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. 2016 Oct 7;11(10):e0164319.
doi: 10.1371/journal.pone.0164319. eCollection 2016.

Low Levels of NDRG1 in Nerve Tissue Are Predictive of Severe Paclitaxel-Induced Neuropathy

Raghav Sundar  1 , Anand D Jeyasekharan  1   2 , Brendan Pang  2   3 , Richie Chuan Teck Soong  2   3 , Nesaretnam Barr Kumarakulasinghe  1 , Samuel Guan Wei Ow  1 , Jingshan Ho  1 , Joline Si Jing Lim  1 , David Shao Peng Tan  1 , Einar P V Wilder-Smith  4   5   6 , Aishwarya Bandla  4   7 , Stacey Sze Hui Tan  4 , Bernadette Reyna Asuncion  2 , Zul Fazreen  2 , Michal Marek Hoppe  2 , Thomas Choudary Putti  3 , Lay Mui Poh  8 , Boon Cher Goh  1   2 , Soo-Chin Lee  1   2
Affiliations

Low Levels of NDRG1 in Nerve Tissue Are Predictive of Severe Paclitaxel-Induced Neuropathy

Raghav Sundar et al. PLoS One. .

Abstract

Introduction: Sensory peripheral neuropathy caused by paclitaxel is a common and dose limiting toxicity, for which there are currently no validated predictive biomarkers. We investigated the relationship between the Charcot-Marie-Tooth protein NDRG1 and paclitaxel-induced neuropathy.

Methods/materials: Archived mammary tissue specimen blocks of breast cancer patients who received weekly paclitaxel in a single centre were retrieved and NDRG1 immunohistochemistry was performed on normal nerve tissue found within the sample. The mean nerve NDRG1 score was defined by an algorithm based on intensity of staining and percentage of stained nerve bundles. NDRG1 scores were correlated with paclitaxel induced neuropathy.

Results: 111 patients were studied. 17 of 111 (15%) developed severe paclitaxel-induced neuropathy. The mean nerve NDRG1 expression score was 5.4 in patients with severe neuropathy versus 7.7 in those without severe neuropathy (p = 0.0019). A Receiver operating characteristic (ROC) curve analysis of the mean nerve NDRG1 score revealed an area under the curve of 0.74 (p = 0.0013) for the identification of severe neuropathy, with a score of 7 being most discriminative. 13/54 (24%) subjects with an NDRG1 score < = 7 developed severe neuropathy, compared to only 4/57 (7%) in those with a score >7 (p = 0.017).

Conclusion: Low NDRG1 expression in nerve tissue present within samples of surgical resection may identify subjects at risk for severe paclitaxel-induced neuropathy. Since nerve biopsies are not routinely feasible for patients undergoing chemotherapy for early breast cancer, this promising biomarker strategy is compatible with current clinical workflow.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. NDRG1 expression in normal nerve tissue.
Photo micrographs (x 40 objective) depicting NDRG1 IHC, scale bar is 50μm. A: Score 0: Nerve highlighted by circles, with no expression of NDRG1. B: Score 1: Minimal expression of NDRG1 in less than 50% of the nerve bundle. C: Score 2: Strong expression of NDRG1 in less than 50% of the nerve bundle. D: Score 3: Strong expression of NDRG1 in more than 50% of the nerve bundle
Fig 2
Fig 2. NDRG1 Analyses.
2A. Correlation of NDRG1 scores between investigator 1 and investigator. 2B. Mean NDRG1 expression scores in nerve tissue in subjects who did or did not develop paclitaxel-induced severe neuropathy. 2C. ROC analysis of predictive validity of NDRG1 for paclitaxel-induced severe neuropathy.
See this image and copyright information in PMC

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