@erosolaraijs/cure 2.3.1 → 2.5.0

package/src/capabilities/precisionMedicineModule.ts

@@ -0,0 +1,952 @@
+/**
+ * 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                                             ║
+ * ╚═══════════════════════════════════════════════════════════════════════════════╝
+ */
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// GENOMIC ALTERATION DEFINITIONS
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export interface GenomicAlteration {
+  gene: string;
+  alteration: string;
+  alterationType: AlterationType;
+  frequency: string;
+  cancerTypes: string[];
+  actionability: ActionabilityLevel;
+  therapies: TargetedTherapy[];
+  clinicalTrials: string[];
+  resistance: ResistanceMutation[];
+  prognosticValue: PrognosticValue;
+}
+
+export type AlterationType =
+  | 'Missense Mutation'
+  | 'Nonsense Mutation'
+  | 'Frameshift'
+  | 'In-frame Deletion'
+  | 'In-frame Insertion'
+  | 'Splice Site'
+  | 'Amplification'
+  | 'Deletion'
+  | 'Fusion'
+  | 'Rearrangement'
+  | 'Copy Number Gain'
+  | 'Copy Number Loss';
+
+export interface ActionabilityLevel {
+  level: 'Level 1' | 'Level 2' | 'Level 3A' | 'Level 3B' | 'Level 4' | 'Not Actionable';
+  description: string;
+  source: string;
+}
+
+export interface TargetedTherapy {
+  drug: string;
+  class: string;
+  approvalStatus: 'FDA-Approved' | 'EMA-Approved' | 'Off-Label' | 'Clinical Trial';
+  indication: string;
+  responseRate: string;
+  medianPFS: string;
+  keyTrial: string;
+}
+
+export interface ResistanceMutation {
+  mutation: string;
+  frequency: string;
+  overcomingStrategy: string[];
+}
+
+export interface PrognosticValue {
+  impact: 'Favorable' | 'Unfavorable' | 'Neutral' | 'Context-Dependent';
+  description: string;
+}
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// ACTIONABLE GENOMIC DATABASE
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export const ACTIONABLE_GENOMIC_DATABASE: GenomicAlteration[] = [
+  // 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' }
+  }
+];
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// PHARMACOGENOMICS FOR ONCOLOGY
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export interface PharmacogenomicMarker {
+  gene: string;
+  variant: string;
+  affectedDrugs: DrugPGx[];
+  testingRecommendation: 'Required' | 'Strongly Recommended' | 'Consider' | 'Optional';
+  guidelineSource: string;
+}
+
+export interface DrugPGx {
+  drug: string;
+  effect: string;
+  recommendation: string;
+  doseAdjustment?: string;
+}
+
+export const PHARMACOGENOMIC_MARKERS: PharmacogenomicMarker[] = [
+  {
+    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'
+  }
+];
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// TUMOR MICROENVIRONMENT ANALYSIS
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export interface TumorMicroenvironment {
+  immuneInfiltration: ImmuneInfiltration;
+  stromalPhenotype: StromalPhenotype;
+  vascularization: VascularStatus;
+  immunePhenotype: 'Inflamed' | 'Excluded' | 'Desert';
+  therapeuticImplications: TherapeuticImplication[];
+}
+
+export interface ImmuneInfiltration {
+  cd8TILs: 'High' | 'Intermediate' | 'Low' | 'Absent';
+  cd4TILs: 'High' | 'Intermediate' | 'Low';
+  tregs: 'High' | 'Low';
+  myeloidCells: MDSCStatus;
+  nkCells: 'Present' | 'Absent';
+  bCells: 'Present' | 'Absent' | 'TLS Present';
+}
+
+export interface MDSCStatus {
+  mdscLevel: 'High' | 'Low';
+  m1m2Ratio: 'M1-predominant' | 'M2-predominant' | 'Mixed';
+}
+
+export interface StromalPhenotype {
+  cafPresence: 'High' | 'Low';
+  ecmDensity: 'Dense' | 'Moderate' | 'Loose';
+  fibrosis: boolean;
+}
+
+export interface VascularStatus {
+  vascularDensity: 'High' | 'Moderate' | 'Low';
+  vascularNormalization: boolean;
+  hypoxia: boolean;
+}
+
+export interface TherapeuticImplication {
+  finding: string;
+  implication: string;
+  recommendation: string;
+}
+
+export const TME_THERAPEUTIC_IMPLICATIONS: Record<string, TherapeuticImplication[]> = {
+  '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'
+    }
+  ]
+};
+
+// ═══════════════════════════════════════════════════════════════════════════════
+// LIQUID BIOPSY / ctDNA INTERPRETATION
+// ═══════════════════════════════════════════════════════════════════════════════
+
+export interface LiquidBiopsyResult {
+  sampleDate: string;
+  ctdnaFraction: number;
+  alterationsDetected: CtDNAAlteration[];
+  clinicalInterpretation: CtDNAInterpretation;
+}
+
+export interface CtDNAAlteration {
+  gene: string;
+  alteration: string;
+  vaf: number; // Variant allele frequency
+  clinicalSignificance: 'Actionable' | 'Resistance' | 'Prognostic' | 'VUS' | 'Benign';
+}
+
+export interface CtDNAInterpretation {
+  summary: string;
+  actionableFindings: string[];
+  resistanceMutations: string[];
+  monitoringRecommendation: string;
+  tissueConfirmationNeeded: boolean;
+}
+
+export function interpretCtDNA(result: LiquidBiopsyResult): CtDNAInterpretation {
+  const actionableFindings: string[] = [];
+  const resistanceMutations: string[] = [];
+
+  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: string): GenomicAlteration[] {
+    return ACTIONABLE_GENOMIC_DATABASE.filter(a =>
+      a.gene.toLowerCase() === gene.toLowerCase()
+    );
+  }
+
+  getAlterationByType(alteration: string): GenomicAlteration | undefined {
+    return ACTIONABLE_GENOMIC_DATABASE.find(a =>
+      a.alteration.toLowerCase().includes(alteration.toLowerCase()) ||
+      alteration.toLowerCase().includes(a.alteration.toLowerCase())
+    );
+  }
+
+  getTherapiesForAlteration(gene: string, alteration: string): TargetedTherapy[] {
+    const genomicAlt = ACTIONABLE_GENOMIC_DATABASE.find(a =>
+      a.gene.toLowerCase() === gene.toLowerCase() &&
+      a.alteration.toLowerCase().includes(alteration.toLowerCase())
+    );
+    return genomicAlt?.therapies || [];
+  }
+
+  getPharmacogenomicRecommendation(drug: string): PharmacogenomicMarker | undefined {
+    return PHARMACOGENOMIC_MARKERS.find(p =>
+      p.affectedDrugs.some(d => d.drug.toLowerCase().includes(drug.toLowerCase()))
+    );
+  }
+
+  assessActionability(alterations: { gene: string; alteration: string }[]): {
+    level1: GenomicAlteration[];
+    level2: GenomicAlteration[];
+    level3: GenomicAlteration[];
+    notActionable: string[];
+  } {
+    const result = {
+      level1: [] as GenomicAlteration[],
+      level2: [] as GenomicAlteration[],
+      level3: [] as GenomicAlteration[],
+      notActionable: [] as string[]
+    };
+
+    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: TumorMicroenvironment['immunePhenotype']): TherapeuticImplication[] {
+    return TME_THERAPEUTIC_IMPLICATIONS[phenotype] || [];
+  }
+
+  interpretLiquidBiopsy(result: LiquidBiopsyResult): CtDNAInterpretation {
+    return interpretCtDNA(result);
+  }
+
+  generatePrecisionReport(
+    patientId: string,
+    genomicProfile: { gene: string; alteration: string; type: string }[],
+    pharmacogenomics: string[],
+    tmeIfAvailable?: TumorMicroenvironment
+  ): {
+    actionableTargets: GenomicAlteration[];
+    pgxRecommendations: PharmacogenomicMarker[];
+    tmeImplications: TherapeuticImplication[];
+    clinicalTrialTargets: string[];
+    summary: string;
+  } {
+    const actionability = this.assessActionability(genomicProfile);
+
+    const pgxRecommendations: PharmacogenomicMarker[] = [];
+    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();