Abstract P5-14-13: An observational study using g-H2AX foci to investigate cardiac doses of radiation in women following adjuvant radiotherapy for breast cancer: External beam radiotherapy versus targeted intraoperative radiotherapy
Authors: Woolf DK , Williams NR , Bakhshi R , Madani Y , Fawcitt S , Pigott K , Short SC , Keshtgar M 
Published: August 2014

Background

External beam radiotherapy (EBRT) is the gold standard adjuvant treatment after breast conserving surgery for localised breast cancer. A recent phase 3 trial has shown the non-inferiority of intraoperative radiotherapy (IORT) compared with EBRT in terms of short-term safety and efficacy (TARGIT A Trial; Lancet 2010). IORT also has advantages in cost saving and patient convenience.

Radiation exposure of the heart and cardiac vessels is associated with an increase in morbidity and mortality following EBRT for breast cancer and has been shown to increase the rate of major coronary events by 7.4% per gray of exposure to the heart (Darby; NEJM 2013). IORT uses low energy x-rays (50 kV) and is likely to reduce the radiation exposure of the cardiovascular system compared with EBRT.

We have used γ-H2AX foci formation in peripheral blood lymphocytes as a surrogate marker of radiation dose to the heart and great vessels. The phosphorylated histone H2AX protein (γ-H2AX) is expressed after induction of DNA double strand breaks caused by ionising radiation, created as the lymphocytes pass through and adjacent to the irradiated field.

Methods

34 patients were recruited, having either EBRT or IORT as part of a randomised controlled trial. The main inclusion criteria were adult females with early breast cancer suitable for breast conserving surgery and the main exclusion criteria were previous malignancy, recent exposure to radiation (excluding CT planning scan) and prior chemotherapy. Blood samples were taken immediately prior to and 30 minutes after either first fraction of EBRT or after IORT treatment, and then rapidly processed to allow quantification of the γ-H2AX biomarker in lymphocytes (Rothkamm; Radiology 2007). This study had approval from the Local Research and Ethics Committee.

Results

Data were available for 31 patients. Means and standard deviations for the change in γ-H2AX foci number per cell for each group are summarised in table 1. Following IORT there was an increase of 0.203 foci per cell (range -1.436 to 1.275) compared with an increase of 0.935 foci per cell (range -0.679 to 2.216) in the EBRT group; this difference was highly significant (p = 0.009).

Table 1: γ-H2AX foci per cell IORTEBRTMean0.2030.935SD0.6330.764n1318

Conclusions

These data show a significantly greater change in γ-H2AX foci number per cell following one fraction of EBRT compared to IORT. IORT is a single treatment (20Gy at the applicator surface) whereas EBRT is repeated 15 times (2.67Gy x 15 fractions) multiplying the effect on the patients’ cardiovascular system.

It may be hypothesised that this reduced radiotherapy dose from IORT will reduce the risk of cardiovascular morbidity and mortality compared to EBRT. This is the first study to demonstrate the real time effect of radiotherapy to the heart and great vessels using a biomarker and demonstrates a proof of concept methodology for similar applications.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-13.