/**
 * 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();