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Teaching pack: Gastrointestinal stromal tumour (GIST)

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  1. Teaching pack · Cancer · gastrointestinal

    Gastrointestinal stromal tumour (GIST)

    GIST is a sarcoma of the gut wall driven almost always by a KIT or PDGFRA mutation. It was the proof that a pill can control a solid tumour: imatinib turned a median survival of about a year into one of eight years or more, and the mutation now dictates which drug to use.

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  2. What it is

    In two paragraphs

    GIST arises from interstitial cells of Cajal and carries activating KIT mutations (~75%, mostly exon 11, some exon 9) or PDGFRA mutations (~10%, including the imatinib-resistant D842V); the remainder are SDH-deficient (young patients, Carney-Stratakis), NF1-associated, or BRAF/NTRK-driven. Risk after resection is estimated from size, mitotic rate and site (Miettinen/AFIP, modified NIH).

    Surgery is the only cure; adjuvant imatinib for three years improves survival in high-risk disease (SSGXVIII), with five years or longer under study. Advanced disease is treated with imatinib (400 mg; 800 mg for exon 9), then sunitinib (2006), regorafenib (2013) and ripretinib (INVICTUS, 2020) in sequence; avapritinib is the drug for PDGFRA D842V (2020). Resistance comes from secondary KIT mutations in the ATP-binding pocket (exon 13/14) or activation loop (exon 17/18) and is heterogeneous across lesions, which is why single next-generation inhibitors have struggled (INTRIGUE: ripretinib not superior to sunitinib overall, but better in ctDNA-defined exon 11 + 17/18 disease, now tested in INSIGHT) and why combinations (bezuclastinib + sunitinib, Peak) and ctDNA-guided selection are the current strategy. SDH-deficient GIST is TKI-insensitive and slow-growing; temozolomide has activity.

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  3. Standard of care

    What is given today, by setting

    SettingApproachGuideline
    Localised, resectableComplete resection without lymphadenectomy; adjuvant imatinib 3 years for high-risk (SSGXVIII); neoadjuvant imatinib to downsize when organ-sparing matters.NCCN Category 1 (adjuvant imatinib, high risk), ESMO-MCBS A
    Advanced, first lineImatinib 400 mg (800 mg for KIT exon 9); avapritinib for PDGFRA D842V; continue until progression.NCCN Category 1
    Advanced, second lineSunitinib (or ripretinib for KIT exon 11 + 17/18 secondary mutations per ctDNA, INSIGHT).NCCN Category 1 (sunitinib)
    Advanced, third/fourth lineRegorafenib, then ripretinib (INVICTUS); rechallenge or continue TKI beyond progression; clinical trials (bezuclastinib-sunitinib).NCCN Category 1 (regorafenib, ripretinib)
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  4. State of the art

    Where the field stands

    • Five approved TKIs sequenced by genotype; median survival in advanced GIST is now around 8 years.
    • ctDNA genotyping of secondary KIT mutations is becoming the way to pick second-line therapy (INSIGHT).
    • Avapritinib solved the PDGFRA D842V problem with ~90% response.
    • Combination inhibition (bezuclastinib + sunitinib) aims to cover both ATP-pocket and activation-loop resistance at once.
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  5. History

    How we got here

    1. 1998KIT mutations discovered in GIST (Hirota, Science)
    2. 2000Imatinib: dramatic response in a single GIST patient (Joensuu, NEJM 2001)
    3. 2002Imatinib approved for advanced GIST
    4. 2003PDGFRA mutations in KIT-wild-type GIST (Heinrich, Science)
    5. 2006Sunitinib approved after imatinib failure
    6. 2012SSGXVIII: three years of adjuvant imatinib improves overall survival
    7. 2013Regorafenib approved (GRID)
    8. 2020Avapritinib (PDGFRA D842V) and ripretinib (INVICTUS) approved
    9. 2022INTRIGUE: ctDNA genotype predicts ripretinib vs sunitinib benefit
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  6. Pipeline

    What is coming

    • Ripretinib (product)
    • Avapritinib (product)
    • Liquid biopsy (ctDNA) (technology)
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  7. Open problems

    What nobody has solved

    • Polyclonal resistance: different lesions carry different secondary KIT mutations.
    • SDH-deficient and other wild-type GIST have no effective TKI.
    • Optimal duration of adjuvant imatinib (3 vs 5-6 years).
    • Long-term imatinib toxicity and adherence.
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  8. Quiz

    Check understanding

    1. What is a liquid biopsy used for in cancer care today?
      Answer
      A blood test reading tumour DNA fragments: to genotype a tumour when tissue is scarce, to track resistance mutations (EGFR T790M, ESR1), to detect minimal residual disease after surgery, and, experimentally, to screen for cancer.
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  9. Sources

    Read the primary sources

    • NCCN Guidelines: GIST: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1507
    • ESMO-EURACAN GIST guideline (2022): https://doi.org/10.1016/j.annonc.2021.09.005
    • Life Raft Group (patient organisation): https://liferaftgroup.org/
    • Wikipedia: https://en.wikipedia.org/wiki/Gastrointestinal_stromal_tumor
    • Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1507
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