Progression of advanced gastrointestinal stromal tumour after over 20-year response to imatinib

Summary

Imatinib is the standard first-line treatment for advanced gastrointestinal stromal tumours (GISTs). Most patients either respond to imatinib or achieve disease stabilisation for several years, but only approximately 10% remain free from GIST progression 10 years after starting therapy. The maximum duration of response to imatinib remains uncertain. We report the case of a woman with multiple liver metastases from a gastric GIST at the time imatinib was initiated. The metastases responded to the standard dose of imatinib, which was continued and the patient was monitored with periodic abdominal imaging. GIST recurrence was detected in the distal oesophagus 20.8 years after starting imatinib. In addition to a KIT exon 11 deletion mutation, the recurrent tumour harboured an imatinib resistance mutation in exon 13 (p.Val654Ala). This case demonstrates that GIST may progress as late as 20 years after initiation of imatinib. Periodic abdominal imaging is essential even for long-term responders.

Background

Gastrointestinal stromal tumour (GIST) is the most common type of soft tissue sarcoma, with an annual incidence of approximately 10 cases per million.¹ GISTs can arise anywhere along the gastrointestinal tract. Most localised GISTs can be cured by surgery, but they may give rise to metastases, which are usually found in the liver or elsewhere in the abdomen.

The first-line treatment of advanced GIST has been imatinib since 2002.² Imatinib is an orally administered tyrosine kinase inhibitor that effectively inhibits kinases frequently activated in GIST due to gene mutations, namely KIT and platelet-derived growth factor receptor alpha (PDGFRA). Among all GIST patients, approximately 75% harbour mutations in KIT, 10%–15% in PDGFRA and the remaining 10%–15% lack mutations in either gene.³

Imatinib is generally well tolerated, and around 85% of patients either respond or achieve stable disease.⁴ In randomised trials, the median time to progression of GIST on imatinib was about 2 years,^{4 5} and approximately 10% of patients remain progression-free for up to 10 years after randomisation.⁵ It is evident that in the great majority of patients with advanced GIST, imatinib is not curative. However, in the absence of studies with long-term follow-up, it is currently unknown whether imatinib could be curative in a small minority of patients. The most important reason for imatinib resistance is the occurrence of secondary mutations, most frequently in KIT exons 13/14 or 17/18.⁶

In this case report, we describe a patient with overtly metastatic GIST whose response to imatinib lasted over 20 years after initiation of imatinib therapy. To our knowledge, this is the longest response reported in the literature that ultimately ended in progression. This case demonstrates how imatinib can suppress the growth of GIST metastases for prolonged periods.

Case presentation

A woman in her late 40s presented in 2001 with fatigue, a collapse during exercise, upper abdominal discomfort and low-grade fever that prompted medical investigation. She had previously smoked. Her medical history was unremarkable. Her mother’s father had suffered from gastrointestinal cancer, but otherwise she had no family history of cancer. Abdominal ultrasound had shown liver metastasis and a tumour in the distal oesophagus had been detected and biopsied during gastroscopy. CT of the abdomen revealed an 8 cm tumour in the gastric corpus. In addition, multiple liver metastases were visible, the largest measuring over 5 cm (figure 1A). Her performance status was 0 on the WHO scale (range 0–5), indicating good functional capacity.

Figure 1. (A) A CT image showing the gastric primary tumour (large arrow) and liver metastases at the time of gastrointestinal stromal tumour diagnosis in 2001 (smaller black arrows). (B) Only remnants of the primary tumour and the liver metastases are visible after 24-month treatment with imatinib.

Differential diagnosis

The disease was initially diagnosed as metastatic carcinoma following histological examination of a core needle biopsy obtained from the gastric tumour during endoscopy. The patient underwent chemotherapy with cisplatin, etoposide and paclitaxel for 6 months, achieving stable disease as the best response.

In the summer of 2002, the histopathological diagnosis was re-evaluated by the pathology department, as the clinical presentation of a gastric tumour with liver metastases was also compatible with GIST. Immunohistochemical staining of tumour tissue demonstrated strong positivity for KIT (CD117) (figure 2) and CD34, while staining for desmin and cytokeratin was negative. The tumour morphology together with the immunohistochemical profile supported the diagnosis of GIST. KIT mutation analysis was not performed, as this assay was not routinely performed in 2002.

Figure 2. Histopathological images of the primary tumour and gastrointestinal stromal tumour recurrence. (A) H&E-staining of the gastric primary tumour (100× magnification); (B) immunohistochemistry staining of the primary tumour for KIT (200×); (C) H&E-staining of the recurrent tumour (100×); and (D) immunohistochemistry staining of the recurrent tumour for KIT (100×). *Tumour tissue.

Treatment

Treatment with imatinib was initiated in 2002 at the standard dose of 400 mg once daily. After 2 months, the primary tumour and liver metastases had decreased in size by approximately 10%, and within several additional months, only small remnants of liver metastases were visible and the primary tumour had also responded (figure 1B). The robust partial response to imatinib further confirmed the diagnosis of GIST. In 2004, the imatinib dose was increased to 500 mg daily, which continued until 2016, when the dose was reduced back to 400 mg due to increasing creatinine and slightly (grade 1) decreasing haemoglobin levels.

The patient generally tolerated imatinib well, experiencing only mild (grade 1) periorbital oedema, muscle cramps, nausea and occasional diarrhoea. Renal function declined gradually, with serum creatinine rising to 150 µmol/L and estimated glomerular filtration rate falling below 30 mL/min/1.73 m² 19 years after initiation of therapy. Despite this, imatinib was continued without dose interruptions or further reductions.

Outcome and follow-up

During imatinib treatment, the patient was followed longitudinally with contrast-enhanced abdominal CT scans until 2021, when use of the contrast agent administration was discontinued due to progressive impairment of renal function. In 2023—20.8 years after initiation of imatinib therapy—a radiologist noted an increasing prominence of the distal oesophagus. This finding had gradually become apparent on 2–3 CT scans obtained during the preceding 1–2 years but had not been detectable on the more than 50 earlier CT scans performed during the preceding 20 years of treatment. Gastroscopy at the site of the prominence revealed a small ulceration, and endoscopic ultrasound demonstrated a well-defined hypoechoic tumour measuring 33 mm in diameter, clinically consistent with recurrence of GIST. Histological examination of a biopsy confirmed GIST recurrence, with tumour cells staining positively for KIT, CD34 and anoctamin-1 (DOG1) (figure 2). Two mutations were detected by next-generation sequencing of KIT. Consistent with the known imatinib responsiveness of GIST, a deletion mutation c.1669_1683del (p.Trp557_Glu561del) was identified in KIT exon 11, likely representing the primary oncogenic driver mutation.⁷ A second mutation was detected in KIT exon 13, c.1961T>C (p.Val654Ala), likely representing a secondary resistance mutation explaining acquired resistance to imatinib.⁶

The management of recurrent GIST was discussed at a multidisciplinary team meeting. Local treatment of the recurrent tumour with continuation of imatinib therapy was considered feasible, given the unusually durable response to imatinib and the presence of a single recurrent lesion on CT imaging. Oesophagectomy was deemed too invasive due to the patient’s performance status and the presence of metastatic disease, and palliative radiotherapy was preferred over definitive radiotherapy. The patient subsequently received palliative radiotherapy to a total dose of 35 Gy.

Imatinib was continued as systemic therapy for 14 months following radiotherapy. In early 2025, the patient reported progressive dysphagia. CT imaging revealed a slight increase in the size of the oesophageal tumour, a new mediastinal lesion and two new liver metastases. Sunitinib, the standard second-line treatment for advanced GIST, was initiated in 2025. The patient currently remains on sunitinib, achieving stable disease as the best response.

Discussion

We describe a patient with gastric GIST who had multiple liver metastases and was treated with first-line imatinib at the dose of 400–500 mg daily, achieving a response that was maintained for approximately 20 years. Following confirmation of oligometastatic GIST recurrence, which was treated with palliative radiotherapy, the patient continued imatinib for an additional 14 months before systemic therapy was switched to sunitinib, the standard second-line treatment for advanced GIST. This case report illustrates, to our knowledge, the first reported instance of advanced GIST progressing after sustained response to imatinib for as long as 20 years.

Mutation analysis provides useful information for the diagnosis of GIST and is essential for planning clinical management. It helps determine prognosis, provides information on the expected response to imatinib, and assesses the potential benefits of dose escalation during imatinib treatment. If no imatinib-sensitive target mutations are identified, alternative treatment options may be considered. The imatinib-resistant oesophageal tumour harboured a KIT exon 11 deletion mutation (p.Trp557_Glu561del), located at the mutational hotspot in exon 11 and encompassing the frequently deleted codons 557 and 558. Together with the tumour immunoprofile and the previous durable response to imatinib, the presence of p.Trp557_Glu561del further confirmed the diagnosis of GIST. In general, KIT exon 11 deletion mutations are associated with high sensitivity to imatinib.⁷ We therefore considered the KIT exon 11 deletion mutation to be a likely primary mutation already present in the 2001 tumour, although we could not verify this from the primary tumour due to tissue sample size and quality limitations. The recurrent tumour also harboured a KIT exon 13 mutation (p.Val654Ala), which is known to confer resistance to imatinib.⁶ The presence of p.Val654Ala in the oesophageal tumour confirmed that this lesion represented a recurrence of the previous primary tumour or a GIST metastasis rather than a new primary GIST, since p.Val654Ala is one of the most common imatinib resistance mutations but occurs exceedingly rarely in primary imatinib-naïve GISTs.^{6 8 9} While GISTs with p.Val654Ala are resistant to imatinib, they often stabilise on sunitinib,¹⁰ as was observed in the present patient.

The median time to disease progression in patients treated with first-line imatinib is 2–3 years,^{4 5} although some patients experience much longer times to progression. In a trial that compared two different dose levels of imatinib as first-line treatment for advanced GIST (400 mg or 800 mg daily) among 946 randomised patients, the estimated 10-year PFS rate was 9%.⁵ Therefore, the great majority of patients with advanced GIST treated with imatinib will eventually progress, and it remains unknown whether any patients with advanced GIST can be cured with currently available systemic therapies. The present patient history suggests that while response to imatinib may be very durable, late disease progression may occur even after as long as two decades of response.

We administered imatinib continuously to the patient for over 20 years, which is the recommended practice in the treatment of advanced GIST. In a randomised trial, discontinuation of imatinib led to earlier GIST recurrence compared with continuous treatment.¹¹ Similarly, in a small multicentre phase II study including 12 highly selected GIST patients with ≤3 metastases who had received imatinib for more than 5 years and had no radiologically detectable disease after surgical removal of metastases, most patients progressed after discontinuation of imatinib. The 3-year progression-free survival rate in that study was 41%.¹²

Patients who experience a very durable response to imatinib need to be followed clinically and with repeated abdominal imaging to enable early detection of recurrence. In the present patient, abdominal CT was performed every 3–4 months during the first years of imatinib treatment, and later approximately two times a year. During long-term follow-up, switching to MRI may be considered in patients with unusually durable responses to imatinib to reduce radiation exposure from repeated CT scans.¹³ The accumulating radiation hazard must be balanced against the benefits of early detection of GIST recurrence. Most GIST recurrences detected by longitudinal CT imaging are asymptomatic, and early detection when the tumour bulk is still small may reduce the risk of multiple drug-resistant clones emerging and may allow locoregional treatment of recurrent disease. Long-term follow-up is also needed to detect and manage late adverse effects of imatinib. The impaired renal function in this patient may have been imatinib-related, as imatinib has been associated with impaired kidney function.¹⁴

In general, GISTs are moderately radiosensitive tumours,¹⁵ and the patient’s single recurrent lesion was treated with palliative radiotherapy. This enabled continued imatinib treatment for 14 months after radiotherapy, which may have benefited the patient, as imatinib is generally better tolerated than sunitinib. The median progression-free survival with second-line sunitinib is approximately 6 months.¹⁶

At present, robust tools for identifying patients who will achieve a very durable response to imatinib are lacking. Presence of a KIT exon 11 mutation is associated with durable progression-free survival,^{4 5} which mutation was present in the current GIST. A small tumour bulk at the time of imatinib initiation generally predicts a favourable response,^{4 5} but in the present patient the tumour bulk was large with multiple liver metastases at the time of imatinib initiation. The patient was female and had good performance status, which factors are also associated with favourable progression-free survival.^{4 5}

Learning points.

• Response to first-line imatinib can be highly durable, lasting up to 20 years in patients with advanced gastrointestinal stromal tumour.

• Continuous daily administration of imatinib is regarded as the safest strategy for patients who maintain a long-term response.

• Long-term abdominal imaging is essential to detect progressive disease while the tumour burden remains small.