Radiation Research

Published by: Radiation Research Society

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Radiation Research 168(4):415-422. 2007
doi: 10.1667/RR0746.1

Radiation-Induced DNA Damage as a Predictor of Long-Term Toxicity in Locally Advanced Breast Cancer Patients Treated with High-Dose Hyperfractionated Radical Radiotherapy

Beatriz Pinarab, Pedro Carlos Laraab, Marta Lloretab, Elisa Bordóna, María Isabel Núñezc, Mercedes Villalobosc, Rosa Guerreroc, J. D. Lunad, and J. M. Ruiz de Almodóvar1c

aInstituto Canario de Investigación del Cáncer (ICIC)

bServicio de Oncología Radioterápica, Hospital Dr. Negrín, Gran Canaria

cInstituto de Biopatología y Medicina Regenerativa, Universidad de Granada

dDepartamento de Bioestadística, Facultad de Medicina, Universidad de Granada, Grenada, Spain

1011 Address for correspondence: Instituto de Biopatología y Medicina Regenerativa, Facultad de Medicina, Avenida de Madrid s/n, 18071 Granada, Spain;

Abstract

Pinar, B., Lara, P. C., Lloret, M., Bordón, E., Núñez, M. I., Villalobos, M., Guerrero, R., Luna, J. D. and Ruiz de Almodóvar, J. M. Radiation-Induced DNA Damage as a Predictor of Long-Term Toxicity in Locally Advanced Breast Cancer Patients Treated with High-Dose Hyperfractionated Radical Radiotherapy. Radiat. Res. 168, 415–422 (2007).

This 14-year-long study makes a novel contribution to the debate on the relationship between the in vitro radiosensitivity of peripheral blood lymphocytes and normal tissue reactions after radiation therapy. The aims were (1) to prospectively assess the degree and time of onset of skin side effects in 40 prospectively recruited consecutive patients with locally advanced breast cancer treated with a hyperfractionated dose-escalation radiotherapy schedule and (2) to assess whether initial radiation-induced DNA damage in peripheral blood lymphocytes of these patients could be used to determine their likelihood of suffering severe late damage to normal tissue. Initial radiation-induced DNA double-strand breaks (DSBs) were assessed in peripheral blood lymphocytes of these patients by pulsed-field electrophoresis. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity score. A wide interindividual variation was observed in toxicity grades and in radiation-induced DNA DSBs in peripheral blood lymphocytes (mean 1.61 ± 0.76 DSBs/Gy per 200 MBp, range 0.63– 4.08), which were not correlated. Multivariate analysis showed a correlation (P < 0.008) between late toxicity and higher prescribed protocol dose (81.6 Gy). Analysis of the 29 patients referred to 81.6 Gy revealed significantly (P < 0.031) more frequent late subcutaneous toxicity in those with intrinsic sensitivity to radiation-induced DNA DSBs of >1.69 DSBs/Gy per DNA unit. Our demonstration of a relationship between the sensitivity of in vitro-irradiated peripheral blood lymphocytes and the risk of developing late toxic effects opens up the possibility of predicting normal tissue response to radiation in individual patients, at least in high-dose non-conventional radiation therapy regimens.

Received: July 4, 2006; Accepted: May 18, 2007



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FIG. 1. Panel A: DNA fragmentation in a lymphocyte sample taken from a breast cancer patient. MW are the yeast chromosome weight markers (S. pombe and S. cerevisiae). The remaining lines represent different radiation doses (C = 0 Gy and from 5 to 40 Gy). Panel B: Molecular damage measured in DSBs per DNA unit. Experimental data were fitted to a straight line (present case, r = 0.927); the slope was the molecular radiosensitivity parameter considered for each patient (present case, slope = 1.27 ± 0.15, Y intercept = 18.57 ± 3.7; P = 0.0001)

FIG. 2. Actuarial freedom from grade 3–4 cutaneous (□) and subcutaneous (•) late toxicity

FIG. 3. Actuarial freedom from grade 3–4 late subcutaneous toxicity in patients referred to the 81.6-Gy dose protocol

FIG. 4. Subcutaneous grade 3–4 fibrosis as a function of time after start of treatment in the whole group of locally advanced breast cancer patients treated at high radiation doses with altered fractionation

FIG. 5. Subcutaneous grade 3–4 fibrosis as a function of time after start of treatment. Open squares: subgroup of patients referred to 81.6-Gy dose protocol and with lower sensitivity to radiation-induced DNA DSBs. Black squares: subgroup of patients referred to 81.6-Gy dose protocol and with higher sensitivity to radiation-induced DNA DSBs. Differences between slopes are highly significant, P < 0.0001

table

TABLE 1 Results of Univariate and Multivariate Analyses of Late Grade 3–4 Cutaneous and Subcutaneous Toxicity

Cited by

Yaacov Richard Lawrence, Maria Werner-Wasik, Adam P Dicker. (2008) Biologically conformal treatment: biomarkers and functional imaging in radiation oncology. Future Oncology 4:5, 689-704
Online publication date: 1-Nov-2008.
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