Adjuvant Imatinib in Patients with GIST Harboring Exon 9 KIT Mutations: Results from a Multi-institutional European Retrospective Study

Vincenzi, Bruno; Napolitano, Andrea; Fiocco, Marta; Mir, Olivier; Rutkowski, Piotr; Blay, Jean‐Yves; Reichardt, Peter; Joensuu, Heikki; Fumagalli, Elena; Gennatas, Spyridon; Hindi, Nadia; Nannini, Margherita; Ceruso, Mariella Spalato; Italiano, Antoîne; Grignani, Giovanni; Brunello, Antonella; Gasperoni, Silvia; Pas, Tommaso De; Badalamenti, Giuseppe; Pantaleo, Maria A.; Houdt, Winan J. van; IJzerman, Nikki S.; Steeghs, Neeltje; Gelderblom, Hans; Desar, Ingrid M.E.; Falkenhorst, Johanna; Silletta, Marianna; Sbaraglia, Marta; Tonini, Giuseppe; Martin‐Broto, Javier; Hohenberger, Peter; Cesne, Axel Le; Jones, Robin L.; Tos, Angelo Paolo Dei; Gronchi, Alessandro; Bauer, Sebastian; Casali, Paolo G.

doi:10.1158/1078-0432.ccr-21-1665

Cited by 22 publications

(13 citation statements)

References 33 publications

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“…However, some patients have GISTs that do not show any response to imatinib (primary resistance), and most GISTs eventually develop secondary resistance (defined as resistance occurring after > 6 months of clinical response) to imatinib. KIT exon 9 duplications confer limited response to imatinib and the requirement for higher doses [ 18 , 19 ], while PDGFRA D842V substitution causes primary resistance to the drug [ 20 ]. Secondary imatinib resistance results from the development of newly acquired mutations in KIT or PDGFRA [ 21 – 23 ], which allows reactivation of tyrosine kinase.…”

Section: Current Status Of Treatment For Unresectable and Advanced Gistmentioning

confidence: 99%

Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours

2023

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Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody–drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal.

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Section: Current Status Of Treatment For Unresectable and Advanced Gistmentioning

confidence: 99%

Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours

2023

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“…However, an analysis showed that high-dose imatinib (800 mg/day) demonstrated longer progression-free survival compared with the standard dose for patients with metastatic GISTs with exon 9 mutations 37 . However, in a retrospective series of adjuvant therapy for exon 9-mutated GISTs, high-dose imatinib did not achieve better survival outcomes compared with the standard dose 38 . In the present study, all patients received the standard dose because the national health insurance system in Japan allows administration of only up to 400 mg/day, and the median reduction in tumour size was 30 per cent.…”

Section: Discussionmentioning

confidence: 84%

Clinical outcomes of surgical and imatinib treatment for rectal gastrointestinal stromal tumours: retrospective cohort study

et al. 2022

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Background Rectal gastrointestinal stromal tumours (GISTs) are rare and treated mainly by radical surgery. Although the importance of perioperative imatinib has been recognized, there are few reports on its outcomes. Method Consecutive patients diagnosed with rectal GISTs between July 2008 and February 2021 were identified from a prospective database. Effects of perioperative imatinib were investigated, and surgical and survival outcomes were compared between neoadjuvant imatinib and upfront surgery. Results 34 patients meeting the inclusion criteria were identified. Compared with upfront surgery (n = 11), the neoadjuvant imatinib group (n = 23) had significantly larger tumours (median size 8.3 versus 2.5 cm; P = 0.01) and included a significantly greater proportion of high-risk patients according to the modified Fletcher classification (20/23 (87.0%) versus 6/11 (54.5%); P = 0.02). Comparing the operation planned based on imaging before neoadjuvant imatinib and the operation performed, there was an increase in sphincter-preserving surgery (4/23 (17.4%) to 11/23 (47.8%); P = 0.02), abdominoperineal resection 11/23 (47.8%) reduced to 7/23 (30.4%); P = 0.13) and total pelvic exenteration reduced from 8/23 (34.8%) to 5/23 (21.7%); P = 0.01). Tumours were downsized by a median of 30 per cent (range 0 per cent to −56 per cent; P = 0.01). During follow-up (median 42, range 5–131 months), there was no postoperative recurrence in 29 patients who received perioperative imatinib. One of the five patients who underwent surgery without neoadjuvant or adjuvant imatinib developed local recurrence. Conclusion Treatment with imatinib for rectal GISTs seems to improve outcomes, and neoadjuvant imatinib increases the rate of sphincter-preserving surgery.

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“…The P-value for statistically significant comparisons was less than 0.05. The IPTW analyses were performed via the "RISCA" R package, v1.0.1 (31). P-value and SMD of baseline characteristics were calculated using the "TableOne" R package, v 0.13.2 (32).…”

Section: Discussionmentioning

confidence: 99%

GnRH-agonist pretreatment in hormone replacement therapy improves pregnancy outcomes in women with male-factor infertility

Chen

Luo

et al. 2022

Front. Endocrinol.

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ObjectiveThis study aimed to examine the efficacy of HRT with gonadotropin-releasing hormone agonist (GnRH-a) pre-treatment in women with male-factor infertility who underwent a frozen embryo transfer (FET) programme.DesignBetween January 2016 and October 2020, 2733 women with male-factor infertility who underwent the HRT protocol as the endometrial preparation method were enrolled at two Reproductive Medicine Centres. Patients were divided into two groups based on whether they had GnRH-a pre-treatment before HRTs: the GnRHa-HRT group and the HRT group. The inverse probability of treatment weighting (IPTW) method was conducted to balance patient baseline characteristics between treatment cohorts to reduce selection bias. The live birth rate was considered regarded as the primary pregnancy outcome.ResultsMultivariate logistic regression adjusted for confounding factors, the GnRHa-HRT group showed a notably higher rate of live birth (OR 2.154, 95% CI 1.636~2.835, P<0.001) when compared to the HRT group. Additionally, the rate of miscarriage was significantly lower in the GnRHa-HRT group. The GnRHa-HRT group had significantly higher rates of biochemical pregnancy, clinical pregnancy, multiple pregnancy, and term birth.ConclusionThe endometrial preparation protocol of HRT with GnRH-a pre-treatment could obviously increase the live birth rate for women with male-factor infertility undergoing the FET programme.

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Adjuvant Imatinib in Patients with GIST Harboring Exon 9 KIT Mutations: Results from a Multi-institutional European Retrospective Study

Cited by 22 publications

References 33 publications

Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours

Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours

Clinical outcomes of surgical and imatinib treatment for rectal gastrointestinal stromal tumours: retrospective cohort study

GnRH-agonist pretreatment in hormone replacement therapy improves pregnancy outcomes in women with male-factor infertility

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