Oncotarget

Research Papers:

Critically short telomeres and toxicity of chemotherapy in early breast cancer

Miguel Quintela-Fandino, Nora Soberon, Ana Lluch, Luis Manso, Isabel Calvo, Javier Cortes, Fernando Moreno-Antón, Miguel Gil-Gil, Noelia Martinez-Jánez, Antonio Gonzalez-Martin, Encarna Adrover, Raquel de Andres, Gemma Viñas, Antonio Llombart-Cussac, Emilio Alba, Silvana Mouron, Juan Guerra, Begoña Bermejo, Esther Zamora, Jose Angel García-Saenz, Sonia Pernas Simon, Eva Carrasco, María José Escudero, Ruth Campo, Ramón Colomer and Maria A. Blasco _

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Oncotarget. 2017; 8:21472-21482. https://doi.org/10.18632/oncotarget.15592

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Abstract

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

Correspondence to:

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

ABSTRACT

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.


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