Because of their increased risk of breast cancer and possibly an earlier age of onset, high-risk women are offered screening outside the main population screening program. However, the possible benefit of mammography screening could be reduced by the risk of radiation-induced tumors. This article assesses the adverse effects of exposure to low-dose radiation through evaluation of the published literature.
by Dr Marijke C. Jansen-van der Weide, Marcel J.W. Greuter,
Geertruida H. de Bock

Breast cancer is a common malignancy and one of the main causes of death among women in Western countries; the average woman has about a 12% chance of developing breast cancer during her life. The incidence varies over the world and is highest in the USA, followed by Europe [1-3]. Women with affected first or second degree relatives are at increased risk, having a chance of 17% or higher of developing breast cancer [4]. About 20% of the familial aggregation of breast cancer is a result of mutations of the breast cancer susceptibility genes BRCA1 and BRCA2 [5, 6]. BRCA1/2 mutation carriers have a breast cancer risk at 70 years of 57% and 49%, respectively [7].

Because of the high prevalence of breast cancer, several Western countries offer breast cancer screening for all women from around 40 to around 70 years of age, anually or biennially  [8]. In America, the US Preventive Services Task Force recently published new recommendations on breast cancer screening, advising against routine screening mammography in women aged 40 to 49 years. Instead, the USPSTF recommended biennial screening mammography for women aged 50 to 74 years and advised that the decision to be screened before age 50 should be an individual one, taking into account patients’ values regarding specific benefits and possible harm [9]. These recommendations have led to diverse responses indicating that the issue of screening and prevention is a complex one, which will require the attention and efforts of clinicians to provide the best individualized care for their patients [10].

Women with a genetic predisposition for breast cancer in their family are because of their increased risk often offered screening outside the population screening program. This mostly consists of annual mammography screening, frequently combined with MRI and clinical breast examination, from about 25 years of age [11-13]. The breast imaging commission of the American College of Radtiation (ACR) recommends annual mammography and MRI screening for some women at high risk (greater than 20 percent lifetime risk) starting at age 30, but not before age 25 [14].

Radiation risk
The possible benefit of early detection by mammography screening could, however, be reduced by the risk of tumor induction through radiation. Exposure to moderate-to-high doses of radiation has been shown to be an established risk factor for breast cancer incidence and mortality [15, 16]. It is known that high doses of radiation evoke a higher risk of radiation-induced tumors than do low doses. In addition, the risk of radiation-induced breast tumors is inversely related to the age at exposure: exposure at younger ages results in a higher risk of breast cancer than exposure at older ages [15, 17, 18].

Women with a BRCA1 or BRCA2 mutation, or with a strong family history of breast cancer, are screened at younger ages, often more frequently, and in most cases, for a longer period of time. Although women attending mammography screening are exposed to relatively low radiation doses (3 mSv) [19], there are concerns that these low radiation doses, when received at younger age and for a longer period, could increase the risk of breast cancer [20]. Moreover, these women are expected to be more sensitive to radiation tumor induction, because of a defect in one of the breast cancer susceptibility genes [21]. It is Therefore important to know to what extent these women could encounter adverse effects from mammography screening or other diagnostic low-dose radiation.
A systematic search of the literature was thus conducted, addressing the question of how low-dose radiation exposure affects breast cancer risk among high-risk women. The systematic search pinpointed 127 papers, of which seven were selected. The effects of low-dose radiation on breast cancer risk were presented in terms of pooled odds ratios (OR).
 
Included studies
Of these studies, five investigated the adverse effects of exposure to low-dose radiation among mutation carriers. Two studies were conducted among women with a family history of breast cancer. The women, who were either exposed to chest x-rays or mammography screening, received a cumulative radiation dose ranging from about 0.3 to 33 mSv.

Among all high-risk women in the study, the average increased risk of breast cancer due to low-dose radiation exposure was 1.4 times greater than that of high-risk women not exposed to low-dose radiation (95% CI: 0.9- 2.1). When stratified for the total number of exposures, it was shown that exposure to a mean of ≥ 5 X-rays or mammograms doubled the risk compared with no radiation exposure (95% CI: 1.3-3.4) High-risk women exposed before age 20 were 2.5 times more likely to develop breast cancer than young high-risk women not exposed to low-dose radiation (95% CI: 1.9-3.2). When stratified by exposure, breast cancer risk was again increased between age >20 to 40; the pooled OR showed an increased risk of 1.6 (95% CI: 1.0-2.3).

Conclusion
These findings show a relation between exposure to low-dose radiation and an additional increase in breast cancer risk among women with a familial or genetic predisposition. Breast cancer risk is higher in high-risk women exposed before the age of 20 or in women who are frequently exposed (mean ≥5). Women exposed between 20 and 40 years of age are also at increased risk. Therefore, a careful approach is recommended when considering repeated mammography for screening young women, particularly under the age of 30. This is in line with the recommendations from the society of breast imaging and the breast imaging commission of the ACR in America, which recommends annual mammography and MRI screening for BRCA1 and BRCA2 carriers and first-degree relatives of mutation carriers starting at age 30 [14]. For these cases, because mammography screening has a low sensitivity for detecting invasive tumors in younger women, presumably because they have  denser breasts, MRI is promising, as it is unaffected by breast density, ionising radiation is not used, and sensitivity is high. However, exclusive use is limited by the high cost, limited availability, lower sensitivity for ductal carcinoma in situ (DCIS), and lower specificity of MRI [13].

Nevertheless, our results do not undermine the importance of screening among young high-risk women. It is important that, once it is known what risk high-risk women encounter with low-dose radiation such as  mammography screening, attempts are made to balance this risk against the benefit of screening. In this case model studies, in which all risks and benefits are accounted for, could give a good estimate of which screening strategy is the most appropriate for high-risk women. Thus, women at increased risk of breast cancer should discuss the potential benefits and risks of screening mammography with their clinicians in order to arrive at an individualized decision about their optimal screening strategy. They should also be informed about alternative, non-ionizing imaging modalities such as MRI.  

References
1. Dutch Cancer Registry, www.ikcnet.nl, 2006.
2. Jemal A et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 10-30.
3. Loman N et al. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Nat Cancer Inst 2001; 93: 1215-1223.
4. Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 2001; 358:1389-1399.
5. Nathanson KN, Wooster R, Weber BL. Breast cancer genetics: What we know and what we need. Nature Medicine 2001; 7:552-556.
6. Verhoog LC et al. Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families. Eur J Cancer 2001; 37: 2082-2090.
7. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007; 25: 1329-1333.
8. Shapiro S et al. Breast cancer screening programmes in 22 countries: current policies, administration and guidelines. International Breast Cancer Screening Network (IBSN) and the European Network of Pilot Projects for Breast Cancer Screening. Int J Epidemiol 1998; 27: 735-742.
9. U.S. Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Task Force Recommendation Statement. Ann Intern Med 2009; 151: 716-726.
10. Murphy AM. Mammography screening for breast cancer. A view from 2 worlds. JAMA 2010; 303: 166-167.
11. Kriege M et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 2004; 351(5): 427-437.
12. Leach MO et al. The MARIBS study group. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet. 2005; 365(9473): 1769-1778.
13. Warner E et al. Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer. Ann Intern Med 148 (9):
671-679.
14. Lee CH et al. Breast cancer screening with imaging: recommendations from the society of breast imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer. J Am Coll Radiol 2010; 7: 18-27
15. Preston DL et al. Radiation effects on breast cancer risk: a pooled analysis of eight cohorts, Radiat Res 2002; 158: 220-235.
16. Ronckers CM, Erdmann CA, Land CE. Radiation and breast cancer: a review of current evidence. Breast Cancer Res 2005; 7: 21-32.
17. BEIR 7. National Research Council, Committee on the Biological Effects of Ionizing Radiation. Health effects of exposure to low levels of ionizing radiation (BEIR VII Phase 2). National Academy Press, Washington DC, 2006.
18. Thompson DE et al. Cancer incidence in atomic bomb survivors. Part II: Solid tumours, 1958-1987. Radiat Res 1994; 137: S17-67.
19. Van der Helm OM et al. Results of Technical Quality Control in the Dutch Screening Programma (2003-2004), National Expert and Training Centre for Breast Cancer Screening, The Netherlands, (2006).
20. Wakeford R. The cancer epidemiology of radiation. Oncogene 2004; 23:
6404-6438.
21. Broeks A et al. Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study. Breast Cancer Res 2007; 9: 106-114.

The authors
Marijke C. Jansen-van der Weide PhD,
Epidemiologist
& Marcel. JW Greuter, Geertuida H De Bock
Department of Radiology
University Medical Center Groningen, Groningen, The Netherlands
Tel +31 50 3614467; e-mail  m.c.jansen@rad.umcg.nl