Roxanne Nelson

May 19, 2011

May 19, 2011 — Taxanes are common chemotherapeutic agents, but they induce neuropathy in about one third of patients. A new study has identified the first genetic markers for taxane-induced peripheral neuropathy, which might make it possible to predict which patients are most at risk for this adverse effect.

"Some risk factors have been previously established," explained lead author Bryan P. Schneider, MD, who presented his findings at a press briefing held in advance of the American Society of Clinical Oncology (ASCO) 2011 Annual Meeting. "These include advanced age, diabetes, and dose and schedule of paclitaxel."

"Unfortunately, there are no established biomarkers to predict which patients will experience this toxicity prior to receiving the drug," said Dr. Schneider, a physician/researcher at the Indiana University Melvin and Bren Simon Cancer Center and associate director of the Indiana Institute for Personalized Medicine, in Indianapolis.

The patients were drawn from the Eastern Cooperative Oncology Group clinical trial (E5103), a randomized phase 3 trial that compared standard adjuvant chemotherapy for patients with early-stage breast cancer with the same chemotherapy plus concurrent bevacizumab or concurrent and sequential bevacizumab. All 3 study groups also received weekly paclitaxel for a period of 12 weeks.

The researchers conducted a genome-wide association study on 2204 patients enrolled in this trial, and evaluated more than 1.2 million single-nucleotide polymorphisms (SNPs) in each patient.

"Our study plan was [to look] for an association between these genetic variations and the likelihood of a patient experiencing peripheral neuropathy," explained Dr. Schneider. "The trial is ongoing, but completed its enrollment in February of this year."

SNPs Identified

To date, at a median follow-up 15 months, 613 patients have experienced neuropathy. In this cohort, significant clinical predictors of neuropathy included advanced age — there was a 12.9% increase with each 10 years (P = .004) — and black race, which had a more than 2-fold likelihood of neuropathy, compared with other races (hazard ratio [HR], 2.1; P = 2.3 × 10–11).

In the genome-wide association study, the researchers found that 6 SNPs with a minor allele frequency of more than 5% were associated with time to neuropathy (P < 5 × 10–7). These SNPs were located in 2 genes: RWDD3 and TECTA.

"We found SNPs in multiple genes that were associated with the likelihood of experiencing neuropathy," said Dr. Schneider. "The strongest association was in RWDD3."

At 15 months, a missense SNP in RWDD3 was associated with a 27% likelihood of neuropathy in patients with a homozygous wild-type allele, a 40% likelihood for patients with a heterozygous allele, and a 60% likelihood for patients with a homozygous variant allele (dose effect: HR, 1.5; P = 8.5 × 10–8).

In addition, a TECTA SNP was associated with a 29% likelihood of neuropathy in patients with a homozygous wild-type allele, a 32% likelihood for patients with a heterozygous allele, and 57% likelihood for patients with a homozygous variant allele (recessive effect: HR, 2.1; P = 3.2 × 10–7). The authors also found SNPs with a minor allele frequency below 5% that were associated with neuropathy (P < 5 × 10–7).

A subgroup analysis of black patients is currently underway.

"We are hopeful that with further validation, these findings may help in the counseling of the optimal risk/benefit ratio for each patient," concluded Dr. Schneider. "We ultimately hope that this will promote the discovery of new therapies for neuropathy."

Supportive Care Gets Boost

Dr. Mark Kris

Mark G. Kris, MD, chair of ASCO's Cancer Communications Committee, noted that this study represents one of the first times that "molecular biology has melded into the area of supportive care."

"In the supportive care field, we have not had the power of the revolution in biology, the revolution in molecular biology," said Dr. Kris, who comoderated the briefing. He pointed out that much of this new research has been used in cancer treatment, but not for the adverse events that can result from the treatment.

This study evaluated a person's propensity to be at risk for adverse effects, he said. "Potentially, we can find people at high risk for neuropathy, we can offer them an alternative treatment, we can offer them closer surveillance, and we may be able to give them some sort of prophylactic treatment or design a trial for that."

"At the very least, we can advise the patient of an increased risk, and they can be part of the decision making as to whether or not to be part of that treatment," he added. "Being able to give the drug at full dose enhances a person's chance of cure; that is our most important goal, and I think the most important goal of our patient.

Dr. Schneider reports consulting, serving in an advisory role, and receiving honoraria from Genentech. Several coauthors also report relationships with Genentech.

American Society of Clinical Oncology (ASCO) 2011 Annual Meeting: Abstract 1000. To be presented June 4, 2011.


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