@erosolaraijs/cure 2.2.0 → 2.3.1

package/dist/capabilities/resistanceManagement.js

@@ -0,0 +1,713 @@
+/**
+ * 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                    ║
+ * ╚═══════════════════════════════════════════════════════════════════════════════╝
+ */
+export const RESISTANCE_MECHANISM_DATABASE = [
+    // ═══════════════════════════════════════════════════════════════════════════
+    // 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'
+    }
+];
+export const RESISTANCE_MONITORING_PROTOCOLS = {
+    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, target, detectedMechanism, patientProfile) {
+        // 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, targetedTherapy, biomarkers) {
+        const strategies = [];
+        const combinationOptions = [];
+        // 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) {
+        return RESISTANCE_MECHANISM_DATABASE.filter(m => m.originalTarget.toLowerCase().includes(target.toLowerCase()) ||
+            m.originalDrugs.some(d => d.toLowerCase().includes(target.toLowerCase())));
+    }
+}
+export class CureVerificationEngine {
+    /**
+     * Verify cure status based on multiple criteria
+     */
+    verifyCureStatus(cancerType, treatmentDuration, imagingResult, mrdStatus, ctdnaStatus, timeOffTherapy, // months
+    lastProgression // months since
+    ) {
+        const evidence = [];
+        let 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
+        };
+    }
+    generateSurveillancePlan(cancerType, status) {
+        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;
+    }
+    assessLongTermRisks(cancerType, treatmentDuration) {
+        const risks = [];
+        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;
+    }
+    getNextAssessmentTime(status) {
+        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();
+//# sourceMappingURL=resistanceManagement.js.map