Teaching pack: Sarcomas (soft tissue, bone, GIST)

Sarcomas are cancers of connective tissue: more than 70 subtypes of soft-tissue sarcoma (liposarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, angiosarcoma and others), bone sarcomas (osteosarcoma, Ewing sarcoma, chondrosarcoma), gastrointestinal stromal tumour (GIST), and locally aggressive but non-metastasising tumours such as desmoid fibromatosis and tenosynovial giant cell tumour. Together they are about 1% of adult and 15% of childhood cancers. Because each subtype is rare, expertise concentrates in reference centres, and treatment is increasingly by histotype and genotype: FNCLCC grade, size and depth define risk in soft-tissue sarcoma; KIT/PDGFRA mutations define GIST therapy; fusion genes (SS18-SSX, EWSR1-FLI1, FUS-DDIT3) define entities and, increasingly, targets.

Surgery with negative margins remains the curative act, with limb-salvage now standard and radiotherapy improving local control in soft-tissue sarcoma. Neoadjuvant anthracycline-ifosfamide benefits high-risk localised soft-tissue sarcoma (ISG-STS 1001), and multi-agent chemotherapy cures the majority of localised osteosarcoma (MAP) and Ewing sarcoma (VDC/IE, INT-0091 and Euro Ewing 2012). Advanced soft-tissue sarcoma still depends on doxorubicin with a median survival around 18-20 months; olaratumab's failure (ANNOUNCE) showed how hard that bar is to move. Subtype-specific drugs then fill in: trabectedin and eribulin for L-sarcomas, pazopanib for non-adipocytic sarcomas, and, in GIST, the sequence imatinib (3 years adjuvant, SSGXVIII), sunitinib, regorafenib and ripretinib (INVICTUS), with avapritinib for PDGFRA D842V and ctDNA-genotype-directed selection (INSIGHT) arriving. Desmoid tumours gained their first drug in nirogacestat (DeFi, 2023) and tenosynovial giant cell tumour its second in vimseltinib (MOTION, February 2025); tazemetostat for epithelioid sarcoma was withdrawn worldwide in March 2026 over secondary blood cancers.

• Subtype-specific targeted and cellular therapies.
• First engineered T-cell therapies for a solid tumour: afami-cel (full approval and age ≥12 in June 2026) and lete-cel (BLA due 2026) for synovial sarcoma and MRCLS.
• GIST as a model of genotype-directed sequencing: four approved TKIs, a mutation-specific drug for D842V, and ctDNA-selected phase 3 (INSIGHT).
• New indications for benign but destructive tumours: nirogacestat (desmoid, 2023) and vimseltinib (TGCT, 2025).
• Neoadjuvant chemotherapy for high-risk soft-tissue sarcoma validated (ISG-STS 1001), while histotype-tailored chemotherapy was not superior.
• Ewing sarcoma treatment unified on VDC/IE after Euro Ewing 2012; interval compression and busulfan-melphalan refine it.

1. 1970Adjuvant chemotherapy for osteosarcoma (Jaffe, Rosen) turns a 20% survival into 60%
2. 1980Limb-salvage surgery shown equivalent to amputation (Rosenberg, NCI)
3. 1982Adjuvant radiotherapy improves local control after limb-sparing surgery (NCI randomised trial)
4. 1998KIT mutations discovered in GIST (Hirota)
5. 2002Imatinib for GIST
6. 2002Imatinib approved for GIST: the first solid tumour controlled by a targeted pill
7. 2003INT-0091: ifosfamide-etoposide added to Ewing sarcoma therapy
8. 2007Trabectedin approved in Europe for soft-tissue sarcoma
9. 2010EORTC 62961: regional hyperthermia with chemotherapy improves survival in high-risk STS
10. 2012SSGXVIII: 3-year adjuvant imatinib; pazopanib approved (PALETTE)

• FAP-2286 (177Lu / 68Ga) (product)
• Carbon-ion therapy (technology)
• Letetresgene autoleucel (product)
• IGNYTE-ESO (trial)
• INSIGHT (trial)
• ctDNA KIT genotyping → TKI selection in GIST (pairing)
• Extending sarcoma TCR-T beyond HLA-A*02 (idea)
• Intermittent or stop-and-restart nirogacestat in desmoid tumours (idea)
• Vimseltinib (product)
• Nirogacestat (product)
• Limb-salvage surgery and endoprosthetic reconstruction (technology)

• ISG-STS 1001 (phase 3, n=287): Overall survival at 46 months: 89% vs 64%
• Euro Ewing 2012 (phase 3, n=640): Event-free survival at 3 years: 67% vs 61%, HR 0.71
• INT-0091 (Ewing sarcoma) (phase 3, n=518): Event-free survival at 5 years (localised): 69% vs 54%
• SSGXVIII/AIO (adjuvant imatinib in GIST) (phase 3, n=400): Recurrence-free survival at 5 years: 65.6% vs 47.9%, HR 0.46
• DeFi (phase 3, n=142): Progression-free survival: pending
• INVICTUS (phase 3, n=129): Progression-free survival (median): 6.3 months vs 1 months, HR 0.15

• Rarity limits trials.
• Chemoresistance of most subtypes.
• Metastatic osteosarcoma and Ewing sarcoma: survival ~20-30%, unchanged for three decades; no targeted or immune therapy has worked.
• Advanced soft-tissue sarcoma still depends on a 1970s drug (doxorubicin); every attempt to improve first-line survival (olaratumab, evofosfamide, aldoxorubicin) failed.
• TCR-T is limited to HLA-A*02 carriers, requires antigen screening, and is available at few centres.
• Most sarcomas are immunologically cold; checkpoint inhibitors help only alveolar soft-part sarcoma, some UPS and angiosarcoma.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. What happened to tazemetostat in 2026?
   Answer

   Ipsen withdrew Tazverik from all markets and indications on 9 March 2026 after SYMPHONY-1 showed excess secondary haematologic malignancies (5.7% vs none), and stopped its trials.

• Wikipedia: https://en.wikipedia.org/wiki/Sarcoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1464