KIT and PDGFRA Variants and the Survival of Patients with Gastrointestinal Stromal Tumor Treated with Adjuvant Imatinib
Abstract
:Simple Summary
Abstract
1. Introduction
2. Identification of Patients with High-Risk GISTs
3. Randomized Trials Evaluating Adjuvant Imatinib
4. Adjuvant Imatinib and Overall Survival
5. KIT and PDGFRA Mutational Types in Patient Selection for Adjuvant Treatment
5.1. KIT Exon 11 Deletion and Indel Variants
5.2. KIT Exon 11 Substitution Variants
5.3. KIT Exon 11 Insertion/Duplication Variants
5.4. KIT Exon 9 Variants
5.5. PDGFRA Mutations
5.6. GISTS with No KIT Or PDGFRA Mutation
6. Influence of Adjuvant Imatinib on Imatinib Efficacy after GIST Recurrence
7. Adjuvant Imatinib Treatments Longer Than Three Years
8. Adjuvant Imatinib and Cure from GIST
9. Conclusions
10. Future Directions
Funding
Data Availability Statement
Conflicts of Interest
References
- Corless, C.L.; Barnett, C.M.; Heinrich, M.C. Gastrointestinal stromal tumours: Origin and molecular oncology. Nat. Rev. Cancer 2011, 11, 865–878. [Google Scholar] [CrossRef]
- Von Mehren, M.; Joensuu, H. Gastrointestinal stromal tumors. J. Clin. Oncol. 2018, 36, 136–143. [Google Scholar] [CrossRef]
- Kawanowa, K.; Sakuma, Y.; Sakurai, S.; Hishima, T.; Iwasaki, Y.; Saito, K.; Hosoya, Y.; Nakajima, T.; Funata, N. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum. Pathol. 2006, 37, 1527–1535. [Google Scholar] [CrossRef]
- Agaimy, A.; Wünsch, P.H.; Hofstaedter, F.; Blaszyk, H.; Rümmele, P.; Gaumann, A.; Dietmaier, W.; Hartmann, A. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am. J. Surg. Pathol. 2007, 31, 113–120. [Google Scholar] [CrossRef]
- Woodall, C.E.; Brock, G.N.; Fan, J.; Byam, J.A.; Scoggins, C.R.; McMasters, K.M.; Martin, R.C., II. An evaluation of 2537 gastrointestinal stromal tumors for a proposed clinical staging system. Arch. Surg. 2009, 144, 670–678. [Google Scholar] [CrossRef] [Green Version]
- Joensuu, H.; Vehtari, A.; Riihimäki, J.; Nishida, T.; Steigen, S.E.; Brabec, P.; Plank, L.; Nilsson, B.; Cirilli, C.; Braconi, C.; et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: An analysis of pooled population-based cohorts. Lancet Oncol. 2012, 13, 265–274. [Google Scholar] [CrossRef]
- Emile, J.F.; Brahimi, S.; Coindre, J.M.; Bringuier, P.P.; Monges, G.; Samb, P.; Doucet, L.; Hostein, I.; Landi, B.; Buisine, M.P.; et al. Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs. Med. Oncol. 2012, 29, 1765–1772. [Google Scholar] [CrossRef]
- Joensuu, H.; Rutkowski, P.; Nishida, T.; Steigen, S.E.; Brabec, P.; Plank, L.; Nilsson, B.; Braconi, C.; Bordoni, A.; Magnusson, M.K.; et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J. Clin. Oncol. 2015, 33, 634–642. [Google Scholar] [CrossRef]
- Buchdunger, E.; Cioffi, C.L.; Law, N.; Stover, D.; Ohno-Jones, S.; Druker, B.J.; Lydon, N.B. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J. Pharmacol. Exp. Ther. 2000, 295, 139–145. [Google Scholar]
- Demetri, G.D.; von Mehren, M.; Blanke, C.D.; Van den Abbeele, A.D.; Eisenberg, B.; Roberts, P.J.; Heinrich, M.C.; Tuveson, D.A.; Singer, S.; Janicek, M.; et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 2002, 347, 472–480. [Google Scholar] [CrossRef] [Green Version]
- Blanke, C.D.; Demetri, G.D.; von Mehren, M.; Heinrich, M.C.; Eisenberg, B.; Fletcher, J.A.; Corless, C.L.; Fletcher, C.D.; Roberts, P.J.; Heinz, D.; et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J. Clin. Oncol. 2008, 26, 620–625. [Google Scholar] [CrossRef]
- Verweij, J.; Casali, P.G.; Zalcberg, J.; LeCesne, A.; Reichardt, P.; Blay, J.Y.; Issels, R.; van Oosterom, A.; Hogendoorn, P.C.; Van Glabbeke, M.; et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004, 364, 1127–1134. [Google Scholar] [CrossRef]
- Heinrich, M.C.; Corless, C.L.; Blanke, C.D.; Demetri, G.D.; Joensuu, H.; Roberts, P.J.; Eisenberg, B.L.; von Mehren, M.; Fletcher, C.D.; Sandau, K.; et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J. Clin. Oncol. 2006, 24, 4764–4774. [Google Scholar] [CrossRef] [Green Version]
- Demetri, G.D.; van Oosterom, A.T.; Garrett, C.R.; Blackstein, M.E.; Shah, M.H.; Verweij, J.; McArthur, G.; Judson, I.R.; Heinrich, M.C.; Morgan, J.A.; et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 2006, 368, 1329–1338. [Google Scholar] [CrossRef]
- Demetri, G.D.; Reichardt, P.; Kang, Y.K.; Blay, J.Y.; Rutkowski, P.; Gelderblom, H.; Hohenberger, P.; Leahy, M.; von Mehren, M.; Joensuu, H.; et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013, 381, 295–302. [Google Scholar] [CrossRef] [Green Version]
- Blay, J.Y.; Serrano, C.; Heinrich, M.C.; Zalcberg, J.; Bauer, S.; Gelderblom, H.; Schöffski, P.; Jones, R.L.; Attia, S.; D’Amato, G.; et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020, 21, 923–934. [Google Scholar] [CrossRef]
- Heinrich, M.C.; Corless, C.L.; Demetri, G.D.; Blanke, C.D.; von Mehren, M.; Joensuu, H.; McGreevey, L.S.; Chen, C.J.; Van den Abbeele, A.D.; Druker, B.J.; et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J. Clin. Oncol. 2003, 21, 4342–4349. [Google Scholar] [CrossRef]
- Heinrich, M.C.; Owzar, K.; Corless, C.L.; Hollis, D.; Borden, E.C.; Fletcher, C.D.; Ryan, C.W.; von Mehren, M.; Blanke, C.D.; Rankin, C.; et al. Correlation of kinase genotype and clinical outcome in the North American intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J. Clin. Oncol. 2008, 26, 5360–5367. [Google Scholar]
- Cassier, P.A.; Fumagalli, E.; Rutkowski, P.; Schöffski, P.; Van Glabbeke, M.; Debiec-Rychter, M.; Emile, J.F.; Duffaud, F.; Martin-Broto, J.; Landi, B.; et al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin. Cancer Res. 2012, 18, 4458–4464. [Google Scholar] [CrossRef] [Green Version]
- Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). 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. 2010, 28, 1247–1253. [Google Scholar] [CrossRef] [Green Version]
- Jones, R.L.; Serrano, C.; von Mehren, M.; George, S.; Heinrich, M.C.; Kang, Y.K.; Schöffski, P.; Cassier, P.A.; Mir, O.; Chawla, S.P.; et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumors: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur. J. Cancer 2021, 145, 132–142. [Google Scholar] [CrossRef]
- National Comprehensive Cancer Network Guidelines Version 1.2023. Available online: https://www.nccn.org/guidelines/category_1 (accessed on 27 June 2023).
- Casali, P.G.; Blay, J.-Y.; Abecassis, N.; Bajpai, J.; Bauer, S.; Biagini, R.; Bielack, S.; Bonvalot, S.; Boukovinas, I.; Bovee, J.V.M.G.; et al. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2022, 33, 20–33. [Google Scholar] [CrossRef]
- Liu, Z.; Zhang, Z.; Sun, J.; Li, J.; Zeng, Z.; Ma, M.; Ye, X.; Feng, F.; Kang, W. Comparison of prognosis between neoadjuvant imatinib and upfront surgery for GIST: A systematic review and meta-analysis. Front. Pharmacol. 2022, 13, 966486. [Google Scholar] [CrossRef]
- Brinch, C.M.; Aggerholm-Pedersen, N.; Hogdall, E.; Krarup-Hansen, A. Medical oncological treatment for patients with gastrointestinal stromal tumor (GIST)—A systematic review. Crit. Rev. Oncol. Hematol. 2022, 172, 103650. [Google Scholar] [CrossRef]
- Joensuu, H.; Hohenberger, P.; Corless, C.L. Gastrointestinal stromal tumour. Lancet 2013, 382, 973–983. [Google Scholar] [CrossRef]
- Fletcher, C.D.; Berman, J.J.; Corless, C.; Gorstein, F.; Lasota, J.; Longley, B.J.; Miettinen, M.; O’Leary, T.J.; Remotti, H.; Rubin, B.P.; et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum. Pathol. 2002, 33, 459–465. [Google Scholar] [CrossRef] [Green Version]
- Joensuu, H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum. Pathol. 2008, 39, 1411–1419. [Google Scholar] [CrossRef]
- Miettinen, M.; Lasota, J. Gastrointestinal stromal tumors: Pathology and prognosis at different sites. Semin. Diagn. Pathol. 2006, 23, 70–83. [Google Scholar] [CrossRef]
- Rutkowski, P.; Bylina, E.; Wozniak, A.; Nowecki, Z.I.; Osuch, C.; Matlok, M.; Switaj, T.; Michej, W.; Wroński, M.; Głuszek, S.; et al. Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour: The impact of tumour rupture on patient outcomes. Eur. J. Surg. Oncol. 2011, 37, 890–896. [Google Scholar] [CrossRef]
- Wilkinson, M.J.; Fitzgerald, J.E.; Strauss, D.C.; Hayes, A.J.; Thomas, J.M.; Messiou, C.; Fisher, C.; Benson, C.; Tekkis, P.P.; Judson, I. Surgical treatment of gastrointestinal stromal tumour of the rectum in the era of imatinib. Br. J. Surg. 2015, 102, 965–971. [Google Scholar] [CrossRef]
- Boye, K.; Gorunova, L.; Gunawan, B.; Hompland, I.; Sander, B.; Panagopoulos, I.; Langer, C.; Golas, M.; Heim, S.; Füzesi, L.; et al. Genomic complexity as a biomarker to de-escalate adjuvant imatinib treatment in high-risk gastrointestinal stromal tumor. JCO Precis. Oncol. 2023, 7, e2200351. [Google Scholar] [CrossRef] [PubMed]
- DeMatteo, R.P.; Ballman, K.V.; Antonescu, C.R.; Corless, C.; Kolesnikova, V.; von Mehren, M.; McCarter, M.D.; Norton, J.; Maki, R.G.; Pisters, P.W.; et al. Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) intergroup phase 2 trial. Ann. Surg. 2013, 258, 422–449. [Google Scholar] [CrossRef] [Green Version]
- Casali, P.G.; Le Cesne, A.; Poveda Velasco, A.; Kotasek, D.; Rutkowski, P.; Hohenberger, P.; Fumagalli, E.; Judson, I.R.; Italiano, A.; Gelderblom, H.; et al. Time to definitive failure to the first tyrosine kinase inhibitor in localized GI stromal tumors treated with imatinib as an adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup randomized trial in collaboration with the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J. Clin. Oncol. 2015, 33, 4276–4283. [Google Scholar]
- Casali, P.G.; Le Cesne, A.; Velasco, A.P.; Kotasek, D.; Rutkowski, P.; Hohenberger, P.; Fumagalli, E.; Judson, I.R.; Italiano, A.; Gelderblom, H.; et al. Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS). Ann. Oncol. 2021, 32, 533–541. [Google Scholar] [PubMed]
- Dematteo, R.P.; Ballman, K.V.; Antonescu, C.R.; Maki, R.G.; Pisters, P.W.; Demetri, G.D.; Blackstein, M.E.; Blanke, C.D.; von Mehren, M.; Brennan, M.F.; et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial. Lancet 2009, 373, 1097–1104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Corless, C.L.; Ballman, K.V.; Antonescu, C.R.; Kolesnikova, V.; Maki, R.G.; Pisters, P.W.; Blackstein, M.E.; Blanke, C.D.; Demetri, G.D.; Heinrich, M.C.; et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: The ACOSOG Z9001 trial. J. Clin. Oncol. 2014, 32, 1563–1570. [Google Scholar] [CrossRef]
- Joensuu, H.; Eriksson, M.; Sundby Hall, K.; Hartmann, J.T.; Pink, D.; Schütte, J.; Ramadori, G.; Hohenberger, P.; Duyster, J.; Al-Batran, S.E.; et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: A randomized trial. JAMA 2012, 307, 1265–1272. [Google Scholar] [CrossRef] [Green Version]
- Joensuu, H.; Eriksson, M.; Sundby Hall, K.; Reichardt, A.; Hermes, B.; Schütte, J.; Cameron, S.; Hohenberger, P.; Jost, P.J.; Al-Batran, S.E.; et al. 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. 2020, 6, 1241–1246. [Google Scholar] [CrossRef]
- Li, J.; Gong, J.F.; Wu, A.W.; Shen, L. Post-operative imatinib in patients with intermediate or high risk gastrointestinal stromal tumor. Eur. J. Surg. Oncol. 2011, 37, 319–324. [Google Scholar] [CrossRef]
- Raut, C.P.; Espat, N.J.; Maki, R.G.; Araujox, D.M.; Trent, J.; Williams, T.F.; Purkayastha, D.D.; DeMatteo, R.P. Efficacy and tolerability of 5-year adjuvant imatinib treatment for patients with resected intermediate- or high-risk primary gastrointestinal stromal tumor: The PERSIST-5 clinical trial. JAMA Oncol. 2018, 4, e184060. [Google Scholar] [CrossRef] [Green Version]
- Kanda, T.; Nishida, T.; Wada, N.; Kobayashi, O.; Yamamoto, M.; Sawaki, A.; Boku, N.; Koseki, M.; Doi, T.; Toh, Y.; et al. Adjuvant therapy with imatinib mesylate after resection of primary high-risk gastrointestinal stromal tumors in Japanese patients. Int. J. Clin. Oncol. 2013, 18, 38–45. [Google Scholar] [CrossRef] [PubMed]
- Joensuu, H.; Wardelmann, E.; Sihto, H.; Eriksson, M.; Sundby Hall, K.; Reichardt, A.; Hartmann, J.T.; Pink, D.; Cameron, S.; Hohenberger, P.; et al. Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib. JAMA Oncol. 2017, 3, 602–609. [Google Scholar] [CrossRef] [Green Version]
- Wong, N.A.C.S.; Garcia-Petit, C.; Dangoor, A.; Andrew, N. A literature review and database of how the primary KIT/PDGFRA variant of a gastrointestinal stromal tumour predicts for sensitivity to imatinib. Cancer Genet. 2022, 268–269, 46–54. [Google Scholar] [CrossRef]
- Joensuu, H.; Wardelmann, E.; Eriksson, M.; Reichardt, A.; Sundby Hall, K.; Schütte, J.; Cameron, S.; Hohenberger, P.; Sihto, H.; Jost, P.J.; et al. KIT and PDGFRA mutations and survival of gastrointestinal stromal tumor patients treated with adjuvant imatinib in a randomized trial. Clin. Cancer Res. 2023. online ahead of print. [Google Scholar] [CrossRef] [PubMed]
- Vanden Bempt, I.; Vander Borght, S.; Sciot, R.; Spans, L.; Claerhout, S.; Brems, H.; Lehnert, S.; Dehaspe, L.; Fransis, S.; Neuville, B.; et al. Comprehensive targeted next-generation sequencing approach in the molecular diagnosis of gastrointestinal stromal tumor. Genes Chromosomes Cancer 2021, 60, 239–249. [Google Scholar] [CrossRef] [PubMed]
- Vincenzi, B.; Napolitano, A.; Fiocco, M.; Mir, O.; Rutkowski, P.; Blay, J.-Y.; Reichardt, P.; Joensuu, H.; Fumagalli, E.; Gennatas, S.; et al. Adjuvant imatinib in patients with GIST harboring exon 9 KIT mutations: Results from a multi-institutional European retrospective study. Clin. Cancer Res. 2022, 28, 1672–1679. [Google Scholar] [CrossRef] [PubMed]
- Heinrich, M.C.; Jones, R.L.; von Mehren, M.; Schöffski, P.; Serrano, C.; Kang, Y.K.; Cassier, P.A.; Mir, O.; Eskens, F.; Tap, W.D.; et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): A multicentre, open-label, phase 1 trial. Lancet Oncol. 2020, 21, 935–946. [Google Scholar] [CrossRef]
- Boikos, S.A.; Pappo, A.S.; Killian, J.K.; LaQuaglia, M.P.; Weldon, C.B.; George, S.; Trent, J.C.; von Mehren, M.; Wright, J.A.; Schiffman, J.D.; et al. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: A report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016, 2, 922–928. [Google Scholar] [CrossRef] [Green Version]
- Salvi, P.F.; Lorenzon, L.; Caterino, S.; Antolino, L.; Antonelli, M.S.; Balducci, G. Gastrointestinal stromal tumors associated with neurofibromatosis 1: A single centre experience and systematic review of the literature including 252 cases. Int. J. Surg. Oncol. 2013, 2013, 398570. [Google Scholar] [CrossRef]
- Nishida, T.; Sato, S.; Ozaka, M.; Nakahara, Y.; Komatsu, Y.; Kondo, M.; Cho, H.; Hirota, S.; Kagimura, T.; Kurokawa, Y.; et al. Long-term adjuvant therapy for high-risk gastrointestinal stromal tumors in the real world. Gastric Cancer 2022, 25, 956–965. [Google Scholar] [CrossRef]
- Liu, R.; Wu, Y.; Gong, J.; Zhao, R.; Li, L.; Wan, Q.; Lian, N.; Shen, X.; Xia, L.; Shen, Y.; et al. Development and external validation of a nomogram for individualized adjuvant imatinib duration for high-risk gastrointestinal stromal tumors: A multicenter retrospective cohort study. Cancer Med. 2022, 11, 3093–3105. [Google Scholar] [CrossRef] [PubMed]
- Hohenberger, P.; Ronellenfitsch, U.; Oladeji, O.; Pink, D.; Ströbel, P.; Wardelmann, E.; Reichardt, P. Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour. Br. J. Surg. 2010, 97, 1854–1859. [Google Scholar] [CrossRef] [PubMed]
- Nishida, T.; Hølmebakk, T.; Raut, C.P.; Rutkowski, P. Defining tumor rupture in gastrointestinal stromal tumor. Ann. Surg. Oncol. 2019, 26, 1669–1675. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hølmebakk, T.; Hompland, I.; Bjerkehagen, B.; Stoldt, S.; Bruland, Ø.S.; Hall, K.S.; Boye, K. Recurrence-free survival after resection of gastric gastrointestinal stromal tumors classified according to a strict definition of tumor rupture: A population-based study. Ann. Surg. Oncol. 2018, 25, 1133–1139. [Google Scholar] [CrossRef]
- Joensuu, H.; Eriksson, M.; Hall, K.S.; Hartmann, J.T.; Pink, D.; Schütte, J.; Ramadori, G.; Hohenberger, P.; Duyster, J.; Al-Batran, S.E.; et al. Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib. Cancer 2014, 120, 2325–2333. [Google Scholar] [CrossRef] [Green Version]
Trial Name; No. of Accrued Patients | Investigational Group | Control Group | Patient Eligibility | Primary Endpoint | Mutation Analysis Available | Main Results |
---|---|---|---|---|---|---|
ACOSOG Z9001 (NCT00041197) n = 713 [36,37] | Imatinib 400 mg/d for 12 mo | Placebo for 12 mo | Size ≥ 3 cm | RFS | Yes | Median FU: 1.6 yrs 1-y RFS: IM, 98%; C, 83%; HR (CI): 0.35 (0.22–0.53) 1-y OS: IM, 99.2%; C, 99.7%; HR (CI): 0.66 (0.22–2.03) |
EORTC/Intergroup (NCT00103168) n = 908 [34,35] | Imatinib 400 mg/d for 24 mo | Observation | Intermediate or high risk (NIH Consensus) | IFFS | No | Median FU: 9.1 yrs 5-y IFFS: IM, 87%; C, 83%; HR (CI): 0.87 (0.65–1.15) 5-y RFS: IM, 70%; C, 63%; HR (CI) 0.71 (0.57–0.89); 10-y RFS: IM, 63%; C, 61% 5-y OS: 5-y OS; IM, 93%; C, 92%; HR 0.88 (0.65–1.21); 10-y OS: IM, 80%, C, 78% |
SSGXVIII (NCT00116935) n = 400 1 [38,39] | Imatinib 400 mg/d for 3 yrs | Imatinib 400 mg/d for 1 yr | High risk (modified NIH) | RFS | Yes | Median FU: 9.9 yrs 10-y RFS: 3-y, 52.5%; C: 41.8%; HR (CI): 0.66 (0.49–0.87) 10-y OS: 3-y, 79.0%; C: 65.3%; HR (CI): 0.55 (0.37–0.83) |
Trial Name; No. of Accrued Patients | Adjuvant Treatment | Patient Eligibility | Primary Endpoint | Mutation Analysis Available | Main Results |
---|---|---|---|---|---|
ACOSOG Z9000 (NCT00025246) n = 106 [33] | Imatinib 400 mg/d for 12 mo | High risk 1 | OS | Yes | Median FU: 7.7 yrs 5-yr RFS 40%; 5-y OS 83% |
Kanda et al. (NCT00171977) n = 64 [42] | Imatinib 400 mg/d for 12 mo | High risk (NIH Consensus) | RFS | Yes | Median FU: 2.1 yrs 3-yr RFS 57%; 3-y OS 87% |
Li et al. (ChiCTR-TCC-00000582) n = 56 [40] | Imatinib 400 mg/d for 3 yrs | High or intermediate risk (NIH Consensus) | RFS | Yes 2 | Median FU: 3.8 yrs 3-yr RFS 89% |
PERSIST-5 (NCT00867113) n = 91 [41] | Imatinib 400 mg/d for 5 years | High or intermediate risk (AFIP) | RFS | Yes | Median FU: not provided 46 (50.5%) completed treatment 5-yr RFS 90%; 5-y OS 95% |
KIT/PDGFRA Aberration | ACOSOG Z9001 N = 713 [36] n (%) | SSGXVIII/AIO N = 358 1 [38] n (%) | ACOSOG Z9000 N = 106 [33] n (%) | Kanda et al. N = 64 [34] n (%) | PERSIST-5 N = 91 [41] n (%) |
---|---|---|---|---|---|
Mutational data available | 507 (71.1) | 341 (95.3) | 78 (73.6) | 62 (96.9) | 85 (93.4) |
KIT | 386 (76.1) | 273 (80.1) | 59 (75.6) | 55 (88.7) | 64 (75.3) |
KIT exon 11 | 341 (67.3) | 239 (70.1) | 45 (57.7) | 49 (79.0) | 57 (67.1) |
Deletion/indel | 184 (36.3) | 149 (43.7) | N.P. | N.P. | N.P. |
Substitution | 111 (21.9) | 68 (19.9) | N.P. | N.P. | N.P. |
Insertion/duplication | 46 (9.1) | 22 (6.5) | N.P. | N.P. | N.P. |
KIT exon 9 | 35 (6.9) | 26 (7.6) | 10 (12.8) | 6 (9.7) | 3 (3.5) |
KIT other | 10 (2.0) | 8 (2.3) | 4 (5.1) | 1 (1.6) | 4 (4.7) |
PDGFRA | 57 (11.2) | 43 (12.6) | 10 (12.8) | 3 (4.8) | 9 (10.6) |
Exon 18 D842V | 27 (5.3) | 30 (8.8) | N.P. | N.P. | 5 (5.9) |
Other | 30 (5.9) | 13 (3.8) | N.P. | N.P. | 4 (4.7) |
Non-KIT/non-PDGFRA | 64 (12.6) | 24 (7.0) | 9 (11.5) | 3 (4.8) | 12 (14.1) |
Other | 0 (0) | 1 (0.3) 2 | 0 | 0 | 0 |
Mutation Type | Survival Benefit from Adjuvant Imatinib | Comment |
---|---|---|
Kit | ||
Exon 11 | ||
Deletion/indel | Substantial | 66% of deaths avoided with 3 yr imatinib [45] |
Substitution | Probable but not demonstrated | Benefit likely less than with deletion/indel mutations [37,44,45] |
Insertion/duplication | Probable but not demonstrated | Sensitive to imatinib in vitro [37,44,45] |
Exon 9 | Unknown, but possible | Only an imatinib dose of 400 mg/day has been studied [37,44,45] |
PDGFRA | ||
D842V | No benefit | Recurrence infrequent; imatinib-resistant [23] |
Other | Probable but not demonstrated | Most imatinib-sensitive [44] |
Non-KIT/non-PDGFRA | No benefit | KIT/PDGFRA mutation sometimes missed in testing [46] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Joensuu, H. KIT and PDGFRA Variants and the Survival of Patients with Gastrointestinal Stromal Tumor Treated with Adjuvant Imatinib. Cancers 2023, 15, 3879. https://doi.org/10.3390/cancers15153879
Joensuu H. KIT and PDGFRA Variants and the Survival of Patients with Gastrointestinal Stromal Tumor Treated with Adjuvant Imatinib. Cancers. 2023; 15(15):3879. https://doi.org/10.3390/cancers15153879
Chicago/Turabian StyleJoensuu, Heikki. 2023. "KIT and PDGFRA Variants and the Survival of Patients with Gastrointestinal Stromal Tumor Treated with Adjuvant Imatinib" Cancers 15, no. 15: 3879. https://doi.org/10.3390/cancers15153879