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Outcomes
of Adjuvant Radiation Therapy for Breast Cancer in Women With
Ataxia-Telangiectasia Mutations
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
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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 %202233-_files\chi.gif) 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
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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.
Comment
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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.
ISI | MEDLINE
2.
Kastan M. Ataxia-telangiectasia—broad
implications for a rare disorder. N Engl J
Med. 1995;333:662-663. 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. ISI | MEDLINE
4.
McNeil C. Postmastectomy radiation: back to
center stage? J Natl Cancer Inst.
1999;91:1800-1801. 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.
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