Critically short telomeres and toxicity of chemotherapy in early breast cancer
Metrics: PDF 2176 views | HTML 3023 views | ?
Miguel Quintela-Fandino1, Nora Soberon2, Ana Lluch3, Luis Manso4, Isabel Calvo5, Javier Cortes6,7, Fernando Moreno-Antón8, Miguel Gil-Gil9, Noelia Martinez-Jánez7, Antonio Gonzalez-Martin10, Encarna Adrover11, Raquel de Andres12, Gemma Viñas13, Antonio Llombart-Cussac14, Emilio Alba15, Silvana Mouron1, Juan Guerra16, Begoña Bermejo3, Esther Zamora6, Jose Angel García-Saenz8, Sonia Pernas Simon9, Eva Carrasco17, María José Escudero17, Ruth Campo17, Ramón Colomer18, Maria A. Blasco2
1Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain
2Telomeres and Telomerase Group, Molecular Oncology Programme, CNIO-Spanish National Cancer Research Center, Madrid, Spain
3Medical Oncology Department, Hospital Clinico Universitario, Valencia, Spain
4Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain
5Medical Oncology Department, Hospital de Montepríncipe, Madrid, Spain
6Medical Oncology Department, Hospital Vall d´Hebron, Barcelona, Spain
7Medical Oncology Department, Hospital Ramón y Cajal, Madrid, Spain
8Medical Oncology Department, Hospital Clinico San Carlos, Madrid, Spain
9Medical Oncology Department, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
10Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain
11Medical Oncology Department, Hospital General de Albacete, Albacete, Spain
12Medical Oncology Department, Hospital Lozano Blesa, Zaragoza, Spain
13Medical Oncology Department, Institut Catala d'Oncologia-Hospital Dr. Josep Trueta, Girona, Spain
14Medical Oncology Department, Hospital Arnau de Vilanova, Valencia, Spain
15Medical Oncology Department, Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain
16Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain
17GEICAM, Madrid, Spain
18Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain
Miguel Quintela-Fandino, email: [email protected]
Maria A. Blasco, email: [email protected]
Keywords: telomere length, critically short telomeres, breast cancer, weekly paclitaxel, toxicity
Received: October 25, 2016 Accepted: January 27, 2017 Published: February 21, 2017
Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres (< 3 kilobases, CSTs), but not average telomere length by itself, accounts for limited tissue renewal and turnover capacity. The impact of this parameter (which can be modified with different therapies) in chemotherapy-derived toxicity has not been studied.
Blood from 115 treatment-naive patients from a clinical trial in early HER2-negative breast cancer that received weekly paclitaxel (80 mg/m2 for 12 weeks) either alone or in combination with nintedanib and from 85 healthy controls was prospectively obtained and individual CSTs and average telomere lenght were determined by HT Q-FISH (high-throughput quantitative FISH). Toxicity was graded according to NCI common toxicity criteria for adverse events (NCI CTCAE V.4.0). The variable under study was “number of toxic episodes” during the 12 weeks of therapy.
The percentage of CSTs ranged from 6.5%–49.4% and was directly associated with the number of toxic events (R2 = 0.333; P < 0.001). According to a linear regression model, each 18% increase in the percentage of CSTs was associated to one additional toxic episode during the paclitaxel cycles; this effect was independent of the age or treatment arm. Patients in the upper quartile (> 21.9% CSTs) had 2-fold higher number of neuropathy (P = 0.04) or fatigue (P = 0.019) episodes and >3-fold higher number of myalgia episodes (P = 0.005). The average telomere length was unrelated to the incidence of side effects.
The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.