Skip to main content
Erschienen in: Wiener klinisches Magazin 2/2023

07.03.2023 | Onkologie

Molekularpathologisch determinierte multimodale Therapie gastrointestinaler Stromatumoren

verfasst von: Lennart Schardt, PD Dr. Moritz Kaths, Prof. Dr. Sebastian Bauer

Erschienen in: Wiener klinisches Magazin | Ausgabe 2/2023

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat Casali PG et al (2022) Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 33:20–33PubMedCrossRef Casali PG et al (2022) Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 33:20–33PubMedCrossRef
2.
Zurück zum Zitat Duensing A et al (2004) Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23:3999–4006PubMedCrossRef Duensing A et al (2004) Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23:3999–4006PubMedCrossRef
3.
Zurück zum Zitat 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 26:7560–7568PubMedCrossRef 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 26:7560–7568PubMedCrossRef
4.
Zurück zum Zitat Heinrich MC et al (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710PubMedCrossRef Heinrich MC et al (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710PubMedCrossRef
5.
Zurück zum Zitat Li B et al (2016) Conjoined hyperactivation of the RAS and PI3K pathways in advanced GIST. J Clin Oncol 34:e22520CrossRef Li B et al (2016) Conjoined hyperactivation of the RAS and PI3K pathways in advanced GIST. J Clin Oncol 34:e22520CrossRef
6.
Zurück zum Zitat Blay JY, Kang YK, Nishida T, von Mehren M (2021) Gastrointestinal stromal tumours. Nat Rev Dis Primers 7:22PubMedCrossRef Blay JY, Kang YK, Nishida T, von Mehren M (2021) Gastrointestinal stromal tumours. Nat Rev Dis Primers 7:22PubMedCrossRef
7.
Zurück zum Zitat 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 344:1052–1056PubMedCrossRef 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 344:1052–1056PubMedCrossRef
8.
Zurück zum Zitat Joensuu H et al (2016) Adjuvant Imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol 34:244–250PubMedCrossRef Joensuu H et al (2016) Adjuvant Imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol 34:244–250PubMedCrossRef
10.
Zurück zum Zitat Casali PG et al (2018) Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv68–iv78PubMedCrossRef Casali PG et al (2018) Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv68–iv78PubMedCrossRef
11.
Zurück zum Zitat Fletcher CD et al (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465PubMedCrossRef Fletcher CD et al (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465PubMedCrossRef
12.
Zurück zum Zitat Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83PubMedCrossRef Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83PubMedCrossRef
13.
Zurück zum Zitat Joensuu H (2008) Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 39:1411–1419PubMedCrossRef Joensuu H (2008) Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 39:1411–1419PubMedCrossRef
14.
Zurück zum Zitat Joensuu H et al (2012) Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 13:265–274PubMedCrossRef Joensuu H et al (2012) Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 13:265–274PubMedCrossRef
15.
Zurück zum Zitat 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. 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.
16.
Zurück zum Zitat Heinrich MC et al (2020) Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 21:935–946PubMedCrossRef Heinrich MC et al (2020) Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 21:935–946PubMedCrossRef
17.
Zurück zum Zitat 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 145:132–142PubMedPubMedCentralCrossRef 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 145:132–142PubMedPubMedCentralCrossRef
18.
Zurück zum Zitat 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 28:1247–1253CrossRef 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 28:1247–1253CrossRef
19.
Zurück zum Zitat 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 28:1672–1679PubMedCrossRef 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 28:1672–1679PubMedCrossRef
20.
Zurück zum Zitat Cavnar MJ et al (2017) Rectal gastrointestinal stromal tumor (GIST) in the era of Imatinib: organ preservation and improved oncologic outcome. Ann Surg Oncol 24:3972–3980PubMedPubMedCentralCrossRef Cavnar MJ et al (2017) Rectal gastrointestinal stromal tumor (GIST) in the era of Imatinib: organ preservation and improved oncologic outcome. Ann Surg Oncol 24:3972–3980PubMedPubMedCentralCrossRef
21.
Zurück zum Zitat Hawkins AT et al (2017) Preoperative chemotherapy and survival for large anorectal gastrointestinal stromal tumors: a national analysis of 333 cases. Ann Surg Oncol 24:1195–1201PubMedCrossRef Hawkins AT et al (2017) Preoperative chemotherapy and survival for large anorectal gastrointestinal stromal tumors: a national analysis of 333 cases. Ann Surg Oncol 24:1195–1201PubMedCrossRef
22.
Zurück zum Zitat Jakob J, Hohenberger P (2018) Neoadjuvant therapy to downstage the extent of resection of gastrointestinal stromal tumors. Visc Med 34:359–365PubMedPubMedCentralCrossRef Jakob J, Hohenberger P (2018) Neoadjuvant therapy to downstage the extent of resection of gastrointestinal stromal tumors. Visc Med 34:359–365PubMedPubMedCentralCrossRef
23.
Zurück zum Zitat Lv A et al (2017) Organ-preserving surgery for locally advanced duodenal gastrointestinal stromal tumor after neoadjuvant treatment. Biosci Trends 11:483–489PubMedCrossRef Lv A et al (2017) Organ-preserving surgery for locally advanced duodenal gastrointestinal stromal tumor after neoadjuvant treatment. Biosci Trends 11:483–489PubMedCrossRef
24.
Zurück zum Zitat von Mehren M, Joensuu H (2018) Gastrointestinal stromal tumors. J Clin Oncol 36:136–143CrossRef von Mehren M, Joensuu H (2018) Gastrointestinal stromal tumors. J Clin Oncol 36:136–143CrossRef
25.
Zurück zum Zitat Boye K et al (2018) Genotype and risk of tumour rupture in gastrointestinal stromal tumour. Br J Surg 105:e169–e175PubMedCrossRef Boye K et al (2018) Genotype and risk of tumour rupture in gastrointestinal stromal tumour. Br J Surg 105:e169–e175PubMedCrossRef
26.
Zurück zum Zitat 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 20:586–592PubMedCrossRef 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 20:586–592PubMedCrossRef
27.
Zurück zum Zitat 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 40:420–428PubMedCrossRef 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 40:420–428PubMedCrossRef
28.
Zurück zum Zitat 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. 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.
29.
Zurück zum Zitat 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 40:412–419PubMedCrossRef 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 40:412–419PubMedCrossRef
30.
Zurück zum Zitat Mussi C et al (2010) Post-imatinib surgery in advanced/metastatic GIST: is it worthwhile in all patients? Ann Oncol 21:403–408PubMedCrossRef Mussi C et al (2010) Post-imatinib surgery in advanced/metastatic GIST: is it worthwhile in all patients? Ann Oncol 21:403–408PubMedCrossRef
31.
Zurück zum Zitat Raut CP et al (2006) Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24:2325–2331PubMedCrossRef Raut CP et al (2006) Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24:2325–2331PubMedCrossRef
32.
Zurück zum Zitat 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 47:58–64PubMedCrossRef 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 47:58–64PubMedCrossRef
33.
Zurück zum Zitat Ford SJ, Gronchi A (2016) Indications for surgery in advanced/metastatic GIST. Eur J Cancer 63:154–167PubMedCrossRef Ford SJ, Gronchi A (2016) Indications for surgery in advanced/metastatic GIST. Eur J Cancer 63:154–167PubMedCrossRef
34.
Zurück zum Zitat 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 23:5795–5804PubMedCrossRef 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 23:5795–5804PubMedCrossRef
35.
Zurück zum Zitat Keung EZ, Fairweather M, Raut CP (2016) The role of surgery in metastatic gastrointestinal stromal tumors. Curr Treat Options Oncol 17:8PubMedCrossRef Keung EZ, Fairweather M, Raut CP (2016) The role of surgery in metastatic gastrointestinal stromal tumors. Curr Treat Options Oncol 17:8PubMedCrossRef
36.
Zurück zum Zitat 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 50:1772–1778PubMedCrossRef 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 50:1772–1778PubMedCrossRef
37.
Zurück zum Zitat 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 117:879–885PubMedPubMedCentralCrossRef 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 117:879–885PubMedPubMedCentralCrossRef
38.
Zurück zum Zitat 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 20:4212–4218PubMedCrossRef 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 20:4212–4218PubMedCrossRef
39.
Zurück zum Zitat Raut CP et al (2010) Cytoreductive surgery in patients with metastatic gastrointestinal stromal tumor treated with sunitinib malate. Ann Surg Oncol 17:407–415PubMedCrossRef Raut CP et al (2010) Cytoreductive surgery in patients with metastatic gastrointestinal stromal tumor treated with sunitinib malate. Ann Surg Oncol 17:407–415PubMedCrossRef
40.
Zurück zum Zitat 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 105:232–237PubMedPubMedCentral 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 105:232–237PubMedPubMedCentral
41.
Zurück zum Zitat Luber V et al (2018) The use of tumor therapeutics in the perioperative period. Chirurg 89:108–115PubMedCrossRef Luber V et al (2018) The use of tumor therapeutics in the perioperative period. Chirurg 89:108–115PubMedCrossRef
42.
Zurück zum Zitat 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 21:923–934PubMedPubMedCentralCrossRef 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 21:923–934PubMedPubMedCentralCrossRef
43.
Zurück zum Zitat Grunewald S et al (2021) Resistance to avapritinib in PDGFRA-driven GIST is caused by secondary mutations in the PDGFRA kinase domain. Cancer Discov 11:108–125PubMedCrossRef Grunewald S et al (2021) Resistance to avapritinib in PDGFRA-driven GIST is caused by secondary mutations in the PDGFRA kinase domain. Cancer Discov 11:108–125PubMedCrossRef
Metadaten
Titel
Molekularpathologisch determinierte multimodale Therapie gastrointestinaler Stromatumoren
verfasst von
Lennart Schardt
PD Dr. Moritz Kaths
Prof. Dr. Sebastian Bauer
Publikationsdatum
07.03.2023
Verlag
Springer Vienna
Erschienen in
Wiener klinisches Magazin / Ausgabe 2/2023
Print ISSN: 1869-1757
Elektronische ISSN: 1613-7817
DOI
https://doi.org/10.1007/s00740-023-00488-x

Weitere Artikel der Ausgabe 2/2023

Wiener klinisches Magazin 2/2023 Zur Ausgabe

Panorama

Panorama