Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

The aim was to determine whether peripheral blood lymphocytes can be used retrospectively to detect hypersensitivity to radiation in breast cancer patients who had exhibited severe reactions to radiotherapy. Blood samples were obtained from patients who developed both acute and late complications. For comparison, samples were also taken from a group of normal individuals, ataxia-telangiectasia (A-T) patients, A-T gene carriers and breast cancer patients previously treated with radiotherapy who failed to develop treatment-related complications. Radiosensitivity was assessed using a limiting dilution clonogenic assay following both high (HDR) and low (LDR) dose-rate irradiation. Following HDR irradiation, only lymphocytes from individuals with A-T were significantly more radiosensitive than those from normal donors. In contrast, at LDR, lymphocytes from A-T heterozygotes and breast cancer over reactors were also, on average, more sensitive than those from normal donors. Lymphocytes from breast cancer patients treated with radiotherapy without developing complications showed no significant differences in radiosensitivity compared with normals. This work has shown that peripheral blood lymphocytes from cancer patients who suffered severe reaction to radiotherapy are, on average, more radiosensitive than those from normal donors, and suggests that lymphocytes may be useful in the future for the development of rapid predictive assays for normal tissue tolerance to radiotherapy.

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The work described highlights the importance of cellular radiosensitivity as a parameter determining the clinical response to radiotherapy.

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A study has been made of the intrinsic radiosensitivity of peripheral blood lymphocytes from normal individuals. Cell survival following in vitro high (1.55 Gy min-1) and low (0.0098 Gy min-1) dose-rate irradiation was obtained for single lymphocyte samples from three individuals in six experiments. Despite wide interexperimental variability the ranking of intrinsic radiosensitivity for these individuals was reproducible. Further studies were carried out using low dose-rate irradiation only, on: (1) single lymphocyte samples from 18 people; (2) 14 samples taken on different occasions from one of these donors over a period of 5 months; and (3) a large store of lymphocytes from another individual. The latter was assayed in every experiment and served as an internal standard to which results could be normalized. In comparison with uncorrected values, the normalized results for the 14 samples from the single individual showed a reduction in the spread of data while those for the 18 different donors were unchanged. An analysis of variance was carried out on a larger data set of 38 measurements which included repeat assays on several of the samples (two samples from the multiply-sampled individual and five samples from other donors were assayed twice). In comparison with the uncorrected values, the normalized results showed a reduction in experimental variability such that the coefficient of variation (CV) for surviving fraction at 4 Gy for the multiple samples from a single individual decreased from 41 to 19%. In contrast, there was little change in the variation between 18 individuals with CVs of 56 and 62%, respectively, for uncorrected and normalized results. These data suggest that the use of an internal standard for the determination of the intrinsic radiosensitivity of individuals using peripheral blood lymphocytes should aid the development and evaluation of predictive tests for the radiotherapy of cancer.