Since mammography was first introduced, some concerns have been raised about the potential risks associated with repeated exposure of the breast to ionizing radiation (i.e., X rays). There is no direct evidence of carcinogenic risk from mammography, but there is a hypothetical risk from screening because higher than normal rates of breast cancer have been noted in women with high-level radiation exposures to the breast that occurred from the 1930s to the 1950s as a result of exposure to atomic bomb radiation, multiple chest X rays, and radiation therapy treatments for benign disease or Hodgkin’s lymphoma (Clemons et al., 2000; Feig and Hendrick, 1997).
However, extrapolation of cancer risk from these very high radiation doses, which are unlike any dose a woman might receive from mammography, is difficult, if not impossible (Land, 1980), and most experts agree that the potential benefits of mammography outweigh the risks from radiation (Feig and Hendrick, 1997). Furthermore, technical improvements to mammographic methods over the years have greatly reduced the dose of radiation necessary to obtain quality mammograms.
Nonetheless, the risk of cancer following radiation exposure may not be uniform among all women. For example, a number of rare hereditary syndromes, usually diagnosed in children, are associated with cancer predisposition as well as sensitivity to ionizing radiation. Among these is ataxia telangiectasia (AT), a rare autosomal recessive disorder. It was observed by Swift and coworkers that mothers of children with AT developed breast cancer more frequently than predicted for the general population and that the breast cancers in these individuals were often associated with exposure to diagnostic radiation (Swift et al., 1991).
Because 1 percent of the general population was predicted to be carriers of mutations of the AT gene, there was a concern that a large subset of women would be more susceptible to diagnostic radiographic procedures. Since the identification and cloning of the AT gene, a number of studies have been designed to address this important public health question. Of five studies conducted to date, only one reveals an increased risk for breast cancer in AT heterozygotes (Table 1-6).
TABLE 1-6 Prevalence of AT Mutations in Women with Early Onset or Bilateral Breast Cancer In addition to these studies of early-onset or contralateral breast cancers occurring after radiation therapy, other study designs have thus far failed to reveal a significant role of AT heterozygosity as a risk factor for radiation-associated breast cancer. One of these studies included 52 patients with a second malignancy after receiving therapeutic radiation for Hodgkin’s disease (Nichols et al., 1999). In addition, the adverse effects of radiation were not associated with AT mutations in 57 patients in two studies (Appelby et al., 1997; Shayeghi et al., 1998). Thus, the current literature does not support the theory that mutation of the AT gene is a major risk factor for radiation-induced breast cancer, although additional studies are needed.
Recent studies have also raised concerns regarding the radiation sensitivity of carriers of BRCA mutations. Initial reports showed that mice lacking the protein products of the BRCA1 and BRCA2 genes were extremely sensitive to ionizing radiation (Connor et al., 1997; Sharan et al., 1997). Recently, human tumor cell lines containing one normal copy and one mutated copy of the BRCA1 gene also showed many classical signs of radiation sensitivity (Foray et al., 1999). These results raise the possibility that BRCA mutations in humans may result in deleterious effects (due to the accumulation of radiation-induced mutations) in women exposed to ionizing radiation. However, the doses of gamma radiation used in these cell line experiments (in the range of 1 to 2 grays [Gy]) were far in excess of the doses that normal tissues receive during diagnostic irradiation (in the range of 1 rad, or 0.01 Gy). Further study is needed to address this issue.