Longitudinal multi-omics analyses of chemotherapy-induced peripheral neuropathy in response to taxanes

BACKGROUND: Taxanes are an effective class of chemotherapeutics, but they frequently cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN complicates treatment, often leading to alterations or discontinuation. This study aims to elucidate mechanisms underlying CIPN associated with taxane administration in breast cancer patients, utilizing a multi-omic, longitudinal approach to characterize molecular changes over time that can help gain insight into the pathophysiology of CIPN. METHODS: We assessed 358 patients receiving taxanes in (neo)adjuvant chemotherapy regimens over 12 months, evaluating CIPN at seven time-points, including pre- and post-treatment. CIPN was defined as an increase of eight or more points from baseline linearized CIPN20 scores. Changes in 194 mRNAs, 798 miRNAs, and 85 metabolites were analyzed at each of the seven time points, representing changes across six time-intervals. Molecular marker changes were analyzed using the semi-parametric OmicsLonDA package. Features identified through this analysis were then employed in Ingenuity Pathway Analysis (IPA) to evaluate the activation (Z score > 0) and inhibition (Z score < 0) of pathways related to CIPN. RESULTS: Our analysis revealed significant differences (FDR-P < 0.05) in the expression levels of 99 mRNAs, 55 miRNAs, and ten metabolites between CIPN-positive and negative patients at various time points. Notably, Opioid-receptor-mu-1 (OPRM1) mRNA levels were elevated in CIPN-negative patients while CAMK1D mRNA was higher in CIPN-positive patients from two to 12 months post-infusion. Tyrosine and capric acid metabolites were elevated in the CIPN-positive group from one to nine months post-infusion. Specific neuropathy-associated miRNAs, hsa-miR-31-5p and hsa-miR-184, showed differential expression between groups. Differentially expressed mRNAs were linked to 120 pathways, particularly in the Cyclic AMP Response Element-Binding Protein (CREB) signaling, opioid signaling, and endocannabinoid signaling pathways. Longitudinal analyses revealed activation-inhibition patterns in CREB and opioid signaling pathways over time. CONCLUSIONS: Our study offers valuable insights into the molecular mechanisms of CIPN in breast cancer patients treated with taxanes. By identifying key molecular markers and pathways, such as CREB and opioid signaling, we provide initial evidence for hypothesis generation and future research. While these findings are correlative and require further validation, they highlight potential biological mechanisms and serve as a basis for validating candidates as biomarkers or therapeutic targets.