Abstract
Major advances in early detection and therapy have significantly increased the survival of breast cancer patients. Unfortunately, most cancer therapies are known to carry a substantial risk of adverse long-term treatment-related effects. Little is known about patient susceptibility to severe side effects after chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxanes. Recent advances in genome-wide genotyping and sequencing technologies have supported the discoveries of a number of pharmacogenetic markers that predict response to chemotherapy. However, effectively implementing these pharmacogenetic markers in the clinic remains a major challenge. On the other hand, recent advances in proteomic technologies incorporating mass spectrometry (MS) for biomarker discovery show great promise to provide clinically relevant protein biomarkers. In this study, we evaluated the association between protein content in serum exosomes and severity of CIPN. Women with early stage breast cancer receiving adjuvant taxane chemotherapy were assessed with the FACT-Ntx score and serum was collected before and after the taxane treatment. Based on the change in FACT-Ntx score from baseline to 12 month follow-up, we separated patients into two groups: those who had no change (Group 1, N = 9) and those who had a ≥20% worsening (Group 1, N = 8). MS-based proteomics technology was used to identify proteins present in serum exosomes to determine potential biomarkers. Mann–Whitney–Wilcoxon analysis was applied and maximum FDR was controlled at 20%. From the serum exosomes derived from this cohort, we identified over 700 proteins known to be in different subcellular locations and have different functions. Statistical analysis revealed a 12-protein signature that resulted in a distinct separation between baseline serum samples of both groups (q<0.2) suggesting that the baseline samples can predict subsequent neurotoxicity. These toxicity-associated biomarkers can be further validated in larger retrospective cohorts for their utility in identifying patients at high risk for CIPN.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially disabling side effect of many anticancer drugs.[1]
We have identified a novel panel of biomarkers from serum exosomes that were associated with the development of taxaneinduced peripheral neuropathy
Our data suggests that patients who had depressed or low inflammatory and detoxification responses prior to taxane treatment are at increased risk to develop taxane-induced peripheral neuropathy
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially disabling side effect of many anticancer drugs.[1] The symptoms are predominantly sensory and present in a “stocking-glove” distribution as pain, numbness, or tingling in the hands or feet.[2] The pathogenesis of CIPN is not well understood.[2, 3] In a recent meta-analysis of 31 CIPN studies involving 4179 patients on various neurotoxic chemotherapy agents, the aggregate prevalence of CIPN was 48%.[4] CIPN has important clinical implications in the treatment of cancer patients as it can result in dose reductions or discontinuation, which may affect overall survival.[2] Further, for cancer survivors, the CIPN symptoms can significantly impact quality of life.[1, 5, 6] The course of CIPN can be unpredictable and some symptoms may improve with time, other symptoms may persist or worsen as a result of permanent nerve damage.[1] While there has been extensive research on agents for the prevention and treatment of CIPN, therapeutic options remain limited.[7]
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