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Originally published as JCO Early Release 10.1200/JCO.2006.05.8586 on June 26 2006 © 2006 American Society of Clinical Oncology.
The Case for Individualized Screening Recommendations for Breast CancerUniversity of Chicago, Chicago, IL Epidemiologic data from atomic bomb survivors (the Life Span Study)1 and populations exposed to medical and occupational irradiation have established that moderate to high doses of radiation are associated with an increased risk of developing several types of cancer, including breast cancer.2-4 The link between breast cancer and lower levels of radiation, such as those in diagnostic chest x-rays, computed tomography5 scans, or mammograms, remains controversial. Studies to date suggest some excess risk even with low levels of radiation exposure, although the magnitude is ill defined.4 Annual mammography is currently the cornerstone of breast cancer surveillance and has been shown to provide a mortality benefit for women over the age of 40 years old.6 Thus, the benefits of mammographic screening outweigh the risks for women of average risk over the age of 40 years old. Epidemiologic studies have consistently described a higher risk of breast cancer for women exposed to atomic and medical irradiation before the age of 20 years old,2-4 and it seems that there is little to no increased risk with exposure after the age of 50 years old.2 It is likely that the impact of radiation-associated breast cancer is small to nonexistent among women who begin standard mammographic screening at 40 years old, but we do not know if this is also the case for women at high genetic risk. In this issue, Andrieu et al7 address the risk of low-dose radiation exposure in high-risk women by assessing exposure to diagnostic chest x-rays among BRCA1 and BRCA2 mutation carriers from the International BRCA1/2 Carrier Cohort Study. Exposure to ionizing radiation was determined through standardized questionnaires asking participants to recall exposure to chest x-rays as far back as childhood. In their analysis, individuals who reported any exposure to chest x-rays were 54% more likely to develop breast cancer compared with individuals without exposure. In addition, they found that the risk was greatest in those mutation carriers who reported more than five chest x-rays (hazard ratio [HR] = 2.69) and in women who reported exposures before the age of 20 years old (HR = 5.21). These associations with dose and age are consistent with a recent update of the Life Span Study1 and a pooled analysis of eight cohorts exposed to a variety of exposures.2 Thus, this study adds to the body of literature suggesting an association between age and cumulative dose in determining breast cancer risk after radiation exposure and specifically addresses these associations in BRCA1 and BRCA2 mutation carriers. The limitations of this report, including the imprecise measurement of radiation exposure and the potential for differential recall among participants, lessen the clinical relevance of the study. Moreover, radiation exposure to breast tissue with a standard chest x-ray is significantly lower than the exposure with mammography. Thus, the data do not address the important clinical question of the risk of breast cancer for women undergoing early mammographic screening. Narod et al8 recently evaluated mammographic exposure among BRCA1 and BRCA2 mutation carriers and found no association between screening mammography and risk of breast cancer (odds ratio = 1.03; 95% CI, 0.85 to 1.25) adjusted for parity, oral contraceptive use, family history of breast cancer, and ethnicity. In their study, the time of radiation exposure was later, with a mean age at first screening mammography of 35 years, but subgroup analysis demonstrated a slightly increased risk of breast cancer diagnosis by age 40 years for women who initiated screening between ages 31 and 40 years. Thus, the debate continues, underscoring the need for prospective studies evaluating the risks of early radiation exposure among individuals at hereditary risk for breast cancer. Scientific advances in molecular biology and genetics have led to individualized medical care. We have learned that breast cancer is a heterogeneous disease, with new targeted therapies, such as trastuzumab, for patients with HER2/neu–amplified breast cancers. Likewise, there is evidence of heterogeneity in drug metabolism, leading to variability in drug efficacy and toxicities. In a similar fashion, there is heterogeneity in cancer risk. A key component of cancer control will be identifying high-risk individuals to initiate cancer prevention interventions that can ultimately reduce overall mortality. There is a strong argument for individualizing cancer surveillance based on individual estimates of cancer risk, such as those currently provided with predictive genetic testing. Such individualized screening has been suggested in the American Cancer Society recommendations for breast cancer screening for high-risk women, emphasizing shared decision making in considering the risks and benefits of available screening technologies.9 The radiation-associated risk of early mammographic exposure will be an important component of this analysis. If confirmed in other studies, we may find that mammography will be limited to specific risk groups or age groups, whereas others will benefit from newer modalities such as breast magnetic resonance imaging (MRI). Although mammographic screening has been shown to decrease breast cancer deaths in the general population of women over 40 years old,6,10-13 the utility in younger women and women at increased risk for breast cancer remains controversial. Studies suggest that mammograms have a lower sensitivity in younger women14,15 and women with a family history of breast cancer.16,17 The few studies that have evaluated mammography in BRCA mutation carriers have reported significantly lower sensitivities, ranging from 25% to 56%, for mammography compared with other high-risk women.15,18-20 In addition, studies have repeatedly noted that interval cancers (cancers detected between two regular screening examinations) are more common among women with a strong family history or a known BRCA1/2 mutation,17,21 and false-negative mammograms are more frequent among BRCA1/2 mutation carriers and women with dense breast tissue.22 This association with BRCA mutations may be a result of different radiographic and pathologic characteristics of BRCA-associated tumors, making them more difficult to detect by mammogram.23-25 Given the decreased sensitivity in young women and mutation carriers, the significant number of interval cancers, and the potential radiation risk highlighted by this study, additional imaging tools to detect early breast cancers in high-risk women must be urgently pursued. There is emerging evidence that breast MRI may be superior to mammography. Since 2000, several large prospective studies evaluating breast MRI for breast cancer surveillance in asymptomatic high-risk women have been published.19,20,26-31 In all of these studies, breast MRI was superior to mammography in detecting early breast cancers, with sensitivities ranging from 77% to 100%19,20,26-31 and the greatest gains in sensitivity among women at the highest risk or with a known BRCA mutation.20,21,31 Although the most recent studies have reported lower sensitivities for MRI alone (77% to 91%)19,21,30,31 than the initial studies reporting sensitivities of up to 100%,22,26,28,29 combination screening with mammography and MRI has been associated with sensitivities of 86% to 96%,21,30,31 and 95% sensitivity has been reported for combined screening with MRI, ultrasound, and mammography.19 Although research to date has not established a mortality benefit with screening programs incorporating breast MRI, studies have reported smaller cancers at diagnosis, fewer node-positive cancers, and fewer interval cancers than external or historical controls.21,30 Thus, it is reasonable to expect that breast MRI may dramatically improve breast cancer screening for high-risk women and ultimately decrease breast cancer mortality. A careful assessment of a patient's individual risk for cancer and the associated risks and benefits of various screening modalities will likely drive the clinical incorporation of this new technology. Despite the excitement surrounding breast MRI, mammography remains the standard screening tool available to women at high risk for breast cancer, and there is currently not enough evidence to replace mammography with breast MRI. In addition, the studies to date have reported the highest sensitivities with the combination of mammography and breast MRI. Thus, future studies are needed to confirm the suggested association between radiation exposure and breast cancer risk and should assess radiation risk across the age spectrum, including specific risks from 20 to 30 years old and 30 to 40 years old, which are prime periods for mammographic screening in BRCA mutation carriers. It has been hypothesized that chemopreventive agents (such as tamoxifen) or hormonal manipulation may be able to mitigate the effect of ionizing radiation,32 and these hypotheses should be investigated in individuals at risk for radiation-induced breast cancer. If confirmed, the findings in this study could have significant practice implications for BRCA mutation carriers and could potentially eliminate mammographic screening as a surveillance method for early detection of breast cancer in young women. Mammograms are already known to be suboptimal in young women and women at high familial or genetic risk. With increasing evidence supporting the high sensitivity of breast MRI for breast cancer screening in high-risk women and with ongoing research using other imaging modalities, surveillance recommendations will likely be individualized in the future. Hopefully, we will have sufficient evidence describing the risks and benefits of mammographic screening at a young age to optimize cancer prevention for individuals at high genetic risk. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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