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

• Published in: PloS one 2016-10, Vol.11 (10), p.e0164319
• Main Authors: Sundar, Raghav, Jeyasekharan, Anand D, Pang, Brendan, Soong, Richie Chuan Teck, Kumarakulasinghe, Nesaretnam Barr, Ow, Samuel Guan Wei, Ho, Jingshan, Lim, Joline Si Jing, Tan, David Shao Peng, Wilder-Smith, Einar P V, Bandla, Aishwarya, Tan, Stacey Sze Hui, Asuncion, Bernadette Reyna, Fazreen, Zul, Hoppe, Michal Marek, Putti, Thomas Choudary, Poh, Lay Mui, Goh, Boon Cher, Lee, Soo-Chin
• Format: Article
• Language: English
• Subjects: Adult; Aged; Algorithms; Analysis; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - therapeutic use; Biocompatibility; Biology and Life Sciences; Biomarkers; Breast cancer; Breast Neoplasms - drug therapy; Cancer; Cancer therapies; Cell Cycle Proteins - metabolism; Cellular biology; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - metabolism; Chemotherapy; Correlation analysis; Drug dosages; Female; Hematology; Humans; Hypoxia; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - metabolism; Male; Medical research; Medicine; Medicine and Health Sciences; Middle Aged; Mutation; Nerve Tissue - metabolism; Oncology; Paclitaxel; Paclitaxel - adverse effects; Paclitaxel - therapeutic use; Pain; Pathology; Patients; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - metabolism; Peripheral neuropathy; Research and Analysis Methods; Science; Surgery; Toxicity; Workflow
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0164319

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. 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. 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). 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.