Genetics of Chemotherapy Induced Peripheral Neuropathy in N08C1 and N08CB

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting toxicity of chemotherapy treatment. CIPN severity varies widely between cancer patients, and previous studies had found evidence of genes and single nucleotide variants (SNV) being associated with CIPN. The goal of this study was to further identify genetic markers and pathways associated with CIPN severity using whole exome sequencing (WES) and whole genome sequencing (WGS) of participants in two clinical studies which collected longitudinal patient-reported outcome (PRO) measures of CIPN. NCCTG/Alliance study N08C1 was a prospective cohort study of the natural history of paclitaxel-associated acute pain syndrome (P-APS) and CIPN. NCCTG/Alliance trial N08CB was a randomized, placebo-controlled trial of calcium and magnesium for prevention of oxaliplatin-induced sensory neuropathy in which the treatment had no significant effect on either acute pain or sensory neuropathy. Both N08C1 and N08CB collected patient assessments of CIPN symptoms before each cycle of chemotherapy using the EORTC QLQ-CIPN20 instrument. For this study, CIPN cases were selected from each of N08C1 and N08CB as those patients with the most severe CIPN symptoms (assessed longitudinally). CIPN controls were selected as those with the least severe symptoms. WGS was obtained for N08C1 samples (WES had been obtained and analyzed previously), and WES was obtained for N08CB samples.]]>
N08C1Inclusion criteria: Scheduled to receive paclitaxel at a dose of at least 175 mg/m2 every 2 to 4 weeks or 70 to 90 mg/m2 weekly; at least 18 years old; able to provide written consent; able to complete study questionnaires; life expectancy greater than 6 months; ECOG performance status of 0 or 1.Exclusion criteria: Diagnosed with peripheral neuropathy from any cause; diagnosed with fibromyalgia; planned to receive concurrent neutrophil colony-stimulating factor therapy; had previous exposure to paclitaxel or another neurotoxic chemotherapy drug.Retrospective selection of CIPN cases and controls: A Rasch-type statistical model was fit to patient responses (obtained before each cycle of chemotherapy) for the CIPN20 instrument. A "slope" representing change in symptom severity over time was estimated for each patient with a 95% confidence interval (CI). Patients whose 95% CI overlapped the sample median of patient slopes were excluded from sequencing. Remaining patients with slope estimates above the sample median were selected as cases, and those with slope estimates below the sample median were selected as controls.N08CBInclusion criteria: Adult patients with adenocarcinoma of the colon who, after curative-intent resection, were scheduled to receive 6 months of adjuvant FOLFOX chemotherapy (fluorouracil, leucovorin, and oxaliplatin) involving oxaliplatin at a dose of 85 mg/m2 every 2 weeks; adequate hematologic parameters to allow chemotherapy; serum total bilirubin and creatinine no more than 1.5 times upper limit of normal and calcium and magnesium no more than 1.2 times upper limit of normal; negative pregnancy test if a woman of childbearing potential.Exclusion criteria: Pre-existing peripheral neuropathy of any grade; had received prior treatment with neurotoxic chemotherapy; had a history of second- or third-degree atrioventricular heart block; were receiving digoxin, carbamazepine, phenytoin, valproic acid, gabapentin, pregabalin, venlafaxine, desvenlafaxine, milnacipran, duloxetine, a tricyclic antidepressant, or any other agent specifically being given to prevent or treat neuropathy; had a family history of a genetic/familial neuropathy; had other medical conditions which, in the opinion of the treating physician, would make the protocol unreasonably hazardous for the patient; or were not considered to be able to comply with the protocol.Retrospective selection of CIPN cases and controls: Similar to selection in N08C1. A Rasch-type statistical model was fit to patient responses (obtained before each cycle of chemotherapy) for the sensory items of the CIPN20 instrument. A "slope" representing change in symptom severity with increasing cumulative dose of oxaliplatin was estimated for each patient using a 95% CI. Ranking all patients by the upper limit of the 95% CI, the lowest 25% of patients were selected as controls. Ranking all patients by the lower limit of the 95% CI, the highest 25% of patients were selected as cases. Thus, approximately half of the eligible N08CB participants were selected for sequencing and analysis.]]>