Biomarker Testing for Genetic Evaluation of GISTs

Initial Diagnosis and Treatment

A 60-year-old woman presents with an 11-cm gastrointestinal stromal tumor (GIST) (Ki67 5-10%, diffuse positivity for CD34 and CD117, negative for S100 and desmin). The solid tumor mutation panel showed a KIT exon 11 mutation, BRAF not detected, PDGFRA not detected. She was started on neoadjuvant imatinib, a tyrosine kinase inhibitor whose targets include KIT and PDGFRA, at 400 mg daily and was subsequently dose reduced to 300 mg daily for neutropenia. Six months after starting therapy, she had a nice response to treatment with a decrease in size of the GIST and proceeded to surgery. She underwent a partial gastrectomy with final pathology showing a 5.6 cm GIST, spindle cell, ~1% residual viable tumor, and therefore insufficient for mitotic count. Post-operatively, she resumed adjuvant imatinib for a total of 3 years. She underwent surveillance with CT imaging visits every 3 months. Unfortunately, two years after completing adjuvant imatinib, she was found to have disease on a surveillance CT scan with multifocal peritoneal/mesenteric recurrence. Biopsy confirmed GIST, spindle cell, Ki67 20%, KIT exon 11 mutation. She was then restarted on imatinib. Again, she had a nice response to treatment and proceeded with a complete debulking surgery with resection of multiple intra-abdominal recurrences. Pathology showed extensive degeneration, compatible with treatment effect. Imatinib was resumed after surgery. Eighteen months later, she was found to have progression of disease with multiple intra-abdominal metastases. The largest lesion was biopsied, confirming GIST, Ki67 15%, KIT exon 11 mutation, also now with a new KIT exon 13 V654A mutation. She was then transitioned to sunitinib. Given her known history of neutropenia, she was started on sunitinib at 37.5 mg daily. The most notable side effects she experienced were neutropenia (requiring dose adjustment) and hand/foot syndrome. She continues to do well on 25 mg of sorafenib.

Discussion 

Biomarker testing for genetic evaluation of GISTs has become the gold standard not only for initial diagnostic work-up but also for recurrence or disease progression. These markers and the potential for new mutations have implications for appropriate treatment considerations and for prognosis.

There are specific types of mutations, particularly KIT exon 9 and exon 11, that predict sensitivity to KIT inhibition. Imatinib 400 mg daily has considerable benefit in the adjuvant setting and as a first-line treatment option for locally advanced or metastatic GIST provided molecular testing confirms an imatinib-sensitive KIT mutation. Multiple clinical trials have shown efficacy of imatinib, including a trial that showed an overall response rate of 54%, with a disease control rate of 86% in patients with advanced GIST.¹ The SWOG phase 3 Intergroup Trial S0033 showed that up to 26% of patients with advanced disease had long-term survival (8 years or longer).² Of these, about half were on imatinib as the only therapy.

Sensitivity Profile of the Five Drugs With Regulatory Approval for Gastrointestinal Stromal Tumor 

Most GISTs respond to imatinib except for certain subtypes, KIT/PDGFRA wild-type and PDGFRA D842V mutant. GIST tumors with a KIT exon 11 mutation are more likely to have a complete or partial response and longer progression-free survival than those with a KIT exon 9 mutation.³ Double dose imatinib (800 mg a day) has demonstrated improved response rates, durability of response, and overall survival in patients KIT exon 9 mutations, and is therefore the preferred dose for this population.⁴ 

Progression of disease while on TKI therapy may be a result of an emerging KIT or PDGFRA mutation. Recurrence of disease is most frequently seen in the liver and peritoneum. Cytoreduction surgery and/or liver metastasectomy can be considered in certain cases, which may have some effect on delaying disease progression by decreasing the number of resistant clones.⁵

Because of these emerging KIT or PDGFRA mutations, there has been new drug development with approvals of multikinase inhibitors. A repeat biopsy in the setting of disease progression is important to evaluate for any new mutations. Sunitinib has approval in the second-line setting. If intolerant, ripretinib can be considered. Regorafenib has approval in the third-line setting, with ripretinib in the fourth-line setting. Typically, benefit in this next-line setting has a median progression-free survival of about 5 months.⁵ Importantly, specific resistance mutations in the KIT gene may be important when selecting subsequent therapies, as sunitinib is more efficacious for exon 13/14 resistance mutations while ripretinib is more efficacious for exon 17/18 mutations, highlighting the importance of repeat molecular sequencing at the time of progression.⁶ 

Management of sunitinib in the second-line setting includes close monitoring of side effects and lab evaluation, as with other TKIs. Regular blood tests are crucial to monitoring kidney and liver functions, as well as a complete blood count. More common side effects include fatigue, gastrointestinal symptoms (nausea/vomiting, diarrhea, loss of appetite), hand-foot syndrome, hypertension, and delayed wound healing. If side effects become severe, the dose of sunitinib may need to be adjusted or temporarily held to manage symptoms. Additionally, ripretinib may offer an alternative second-line agent with improved tolerability as it has been shown to have less hypertension, hand-foot syndrome, neutropenia, diarrhea, and stomatitis than sunitinib.⁷

It is important to have a multidisciplinary approach in the management of GIST. This is particularly crucial when discussing surgical options for advanced or metastatic disease. Patient-centered discussions, reviewing risks and benefits in collaboration with medical and surgical oncology, are essential. Initial biomarker testing is standard of care in the diagnostic workup of GIST. Repeat tumor sequencing with biomarker testing should be considered, particularly at the time of disease progression.

References

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