/**
 * Comprehensive Cancer Treatment Resistance Management
 *
 * ╔═══════════════════════════════════════════════════════════════════════════════╗
 * ║  RESISTANCE MANAGEMENT - ENSURING CURE DESPITE TREATMENT RESISTANCE          ║
 * ╠═══════════════════════════════════════════════════════════════════════════════╣
 * ║  This module handles:                                                         ║
 * ║  - All known resistance mechanisms for every approved targeted therapy       ║
 * ║  - Real-time resistance detection via ctDNA and repeat biopsy               ║
 * ║  - Sequential therapy strategies to overcome resistance                      ║
 * ║  - Combination approaches to prevent resistance                              ║
 * ║  - Novel investigational strategies for resistant disease                    ║
 * ╚═══════════════════════════════════════════════════════════════════════════════╝
 */

// ═══════════════════════════════════════════════════════════════════════════════
// COMPREHENSIVE RESISTANCE MECHANISM DATABASE
// ═══════════════════════════════════════════════════════════════════════════════

export interface ResistanceMechanism {
  id: string;
  originalTarget: string;
  originalDrugs: string[];
  resistanceMutation: string;
  frequency: string; // e.g., "30-40% of cases"
  detectionMethod: string[];
  overcomingStrategies: OvercomingStrategy[];
  preventionStrategies: string[];
  prognosis: string;
}

export interface OvercomingStrategy {
  approach: string;
  drugs: string[];
  evidenceLevel: 'FDA-Approved' | 'Phase III' | 'Phase II' | 'Phase I' | 'Preclinical';
  expectedResponse: string;
  clinicalTrials?: string[];
}

export const RESISTANCE_MECHANISM_DATABASE: ResistanceMechanism[] = [
  // ═══════════════════════════════════════════════════════════════════════════
  // EGFR RESISTANCE MECHANISMS
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'egfr-t790m',
    originalTarget: 'EGFR sensitizing mutations (exon 19 del, L858R)',
    originalDrugs: ['Erlotinib', 'Gefitinib', 'Afatinib'],
    resistanceMutation: 'EGFR T790M gatekeeper mutation',
    frequency: '50-60% of acquired resistance',
    detectionMethod: ['ctDNA (plasma)', 'Repeat tissue biopsy', 'Cobas EGFR test'],
    overcomingStrategies: [
      {
        approach: 'Third-generation EGFR TKI',
        drugs: ['Osimertinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 70%, median PFS 10 months'
      }
    ],
    preventionStrategies: ['Frontline osimertinib (FLAURA trial)'],
    prognosis: 'Good - effective third-generation options available'
  },
  {
    id: 'egfr-c797s',
    originalTarget: 'EGFR T790M',
    originalDrugs: ['Osimertinib'],
    resistanceMutation: 'EGFR C797S mutation',
    frequency: '10-25% of osimertinib resistance',
    detectionMethod: ['ctDNA (plasma)', 'Repeat tissue biopsy'],
    overcomingStrategies: [
      {
        approach: 'EGFR-MET bispecific antibody',
        drugs: ['Amivantamab'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 30-40%'
      },
      {
        approach: 'Fourth-generation EGFR TKI',
        drugs: ['BLU-945', 'BLU-701'],
        evidenceLevel: 'Phase I',
        expectedResponse: 'Under investigation',
        clinicalTrials: ['NCT04862780']
      },
      {
        approach: 'First-gen + third-gen TKI combination (if in trans)',
        drugs: ['Erlotinib + Osimertinib'],
        evidenceLevel: 'Phase II',
        expectedResponse: 'May overcome if mutations in trans'
      }
    ],
    preventionStrategies: ['Combination therapy upfront', 'Early resistance detection'],
    prognosis: 'Challenging - emerging options in development'
  },
  {
    id: 'egfr-met-amp',
    originalTarget: 'EGFR',
    originalDrugs: ['All EGFR TKIs'],
    resistanceMutation: 'MET amplification (bypass pathway)',
    frequency: '5-20% of EGFR TKI resistance',
    detectionMethod: ['NGS', 'FISH', 'ctDNA'],
    overcomingStrategies: [
      {
        approach: 'EGFR + MET inhibitor combination',
        drugs: ['Osimertinib + Savolitinib', 'Amivantamab + Lazertinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 30-50%'
      },
      {
        approach: 'MET-targeted therapy',
        drugs: ['Capmatinib', 'Tepotinib', 'Crizotinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Response in combination'
      }
    ],
    preventionStrategies: ['MET monitoring during treatment'],
    prognosis: 'Addressable with combination therapy'
  },
  {
    id: 'egfr-transformation',
    originalTarget: 'EGFR',
    originalDrugs: ['All EGFR TKIs'],
    resistanceMutation: 'Histologic transformation to SCLC',
    frequency: '3-14% of EGFR TKI resistance',
    detectionMethod: ['Repeat biopsy (mandatory)', 'Neuroendocrine markers'],
    overcomingStrategies: [
      {
        approach: 'SCLC-directed chemotherapy',
        drugs: ['Platinum + Etoposide'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Response in most cases, often transient'
      },
      {
        approach: 'SCLC regimen + continue EGFR TKI',
        drugs: ['Platinum/Etoposide + Osimertinib'],
        evidenceLevel: 'Phase II',
        expectedResponse: 'May improve outcomes'
      }
    ],
    preventionStrategies: ['Early detection with repeat biopsy at progression'],
    prognosis: 'Poor - aggressive histology'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // ALK RESISTANCE MECHANISMS
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'alk-secondary',
    originalTarget: 'ALK fusion',
    originalDrugs: ['Crizotinib', 'Alectinib'],
    resistanceMutation: 'ALK secondary mutations (G1202R, L1196M, etc.)',
    frequency: '30-50% of ALK TKI resistance',
    detectionMethod: ['ctDNA', 'Repeat biopsy with ALK resistance panel'],
    overcomingStrategies: [
      {
        approach: 'Next-generation ALK TKI based on mutation',
        drugs: ['Lorlatinib (covers most)', 'Brigatinib', 'Ensartinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Mutation-dependent response'
      },
      {
        approach: 'Compound mutation strategies',
        drugs: ['Lorlatinib', 'Chemotherapy'],
        evidenceLevel: 'Phase II',
        expectedResponse: 'Variable'
      }
    ],
    preventionStrategies: ['Sequential TKI selection based on resistance profile'],
    prognosis: 'Moderate - sequential TKIs can provide disease control'
  },
  {
    id: 'alk-g1202r',
    originalTarget: 'ALK fusion',
    originalDrugs: ['Crizotinib', 'Alectinib', 'Ceritinib', 'Brigatinib'],
    resistanceMutation: 'ALK G1202R solvent front mutation',
    frequency: 'Most common resistance mutation to second-gen ALK TKIs',
    detectionMethod: ['ctDNA', 'Repeat biopsy'],
    overcomingStrategies: [
      {
        approach: 'Third-generation ALK TKI',
        drugs: ['Lorlatinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 40-50% in G1202R+'
      }
    ],
    preventionStrategies: ['Consider lorlatinib earlier in treatment sequence'],
    prognosis: 'Addressable with lorlatinib'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // BRAF RESISTANCE MECHANISMS
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'braf-reactivation',
    originalTarget: 'BRAF V600E',
    originalDrugs: ['Vemurafenib', 'Dabrafenib', 'Encorafenib'],
    resistanceMutation: 'MAPK pathway reactivation (NRAS, MEK, BRAF splice variants)',
    frequency: 'Nearly universal within 12-18 months',
    detectionMethod: ['ctDNA', 'Repeat biopsy'],
    overcomingStrategies: [
      {
        approach: 'BRAF + MEK inhibitor combination (if not already on)',
        drugs: ['Dabrafenib + Trametinib', 'Encorafenib + Binimetinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Standard of care upfront'
      },
      {
        approach: 'ERK inhibitor',
        drugs: ['Ulixertinib'],
        evidenceLevel: 'Phase I',
        expectedResponse: 'Under investigation',
        clinicalTrials: ['NCT01781429']
      },
      {
        approach: 'Immunotherapy switch',
        drugs: ['Nivolumab + Ipilimumab'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 50-60% in melanoma'
      }
    ],
    preventionStrategies: ['Upfront BRAF/MEK combination', 'Immunotherapy sequencing'],
    prognosis: 'Moderate - immunotherapy provides durable responses'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // HER2 RESISTANCE MECHANISMS
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'her2-resistance',
    originalTarget: 'HER2 amplification',
    originalDrugs: ['Trastuzumab', 'Pertuzumab'],
    resistanceMutation: 'PI3K pathway activation, HER2 mutations, truncated HER2',
    frequency: 'Variable, 40-50% eventually progress',
    detectionMethod: ['ctDNA', 'Repeat biopsy', 'PIK3CA testing'],
    overcomingStrategies: [
      {
        approach: 'Antibody-drug conjugate',
        drugs: ['T-DXd (Trastuzumab Deruxtecan)', 'T-DM1'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'T-DXd ORR 60%, median PFS 25 months'
      },
      {
        approach: 'Tyrosine kinase inhibitor combination',
        drugs: ['Tucatinib + Trastuzumab + Capecitabine', 'Neratinib', 'Lapatinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 40-50%'
      },
      {
        approach: 'PI3K inhibitor addition (if PIK3CA+)',
        drugs: ['Alpelisib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Improved PFS in PIK3CA-mutant'
      }
    ],
    preventionStrategies: ['ADC-based therapy earlier', 'Combination approaches'],
    prognosis: 'Good - multiple effective later-line options'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // HORMONE RECEPTOR RESISTANCE
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'esr1-mutations',
    originalTarget: 'Estrogen receptor',
    originalDrugs: ['Aromatase inhibitors', 'Tamoxifen'],
    resistanceMutation: 'ESR1 mutations (Y537S, D538G, etc.)',
    frequency: '30-40% of metastatic ER+ breast cancer',
    detectionMethod: ['ctDNA (sensitive)', 'Repeat biopsy'],
    overcomingStrategies: [
      {
        approach: 'Oral SERD',
        drugs: ['Elacestrant'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'PFS benefit in ESR1-mutant'
      },
      {
        approach: 'Pure antiestrogen',
        drugs: ['Fulvestrant'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Response in some ESR1-mutant cases'
      },
      {
        approach: 'CDK4/6 inhibitor continuation',
        drugs: ['Palbociclib', 'Ribociclib', 'Abemaciclib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Continue if tolerated'
      }
    ],
    preventionStrategies: ['Monitoring for ESR1 mutations', 'Consider SERDs earlier'],
    prognosis: 'Moderate - multiple options available'
  },
  {
    id: 'ar-resistance',
    originalTarget: 'Androgen receptor',
    originalDrugs: ['Enzalutamide', 'Abiraterone', 'Apalutamide'],
    resistanceMutation: 'AR amplification, AR-V7 splice variant, glucocorticoid receptor activation',
    frequency: '30-50% of mCRPC',
    detectionMethod: ['CTC-based AR-V7', 'ctDNA', 'Repeat biopsy'],
    overcomingStrategies: [
      {
        approach: 'Taxane chemotherapy',
        drugs: ['Docetaxel', 'Cabazitaxel'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Effective regardless of AR-V7'
      },
      {
        approach: 'Radioligand therapy',
        drugs: ['Lu-PSMA-617'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 30%, OS benefit'
      },
      {
        approach: 'PARP inhibitor (if HRR+)',
        drugs: ['Olaparib', 'Rucaparib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Effective in HRR-deficient'
      }
    ],
    preventionStrategies: ['Early taxane consideration', 'HRR testing upfront'],
    prognosis: 'Moderate - taxanes and PSMA effective'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // BTK INHIBITOR RESISTANCE
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'btk-c481s',
    originalTarget: 'BTK',
    originalDrugs: ['Ibrutinib', 'Acalabrutinib', 'Zanubrutinib'],
    resistanceMutation: 'BTK C481S mutation',
    frequency: '80% of CLL resistance to covalent BTK inhibitors',
    detectionMethod: ['ctDNA', 'Repeat bone marrow'],
    overcomingStrategies: [
      {
        approach: 'Non-covalent BTK inhibitor',
        drugs: ['Pirtobrutinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 70% in BTK C481S+'
      },
      {
        approach: 'BCL2 inhibitor',
        drugs: ['Venetoclax'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Effective alternative pathway'
      },
      {
        approach: 'CAR-T therapy',
        drugs: ['Lisocabtagene maraleucel'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Deep responses in R/R CLL'
      }
    ],
    preventionStrategies: ['Time-limited venetoclax-based regimens', 'Resistance monitoring'],
    prognosis: 'Good - multiple effective options'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // BCR-ABL RESISTANCE
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'bcr-abl-t315i',
    originalTarget: 'BCR-ABL',
    originalDrugs: ['Imatinib', 'Dasatinib', 'Nilotinib', 'Bosutinib'],
    resistanceMutation: 'BCR-ABL T315I gatekeeper mutation',
    frequency: '15-20% of TKI-resistant CML',
    detectionMethod: ['BCR-ABL mutation analysis', 'Sanger sequencing', 'NGS'],
    overcomingStrategies: [
      {
        approach: 'Third-generation TKI',
        drugs: ['Ponatinib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'High response rates'
      },
      {
        approach: 'Allosteric inhibitor',
        drugs: ['Asciminib'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Effective in T315I'
      },
      {
        approach: 'Allogeneic stem cell transplant',
        drugs: ['Allo-HSCT'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Curative option'
      }
    ],
    preventionStrategies: ['Adherence monitoring', 'Early mutation detection'],
    prognosis: 'Good - ponatinib and asciminib effective'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // IMMUNOTHERAPY RESISTANCE
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'checkpoint-primary',
    originalTarget: 'PD-1/PD-L1',
    originalDrugs: ['Pembrolizumab', 'Nivolumab', 'Atezolizumab'],
    resistanceMutation: 'Primary resistance (JAK1/2 loss, B2M loss, WNT activation)',
    frequency: '40-60% never respond',
    detectionMethod: ['Repeat biopsy with immune profiling', 'Gene expression analysis'],
    overcomingStrategies: [
      {
        approach: 'Dual checkpoint blockade',
        drugs: ['Ipilimumab + Nivolumab', 'Relatlimab + Nivolumab'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'May convert some non-responders'
      },
      {
        approach: 'Combination with chemotherapy',
        drugs: ['Pembrolizumab + Chemotherapy'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Synergistic effect'
      },
      {
        approach: 'Novel immune targets',
        drugs: ['TIGIT inhibitors', 'LAG-3 inhibitors', 'TIM-3 inhibitors'],
        evidenceLevel: 'Phase II',
        expectedResponse: 'Under investigation',
        clinicalTrials: ['Multiple ongoing']
      }
    ],
    preventionStrategies: ['Biomarker selection (PD-L1, TMB, MSI-H)', 'Combination upfront'],
    prognosis: 'Variable - depends on mechanism'
  },
  {
    id: 'checkpoint-acquired',
    originalTarget: 'PD-1/PD-L1',
    originalDrugs: ['All checkpoint inhibitors'],
    resistanceMutation: 'Acquired resistance (antigen loss, neoantigen editing, T-cell exhaustion)',
    frequency: '30-50% of initial responders',
    detectionMethod: ['Repeat biopsy', 'T-cell profiling', 'Neoantigen analysis'],
    overcomingStrategies: [
      {
        approach: 'Rechallenge after break',
        drugs: ['Same or different checkpoint inhibitor'],
        evidenceLevel: 'Phase II',
        expectedResponse: 'Variable, some responses'
      },
      {
        approach: 'Cellular therapy',
        drugs: ['TIL therapy (Lifileucel)', 'TCR-T cells'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'ORR 30-40% in melanoma'
      },
      {
        approach: 'Oncolytic virus combination',
        drugs: ['T-VEC + Pembrolizumab'],
        evidenceLevel: 'Phase II',
        expectedResponse: 'May enhance immune response'
      }
    ],
    preventionStrategies: ['Optimize duration of therapy', 'Early detection of resistance'],
    prognosis: 'Challenging - cellular therapies show promise'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // KRAS INHIBITOR RESISTANCE
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'kras-g12c-resistance',
    originalTarget: 'KRAS G12C',
    originalDrugs: ['Sotorasib', 'Adagrasib'],
    resistanceMutation: 'Secondary KRAS mutations, RTK amplification, SHP2 activation',
    frequency: 'Common within 6-12 months',
    detectionMethod: ['ctDNA', 'Repeat biopsy'],
    overcomingStrategies: [
      {
        approach: 'KRAS G12C + SHP2 inhibitor',
        drugs: ['Sotorasib + RMC-4630'],
        evidenceLevel: 'Phase I',
        expectedResponse: 'Under investigation',
        clinicalTrials: ['NCT04330664']
      },
      {
        approach: 'KRAS G12C + SOS1 inhibitor',
        drugs: ['Adagrasib + BI 1701963'],
        evidenceLevel: 'Phase I',
        expectedResponse: 'Under investigation'
      },
      {
        approach: 'Immunotherapy combination',
        drugs: ['Sotorasib + Pembrolizumab', 'Adagrasib + Pembrolizumab'],
        evidenceLevel: 'Phase II',
        expectedResponse: 'May extend benefit'
      }
    ],
    preventionStrategies: ['Combination approaches upfront', 'Resistance monitoring'],
    prognosis: 'Active area of research - combinations promising'
  },

  // ═══════════════════════════════════════════════════════════════════════════
  // CAR-T RESISTANCE
  // ═══════════════════════════════════════════════════════════════════════════
  {
    id: 'cart-antigen-loss',
    originalTarget: 'CD19, BCMA',
    originalDrugs: ['CD19 CAR-T', 'BCMA CAR-T'],
    resistanceMutation: 'Antigen loss/downregulation, T-cell exhaustion',
    frequency: '30-50% of CAR-T relapses',
    detectionMethod: ['Flow cytometry for antigen', 'Repeat biopsy'],
    overcomingStrategies: [
      {
        approach: 'Alternative target CAR-T',
        drugs: ['CD22 CAR-T (for CD19 loss)', 'GPRC5D CAR-T (for BCMA loss)'],
        evidenceLevel: 'Phase I',
        expectedResponse: 'Responses seen'
      },
      {
        approach: 'Bispecific antibodies',
        drugs: ['Blinatumomab', 'Teclistamab', 'Talquetamab'],
        evidenceLevel: 'FDA-Approved',
        expectedResponse: 'Alternative target engagement'
      },
      {
        approach: 'Dual-targeting CAR-T',
        drugs: ['CD19/CD22 CAR-T', 'BCMA/CD38 CAR-T'],
        evidenceLevel: 'Phase I',
        expectedResponse: 'May prevent escape',
        clinicalTrials: ['Multiple ongoing']
      }
    ],
    preventionStrategies: ['Dual-targeting from start', 'Early CAR-T consideration'],
    prognosis: 'Challenging - alternative targets help'
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// RESISTANCE DETECTION AND MONITORING
// ═══════════════════════════════════════════════════════════════════════════════

export interface ResistanceMonitoringPlan {
  baseline: string[];
  onTreatment: string[];
  atProgression: string[];
  frequency: string;
}

export const RESISTANCE_MONITORING_PROTOCOLS: Record<string, ResistanceMonitoringPlan> = {
  egfr: {
    baseline: ['Comprehensive genomic profiling', 'ctDNA baseline'],
    onTreatment: ['ctDNA every 8 weeks', 'T790M monitoring'],
    atProgression: ['Repeat biopsy if accessible', 'ctDNA comprehensive', 'MET FISH'],
    frequency: 'Every 8-12 weeks'
  },
  alk: {
    baseline: ['ALK FISH/IHC', 'NGS for resistance mutations'],
    onTreatment: ['ctDNA for ALK resistance mutations'],
    atProgression: ['Repeat biopsy', 'Full ALK resistance panel'],
    frequency: 'Every 12 weeks'
  },
  her2: {
    baseline: ['HER2 IHC/FISH', 'PIK3CA mutation status', 'ctDNA'],
    onTreatment: ['ctDNA monitoring'],
    atProgression: ['Repeat HER2 testing', 'PIK3CA status', 'Genomic profiling'],
    frequency: 'Every 12 weeks'
  },
  hormone: {
    baseline: ['ER/PR status', 'ESR1 ctDNA', 'PIK3CA status'],
    onTreatment: ['ESR1 ctDNA every 12 weeks', 'Tumor markers'],
    atProgression: ['Repeat biopsy for ER status', 'ESR1 full panel', 'Genomic profiling'],
    frequency: 'Every 12 weeks'
  },
  immunotherapy: {
    baseline: ['PD-L1', 'TMB', 'MSI status', 'Gene expression profiling'],
    onTreatment: ['ctDNA for response', 'irRC imaging'],
    atProgression: ['Repeat biopsy with immune profiling', 'JAK/B2M status', 'WNT pathway'],
    frequency: 'Every 8-12 weeks'
  }
};

// ═══════════════════════════════════════════════════════════════════════════════
// RESISTANCE MANAGEMENT ENGINE
// ═══════════════════════════════════════════════════════════════════════════════

export class ResistanceManagementEngine {

  /**
   * Analyze resistance and provide next-step recommendations
   */
  analyzeResistance(
    currentTherapy: string,
    target: string,
    detectedMechanism: string,
    patientProfile: { age: number; ps: number; priorLines: number }
  ): {
    mechanism: ResistanceMechanism | undefined;
    recommendedStrategies: OvercomingStrategy[];
    clinicalTrials: string[];
    prognosis: string;
    urgency: 'immediate' | 'soon' | 'planned';
  } {

    // Find matching resistance mechanism
    const mechanism = RESISTANCE_MECHANISM_DATABASE.find(m =>
      m.originalTarget.toLowerCase().includes(target.toLowerCase()) ||
      m.resistanceMutation.toLowerCase().includes(detectedMechanism.toLowerCase())
    );

    if (!mechanism) {
      return {
        mechanism: undefined,
        recommendedStrategies: [{
          approach: 'Comprehensive genomic profiling',
          drugs: ['Clinical trial enrollment recommended'],
          evidenceLevel: 'Phase II',
          expectedResponse: 'Personalized approach needed'
        }],
        clinicalTrials: ['Search clinicaltrials.gov for target + resistance'],
        prognosis: 'Unknown mechanism - further workup needed',
        urgency: 'soon'
      };
    }

    // Filter strategies by patient fitness
    let strategies = [...mechanism.overcomingStrategies];
    if (patientProfile.ps >= 2 || patientProfile.age >= 75) {
      strategies = strategies.filter(s =>
        s.evidenceLevel === 'FDA-Approved' ||
        s.expectedResponse.toLowerCase().includes('tolerable')
      );
    }

    // Collect clinical trials
    const trials = strategies
      .filter(s => s.clinicalTrials)
      .flatMap(s => s.clinicalTrials!);

    // Determine urgency
    const urgency = detectedMechanism.toLowerCase().includes('transform') ? 'immediate' :
                   patientProfile.priorLines >= 3 ? 'immediate' : 'soon';

    return {
      mechanism,
      recommendedStrategies: strategies,
      clinicalTrials: trials,
      prognosis: mechanism.prognosis,
      urgency
    };
  }

  /**
   * Generate resistance prevention strategy
   */
  generatePreventionPlan(
    cancerType: string,
    targetedTherapy: string,
    biomarkers: string[]
  ): {
    strategies: string[];
    monitoring: ResistanceMonitoringPlan;
    combinationOptions: string[];
  } {

    const strategies: string[] = [];
    const combinationOptions: string[] = [];

    // General prevention strategies
    strategies.push('Regular ctDNA monitoring for early detection');
    strategies.push('Consider combination therapy to delay resistance');
    strategies.push('Optimize drug exposure with TDM if available');

    // Target-specific strategies
    if (targetedTherapy.toLowerCase().includes('egfr')) {
      strategies.push('Start with osimertinib to prevent T790M');
      combinationOptions.push('EGFR + MET inhibitor');
      combinationOptions.push('EGFR + antiangiogenic');
    }

    if (targetedTherapy.toLowerCase().includes('braf')) {
      strategies.push('Always use BRAF + MEK combination');
      strategies.push('Consider immunotherapy sequencing');
      combinationOptions.push('BRAF/MEK + immunotherapy');
    }

    if (targetedTherapy.toLowerCase().includes('cdk4')) {
      strategies.push('Monitor ESR1 mutations');
      strategies.push('Consider triplet therapy in high-risk');
      combinationOptions.push('CDK4/6i + endocrine + PI3K inhibitor');
    }

    const monitoringKey = targetedTherapy.toLowerCase().includes('egfr') ? 'egfr' :
                         targetedTherapy.toLowerCase().includes('alk') ? 'alk' :
                         targetedTherapy.toLowerCase().includes('her2') ? 'her2' :
                         'immunotherapy';

    return {
      strategies,
      monitoring: RESISTANCE_MONITORING_PROTOCOLS[monitoringKey] || RESISTANCE_MONITORING_PROTOCOLS.immunotherapy,
      combinationOptions
    };
  }

  /**
   * Get all resistance mechanisms for a target
   */
  getResistanceMechanismsForTarget(target: string): ResistanceMechanism[] {
    return RESISTANCE_MECHANISM_DATABASE.filter(m =>
      m.originalTarget.toLowerCase().includes(target.toLowerCase()) ||
      m.originalDrugs.some(d => d.toLowerCase().includes(target.toLowerCase()))
    );
  }
}

// ═══════════════════════════════════════════════════════════════════════════════
// CURE VERIFICATION SYSTEM
// ═══════════════════════════════════════════════════════════════════════════════

export interface CureVerificationResult {
  status: 'CURED' | 'REMISSION' | 'MRD_NEGATIVE' | 'RESPONDING' | 'STABLE' | 'PROGRESSING';
  confidence: number;
  evidence: string[];
  surveillancePlan: string[];
  nextAssessment: string;
  longTermRisks: string[];
}

export class CureVerificationEngine {

  /**
   * Verify cure status based on multiple criteria
   */
  verifyCureStatus(
    cancerType: string,
    treatmentDuration: number,
    imagingResult: 'CR' | 'PR' | 'SD' | 'PD' | 'NED',
    mrdStatus: 'negative' | 'positive' | 'not_tested',
    ctdnaStatus: 'undetectable' | 'detectable' | 'not_tested',
    timeOffTherapy: number, // months
    lastProgression: number | null // months since
  ): CureVerificationResult {

    const evidence: string[] = [];
    let status: CureVerificationResult['status'] = 'STABLE';
    let confidence = 0.5;

    // Imaging evidence
    if (imagingResult === 'CR' || imagingResult === 'NED') {
      evidence.push('Complete radiographic response / No evidence of disease');
      confidence += 0.2;
    } else if (imagingResult === 'PR') {
      evidence.push('Partial radiographic response');
    }

    // MRD evidence
    if (mrdStatus === 'negative') {
      evidence.push('MRD negative by validated assay');
      confidence += 0.2;
    }

    // ctDNA evidence
    if (ctdnaStatus === 'undetectable') {
      evidence.push('ctDNA undetectable');
      confidence += 0.1;
    }

    // Time-based criteria
    if (timeOffTherapy >= 24 && imagingResult === 'NED') {
      evidence.push('Disease-free for 2+ years off therapy');
      confidence += 0.2;
    }

    // Determine status
    if (confidence >= 0.9 && imagingResult === 'NED' && (mrdStatus === 'negative' || ctdnaStatus === 'undetectable') && timeOffTherapy >= 24) {
      status = 'CURED';
    } else if (confidence >= 0.7 && (mrdStatus === 'negative' || ctdnaStatus === 'undetectable')) {
      status = 'MRD_NEGATIVE';
    } else if (imagingResult === 'CR' || imagingResult === 'NED') {
      status = 'REMISSION';
    } else if (imagingResult === 'PR') {
      status = 'RESPONDING';
    } else if (imagingResult === 'PD') {
      status = 'PROGRESSING';
    }

    // Generate surveillance plan
    const surveillancePlan = this.generateSurveillancePlan(cancerType, status);

    // Long-term risks
    const longTermRisks = this.assessLongTermRisks(cancerType, treatmentDuration);

    return {
      status,
      confidence: Math.min(confidence, 0.98),
      evidence,
      surveillancePlan,
      nextAssessment: this.getNextAssessmentTime(status),
      longTermRisks
    };
  }

  private generateSurveillancePlan(cancerType: string, status: string): string[] {
    const basePlan = [
      'History and physical exam every 3-6 months for 2 years',
      'Annual imaging per cancer-specific guidelines',
      'Tumor markers if applicable'
    ];

    if (status === 'CURED' || status === 'MRD_NEGATIVE') {
      basePlan.push('Transition to annual survivorship visits after 5 years');
      basePlan.push('Long-term effects monitoring');
      basePlan.push('Secondary malignancy screening');
    }

    return basePlan;
  }

  private assessLongTermRisks(cancerType: string, treatmentDuration: number): string[] {
    const risks: string[] = [];

    risks.push('Late recurrence (monitor per guidelines)');
    risks.push('Second primary malignancy');
    risks.push('Treatment-related late effects');

    if (treatmentDuration > 12) {
      risks.push('Cardiovascular monitoring recommended');
      risks.push('Bone health assessment');
    }

    return risks;
  }

  private getNextAssessmentTime(status: string): string {
    switch (status) {
      case 'CURED': return '12 months (annual surveillance)';
      case 'MRD_NEGATIVE': return '3-6 months (confirm durability)';
      case 'REMISSION': return '3 months (confirm stability)';
      case 'RESPONDING': return '2-3 months (assess depth of response)';
      case 'STABLE': return '2-3 months (monitor for progression)';
      case 'PROGRESSING': return 'Immediate (treatment change needed)';
      default: return '3 months';
    }
  }
}

// Export singleton instances
export const resistanceManagementEngine = new ResistanceManagementEngine();
export const cureVerificationEngine = new CureVerificationEngine();