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To the Editor: Women who are carriers of single mutations in the ataxia-telangiectasia (A-T) gene have been shown to have an increased risk of breast cancer.¹ It has been estimated that 8% to 10% of all patients with breast cancer carry an A-T mutation.¹ Since patients who have homozygous or compound heterozygous A-T mutations can experience devastating necrosis of normal tissues if they receive conventional doses of radiation therapy (RT) for lymphoid tumors, patients who have single mutations would theoretically also be vulnerable to excess damage from RT.² However, excessive toxicity has not been observed among such patients who were treated with RT for cancer.³ In fact, it is possible that because tumor cells grow more rapidly than normal cells, RT may be a particularly effective cancer treatment for patients with single A-T mutations. We examined the effects of adjuvant RT on the clinical outcomes of such patients.

Methods
We identified 43 carriers of single A-T mutations with stage I or II breast cancer among female blood relatives of patients with clinically confirmed A-T in the United States and Canada in our continuing study of these families.¹ All diagnoses of breast cancer were made after 1969 and all were pathologically confirmed. Pathological and clinical information including TNM stage, treatment, and outcomes were abstracted from medical records. Recurrence was defined as the first local, regional, or distant recurrence, or the occurrence of a second primary cancer in the contralateral breast, whichever occurred first. Relative risks were estimated using the Cox regression model. The age and year of diagnosis, and other clinical and pathological features of the patients, were compared using the Wilcoxon-Mann-Whitney test, the ² test, or the Fisher exact test, where appropriate. Cumulative survival probabilities were compared using the exact log-rank test (Proc-StatXact version 4.02, Cytel Software Corp, Cambridge, Mass). All other statistical analyses were performed using SAS version 8.0 (SAS Institute Inc, Cary, NC).

Results
The majority of patients (29/43) were treated with mastectomy and other forms of adjuvant therapies, but no RT. Fourteen additional patients received RT in conjunction with surgery. After a median follow-up of 72 months, recurrences and deaths occurred disproportionately in patients who had not received adjuvant RT (Table 1). Patients who received adjuvant RT had a significantly lower relative risk (RR) of recurrence (P = .02 by the exact log-rank test; RR, 0.1 by Cox regression; 95% confidence interval, 0.02-1.0). The only recurrence and related death associated with RT occurred in the only patient treated with cobalt therapy, which is no longer commonly used in the United States. We found no excess of contralateral breast cancer, second primary cancer at other sites, or heart disease among women who received RT. Excessive radiation damage to skin or underlying structures was also absent. Age, year, stage at diagnosis, histological types, grade, nodal status, and the size of the tumors were not significantly different between patients who did or did not receive adjuvant RT. Adjustment for use of other adjuvant therapies, chemotherapy, or tamoxifen, had no significant effect on the results of the survival analysis.

View this table: [in this window] [in a new window] Table. Clinical Outcomes of Women With Single A-T Mutations and Stage I or II Breast Cancer*

Comment
Our results suggest that, contrary to the experience with patients who are homozygous for an A-T mutation or who carry compound heterozygous mutations, adjuvant RT may be differentially beneficial to carriers of single A-T mutations with early stage breast cancer. Such benefit cannot be explained in this sample by other factors such as tumor size, nodal status, or adjuvant chemotherapy. Moreover, the substantial reduction of recurrence risks in carriers of single A-T mutations in our study was much greater than that observed in the general population, in which only a 15% to 30% improvement in disease-free survival has been found with postmastectomy RT.⁴ It is possible that, due to their radiosensitivity,⁵ tumor cells in carriers of A-T mutations are more susceptible to cell killing by ionizing radiation than are tumor cells in noncarriers. Risks of acute or long-term adverse events, if any, were apparently too small to be detected in the current sample. This could be due to the fact that, in a radiosensitive host, tumor cells growing at abnormally rapid rates demonstrate much greater sensitivity to RT than do normal cells.

It is important to confirm the current finding and to obtain more precise relative risk estimates. If women with single A-T mutations were consistently found to benefit differentially from adjuvant RT, a significant number of deaths from breast cancer could be prevented or delayed.

AUTHOR INFORMATION
Financial Disclosure: Dr Swift has applied for a patent for a method using detected A-T mutations to determine whether a woman has an elevated risk of breast cancer. New York Medical College has submitted a patent on a related method for which Drs Swift and Su are coinventors.

Acknowledgment: We wish to thank Ruby Massey for sample and data collection, Ronnie Gorman Swift, MD, for reviewing previous versions of the manuscript, and the participating families who made the study possible. This work was supported by NIH grant CA 14235.

Yun Su, MD, MPH; Michael Swift, MD
Institute for the Genetic Analysis of Common Diseases
Department of Medicine
New York Medical College
New York, NY

1. Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med. 2000;133:770-778. FREE FULL TEXT 2. Kastan M. Ataxia-telangiectasia—broad implications for a rare disorder. N Engl J Med. 1995;333:662-663. FREE FULL TEXT 3. Weissberg JB, Huang DD, Swift M. Radiosensitivity of normal tissues in ataxia-telangiectasia heterozygotes. Int J Radiat Oncol Biol Phys. 1998;42:1133-1136. FULL TEXT | ISI | PUBMED 4. McNeil C. Postmastectomy radiation: back to center stage? J Natl Cancer Inst. 1999;91:1800-1801. FREE FULL TEXT 5. Paterson MC, MacFarlane SJ, Gentner NE, Smith BP. Cellular hypersensitivity to chronic radiation in cultured fibroblasts from ataxia-telangiectasia heterozygotes. In: Gatti RA, Swift M, eds. Ataxia-Telangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Disease of Childhood. New York, NY: Alan R Liss Inc; 1985:73-87.

Letters Section Editors: Stephen J. Lurie, MD, PhD, Senior Editor; Jody W. Zylke, MD, Contributing Editor.

JAMA. 2001;286:2233-2234.