Chemo-induced Nerve Damage Less Likely in Certain CMT Patients, Study Finds

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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The chemotherapy agent oxaliplatin does not increase the risk of chemotherapy-induced peripheral neuropathy (CIPN), one of its most common side effects, in patients with uncommon variants in genes that cause Charcot-Marie-Tooth (CMT) disease, a study found.

Treatment with oxaliplatin should not be interrupted if such genetic variants are identified in these people, its researchers stated.

Their study, “Neurological safety of oxaliplatin in patients with uncommon variants in Charcot-Marie-tooth disease genes,” was published in the Journal of the Neurological Sciences.

Certain anti-cancer agents are known to worsen the symptoms of peripheral neuropathy (nerve damage) associated with CMT. Some of these agents are also more likely to trigger CIPN even in patients carrying uncommon variants in CMT-causing genes, for which no information exists as to whether they cause disease.

However, it is still unclear “whether oxaliplatin carries increased risks of CIPN due to SNV in CMT-associated genes,” the researchers wrote. (SNV stands for single nucleotide variants; a gene variant refers to alterations in a single nucleotide — the building blocks — in the sequence of a gene.)

To investigate if oxaliplatin could be linked to a higher risk of chemotherapy-induced peripheral neuropathy in patients with these uncommon SNVs, researchers at the Mayo Clinic and colleagues re-analyzed data from cancer patients treated with oxaliplatin-based chemotherapy in a Phase 3 clinical trial (NCT00316914).

A total of 353 colorectal cancer patients were evaluated for signs of CIPN  via the CIPN20 questionnaire, a well-established patient-reported outcome measure for this neuropathy. They were then divided into four groups according to their scores: those with the highest scores were viewed as cases, while those with the lowest were assigned to a control group.

Control patients generally reported no worsening of peripheral neuropathy symptoms with each course or chemotherapy, while case patients generally did. The study included 80 controls and 77 cases with available next-generation sequencing data, allowing scientists to look for variants in the DNA sequence of 49 CMT-associated genes.

Researchers found 270 single nucleotide variants in these patients, including 143 variants that were present in only one patient. This corresponded to an average of 0.91 rare variants per person, “highlighting that such genetic findings can be expected in the majority of patients seen in clinical practice,” the researchers wrote.

These rare variants, called “singletons,” were present at an average rate of 0.84 per case patients, and of 0.98 per control patients, showing that rare variants were more common in controls than cases, and do not seem to increase the risk of CIPN.

Some CMT genes had a greater frequency of variants in cases than controls, including the PRX gene that is associated with CMT type 4F, and IGHMBP2 gene that is linked with CMT type 2. But controls also had a greater frequency of variants in the PLEKHG5 gene, whose mutations cause intermediate forms of CMT.

However, the frequency of singletons was relatively balanced in all genes between the two groups.

“Therefore, while singleton SNV were common, they did overall not portend an increased risk of CIPN,” the investigators wrote, adding that “life-saving oxaliplatin therapy should not be withheld if genetic variants in … CMT genes are encountered.”