Diagnosis: 16 year old male, Ewingʼs sarcoma (right 10th rib), CD99+/FLI1+/NKX2.2+, skeletal metastases at presentation.
• Treatment: Progressed through irinotecan+ etoposide (6 cycles) and VACM (6 cycles). Post therapy PET CT: persistent diffuse FDG
uptake in bone marrow- chemorefractory metastatic disease.
• Further Evaluation: OncoIndx Prime (Paired NGS, FFPE + plasma cfDNA) performed after two lines of therapy to identify
actionable drivers and resistance mechanisms.
Clinical Challenges:
• Relapsed/refractory metastatic Ewingʼs sarcoma in an
adolescent with limited evidence-based therapeutic
options beyond second-line NCCN regimens.
• Empiric chemotherapy offers low probability of durable
response; precision strategy urgently needed.
• Need for precision-guided strategy to avoid ineffective
or toxic regimens.
• Germline VUS in CBLB requires longitudinal
reinterpretation and genetic counselling.
• Balancing aggressive treatment strategies with
quality-of-life considerations.
Clinical Implications:
• Homozygous CDKN2A/CDKN2B deletions (tissue and
plasma confirmed) result in dysregulation of the
cyclin-dependent kinase pathway.
• Treatment option 1: CDK4/6 inhibitors (palbociclib etc.) within a clinical trial setting.
• Treatment option 2: Guideline-aligned salvage chemotherapy: Cyclophosphamide/topotecan or irinotecan/temozolomide ±
vincristine.
• TYMS 6-bp deletion: Potential reduced efficacy and/or increased toxicity with antifolate-based agents.
• Low TMB, MSS, absence of CHIP: Low probability of benefit from immune checkpoint inhibitors.
• BARD1 in-frame deletion (Tier II): Emerging evidence; clinical trial enrolment may provide future therapeutic relevance.
• Overall, integrated biopsy profiling shifted management from empiric chemotherapy selection to pathway-informed, biologically
rational strategy.
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