inherent to this lymphoma and associated with the chemotherapy that was also given to many of these patients.

In summary, the absolute risk transport model has greater support for lung cancer than for stomach or liver cancer. Mechanistic considerations suggest that the correct model may be intermediate between relative and absolute risk.

Breast Cancer

Breast cancer is the most common cancer and one of the leading causes of death from cancer among women worldwide, with nearly 1,000,000 new cases per year. Known risk factors for breast cancer include reproductive factors, postmenopausal increased weight, and history of proliferative benign breast disease (IARC 2003). Differences in cancer incidence between U.S. and Japanese populations have been attributed to the tumor promotion effects of hormonal factors (Moolgavkar and others 1980).

In addition, a strong genetic contribution to the risk of spontaneous breast cancer has been shown by the increased cancer incidence among women with a family history of breast cancer. A number of genes involved in DNA damage response pathways, including BRCA1, BRCA2, and less certainly ATM, have been found to confer genetic susceptibility to breast cancer. Alterations in the activity of ATM, BRCA1, and BRCA2 proteins may have far-reaching consequences in the control of genetic stability and the risk of tumor development. The presence of sequence variants that alter either the expression or the function of these genes could therefore influence gene-environment interactions and enhance the increased breast cancer risk in women following radiation exposure (see Chapter 3).

There is no study published on BRCA1 or BRCA2 mutation frequency in the Japanese population. However, since the prevalence of these mutations in relatively large studies of breast and breast-ovarian cancer in Japanese families is similar to that in Europe and North America, it is likely that BRCA1 and BRCA2 mutation frequencies will be the same in Japanese and Caucasians. In Caucasians, the frequency of BRCA1 was estimated to be 0.051% (95% CI 0.021, 0.125) and of BRCA2 0.068% (95% CI 0.033, 0.141; Antoniou and others 2002). Thus, slightly more than one individual in 1000 is a carrier of the BRCA1 or BRCA2 mutation. For ATM there is no information about the frequency of heterozygotes in the Japanese population. However, for ATM and other possible breast cancer genes, as a first approximation it is assumed that there are not major differences in gene frequencies among populations in Japan and Europe or North America.

Thus, in the absence of more detailed data on mutation and polymorphism frequencies in Japan and the United States, the main differences in breast cancer incidence between these two countries are judged to relate to reproductive history and, implicitly, to hormonal factors that would be expected to act as tumor promoters. The above considerations would therefore suggest that the preferred transportation model for breast cancer should be based on a multiplicative model.

The female breast is one of the few cancer sites for which extensive epidemiologic data on predominantly Caucasian populations are available, and this makes it possible to base risk estimates directly on Caucasian data, avoiding the need to transport risks. Nevertheless, it is useful to evaluate what these data tell as about appropriate transportation models.

Land and colleagues (1980) conducted parallel analyses of cancer incidence data in Japanese A-bomb survivors, Massachusetts tuberculosis fluoroscopy patients, and New York women treated with radiation for mastitis, and found that absolute risks were comparable for the three cohorts whereas relative risks were much larger in the Japanese cohort. This was recently confirmed in a pooled analysis of breast cancer incidence in several cohorts by Preston and coworkers (2002a). In this study, models that were similar in form could be used to describe breast cancer incidence in A-bomb survivors and in U.S. women (Massachusetts fluoroscopy patients and the Rochester infant thymus irradiation cohort). The overall ERR/Gy was about three times as large in the Japanese cohort, whereas the EAR/Gy was similar for the LSS and the U.S. cohorts. However, since fluoroscopy exposure is protracted and involves lower-energy photons than A-bomb exposure, these differences in exposures might confound the comparison. Also, in a pooled analysis of breast cancer mortality in Canadian fluoroscopy patients and A-bomb survivors, neither the ERRs nor the EARs were found to differ significantly between the cohorts (Howe and McLaughlin 1996), although the ERR for the combined LSS women was nearly four times that for non-Nova Scotia Canadian women. Little and Boice (1999) and Brenner (1999) provide additional discussion of these issues with a commentary by Ullrich (1999).

In a case-control study of breast cancer among A-bomb survivors, Land and colleagues (1994a) evaluated the interaction of several risk factors for breast cancer with radiation and found that the relationship was better described by a multiplicative model than an additive one. This, together with the etiological and mechanistic considerations above, would seem to favor relative risk transport, in contradiction to the higher ERR/Gy observed in A-bomb survivors and noted in the preceding paragraph; these observations, however, might have come about because of other differences between the Japanese and U.S. cohorts.

In summary, mechanistic considerations and some epidemiologic data support relative risk transport. However, direct use of data on predominantly Caucasian populations results in estimates that are comparable to those based on A-bomb survivors on an absolute risk scale, but not on a relative risk scale.



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