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Molekularpathologisch determinierte multimodale Therapie gastrointestinaler Stromatumoren

Decision-making for multimodal treatment of gastrointestinal stromal tumors based on molecular profiling

  • Leitthema
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Die Onkologie Aims and scope

Zusammenfassung

Hintergrund

Gastrointestinale Stromatumoren (GIST) lassen sich mithilfe moderner molekularpathologischer Methoden zunehmend besser molekular differenzieren. Die Bestimmung des Genotyps ist integraler Bestandteil bei der Entwicklung eines Behandlungskonzepts.

Ziel

Es erfolgt die Darstellung der aktuell verfügbaren Daten mit Relevanz für Therapieentscheidungen.

Resultate und Schlussfolgerungen

Patienten mit KIT-Mutationen in Exon 11 und einem hohen Rückfallrisiko profitieren von einer perioperativen Therapie mit Imatinib. Für Patienten mit Exon-9- oder den noch selteneren primären Exon-13- und –17-Mutationen ist die Studienlage weniger klar. Im Kontext lokal fortgeschrittener Tumoren, bei denen eine erhöhte Operations-bedingte Morbidität zu erwarten ist, haben sich neoadjuvante Therapien bei Imatinib-sensiblen Mutationen etabliert. Der Einsatz multimodaler Therapien in der metastasierten Situation sollte bei Imatinib-sensiblen Genotypen zum Zeitpunkt des maximalen Therapieansprechens erwogen werden – wenn eine makroskopisch komplette Resektion möglich erscheint. Inwieweit operative Therapien im Kontext neuer Inhibitoren wie Ripretinib bei stark vorbehandelten Patienten oder Avapritinib bei GIST mit PDGFRA-D842V-Mutationen („platelet-derived growth factor receptor A“) auch sinnvoll sind, wird sich erst in den kommenden Jahren zeigen.

Abstract

Background

Gastrointestinal stromal tumors (GIST) comprise a broad spectrum of different molecular subtypes. Due to improved accessibility to molecular pathology, genotyping has become an integral part of interdisciplinary case discussions.

Aim

To provide an overview on existing literature on the relevance of genotyping for treatment decisions in GIST.

Results and conclusions

Most patients with KIT exon 11 mutations and high risk of relapse benefit from adjuvant imatinib treatment. The evidence for this benefit is weak for less frequent KIT genotypes (e.g., exon 9, 13, and 17 mutations). Neoadjuvant treatment is particularly relevant in imatinib-sensitive subtypes when significant surgery-related morbidity is expected. For patients in the metastatic setting, multimodal treatment can be considered in responding patients when macroscopically complete resection seems feasible. Next generation inhibitors such as ripretinib in pretreated GIST and particularly avapritinib in GIST with PDGFRA (platelet-derived growth factor receptor A) mutations are associated with relevant tumor regression. The role for multimodal approaches in the respective treatment settings remains to be determined.

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Abb. 1

Abbreviations

AFIP:

Armed Forces Institute of Pathology

BRAF:

„Homolog B, rapidly accelerated fibrosarcoma (serine/threonine-protein kinase)“

GIST:

Gastrointestinaler Stromatumor

KIT:

„Proto-oncogene tyrosine-protein kinase Kit (c-kit), CD117, mast/stem cell growth factor receptor precursor (SCFR)“

mg:

Milligramm

NIH:

National Institutes of Health

PDGFRA:

„Platelet-derived growth factor receptor A“

SDH:

Succinat-Dehydrogenase

Literatur

  1. Casali PG et al (2022) Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 33:20–33

    Article  CAS  Google Scholar 

  2. Duensing A et al (2004) Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23:3999–4006

    Article  CAS  Google Scholar 

  3. Bauer S, Duensing A, Demetri GD, Fletcher JA (2007) KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 26:7560–7568

    Article  CAS  Google Scholar 

  4. Heinrich MC et al (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710

    Article  CAS  Google Scholar 

  5. Li B et al (2016) Conjoined hyperactivation of the RAS and PI3K pathways in advanced GIST. J Clin Oncol 34:e22520

    Article  Google Scholar 

  6. Blay JY, Kang YK, Nishida T, von Mehren M (2021) Gastrointestinal stromal tumours. Nat Rev Dis Primers 7:22

    Article  Google Scholar 

  7. Joensuu H et al (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056

    Article  CAS  Google Scholar 

  8. Joensuu H et al (2016) Adjuvant Imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol 34:244–250

    Article  CAS  Google Scholar 

  9. Joensuu H et al (2020) Survival outcomes associated with 3 years vs 1 year of adjuvant Imatinib for patients with high-risk gastrointestinal stromal tumors: an analysis of a randomized clinical trial after 10-year follow-up. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2020.2091

    Article  Google Scholar 

  10. Casali PG et al (2018) Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv68–iv78

    Article  CAS  Google Scholar 

  11. Fletcher CD et al (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465

    Article  Google Scholar 

  12. Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83

    Article  Google Scholar 

  13. Joensuu H (2008) Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 39:1411–1419

    Article  Google Scholar 

  14. Joensuu H et al (2012) Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 13:265–274

    Article  Google Scholar 

  15. Wozniak A et al (2018) Extended Conticagist analysis adds to the amended prognostication in GIST based on tumor KIT/PDGFRA genotype status. CTOS 2018 Annual MeetingAbstract 3041764.

    Google Scholar 

  16. Heinrich MC et al (2020) Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 21:935–946

    Article  CAS  Google Scholar 

  17. Jones RL et al (2021) Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer 145:132–142

    Article  CAS  Google Scholar 

  18. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) (2010) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 28:1247–1253

    Article  Google Scholar 

  19. Vincenzi B et al (2022) Adjuvant Imatinib in patients with GIST harboring Exon 9 KIT mutations: results from a multi-institutional European retrospective study. Clin Cancer Res 28:1672–1679

    Article  CAS  Google Scholar 

  20. Cavnar MJ et al (2017) Rectal gastrointestinal stromal tumor (GIST) in the era of Imatinib: organ preservation and improved oncologic outcome. Ann Surg Oncol 24:3972–3980

    Article  Google Scholar 

  21. Hawkins AT et al (2017) Preoperative chemotherapy and survival for large anorectal gastrointestinal stromal tumors: a national analysis of 333 cases. Ann Surg Oncol 24:1195–1201

    Article  Google Scholar 

  22. Jakob J, Hohenberger P (2018) Neoadjuvant therapy to downstage the extent of resection of gastrointestinal stromal tumors. Visc Med 34:359–365

    Article  Google Scholar 

  23. Lv A et al (2017) Organ-preserving surgery for locally advanced duodenal gastrointestinal stromal tumor after neoadjuvant treatment. Biosci Trends 11:483–489

    Article  Google Scholar 

  24. von Mehren M, Joensuu H (2018) Gastrointestinal stromal tumors. J Clin Oncol 36:136–143

    Article  Google Scholar 

  25. Boye K et al (2018) Genotype and risk of tumour rupture in gastrointestinal stromal tumour. Br J Surg 105:e169–e175

    Article  CAS  Google Scholar 

  26. Jakob J et al (2013) Gastrointestinal stromal tumor of the rectum: results of surgical and multimodality therapy in the era of imatinib. Ann Surg Oncol 20:586–592

    Article  Google Scholar 

  27. Tirumani SH et al (2014) Radiologic assessment of earliest, best, and plateau response of gastrointestinal stromal tumors to neoadjuvant imatinib prior to successful surgical resection. Eur J Surg Oncol 40:420–428

    Article  CAS  Google Scholar 

  28. Heinrich M et al (2018) Avapritinib is highly active and well-tolerated in patients (PTS) with advanced GIST driven by diverse variety of oncogenic mutations in KIT and PDGFRA. CTOS 2018 Annual MeetingAbstract 3027631.

    Google Scholar 

  29. Bauer S et al (2014) Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib—analysis of prognostic factors (EORTC-STBSG collaborative study). Eur J Surg Oncol 40:412–419

    Article  CAS  Google Scholar 

  30. Mussi C et al (2010) Post-imatinib surgery in advanced/metastatic GIST: is it worthwhile in all patients? Ann Oncol 21:403–408

    Article  CAS  Google Scholar 

  31. Raut CP et al (2006) Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24:2325–2331

    Article  CAS  Google Scholar 

  32. Sato S et al (2017) Role of metastasectomy for recurrent/metastatic gastrointestinal stromal tumors based on an analysis of the Kinki GIST registry. Surg Today 47:58–64

    Article  CAS  Google Scholar 

  33. Ford SJ, Gronchi A (2016) Indications for surgery in advanced/metastatic GIST. Eur J Cancer 63:154–167

    Article  Google Scholar 

  34. Van Glabbeke M et al (2005) Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol 23:5795–5804

    Article  Google Scholar 

  35. Keung EZ, Fairweather M, Raut CP (2016) The role of surgery in metastatic gastrointestinal stromal tumors. Curr Treat Options Oncol 17:8

    Article  Google Scholar 

  36. Du CY et al (2014) Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumours responding to imatinib: a prospective randomised trial in China. Eur J Cancer 50:1772–1778

    Article  Google Scholar 

  37. Roland CL et al (2018) Identification of preoperative factors associated with outcomes following surgical management of intra-abdominal recurrent or metastatic GIST following neoadjuvant tyrosine kinase inhibitor therapy. J Surg Oncol 117:879–885

    Article  CAS  Google Scholar 

  38. An HJ et al (2013) The effects of surgical cytoreduction prior to imatinib therapy on the prognosis of patients with advanced GIST. Ann Surg Oncol 20:4212–4218

    Article  Google Scholar 

  39. Raut CP et al (2010) Cytoreductive surgery in patients with metastatic gastrointestinal stromal tumor treated with sunitinib malate. Ann Surg Oncol 17:407–415

    Article  Google Scholar 

  40. Ivanyi P, Winkler T, Ganser A, Reuter C, Grunwald V (2008) Novel therapies in advanced renal cell carcinoma: management of adverse events from sorafenib and sunitinib. Dtsch Arztebl Int 105:232–237

    Google Scholar 

  41. Luber V et al (2018) The use of tumor therapeutics in the perioperative period. Chirurg 89:108–115

    Article  CAS  Google Scholar 

  42. Blay JY et al (2020) Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 21:923–934

    Article  CAS  Google Scholar 

  43. Grunewald S et al (2021) Resistance to avapritinib in PDGFRA-driven GIST is caused by secondary mutations in the PDGFRA kinase domain. Cancer Discov 11:108–125

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Innere Klinik (Tumorforschung) und Sarkomzentrum am Westdeutschen Tumorzentrum, Universitätsklinik Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Deutschland

    Lennart Schardt,  Moritz Kaths &  Sebastian Bauer

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  1. Lennart Schardt
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  2. Moritz Kaths
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Correspondence to Sebastian Bauer.

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Interessenkonflikt

S. Bauer: Beratende Funktion: Blueprint Medicines, Novartis, Daiichi, Lilly, Plexxikon, Deciphera; CME-Honorare: Novartis, Pfizer, Bayer, PharmaMar; Forschungsunterstützung: Blueprint Medicines, Incyte, Novartis. L. Schardt und M. Kaths geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Schardt, L., Kaths, M. & Bauer, S. Molekularpathologisch determinierte multimodale Therapie gastrointestinaler Stromatumoren. Onkologie 29, 120–126 (2023). https://doi.org/10.1007/s00761-022-01297-3

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