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Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate

Authors' Affiliations: Departments of ¹ Pathology, ² Neuropathology, ³ Internal Medicine, and ⁴ Surgery, University of Bonn Medical School, Bonn, Germany; ⁵ Department of Internal Medicine, Hematology, and Oncology, Robert Roessle Hospital and Tumor Institute, Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany; and ⁶ Department of Surgery, Division of Surgical Oncology and Thoracic Surgery, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Heidelberg, Germany

Requests for reprints: Eva Wardelmann, Department of Pathology, University of Bonn Medical School, P.O. Box 2120, D-53011 Bonn, Germany. Phone: 49-228-287-5353; Fax: 49-228-287-5030; E-mail: eva.wardelmann{at}ukb.uni-bonn.de.

	Abstract

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Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor (PDGFR) gene. Both PDGFR and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

PDGFR

PDGFR

In the present study, we aimed to explore the frequency and nature of secondary KIT mutations occurring under imatinib treatment and leading to secondary resistance, and mutational status was correlated with clinical and pathologic data. For molecular analysis, we used tumor tissue specimens obtained during surgery from 32 patients under imatinib treatment. In 18 patients, tissue was also available from the primary site before treatment. Patients had been scheduled for surgical resection of progressive tumor deposits or of residual tumor after successful imatinib therapy. In addition to the common hotspots for primary mutations (exons 9, 11, 13, and 17 of KIT; exons 12 and 18 of PDGFR), tissues were examined for secondary mutations in exons 13, 14, and 17 of KIT encoding both tyrosine kinase domains. In the majority of cases, more than one tumor manifestation (two to seven) resected under treatment were evaluated to search for different types of secondary mutations in evolving tumor subclones.

	Materials and Methods

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Patients. Tumor samples from 32 patients [21 men and 11 women; median age, 56.5 years (range, 34-73 years)] were studied. They all suffered from histologically confirmed irresectable or metastatic GIST (liver and/or peritoneal metastases). The primary tumors were predominantly located in the small bowel (n = 18), five tumors arose from the stomach, and three tumors from rectum. Five tumors were classified as extragastrointestinal stromal tumors (E-GISTs). In 28 of 32 cases, more than one tumor manifestation (two to seven) was resected under treatment. In 18 of the patients, tumor samples from the primary tumor were available for comparison. The preselection of cases undergoing surgery during imatinib treatment explains why the proportion of patients with secondary tumor progression is higher than in an unselected series of patients with and without surgery under imatinib treatment. Further clinicopathologic data are shown in Table 1 .

Histopathology and immunohistochemistry. Histomorphologic subtype was evaluated as previously described (14) and was given as spindle cell type, epithelioid cell type, and mixed type. GIST diagnosis was confirmed by immunohistochemical analysis using antibodies against CD117 (KIT receptor), CD34, bcl-2, -actin, desmin, S-100 protein, vimentin (all DAKO, Hamburg, Germany), PDGFR (Santa Cruz Biotechnology, Santa Cruz, CA), and Ki-67 (MIB-1, Dianova, Hamburg, Germany) as previously described (15, 16).

Sequence analysis in KIT and PDGFR genes. For mutational analysis, tumor tissue for DNA extraction was marked on H&E-stained slides. Areas for microdissection followed by differential mutational analysis were selected according to morphology or immunohistochemical expressions patterns under treatment with imatinib (Fig. 1 ). Tissue slides were deparaffinized by xylene and microdissected from serial sections (10 µm) of the primary tumors, metastases, and tumor tissue under imatinib treatment. Total DNA was extracted after pretreatment with proteinase K and absorption on silica gel membranes (Qiagen, Hilden, Germany). After estimation of DNA concentration by agarose gelelectrophoresis, relevant exons were amplified with intronic primers as previously described (15–17). The PCR products were purified using Micro Spin columns (Amersham Biosciences, Freiburg, Germany). Bidirectional DNA sequencing of the entire exons and the corresponding exon-intron boundaries was done with the Big Dye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems, Weiterstadt, Germany). Cycle sequencing products were precipitated with 3 mol/L sodium acetate and analyzed on an ABI PRISM 310 capillary electrophoresis system (Applied Biosystems). All sequence alterations were confirmed by an independent PCR amplification and sequencing to exclude PCR artifacts. The identity of the amplicon sequences was confirmed by database search (accession no. HSU63834, National Center for Biotechnology Information database: http://www.ncbi.nlm.nih.gov).

View larger version (59K): [in this window] [in a new window]   Fig. 1. Differential immunohistochemical expression patterns for KIT receptor, CD34, bcl-2, and desmin in a progressive peritoneal GIST lesion (case no. 27) with two different acquired KIT mutations in exon 13 (V654A) and exon 17 (Y823D). Different regions were microdissected and mutational analysis was done separately.

	Results

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Median follow-up from first diagnosis to last evaluation was 51 months (range, 4-144 months). Median duration of response to imatinib treatment (progression-free survival; see Table 1) was 19 months (range, 0-45 months). Under treatment with imatinib, 2 tumors were primarily progressive and 25 others (78.1%) developed secondary tumor progression after 4 to 45 months of response (median, 19 months). The remaining five tumors achieved stable disease (n = 1) or partial remission (n = 4). Median survival after secondary tumor progression was 12 months (range, 1-29 months). Clinical and pathologic data of all cases are given in detail in Table 1.

Histopathologic and immunohistochemical findings. Twenty-two tumors were of spindle cell type; four GISTs showed an epithelioid phenotype; the other six lesions displayed a mixed morphology. In five cases, different morphologic subtypes were found comparing primary tumor and metastases. Before treatment, in all primary tumors, KIT receptor was expressed at least weakly and was lost in some of the metastatic lesions. Furthermore, strong reexpression of KIT receptor was observed in progressive lesions (see Fig. 2 ).

View larger version (126K): [in this window] [in a new window]   Fig. 2. A progressive nodule in a regressive GIST metastasis in the peritoneum (case no. 27) shows a strong reexpression of KIT receptor whereas the surrounding regressive areas are negative (A, H&E; B, KIT receptor; original magnification, x100). In mutational analysis of this area, a secondary KIT mutation was found in exon 17 (Y823D) additionally to the primary exon 11 mutation (W557_K558del).

PDGFR

PDGFR

View larger version (53K): [in this window] [in a new window]   Fig. 3. Primary KIT mutations in exon 11 and secondary KIT mutations in exons 13, 14, and 17. The occurrence of secondary KIT mutations is independent of the type of primary KIT mutation in exon 11.

View larger version (21K): [in this window] [in a new window]   Fig. 4. Sequence analysis in exons 11, 13, and 14 of the KIT gene before and under treatment with imatinib (case no. 26). Primary KIT point mutation in exon 11 led to the substitution of valine-560 by aspartate (A). Secondary KIT point mutations in exon 13 (B) and exon 14 (C) resulted in the exchange of valine-654 to alanine and of threonine-670 to isoleucine.

All 14 patients with one or more secondary KIT mutations belonged to the group of patients with secondary tumor progression whereas in 11 patients of this group, no secondary mutations could be detected. One of two patients with primarily progressive disease developed a secondary mutation in exon 14. Neither the four patients with partial remission nor the patient with stable disease carried a secondary KIT mutation. Details of sequences are summarized in Table 2.

Of the seven cases with primary KIT exon 9 mutation, 2 patients (28.6%) developed resistance due to acquired KIT mutations. In the 22 cases of KIT exon 11 mutated GISTs, 12 tumors (54.5%) were found to develop new mutations. Conclusively, the frequency of secondary KIT mutations was higher in tumors with primary KIT exon 11 mutation than in those with primary KIT exon 9 mutation, although not statistically significant. None of the three cases without any KIT or PDGFR mutation (wt GISTs) developed new mutations. Altogether, the frequency of secondarily acquired KIT mutations under imatinib therapy in our study was 44%.

In summary, the primary KIT mutation was always detectable in all tumor manifestations before and under treatment. All 14 patients with newly acquired KIT mutations carried the secondary mutations only in some of their metastases whereas other lesions exhibited a wild-type sequence in the same genomic region. We never detected more than one acquired mutation in the same sample, indicating that long-term imatinib therapy leads to clonal selection of resistant tumor subclones.

Correlation of mutational and clinical data. There were no significant differences among GISTs with primary mutation in KIT exon 11, KIT exon 9, and wild-type GISTs with regard to the overall survival (from first diagnosis to death or last follow up), the time interval between first diagnosis and metastasis or recurrence, and the duration of response to imatinib. Thirteen of 25 GISTs with secondary progression and one of two primarily progressive tumors harbored secondary KIT mutations. On the other hand, none of five tumors with partial remission or stable disease under imatinib treatment developed secondary mutations in exon 13, 14, or 17. In our cohort, tumors with or without secondary KIT mutations did not differ significantly with respect to overall survival and survival after secondary tumor progression. Comparing the different loci of secondary mutations (i.e., exon 13, 14, or 17), there was no correlation with the primary tumor location (i.e., stomach, small bowel, rectum, or peritoneum) or the primary mutational type. However, tumors with secondary mutations in exon 14 were characterized by a more aggressive phenotype, indicated by a significantly shorter overall survival (mean, 41.0 months; SD, 14.8 months) compared with tumors which harbor secondary mutations in exon 13 or 17 (mean, 61.5 months; SD, 25.8 months; log-rank test, P = 0.0164; Kaplan-Meier curve not shown). Furthermore, GISTs with secondary exon 14 mutations had earlier development of metastases and/or recurrence after first diagnosis (5.5 versus 19.5 months; t test, P = 0.037) and a shorter progression-free survival under treatment (14.7 versus 19.5 months; n.s.) than tumors without exon 14 mutations. In comparison, the mean progression-free survival under imatinib treatment was 19.9 and 24.4 months for tumors with exon 13 and exon 17 mutations, respectively. The mean survival after secondary progress did not significantly differ among the different mutational groups: 13.7 months (exon 13) versus 15.6 months (exon 14) versus 16.8 months (exon 17). Cases with the acquisition of more than one secondary KIT mutation had a comparable prognosis as those with only one or no secondary mutation.

	Discussion

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The prognosis of advanced GISTs has been improved significantly by the introduction of the tyrosine kinase inhibitor imatinib mesylate (Glivec, Novartis). However, with longer duration of treatment, the number of patients developing progressive disease increases continuously. The most recent update of the European Organization for Research and Treatment of Cancer 62005 trials shows a steady decline in progression-free survival (18). Several mechanisms for secondary progression have been proposed: (a) secondary gene amplification leading to overexpression of KIT or PDGFR receptor, (b) activation of alternative receptor tyrosine kinases, or (c) acquisition of secondary mutations of the KIT or PDGFR gene interfering with the inhibitory effect of imatinib. The latter mechanism is also a common reason of resistance to imatinib in chronic myelogenic leukemia (10, 11).

Several reports on secondary KIT mutations provide first evidence that this mechanism might also be a reason for imatinib resistance in GISTs (5–7, 9, 17). In addition to the primary mutation, new KIT mutations occur and are preferentially located in the first or second tyrosine kinase domain. The exchange of single amino acids in these domains probably leads to a change of the three-dimensional receptor conformation, which presumably modifies the ATP-binding pocket and thus might inhibit imatinib binding to the receptor.

In our study, we analyzed 32 cases of advanced progressive GISTs for the occurrence of acquired KIT mutations in both tyrosine kinase domains (exons 13, 14, and 17). From the majority of patients, more than one tumor manifestation was examined (total of 104 samples). In all cases, tumor tissue was resected under treatment because of tumor progression or bleeding. Most patients (78.1%) had secondary progress under treatment and two patients were primarily progressive (6.3%). The others (n = 5) had a partial response or stable disease. We found secondary KIT mutations in 14 cases (43.8%), which were located in exon 13, 14, or 17 encoding the first or the second tyrosine kinase domain, respectively. In four patients, more than one secondary KIT mutation was found. The frequency of acquired KIT mutations in GISTs is comparable with the results of another very recent study (19).

Several mechanisms increasing the risk of development of secondary resistance due to acquired KIT mutations have to be discussed. First, the amount of remaining tumor cells under imatinib treatment might influence the risk of acquisition of new KIT mutations. As shown by several groups (3, 4), location of the primary KIT or PDGFR mutation directly predicts the clinical response to imatinib. If the inhibitory effect of imatinib depending on the underlying activating mutation is low, the larger amount of remaining tumor might be leading to a higher risk of secondary mutation. However, our own results show that tumors with an underlying primary KIT mutation in exon 11 (54.5%), known to be the subgroup with better response rates than other mutational subtypes, are at higher risk to develop secondary mutations than those with an KIT exon 9 mutation (28.6%). This observation supports our hypothesis that the probability of a secondary mutation increases with duration of imatinib treatment, which most often is longer in GISTs with exon 11 mutation than in those with exon 9 mutation or wild-type GISTs. Second, development of proliferating tumor clones could be a result of changed imatinib pharmacokinetics. Decreased imatinib levels under chronic treatment could be due to increased imatinib clearance (20) or to decreased intracellular accumulation of imatinib (21). Another possibility might be a change in the serum level of KIT or KIT ligand as proposed by Bono et al. (22). Furthermore, several drugs known to influence the serum level of imatinib are frequently taken by older GIST patients (23). Reactivation of GIST cells due to decreasing imatinib level during treatment might propagate proliferation and escape mechanisms from treatment. Third, tumor cells might lose their imatinib sensitivity due to still unknown molecular mechanisms such as activation of other tyrosine kinases or amplification of KIT or PDGFR gene.

Interestingly, each tumor nodule under progression apparently develops an individual clonal evolution. Secondary mutations were only found in some of the examined lesions. Further evidence for an individual development of different tumor residues is provided by the detection of multiple acquired mutations in the same patient. Tumor parts with different acquired mutations were found side by side in one nodule and exhibited a different immunohistochemical expression pattern (Fig. 2) or grade of regression.

In our series, GISTs with secondary exon 14 mutation showed a more aggressive behavior with earlier metastasis and shorter progression-free survival. One might conclude that this subgroup of early metastasizing tumors is predisposed to develop exon 14 mutations whereas tumors with a slower progress might acquire secondary mutations in exon 13 or 17 after a longer treatment with imatinib.

Our results indicate that secondary KIT mutations may be one mechanism leading to late resistance to imatinib treatment. In the group of secondarily progressive tumors under imatinib treatment, their occurrence per se is not an indicator of a worse prognosis in comparison with progressive cases without secondary mutations. The latter obviously develop other molecular mechanisms to escape the inhibitory efficacy of imatinib. However, the identification of acquired mutations by analyzing all available progressive lesions under treatment clearly proofs the secondary progress and is particularly important in view of new therapeutic strategies. These might include either surgical resection of individual progressive lesions or treatment with other small molecules such as SU11248 or inhibitors of protein kinase C or phosphatidyle-inositole 3-kinase. The full understanding of the underlying molecular mechanisms of oncogenesis and resistance in GISTs may also help to gain new insights and establish further comparable strategies in other cancers types.

	Acknowledgments

 
We thank Christiane Esch, Susanne Steiner, Barbara Reddemann, Ellen Paggen, Sandra Böhler, Theresa Buhl and Gerrit Klemm for technical assistance.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/ 6/05; revised 11/ 7/05; accepted 1/ 4/06.

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