About this document "Gmail thread": key points here

Key Points from "Gmail thread"

This email thread documents a virtual molecular tumor board hackathon for Marlo "Mo" Kwong, a 2-year-old boy with an ultra-rare, aggressive sarcoma. Here are the critical points:

Patient Case Overview

• Diagnosis: Mo has a high-grade undifferentiated spindle cell sarcoma with EGFR internal tandem duplication (ITD/KDD)
• Evolution: Started as a congenital low-grade tumor that transformed into aggressive high-grade sarcoma
• Current Status: 26 months into treatment, no lung metastases (T4N0M0), showing partial response to current therapy (chemo + radiation + erlotinib)

Key Molecular Findings

1. EGFR ITD (exons 18-25 duplication) - the primary driver mutation
2. Complex karyotype discovered in Oct 2024 transformation:
   • PTEN loss (chromosome 10)
   • RB1 loss (chromosome 13)
   • MDM2/KRAS gains
3. Important correction: No PDGFRB alteration exists (initial reports were incorrect)
4. Untested targets: HER2, B7-H3, GD2, PRAME, PD-L1, TMB, HLA-A24

Treatment Considerations Discussed

Current therapy: Erlotinib (1st generation EGFR TKI) + chemotherapy + radiation

Proposed next steps:

1. Switch to Afatinib (2nd generation TKI) - supported by real-world evidence from a similar Spanish pediatric case
2. CAR-T therapy options:
   • B7-H3-targeted CAR-T (St. Jude trial)
   • HER2-targeted CAR-T (Baylor trial NCT04995003) - now co-ranked as highest priority
3. Additional modalities: ADCs, checkpoint inhibitors, [ID removed] vaccines, organoid testing

Critical Diagnostic Questions Raised

Pathologist Allen Morris emphasized:

• Need for precise subtyping before treatment planning
• Mayo Clinic pathologist's uncertainty: "I must confess I am really not at all certain what it is we are dealing with"
• Recommendation for blinded review by 2+ additional sarcoma pathology groups
• Question about whether tumor represents regional disease vs. metastatic capability

Immediate Action Items

1. Assess tissue availability from Oct 2024 specimen (RNA failed QC twice)
2. Order HER2 and B7-H3 IHC testing (co-equal priorities)
3. Contact CAR-T trial sites: St. Jude ([PHONE]) and Baylor/Texas Children's
4. Discuss afatinib switch with oncology team
5. Schedule echocardiogram (assess cardiac function for CAR-T eligibility)

Three Core Questions for Hackathon

1. Optimal treatment sequence: What's the most rational 6-12 month plan toward cure?
2. Data/model engine: What additional testing is needed to guide decisions?
3. Access and governance: How to structure trial access without closing future options?

Novel Approaches Discussed

• Integrin-targeted therapy (Dr. [NAME], Tufts) - speculative but potentially relevant for sarcomas
• CeGAT peptide vaccines - showing ~20% durable responses in GBM
• Functional drug testing (SageMedic) - to test TKI sensitivity ex vivo
• Bispecific antibodies targeting EGFR + integrins

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This information is for educational purposes only. Always consult your healthcare team for personalized medical advice and decisions.