Pharmacogenetics in the treatment of gastrointestinal stromal tumors – an updated review

ABSTRACT

Introduction

Gastrointestinal stromal tumors (GIST) are the best example of a targeted therapy in solid tumors. The introduction of tyrosine kinase inhibitors (TKIs) deeply improved the prognosis of this tumor. However, a degree of inter-patient variability is still reported in response rates and pharmacogenetics may play an important role in the final clinical outcome.

Areas covered

In this review, the authors provide an updated overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST treatment efficacy and toxicity.

Expert opinion

Besides the primary role of somatic DNA in dictating the clinical response to TKIs, several polymorphisms influencing their pharmacokinetics and pharmacodynamics have been identified as being potentially involved. In the last 10 years, many potential biomarkers have been proposed to predict clinical response and toxicity after TKI administration. However, the evidence is still too limited to promote a clinical translation. To date, the somatic mutational status represents the main player in clinical response to TKIs in GIST treatment; however, pharmacogenetics could still explain the degree of inter-patient variability observed in GIST patients. A combination of different theoretical approaches, experimental model systems, and statistical methods is clearly needed, in order to translate pharmacogenetics to clinical practice in the near future.

KEYWORDS:

• Gastrointestinal stromal tumor
• pharmacogenetics
• polymorphisms
• pharmacokinetics
• tyrosine kinase inhibitors

Article highlights

• Within the so-called ‘personalized medicine era,’ Pharmacogenetics plays a key role in understanding how patient genotype, including mutations and polymorphisms, may influence clinical efficacy and/or toxicity and the development of resistance to pharmacological treatment.

• The inter-individual variability in drug response is still not completely characterized and understood.

• The use of imatinib, the first KIT inhibitor, has completely revolutionized the history of GIST, stimulating enormously the research and leading to the development of secondary TKIs as sunitinib and regorafenib.

• The number of pharmacogenetic studies investigating the inter-patient variability to the approved TKIs in GIST management is quite limited.

• To date, 14 studies have investigated the association between polymorphisms in genes involved in the pharmacokinetics of imatinib, mainly transporter genes and clinical outcomes; three studies analyzed the correlation between polymorphisms and response to sunitinib-related effects (two of these investigated association between genotype and sunitinib-related toxicity).

• No studies have analyzed the impact of SNPs on regorafenib and ripretinib response in GIST but results from other cancer types could be used as a starting point in this tumor.

• So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib and sunitinib have been identified. However, in many cases the investigated GIST series were rather small (mainly due to the rarity of these tumors) and the data are not yet conclusive enough to translate into tailored drug dose adjustment, and/or predict efficacy/toxicity in the adjuvant and neoadjuvant setting.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.