Neurofilament proteins as a potential biomarker in chemotherapy-induced polyneuropathy

Abstract

Background: Paclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. As sensory symptoms are challenging to assess objectively in clinical routine, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as translational surrogate marker for CIPN. Methods: NFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell-derived sensory neurons (iPSC-DSN) to paclitaxel. Breast and ovarian cancer patients undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced, which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFLs) concentrations were measured at both visits with single molecule array technology (SIMOA).Results: NFL is released from iPSC-DSN upon paclitaxel incubation in a dose-and time-dependent manner and inversely correlates with iPSC-DSN viability. NFLs strongly increased in paclitaxel-treated patients with CIPN, but not in chemotherapy patients without CIPN or controls, resulting in an 86 % sensitivity and 87 % specificity.A NFLs increase of +36 pg/ml from baseline was associated with a predicted CIPN probability of >0.5. Conclusion:NFLs correlates with CIPN development and severity, which may guide neurotoxic chemotherapy in the future.

Rationale and design of the prevention of paclitaxel-related neurological side effects with lithium trial – Protocol of a multicenter, randomized, double-blind, placebo- controlled proof-of-concept phase-2 clinical trial

“…Published TNSr values following paclitaxel therapy report mean TNSr values between 11.1 and 11.9 points after chemotherapy with a standard deviation of 3.4–3.6, however, based on low sample sizes ( 34 ). Another study reported pre-chemotherapy mean TNSr values of 1.6 and post-chemotherapy values of 5.6 ( 35 ), which is in line with data from our own pilot study (CICARO, NCT02753036) including 23 breast cancer patients ( 36 ). Here, we observed a mean TNSr value increase from 1.6 at baseline to 5.0 at the follow-up time point (SD 3.5).…”

“…A smaller percentage of patients (triple negative, estrogen receptor negative and HER2neu positive) may require combination therapy of (nab-) paclitaxel with carboplatin, which is also neurotoxic to a lesser extent. In our own cohort of ovarian and breast cancer patients, a combination of (nab-) paclitaxel and carboplatin was, however, not more neurotoxic than (nab-) paclitaxel chemotherapy alone ( 36 ). Therefore, these patients will be enrolled in the PREPARE trial as the primary endpoint is not expected to be compromised.…”

“…The total score is calculated as sum score at V0, V8, V12, and V16. As secondary outcome variables we will assess patient-reported outcome measures pertaining to self-reported symptoms of CIPN [European Organisation for Research and Treatment of Cancer [EORTC]-CIPN20 ( 36 )], quality of life [EORTC-QLQ-C30 ( 39 )] and symptoms of anxiety and depression [Patient Health Questionnaire (PHQ)-4 ( 40 )]. Additionally, patients’ change in cognitive function will be recorded with the Cambridge Neuropsychological Testing Automated Battery (CANTAB) ( 41 ) for the following cognitive domains: processing and psychomotor speed, attention and visual memory, working memory and strategy, verbal learning and memory.…”

“…As additional clinical endpoints, the number and dose of pain medication for CIPN as well as the cumulative dose of (nab-) paclitaxel that each patient received will be evaluated. In addition, we will analyze blood biomarkers such as serum NFL as a marker for neuroaxonal damage ( 36 ). Relevant safety laboratory parameters that are secondary outcome measures are the lithium serum levels from TDM, patients’ serum creatinine and endocrine parameters.…”

“…We assume that we need to screen n = 2408 patients with breast cancer according to punch biopsy or surgical resection pathology for eligibility at five to eight recruiting centers to enroll n = 93 and randomize n = 84 patients aged 18–70 years. The sample size and drop-out rate (15%) is conservatively based on other studies in CIPN ( 34 , 35 ) and data from our own pilot study of CIPN development in breast cancer patients ( 36 ) as well as treatment effects for lithium carbonate in the prevention of CIPN in rodents ( 16 , 21 ). CONSORT, Consolidated Standards of Reporting Trials.…”