Rare gene variants associated with side effects from paclitaxel
The first genetic marker associated with severe neurologic toxicity from paclitaxel has been identified. This finding was published in Clinical Cancer Research (2015; doi:10.1158/1078-0432.CCR-14-1758).
Paclitaxel is a chemotherapeutic drug that has been shown to be highly effective when treating solid tumors, such as breast, ovarian, and lung tumors. However, its use frequently causes peripheral neuropathies that affect the vast majority of patients.
Symptoms include tingling and pain in the extremities, cramping, muscular weakness, and difficulty walking. In severe cases, the severity of these adverse effects mandates dosage reduction, and even stopping the treatment.
A patient's risk of developing peripheral neuropathy from paclitaxel is unknown. To date, other studies had suggested the existence of genetic variants that could explain an increased susceptibility of the patients to suffer from this disorder, although there was no clinical predictive marker for them.
Now, scientists from the Spanish National Cancer Research Centre (CNIO), in collaboration with the Karolinska Institutet in Sweden, have identified the first genetic marker associated with severe neurologic toxicity. The results could be very valuable in hospital clinical practice, given that they would help to evaluate treatment risks on an individual basis, thereby improving the quality of life for patients carrying these variants.
The authors of the research add that this information could be especially valuable for the Spanish population: "Even though these variants are rare or not frequent in the population, their frequency is greater in Spain than in other countries." One of every 35 people in Spain carries one of these genetic variants in their genome.
Researchers initially sequenced the complete exome, which is the part of the genome that translates into proteins, for eight Spanish patients with breast cancer who had developed extreme neuropathies after being treated with paclitaxel.
In this first phase of the research, they discovered genetic variants that were associated with a loss of hepatic CYP3A4 enzyme function, an enzyme that is in charge of eliminating the drug from the body.
"Given these results, we genetically analyzed an independent population of 228 Spanish patients treated with the same drug, in search of these variants. The study confirmed their presence in the patients that experienced the greatest toxicity," said study leader Cristina Rodríguez-Antona, PhD, a researcher from the CNIO Hereditary Endocrine Cancer Group.
The CYP3A4 enzyme is involved in metabolizing more than 50% of the drugs currently used in the clinic. Rodríguez-Antona explained that, "For this reason, identifying patients carrying these variants that decrease its activity is crucial to optimize treatments; especially those using drugs with very small differences between the therapeutic and toxic doses, such as with those used in oncology."
Though all the causes for the development of peripheral neuropathies during treatment with paclitaxel are still unknown, the results from this study indicate the importance of performing screenings to detect loss of function of CYP3A4 variants in patients treated with this drug.
"Our research shows that the recently developed whole-exome sequencing technologies may be useful for identifying genetic markers that predict drug-related adverse effects," said Rodríguez-Antona.