172P Prediction of persistent taxane-induced peripheral neuropathy among early-stage breast cancer survivors using whole-exome sequencing

Abstract

Persistent taxane-induced peripheral neuropathy (TIPN) among early-stage breast cancer survivors (ESBCS) is common and impacts quality of life. We aimed to explore genetic variants as risk factors. A population-based cohort of 884 residual-free ESBCS in Sweden were sent the EORTC chemotherapy-induced PN (CIPN20), 342 agreed to additional whole-exome sequencing for prediction modelling. Analysis focused on the symptoms tingling and numbness in feet, cramps in feet, difficulty opening a jar and difficulty climbing stairs since these showed highest relative risks compared to controls in our previous studies1 and are of clinical importance (under review). The raw sequencing data was aligned to the human reference genome (GRCh38), quality controls according to standard guidelines using the Genome Analysis Toolkit. The final filtered set included 55150 common genetic variants (MAF ≥ 1%). We adjusted for age, taxane, cumulative dose, time since treatment, BMI, and diabetes mellitus. Prediction models (logistic regression) were based on the single-nucleotide variants (SNVs) and insertions/deletions (INDELs) associated with TIPN in a training set of 70% of the ESBCS (N=237) with planned subsequent validation of the remaining 30%. P-value thresholds for permutations with 50-80% false discovery rates (FDR) was ≤ 0.000875, ≤ 0.001125, ≤ 0.001125, ≤ 0.0005, and ≤ 0.0005 for numbness feet, tingling feet, cramps feet, difficulty opening a jar, and difficulty climbing stairs. Using these thresholds 71, 79, 69, 33, and 46 genetic variants were identified representing in total 282 unique variants. Prediction models developed, reaches a max accuracy of 70-90% (Table).Table: 172PAccuracySensitivitySpecificityNumbness feet79,15%52,46%88,51%Tingling feet80,85%41,27%95,35%Cramps feet75,32%31,94%94,48%Diff opening jar77,64%13,79%98,32%Diff climbing stairs90,72%32,14%98,56% Open table in a new tab Genetic prediction models of persistent TIPN may indicate a genetic risk, which could contribute to more individualised adjuvant treatment decisions. Further analysis is needed and ongoing. 1Engvall BJC 2021.