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Quality Assurance Reference Centre, Unit 9 Kingfisher Way, Silverlink Business Park, Wallsend NE28 9ND, UK
Correspondence: K Faulkner, Quality Assurance Reference Centre, Unit 9 Kingfisher Way, Silverlink Business Park, Wallsend NE28 9ND. E-mail: keith.faulkner{at}nhs.net; keith{at}hepscottpark.com
It has been estimated that between 5% and 10% of breast cancer cases are due to genetic predisposition [1]. Originally, a susceptibility gene for breast and ovarian cancer was located on chromosome 17, and is referred to as BRCA1 (BR = breast, CA = cancer). Subsequently a second gene has been identified (BRCA2) [2]. Under half of the breast cancers due to genetic predisposition arise in BRCA1 and BRCA2 carriers. The risk of developing breast cancer by the age of 70 is estimated to be 65% and 45% for BRCA1 and BRCA2 carriers, respectively [3, 4]. These gene carriers are at higher risk of breast cancer because mutations have occurred in genes that normally protect cells from cancerous changes. It has been suggested that these gene mutations may affect cell proliferation and differentiation during developmental stages characterized by rapid growth [5, 6]. BRCA proteins also affect repair [3].
It is because BRCA1/BRCA2 gene mutation carriers are at increased risk of breast cancer that there is interest in developing screening methods for them. When considering whether to use X-ray mammography as a screening approach it is necessary to consider both the benefits and risks associated with this technique. It is therefore important to establish whether this group of women is at increased risk of cancer induction from the use of ionising radiation and whether X-ray mammography would result in earlier detection of breast cancer, reduce their mortality or improve life expectancy.
The National Institute for Health and Clinical Excellence (NICE) has recently considered breast screening in women with a family history and has issued clinical guidance, "Familial breast cancer: the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care" [7]. NICE recommends the use of MRI surveillance for women with a family history of breast cancer, for different age groups and for different degrees of risk.
There is evidence that exposure of the breast to ionizing radiation can lead to cancer induction [8]. There are two models for the dose–response relationship for cancer induction: the excess absolute risk and the excess relative risk models [9]. In the excess absolute risk model, any increase in breast cancer associated with radiation exposure is independent of the underlying incidence of breast cancer. Breast cancer induction is dependent on radiation dose and varies with age at exposure. In the excess relative risk model, the increase in breast cancer associated with exposure to ionizing radiation is proportional to the underlying incidence of breast cancer. Thus for a subgroup of the population at higher risk of breast cancer, such as BRCA1/BRCA2 gene mutation carriers, the radiation risk factor estimated using the excess relative risk would be higher than that for the general population; however, the benefit/risk ratio would remain constant with this model as both the incidence of breast cancer and the radiation risk factor would increase by the same factor. The Department of Health Breast Cancer Screening Programme Advisory Committee recently reviewed the evidence for the effects of ionizing radiation and concluded that there was no clear-cut preferred model [10].
Women below the age of 50 tend to have denser breast tissue which reduces the ability of X-ray mammography to detect breast cancer. The Breast Cancer Screening Programme Advisory Committee also considered in 2006 that there was no evidence that regular X-ray mammography before the age of 50 for BRCA mutation carriers would be any more effective in reducing mortality than it is for women who are not carriers [10].
Recently two papers have been published that examine the effects of X-rays on the risk of breast cancer for BRCA mutation carriers [4, 11].
Narod et al [11] undertook a case–control study of screening mammography and the risk of breast cancer. They used a questionnaire to survey 1600 cases of breast cancer and 1600 controls without breast cancer, matched for BRCA mutation. Women were asked if they had undergone screening mammography and at what age they underwent their first procedure. They discovered that there was no association between ever having had screening mammography and increased rates of breast cancer in BRCA1 and BRCA2 mutation carriers [11]. Andrieu et al [4] reported a retrospective study of 1601 mainly European women older than 18 years of age who were part of the international BRCA1/BRCA2 carrier cohort study (1187/414 women, respectively). The risk of breast cancer was deduced from an analysis of the results obtained from a questionnaire. Women were initially asked whether or not they had ever had a chest radiograph. Women who had undergone chest radiography were then asked how many examinations they had received before and after the age of 20 (in three categories: one, two to four, or more than four). The results were statistically analysed and the authors reported that exposure to chest X-rays was associated with an increased risk of breast cancer. This risk increased in BRCA1/BRCA2 carriers aged 40 and younger and in women born after 1949, particularly those exposed only before the age of 20 years. The authors conclude that these women have a higher risk of breast cancer induction than the general population, although the magnitude of this is not known because of the effects of bias. This paper was reported in the popular press [12], although, in contrast, the negative finding of Narod et al [11] was not widely reported.
The follow up of BRCA1 and BRCA2 mutation carriers to discover if they are at elevated risk of radiation-induced breast cancer is important for two reasons. First, information on radiation risks for these women is required as part of the assessment of approaches to screening these high-risk women, particularly as the increase in radiation risk to BRCA1/BRCA2 carriers could still be outweighed by the potential benefits to this group from screening. Second, the data obtained from such a study will contribute to the debate regarding which radiation risk model applies to breast cancer induction by ionizing radiation. This follow-up will also contribute to our understanding of genetic susceptibility to cancer in general.
These two papers will clearly start a scientific debate on the effect of ionizing radiation on BRCA1/BRCA2 carriers and whether genetic susceptibility to cancer induction substantially alters the radiation risks. Further studies will be necessary to establish whether X-ray mammography will reduce mortality and if these women are at greater risk from ionising radiation than the general population.
Received for publication October 20, 2006. Revision received February 27, 2007. Accepted for publication February 27, 2007.
References
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