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Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib.

Quek R, George S - Biologics (2010)

Bottom Line: In the last decade a tremendous amount has been learned about the biology and treatment of gastrointestinal stromal tumor (GIST).Imatinib mesylate has revolutionized the treatment of metastatic GIST.In addition, the role of imatinib in localized GIST has gained much interest and may improve patient outcomes.

View Article: PubMed Central - PubMed

Affiliation: Visiting Fellow, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;

ABSTRACT
In the last decade a tremendous amount has been learned about the biology and treatment of gastrointestinal stromal tumor (GIST). Imatinib mesylate has revolutionized the treatment of metastatic GIST. In addition, the role of imatinib in localized GIST has gained much interest and may improve patient outcomes. Additionally, research efforts aimed at understanding the biology and the molecular heterogeneity of GIST both at initial presentation and at the time of resistance to imatinib, has helped guide rational approaches to treatment as well as future efforts aimed at treating imatinib-resistant GIST.

No MeSH data available.


Related in: MedlinePlus

Structure of KIT and PDGFRA. The location and relative frequencies of GIST-associated kinase mutations are depicted in relation to the structural features of KIT and PDGFRA. The remainder of GIST (about 12% in this series) do not harbor detectable KIT or PDGFRA mutations.Adapted with permission. © 2004 American Society of Clinical Oncology. All right reserved. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813–3825.30 Adapted with permission. © 2003 American Society of Clinical Oncology. All right reserved. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–4349.31
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Related In: Results  -  Collection


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f2-btt-4-019: Structure of KIT and PDGFRA. The location and relative frequencies of GIST-associated kinase mutations are depicted in relation to the structural features of KIT and PDGFRA. The remainder of GIST (about 12% in this series) do not harbor detectable KIT or PDGFRA mutations.Adapted with permission. © 2004 American Society of Clinical Oncology. All right reserved. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813–3825.30 Adapted with permission. © 2003 American Society of Clinical Oncology. All right reserved. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–4349.31

Mentions: Shortly after the demonstration of imatinib efficacy in metastatic GIST, research efforts were focused on the molecular heterogeneity and impact of genotypic variations on clinical outcomes. It is now appreciated that 85% to 90% of all GISTs harbor activating mutations in either KIT or PDGFRA. As shown in Figure 2, the majority of these mutations occur in KIT; exon 11 (66%) being most commonly affected followed by exon 9 (13%), with low incidences in exon 13 and 17 (about 1% each). Mutations in PDGFRA represent less than 10% of all mutations with exon 18 mutations (about 6%) being more common than exon 12 mutations (about 2%). The remainder of GISTs (12%) are wild-type for both KIT and PDGFRA.30 Tumor genotype has a major influence on clinical outcomes in the setting of imatinib therapy. In one of the earliest studies correlating genotype to clinical response, using tumor tissue available from 127 of 147 patients enrolled on the North American phase II trial of imatinib in patients with advanced GIST, partial response rate in patients with tumors that harbor exon 11 KIT mutation was significantly superior to those patients whose tumors harbor exon 9 KIT mutation and wild-type GIST, 84% versus 48% respectively. In addition, progression-free and overall survival was superior in patients with exon 11 mutation.31 Similar findings were reported in the larger phase III studies evaluating standard and high dose imatinib. In the North American study, the presence of tumor KIT exon 11 mutation correlated with an improved objective response rate to imatinib (72%, 44%, 45% respectively), time to progression (median 25 months, 17 months and 13 months respectively) and overall survival (median 60 months, 38 months and 49 months respectively) when compared to patients with KIT exon 9 mutation and wild-type GIST. Additionally no significant differences were detected between KIT exon 9 mutants and wild-type GIST.32 Likewise in the EORTC-led study, of 946 patients randomized to treatment, 377 had adequate tumor material for mutational analysis. When compared with patients whose tumors harbor exon 11 mutants, presence of exon 9 mutations and wild-type GIST were the strongest adverse prognostic factor for objective response, risk of progression and death.33 Having identified a “high-risk” cohort of patients, investigators next questioned if imatinib dose-escalation could overcome this adverse prognostic feature. In the meta-analysis of the two large phase III imatinib dose-efficacy studies undertaken by Van Glabbeke and colleagues, a statistically significantly progression-free survival benefit in patients who received imatinib 800 mg/day was demonstrated in the subset of patients with KIT exon 9 mutations from EORTC dataset. This finding was not confirmed in the North American dataset. However, the benefit of imatinib 800 mg/day remained significant in the pooled dataset, median progression-free survival of 6 months versus 19 months, in the standard-dose and high-dose imatinib arms respectively, for patients whose tumors harbor exon 9 mutations.26,32,33 This finding may account for the improved overall progression-free survival seen in the EORTC study attributed to high-dose imatinib, where a larger proportion of KIT exon 9 mutants were enrolled (15% of analyzed patients in the EORTC study versus 8% in the North American study).


Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib.

Quek R, George S - Biologics (2010)

Structure of KIT and PDGFRA. The location and relative frequencies of GIST-associated kinase mutations are depicted in relation to the structural features of KIT and PDGFRA. The remainder of GIST (about 12% in this series) do not harbor detectable KIT or PDGFRA mutations.Adapted with permission. © 2004 American Society of Clinical Oncology. All right reserved. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813–3825.30 Adapted with permission. © 2003 American Society of Clinical Oncology. All right reserved. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–4349.31
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2819895&req=5

f2-btt-4-019: Structure of KIT and PDGFRA. The location and relative frequencies of GIST-associated kinase mutations are depicted in relation to the structural features of KIT and PDGFRA. The remainder of GIST (about 12% in this series) do not harbor detectable KIT or PDGFRA mutations.Adapted with permission. © 2004 American Society of Clinical Oncology. All right reserved. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813–3825.30 Adapted with permission. © 2003 American Society of Clinical Oncology. All right reserved. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–4349.31
Mentions: Shortly after the demonstration of imatinib efficacy in metastatic GIST, research efforts were focused on the molecular heterogeneity and impact of genotypic variations on clinical outcomes. It is now appreciated that 85% to 90% of all GISTs harbor activating mutations in either KIT or PDGFRA. As shown in Figure 2, the majority of these mutations occur in KIT; exon 11 (66%) being most commonly affected followed by exon 9 (13%), with low incidences in exon 13 and 17 (about 1% each). Mutations in PDGFRA represent less than 10% of all mutations with exon 18 mutations (about 6%) being more common than exon 12 mutations (about 2%). The remainder of GISTs (12%) are wild-type for both KIT and PDGFRA.30 Tumor genotype has a major influence on clinical outcomes in the setting of imatinib therapy. In one of the earliest studies correlating genotype to clinical response, using tumor tissue available from 127 of 147 patients enrolled on the North American phase II trial of imatinib in patients with advanced GIST, partial response rate in patients with tumors that harbor exon 11 KIT mutation was significantly superior to those patients whose tumors harbor exon 9 KIT mutation and wild-type GIST, 84% versus 48% respectively. In addition, progression-free and overall survival was superior in patients with exon 11 mutation.31 Similar findings were reported in the larger phase III studies evaluating standard and high dose imatinib. In the North American study, the presence of tumor KIT exon 11 mutation correlated with an improved objective response rate to imatinib (72%, 44%, 45% respectively), time to progression (median 25 months, 17 months and 13 months respectively) and overall survival (median 60 months, 38 months and 49 months respectively) when compared to patients with KIT exon 9 mutation and wild-type GIST. Additionally no significant differences were detected between KIT exon 9 mutants and wild-type GIST.32 Likewise in the EORTC-led study, of 946 patients randomized to treatment, 377 had adequate tumor material for mutational analysis. When compared with patients whose tumors harbor exon 11 mutants, presence of exon 9 mutations and wild-type GIST were the strongest adverse prognostic factor for objective response, risk of progression and death.33 Having identified a “high-risk” cohort of patients, investigators next questioned if imatinib dose-escalation could overcome this adverse prognostic feature. In the meta-analysis of the two large phase III imatinib dose-efficacy studies undertaken by Van Glabbeke and colleagues, a statistically significantly progression-free survival benefit in patients who received imatinib 800 mg/day was demonstrated in the subset of patients with KIT exon 9 mutations from EORTC dataset. This finding was not confirmed in the North American dataset. However, the benefit of imatinib 800 mg/day remained significant in the pooled dataset, median progression-free survival of 6 months versus 19 months, in the standard-dose and high-dose imatinib arms respectively, for patients whose tumors harbor exon 9 mutations.26,32,33 This finding may account for the improved overall progression-free survival seen in the EORTC study attributed to high-dose imatinib, where a larger proportion of KIT exon 9 mutants were enrolled (15% of analyzed patients in the EORTC study versus 8% in the North American study).

Bottom Line: In the last decade a tremendous amount has been learned about the biology and treatment of gastrointestinal stromal tumor (GIST).Imatinib mesylate has revolutionized the treatment of metastatic GIST.In addition, the role of imatinib in localized GIST has gained much interest and may improve patient outcomes.

View Article: PubMed Central - PubMed

Affiliation: Visiting Fellow, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;

ABSTRACT
In the last decade a tremendous amount has been learned about the biology and treatment of gastrointestinal stromal tumor (GIST). Imatinib mesylate has revolutionized the treatment of metastatic GIST. In addition, the role of imatinib in localized GIST has gained much interest and may improve patient outcomes. Additionally, research efforts aimed at understanding the biology and the molecular heterogeneity of GIST both at initial presentation and at the time of resistance to imatinib, has helped guide rational approaches to treatment as well as future efforts aimed at treating imatinib-resistant GIST.

No MeSH data available.


Related in: MedlinePlus