Taxane-related Peripheral Neuropathy Associated with Better Outcomes

San Antonio, TX—For patients with early breast cancer, peripheral neurotoxicity is an unfortunate side effect of treatment with taxanes, but there may be a silver lining, according to an analysis of the landmark N9831 trial by the North America Breast Intergroup consortium. “Patients who developed peripheral neuropathy on adjuvant paclitaxel-containing chemotherapy had a significantly better disease-free survival (DFS) than patients who did not develop neuropathy,” said Alvaro Moreno, MD, of the Mayo Clinic in Jacksonville, Florida.

Edith Perez, MD, senior author of the study and principal investigator of N9831, commented, “Our data are very solid. Patients are concerned about developing neuropathy with these commonly used drugs, but it turns out that peripheral neuropathy may be a surrogate marker for a better outcome.”

The study analyzed 1967 patients with HER2-positive early breast cancer who received only paclitaxel-containing chemotherapy (Arm A) or trastuzumab (Herceptin) plus the same chemotherapy regimen (Arm C). Patients in Arm B received sequential chemotherapy and trastuzumab but were not included in this analysis.

Patients in Arm A who developed neuropathy had better 3-year DFS than those who did not develop neuropathy, at 84.2% versus 77.8%, respectively. This translates to a 36% reduction in risk (P = .01), Dr Moreno reported.

“We saw better DFS, in spite of the fact that patients with neuropathy received lower doses of paclitaxel,” he said. The lower doses might have resulted from dose reduction to address neuropathy. The grade of neuropathy did not appear to affect DFS, he added.

For Arm C, the same differences were not observed with patients receiving trastuzumab along with the taxane. Three-year DFS in this arm was 89.8% for patients with neuropathy and 87.6% for those without neuropathy. While this represented a 28% reduction in risk, it was not statistically significant (P = .20). “The effect was possibly abrogated somehow by the use of trastuzumab in Arm C,” Dr Moreno said.

The comparison between patients without neuropathy (n = 852) and those with neuropathy that persisted >6 months (n = 792) was most robust, he continued. In this group, the risk of events was reduced by 42% compared with patients who had neuropathy lasting ≤6 months, which was highly statistically significant (P <.0001).

Possible Explanation

Dr Moreno explained that microtubules are crucial for spindle formation during mitosis and for cellular proliferation. The antineoplastic effect of paclitaxel is mainly related to its ability to bind the beta subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. Tubulins are expressed in human peripheral nerves, and the binding of paclitaxel to tubulin may lead to neuropathy.

“This side effect may represent effective binding of paclitaxel to the target tubulin, lack of point mutations in tubulin at the paclitaxel binding site, increased depletion of target genes at the microtubule site, or lack of selective overexpression of

β

-III tubulin, which confers resistance to paclitaxel,” he suggested. “If drugs attach to the tubulin site in both cancer cells and nerves, the hypothesis is this could lead to better outcomes.”

To confirm these observations, the investigators are examining the E1199 data for this correlation. Findings from the two studies will be combined for future publication. SABCS Abstract 2100.