title: Identifying Predictors of Taxane-Induced Peripheral Neuropathy Using Mass Spectrometry-Based Proteomics Technology.
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.
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, New York, United States of America.|Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, United States of America.|Department of Epidemiology, Columbia University Medical Center, New York, New York, United States of America.|Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Crew
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Meghna
authors.initials: M
authors.lastname: Trivedi
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Awad
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, United States of America.|Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Mathew
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, United States of America.|Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kalinsky
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Antonius
authors.initials: A
authors.lastname: Koller
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Purvi
authors.initials: P
authors.lastname: Patel
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Jenny
authors.initials: J
authors.lastname: Kim Kim
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York, United States of America.|Department of Epidemiology, Columbia University Medical Center, New York, New York, United States of America.|Herbert Irving Comprehensive Cancer Center, Proteomics Shared Resource, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Hershman
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy; D001952:Bridged-Ring Compounds / Q000009:adverse effects*; D016022:Case-Control Studies; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D055354:Exosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D010523:Peripheral Nervous System Diseases / Q000097:blood / Q000139:chemically induced*; D011446:Prospective Studies; D040901:Proteomics / Q000379:methods*; D012307:Risk Factors; D053719:Tandem Mass Spectrometry; D043823:Taxoids / Q000009:adverse effects*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001952:Bridged-Ring Compounds; D009363:Neoplasm Proteins; D043823:Taxoids; C080625:taxane