https://orcid.org/0000-0002-4673-6692
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ABSTRACT
Introduction: Paclitaxel is a microtubule stabilizer that is currently one of the most utilized chemotherapeutic agents. Its efficacy in breast, uterine, lung and other neoplasms made its safety profile enhancement a subject of great interest. Neurotoxicity is the most common paclitaxel-associated toxicities. In addition, hypersensitivity reactions, hematological, gastrointestinal, and cardiac toxicities are all encountered.
Areas covered: The current review explores paclitaxel-induced toxicities mechanisms and risk factors. Studies investigating these toxicities pharmacogenomic biomarkers are reviewed and summarized. There is a limited margin of consistency between the retrieved associations. Variants in genes related to neuro-sensitivity are the most promising candidates for future studies.
Expert opinion: Genome-wide association studies highlighted multiple-candidate biomarkers relevant to neuro-sensitivity. Most of the identified paclitaxel-neurotoxicity candidate genes are derived from congenital neuropathy and diabetic-induced neurotoxicity pathways. Future studies should explore these sets of genes while considering the multifactorial nature of paclitaxel-induced neurotoxicity. In the absence of certain paclitaxel-toxicity biomarkers, future research should avoid earlier studies’ caveats. Genes in paclitaxel’s pharmacokinetic pathways could not provide consistent results in any of its associated toxicities. There is a need to dig deeper into toxicity-development mechanisms and personal vulnerability factors, rather than targeting only the genes suspected to affect drug exposure.
Article highlights
Paclitaxel is a microtubule stabilizer with numerous indications in oncology. Toxicities encountered during paclitaxel treatment include neurological, hematological, gastrointestinal, and cardiac toxicities, besides hypersensitivity reactions.
Genomic biomarkers determining paclitaxel’s pharmacokinetics (PK) failed to show strong associations with peripheral neurotoxicity, the most common paclitaxel adverse event. Simultaneously, genome-wide association studies (GWASs) pointed out genes involved in neuron sensitivity, increasing the patient’s susceptibility to paclitaxel-induced neurotoxicity. Targeted-gene studies replicated some of these findings.
Genes involved in the pathogenesis of Charcot-Mary Tooth (CMT) disease and diabetic neuropathy harbored the most robust association signals. Further, strong associations were retrieved with ephrin receptor genes and other miscellaneous genes.
Hematological toxicity is transient with paclitaxel use, and the previous or simultaneous chemotherapy might interfere with its development risk. No pharmacogenomic biomarkers were identified to be significant predictors of this toxicity.
Gastrointestinal adverse events are widespread with paclitaxel administration, though mostly they are mild. However, colitis is a rare and severe adverse event that has been scarcely studied.
With the absence of consistent results from paclitaxel PK genes-toxicity studies, investigating genes in the toxicity pathogenesis is a promising approach; nevertheless, adjusting for PK variability is indispensable throughout studies investigating pharmacogenomic-toxicities associations.
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.