Identification of a Potentially Radiosensitive Subgroup Among Patients With Breast Cancer

Abstract

The description of genes and genetic syndromes, such as ataxia-telangiectasia, that predispose some women to breast cancer will provide greater insight into the genetic basis of cancer susceptibility. Our goal was to establish cell lines from patients with breast and bladder cancers, to screen for enhanced levels of radiation-induced arrest in the G2 phase of the cell cycle such as is observed in ataxia-telangiectasia heterozygotes, and to correlate G2 arrest with other prognostic indicators of these cancers and in vivo radiosensitivity. Epstein-Barr virus-transformed lymphoblastoid cells were established from 108 female patients with breast cancer and 24 age-matched female control subjects, and from 45 patients with bladder cancer and 18 age-matched control subjects. Cells were exposed to 3 Gy of gamma radiation, and the percentages of cells in G1 and G2 phases were determined at 18 and 24 hours after irradiation by fluorescence-activated cell sorter analysis. Postirradiation delay in G2 phase was determined by calculating the percentage of cells in G2 and by using the ratio G2/G1. When we determined the percentage of cells in G2 phase at 18 hours after irradiation in 108 lymphoblastoid cells from breast cancer patients, we observed an increase of between 3% and 38% in the number of cells in G2 phase in comparison with cells that were not irradiated. Comparison with previous G2-phase arrest data for ataxia-telangiectasia heterozygotes using a cutoff point at 29% delay demonstrated that 20% and 8% of the breast cancer cell lines of the case patients and control subjects, respectively, fell into that category (P < .001). At the same time after irradiation, it was not possible to distinguish between bladder cancer cell lines (7%) and those of the corresponding control group (6%). Assessment of radiation effects by G2/G1 ratio showed that 18% of the breast cancer patients and 8% of the control subjects were in the high range. When G2 arrest was correlated with other prognostic factors, we found that case patients with a greater G2 block were more likely to have had a family history of breast cancer (P < .006) and more aggressive tumors when assessed by number of involved lymph nodes (P < .002) and tumor size (P < .05). Furthermore, an adverse response to radiotherapy was observed in a group of patients with high G2 arrest. While the postirradiation increase in G2-phase arrest in cells from breast cancer patients observed in this study may indicate genetic heterozygosity for ataxia-telangiectasia, it might also reflect other genetic abnormalities important to breast cancer.