What are the factors associated with a poor prognosis in Gastrointestinal Stromal Tumor (GIST)?

From the Guidelines

Poor prognosis in gastrointestinal stromal tumors (GISTs) is associated with several key factors, including tumors larger than 5 cm, high mitotic rates (>5 mitoses per 50 high-power fields), non-gastric locations, tumor rupture, and metastatic disease at diagnosis, as well as specific genetic mutations, such as PDGFRA D842V mutations, which show resistance to standard tyrosine kinase inhibitors like imatinib 1.

Key Factors Associated with Poor Prognosis

• Tumor size: larger than 5 cm
• Mitotic rate: high (>5 mitoses per 50 high-power fields)
• Tumor location: non-gastric, especially small intestine, colon, or rectum
• Tumor rupture
• Metastatic disease at diagnosis
• Genetic mutations: PDGFRA D842V mutations, which show resistance to standard tyrosine kinase inhibitors like imatinib

Treatment Recommendations

• For high-risk patients, adjuvant imatinib therapy is recommended for 3-5 years following surgical resection 1
• In metastatic disease, imatinib is the first-line treatment, with sunitinib and regorafenib as subsequent options upon progression 1
• Regular surveillance with CT scans every 3-6 months is essential for monitoring disease status 1

Prognostic Factors

• The mitotic rate, tumor size, and tumor site are the main prognostic factors in localized GISTs 1
• Tumor rupture is an additional adverse prognostic factor and should be recorded, regardless of whether it took place before or during surgery 1
• Mutational status has not been incorporated in any risk classification at present, although some genotypes have a distinct natural history and, above all, KIT/PDGFRA WT GISTs have peculiar clinical presentations and course 1

From the FDA Drug Label

The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 26 Table 26: Overall Survival, Progression-Free Survival and Tumor Response Rates in the Phase 3 GIST *Trials

• Abbreviation: GIST, gastrointestinal stromal tumors. Imatinib Mesylate 400 mg N = 818 Imatinib Mesylate 800 mg N = 822 Progression-Free Survival (months) Median 18.9 23.2 95% CI 17.4–21.2 20.8–24.9 Overall Survival (months) 49 48.7 95% CI 45.3–60 45.3–51. 6 Best Overall Tumor Response Complete Response 43 (5.3%) 41 (5%) Partial Response 377 (46.1%) 402 (48.9%)

Poor prognosis in GIST is associated with several factors, including:

• Tumor size: larger tumors have a worse prognosis
• Tumor location: tumors located in the stomach have a better prognosis than those located in the small intestine
• Mitotic rate: higher mitotic rates are associated with a worse prognosis
• KIT or PDGFRA mutations: the presence of certain mutations can affect the prognosis and response to treatment

However, the provided drug labels do not directly address the question of poor prognosis in GIST. The labels provide information on the treatment of GIST with imatinib and sunitinib, including response rates and survival data, but do not specifically discuss prognostic factors. Therefore, a conservative clinical decision would be to consider multiple factors when evaluating the prognosis of a patient with GIST, including tumor size, location, mitotic rate, and genetic mutations. 2 3

From the Research

Poor Prognosis in GIST

• The prognosis of Gastrointestinal Stromal Tumors (GISTs) is influenced by several factors, including mitotic rate, tumor size, and tumor site 4, 5.
• Tumor rupture is also recognized as an independent risk factor for poor prognosis in GIST patients 4.
• Gene mutations, such as KIT and PDGFRA, can affect the prognosis of GISTs, with some mutations associated with a poorer outcome 4, 6.
• The Ki67 index, a measure of cell proliferation, has been associated with poor prognosis in GIST patients 4, 5.
• Gastrointestinal bleeding and high Ki67 index have also been linked to poor prognosis in GIST patients 4.

Treatment-Related Factors

• Resistance to tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, is a significant challenge in the treatment of GISTs, leading to poor prognosis 7, 8.
• Second-generation TKIs, such as regorafenib, have shown promise in improving progression-free survival in patients with imatinib-resistant GISTs 7, 8.
• The efficacy of second-generation TKIs in improving overall survival in GIST patients is still uncertain, with some studies showing no significant benefit 8.

Clinical Implications

• Accurate risk stratification and identification of prognostic factors are crucial for optimizing treatment outcomes in GIST patients 4, 6.
• Close monitoring of GIST patients for signs of disease progression and resistance to TKIs is essential for timely intervention and improved prognosis 6, 7.
• Further research is needed to develop more effective treatment strategies for GIST patients with poor prognosis, including those with resistance to TKIs 4, 8.