Pharmacogenomic Analysis of Microtubule Targeting Agent Response and Toxicity

Microtubule targeting agents are commonly prescribed for early and metastatic breast cancer and other solid tumors. However, interindividual variability in microtubule targeting drug response and toxicity can cause limited therapeutic benefit and impact quality of life. In the present study, genome-wide analyses were performed to investigate how genetic factors can be used to increase prediction of treatment response and toxicity, identify genes or gene pathways associated with chemotherapy-induced neurotoxicity, and inform further in vitro studies that may help isolate differences in response and toxicity of microtubule targeting agents.]]>
The patient cohort for this study was selected from CALGB 40502, a phase III trial conducted to determine if weekly 150 mg/m2 nab-paclitaxel or weekly 16 mg/m2 ixabepilone is superior to weekly 90 mg/m2 paclitaxel with bevacizumab as first-line therapy in locally recurrent or metastatic breast cancer. Subjects fulfilled all previously described (https://www.ncbi.nlm.nih.gov/pubmed/26056183) eligibility criteria for the study, including exclusion criteria of those with prior chemotherapy for metastatic disease and those with grade ≥ 2 pre-existing peripheral neuropathy. Patients received treatment every week for 3 weeks followed by a 1-week washout period. Response was defined by progression-free survival, the time from registration until date of first disease progression or death from any cause, censoring at 50 months post treatment. Adverse events, including peripheral neuropathy, were reported during each treatment cycle. The severity of peripheral neuropathy was assessed on a scale of 1-4 according to the NCI Common Terminology Criteria for Adverse Events version 3. Additionally, patient-reported neurotoxicity was also recorded during the trial using the FACT/GOG Neurotoxicity Subscale survey and was reported weekly. Each item on the survey was ranked on a qualitative scale from "Not at all" to "Very much", where the first four items are specifically defined for sensory peripheral neuropathy. DNA was available from patients who were also enrolled in a pharmacogenetic companion study (CALGB 60704) embedded within CALGB 40502.]]>