Genetic Analysis Yields Biomarker for Neuropathy

Bryan P. Schneider, MD

A genetic analysis of more than 2000 breast cancer patients has resulted in the discovery of the first predictive biomarker for taxane-induced peripheral neuropathy, a finding that ultimately could lead to a blood test that would identify high-risk patients and help guide treatment decisions.

The researchers found several single nucleotide polymorphisms (SNPs)—variations in DNA—associated with patients whose nerves were more sensitive to chemotherapy drugs.

The strongest association came from SNPs in the gene RWDD3, according to Bryan P. Schneider, MD, a physician-researcher at the Indiana University Melvin and Bren Simon Cancer Center in Indianapolis who is the lead author of the study.

At 15 months’ follow-up, the likelihood of neuropathy was 27% for patients with homozygous wild-type variant, 40% for heterozygous variant, and 60% for homozygous variant, according to the abstract that will be presented at the conference. Older age and African-American race were significant clinical factors that warrant further study, researchers said.

The study involved 2204 participants who had received weekly paclitaxel for 12 weeks. In all, 613 patients reported experiencing grade 2 to 4 neuropathy, while 1591 did not, the abstract indicated.

Schneider said he was drawn to the study of neuropathy because of the patients he saw in his practice as a medical oncologist. He said patients fear adverse effects such as nausea and hair loss, but those symptoms are temporary, whereas peripheral neuropathy can linger after treatment—sometimes for years.

Although neuropathy is common among chemotherapy patients, the incidence and severity of the symptoms vary widely, and it can hinder some patients from completing therapy.

“It really highlighted to me and some of my colleagues that we really don’t have a good way of counseling patients about their likelihood of getting neuropathy,” Schneider said.

“Our hope is, and our first step in terms of proving this is real, is to redo this [study] as a completely different clinical trial,” he said. “My ultimate hope is that by learning the genetic basis [of neuropathy], we can actually understand the mechanism by which it is caused.”

Mark G. Kris, MD, chair of ASCO’s Cancer Communications Committee, said the study represents “one of the first times that molecular biology has melded over into supportive care” and may offer clinicians an opportunity to counsel patients on their risks and options.

Schneider said the genetic analysis was conducted with patients’ consent on a tube of blood they gave when they enrolled in an Eastern Cooperative Oncology Group clinical trial investigating bevacizumab.

Using microchip technology, investigators then evaluated the blood samples for more than 1.2 million SNPs in each patient.

“This becomes an amazing mathematical problem. You’re looking at literally over a million genetic variants in over 2000 patients,” Schneider said. “From the patient’s standpoint, this was no different to them than checking their blood count.”

Schneider BP, Li L, Miller K, et al. Genetic associations with taxane-induced neuropathy by genome wide association study (GWAS) in E5103. J Clin Oncol. 2011. (abstract 1000).