Neuropathy is a common and potentially disabling adverse effect of taxane therapy, particularly weekly paclitaxel. A number of recent studies have identified single nucleotide polymorphisms that appear to increase risk of grade 2 to 4 neuropathy in patients with breast cancer who receive taxanes. It is thus of interest to examine whether neuropathy is predictive of taxane efficacy. If it is not, it would be more straightforward to use the potential biomarkers for neuropathy. These could be used to identify patients who might benefit from receiving adjuvant taxane regimens that pose lower risk of neuropathy and adjunctive treatment to reduce neuropathy.
In a recent study reported in Journal of Clinical Oncology,1 Schneider and colleagues analyzed the potential relationship between grade 2 to 4 neuropathy and overall survival, disease-free survival, and recurrence-free survival among 4,554 women receiving taxane-containing adjuvant therapy in the E1199 trial. The adjuvant regimens consisted of up to 4 cycles of doxorubicin and cyclophosphamide every 3 weeks followed by: paclitaxel at 175 mg/m2 every 3 weeks for 4 cycles (P3 regimen), paclitaxel at 80 mg/m2 weekly for 12 cycles (P1 regimen), docetaxel at 100 mg/m2 every 3 weeks for 4 cycles (D3 regimen), or docetaxel at 35 mg/m2 weekly for 12 cycles (D1 regimen).
Neuropathy Risk Highest with Weekly Paclitaxel
Overall, grade 2 to 4 neuropathy occurred in 16.9% of patients; 71.8% of cases were grade 2, 27.5% grade 3, and 0.7% grade 4. Neuropathy occurred in 22.0% of the P1 group, 17.5% of the P3 group, 14.7% of the D3 group, and 13.4% of the D1 group. The risk of neuropathy in the P1 group was significantly higher than that in the P3 group (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.09–1.64, P = .006), the risk in the D1 group was significantly lower than that in the P3 group (OR = 0.73, 95% CI = 0.58–0.92, P = .008), and a reduction in risk in the D3 group compared with the P3 group approached significance (OR = 0.81, 95% CI = 0.65–1.02, P = .070). Proportions of patients requiring dose reduction for any reason and median relative dose intensity did not differ between patients with and patients without neuropathy in any treatment group.
Among all patients, premenopausal status was associated with decreased risk of neuropathy (OR = 0.77, P = .025), with trends toward significantly increased risk being observed for black race and obesity. Age as a continuous or categoric variable was not associated with differences in risk, contrary to previously reported findings in study E5103 (in which weekly paclitaxel was the taxane backbone). A significant increase in risk of neuropathy was observed in patients with grade 2 to 4 hyperglycemia (OR = 1.47, P < .001), with significance persisting after adjustment for age, race, obesity, and menopausal status (OR = 1.42). Similar results were yielded by analysis in the P1 group alone, with the reduction in risk associated with premenopausal status approaching significance (OR = 0.70, P = .092) and hyperglycemia being associated with a significantly increased risk (OR = 1.98, P = .004).
Among all patients, obesity, nodal status, and tumor size were significantly associated with overall survival. The only variables significantly associated with overall survival across all four treatment groups were having greater than three involved nodes and having a tumor greater than 2 cm in size.
Neuropathy Not Associated with Survival
On univariate analysis, no significant association of neuropathy with overall, disease-free, or recurrence-free survival was found when all patients were included or in analyses limited to patients with HER2-positive tumors, triple-negative tumors, or estrogen receptor–positive/HER2-negative tumors. Multivariate analysis including adjustment for the covariates of age, race, obesity, menopausal status, tumor size, nodal status, treatment arm, and treatment-related grade 2 to 4 hyperglycemia showed no significant association between grade 2 to 4 neuropathy and overall, disease-free, or recurrence-free survival among all patients or among subgroups of patients with HER2-positive tumors, triple-negative tumors, or estrogen receptor–positive/HER2-negative tumors. No association of neuropathy with overall survival after adjustment for covariates was observed within any individual treatment group.
In E1199, the P1 arm, which had the highest risk for neuropathy, had improved disease-free and overall survival, and the D3 arm had improved disease-free but not overall survival at the time of planned analysis compared with the standard P3 arm. Given the improvement in overall and disease-free survival and the reduced overall toxicity observed with the P1 regimen, this regimen has become commonly used in clinical practice.
Docetaxel-containing regimens have been shown to have benefits in other clinical trials and are also widely used in clinical practice; these regimens are associated with greater overall grade 3 or 4 toxicity but less neuropathy than are observed with weekly paclitaxel. As noted by the investigators, if it is indeed the case that taxane-associated neuropathy is not a pharmacodynamic marker of taxane benefit, availability of biomarkers predictive of neuropathy could provide ‘an important tool for choosing an adjuvant taxane regimen and facilitate improved therapeutic individualization….”
The investigators concluded: “[T]his analysis of greater than 4,500 patients demonstrates that taxane-induced peripheral neuropathy does not correlate with improved outcomes in patients with operable breast cancer treated with adjuvant taxane therapy. This finding provides reassurance that biomarkers predictive for neuropathy will likely not enrich for patients who are more likely to benefit from taxane therapy and may also be useful for the identification of patients who are most likely to benefit from adjunctive therapies to mitigate neuropathy.” ■
Reference
1. Schneider BP, Zhao F, Wang M, et al: Neuropathy is not associated with clinical outcomes in patients receiving adjuvant taxane-containing therapy for operable breast cancer. J Clin Oncol 30:3051-3057, 2012.
