CPIC'
+    }
+];
+export const TME_THERAPEUTIC_IMPLICATIONS = {
+    'Inflamed': [
+        {
+            finding: 'High CD8+ TIL infiltration with PD-L1 expression',
+            implication: 'Likely responsive to PD-1/PD-L1 blockade',
+            recommendation: 'First-line immunotherapy appropriate'
+        },
+        {
+            finding: 'Tertiary lymphoid structures (TLS) present',
+            implication: 'Associated with improved immunotherapy response',
+            recommendation: 'Immunotherapy highly recommended'
+        }
+    ],
+    'Excluded': [
+        {
+            finding: 'T cells present at tumor margin but not infiltrating',
+            implication: 'Physical or immunological barrier to T cell entry',
+            recommendation: 'Consider anti-TGF-beta, CAF-targeting, or combination approaches'
+        },
+        {
+            finding: 'Dense fibrotic stroma',
+            implication: 'Stromal barrier limiting drug penetration',
+            recommendation: 'Consider stromal-targeting agents or chemotherapy to disrupt'
+        }
+    ],
+    'Desert': [
+        {
+            finding: 'Absence of immune infiltrate',
+            implication: 'Poor immunogenicity or immune evasion',
+            recommendation: 'Consider chemotherapy to induce immunogenic cell death, oncolytic viruses, or vaccines'
+        },
+        {
+            finding: 'Low TMB, no neoantigens',
+            implication: 'Limited targets for immune recognition',
+            recommendation: 'Chemotherapy or targeted therapy may be more appropriate than immunotherapy'
+        }
+    ]
+};
+export function interpretCtDNA(result) {
+    const actionableFindings = [];
+    const resistanceMutations = [];
+    for (const alt of result.alterationsDetected) {
+        if (alt.clinicalSignificance === 'Actionable') {
+            actionableFindings.push(`${alt.gene} ${alt.alteration} (VAF: ${alt.vaf}%)`);
+        }
+        if (alt.clinicalSignificance === 'Resistance') {
+            resistanceMutations.push(`${alt.gene} ${alt.alteration}`);
+        }
+    }
+    let summary = '';
+    if (result.ctdnaFraction < 0.5) {
+        summary = 'Low ctDNA fraction - may indicate low tumor burden or shedding; consider repeat testing or tissue biopsy';
+    }
+    else if (result.ctdnaFraction > 10) {
+        summary = 'High ctDNA fraction - indicates significant tumor burden';
+    }
+    else {
+        summary = 'Detectable ctDNA with interpretable results';
+    }
+    const tissueConfirmationNeeded = result.ctdnaFraction < 1 && actionableFindings.length > 0;
+    let monitoringRecommendation = 'Repeat ctDNA in 8-12 weeks or at clinical/radiographic progression';
+    if (resistanceMutations.length > 0) {
+        monitoringRecommendation = 'Resistance mutations detected - consider treatment change; repeat ctDNA after new therapy started';
+    }
+    return {
+        summary,
+        actionableFindings,
+        resistanceMutations,
+        monitoringRecommendation,
+        tissueConfirmationNeeded
+    };
+}
+// ═══════════════════════════════════════════════════════════════════════════════
+// PRECISION MEDICINE ENGINE
+// ═══════════════════════════════════════════════════════════════════════════════
+export class PrecisionMedicineEngine {
+    getActionableAlterations(gene) {
+        return ACTIONABLE_GENOMIC_DATABASE.filter(a => a.gene.toLowerCase() === gene.toLowerCase());
+    }
+    getAlterationByType(alteration) {
+        return ACTIONABLE_GENOMIC_DATABASE.find(a => a.alteration.toLowerCase().includes(alteration.toLowerCase()) ||
+            alteration.toLowerCase().includes(a.alteration.toLowerCase()));
+    }
+    getTherapiesForAlteration(gene, alteration) {
+        const genomicAlt = ACTIONABLE_GENOMIC_DATABASE.find(a => a.gene.toLowerCase() === gene.toLowerCase() &&
+            a.alteration.toLowerCase().includes(alteration.toLowerCase()));
+        return genomicAlt?.therapies || [];
+    }
+    getPharmacogenomicRecommendation(drug) {
+        return PHARMACOGENOMIC_MARKERS.find(p => p.affectedDrugs.some(d => d.drug.toLowerCase().includes(drug.toLowerCase())));
+    }
+    assessActionability(alterations) {
+        const result = {
+            level1: [],
+            level2: [],
+            level3: [],
+            notActionable: []
+        };
+        for (const alt of alterations) {
+            const match = ACTIONABLE_GENOMIC_DATABASE.find(a => a.gene.toLowerCase() === alt.gene.toLowerCase());
+            if (match) {
+                if (match.actionability.level === 'Level 1') {
+                    result.level1.push(match);
+                }
+                else if (match.actionability.level === 'Level 2') {
+                    result.level2.push(match);
+                }
+                else if (match.actionability.level.includes('3')) {
+                    result.level3.push(match);
+                }
+            }
+            else {
+                result.notActionable.push(`${alt.gene} ${alt.alteration}`);
+            }
+        }
+        return result;
+    }
+    getTMEImplications(phenotype) {
+        return TME_THERAPEUTIC_IMPLICATIONS[phenotype] || [];
+    }
+    interpretLiquidBiopsy(result) {
+        return interpretCtDNA(result);
+    }
+    generatePrecisionReport(patientId, genomicProfile, pharmacogenomics, tmeIfAvailable) {
+        const actionability = this.assessActionability(genomicProfile);
+        const pgxRecommendations = [];
+        for (const gene of pharmacogenomics) {
+            const pgx = PHARMACOGENOMIC_MARKERS.find(p => p.gene === gene);
+            if (pgx)
+                pgxRecommendations.push(pgx);
+        }
+        const tmeImplications = tmeIfAvailable
+            ? this.getTMEImplications(tmeIfAvailable.immunePhenotype)
+            : [];
+        const clinicalTrialTargets = [
+            ...actionability.level1.flatMap(a => a.clinicalTrials),
+            ...actionability.level2.flatMap(a => a.clinicalTrials),
+            ...actionability.level3.flatMap(a => a.clinicalTrials)
+        ];
+        const summary = `Found ${actionability.level1.length} Level 1, ${actionability.level2.length} Level 2, and ${actionability.level3.length} Level 3 actionable alterations. ${pgxRecommendations.length} pharmacogenomic considerations identified.`;
+        return {
+            actionableTargets: [...actionability.level1, ...actionability.level2],
+            pgxRecommendations,
+            tmeImplications,
+            clinicalTrialTargets: [...new Set(clinicalTrialTargets)],
+            summary
+        };
+    }
+}
+// Export singleton
+export const precisionMedicineEngine = new PrecisionMedicineEngine();
+//# sourceMappingURL=precisionMedicineModule.js.map