Contralateral Second Breast Cancers: Prediction and Prevention

Long-term survival after a breast cancer diagnosis has increased markedly in the last decade: 15-year relative survival in the United States is now 75% (1), up from 58% in 2001. This increase is due in part to earlier detection but also to improved treatment options (2,3). So it is highly appropriate that increasing attention is being paid to the issue of breast cancer survivorship and, in particular, the issue of second breast cancers. Several long-term studies suggest that contralateral second breast cancer rates range from 10% to 15% at 15 years after treatment and are even higher for still longerterm survivors (4,5). The risk of a breast cancer survivor developing a second breast cancer is much higher than the risk of a comparable healthy woman developing a first breast cancer. For example, a healthy 55-year-old woman has about a 2.5% chance of developing invasive cancer in a given breast over the next 15 years, whereas a 55-year-old breast cancer survivor has a 10%–15% chance of developing invasive cancer in the contralateral breast over the next 15 years. Only a small component of this disturbingly large risk of a second breast cancer is treatment related: If anything, some chemotherapy regimens may reduce the rate of second breast cancers (6), and the comparatively low and inhomogeneous dose of scattered or leakage radiation to the contralateral breast during radiotherapy (7) results in only a small increase in the risk of contralateral breast cancer (5,8–10). These considerations imply that women with breast cancer are prone to develop a second breast cancer. Lifestyle and reproductive factors (11), as well as genetic factors (12), are each presumably major players in the etiology of second breast cancers, as they are in the etiology of primary breast cancers. Thus, there has been much interest in trying to identify genes that are associated with second breast cancers. Not surprisingly, the same genes that have been linked to increased susceptibility to primary breast cancer have been the most studied with regard to susceptibility to second cancers. For example, Graeser et al. (13) investigated the risk of contralateral second breast cancer in BRCA1 and BRCA2 mutation carriers and found that women with these mutations were more likely to develop a contralateral second breast cancer compared with breast cancer survivors without these mutations. Likewise, the clinical signifi cance of mutations in the ATM gene with respect to the risk of a