In the entire cohort, 43% (n=848) of carriers had received a diagnosis of breast cancer (table 2; of these 89% (n=755) were confirmed by medical records or linkage with national registries. There was no difference between cases and unaffected carriers in age at diagnosis of breast cancer and age at censoring (mean 39.5 (SD 7.4) and 39.7 (SD 7.4) for cases and unaffected carriers respectively; P=0.601). Women with breast cancer, however, were older at questionnaire completion (49.7 (SD 8.6) v 42.1 (SD 10.5), P<0.001). In general, there were no differences in characteristics between the entire cohort and the subcohort, though the carriers in the subcohort were on average younger at questionnaire completion than those in the entire cohort (41.1 (SD 9.7) v 50.7 (SD 8.8), P<0.001).
Table 2 Characteristics of entire cohort (n=1993) of BRCA1/2 mutation carriers and subcohort (n=1122) of relatively recent cases. Figures are numbers* (percentage) of participants
Radiography was the most common diagnostic procedure; 48% (n=919) of carriers reported ever having had a radiograph while 33% (n=649) had ever had a mammogram (table 3). The median numbers of procedures before age 40 were 2.5 for radiography and 2.4 for mammography. The mean age at first mammogram was 29.5 (SD 5.8). Only a small proportion (<5%) of carriers were ever exposed occupationally, during pregnancy or during breast feeding, to computed tomography or other diagnostic radiation procedures (table 3). None of the carriers had received radiotherapy before the end of follow-up because cancers other than breast cancer were censored. The mean estimated cumulative breast dose from fluoroscopy, radiography, mammography, and computed tomography combined was 0.0140 Gy and ranged from 0.0005 to 0.6130 Gy (interquartile range 0.0020-0.0174 Gy).
Table 3 Exposure to diagnostic radiation in entire cohort (n=1993) and subcohort (n=1122). Figures are numbers* (percentage) of participants
Table 4 shows the results of the analyses on cumulative breast dose and risk of breast cancer . When compared with no exposure, any exposure before age 30 was associated with an increased risk (hazard ratio 1.90, 95% confidence interval 1.20 to 3.00). We also observed a pattern of increasing risk with increasing dose; for a cumulative dose estimate of more than 0.0174 Gy we observed an almost fourfold increased risk of breast cancer (3.84, 1.67 to 8.79). A similar increased risk was observed for exposure before age 20 even after a lower dose of more than 0.0066 Gy (3.16, 1.19 to 8.39). There was no evidence of an increased risk of breast cancer associated with exposure at ages 30-39. The unweighted excess relative risks per Gy for exposures before ages 40 and 30 were 14.76 (P=0.138) and 29.81 (P=0.100).
Table 4 Analyses of estimated cumulative breast dose of diagnostic radiation and risk of breast cancer for subcohort (n=1122) of BRCA1/2 mutation carriers
In the analysis of specific diagnostic procedures we observed a trend of increasing risk of breast cancer with increasing number of radiographs before age 20 (P=0.041 for trend) and a non-significantly increased risk of breast cancer after more than two fluoroscopies before age 20 (hazard ratio 2.01, 95% confidence interval 0.71 to 5.71, P=0.102 for trend) compared with no exposure (table 5 ). Furthermore, there was a non-significantly increased risk of breast cancer after exposure to mammography before age 30 (1.43, 0.85 to 2.40, P=0.040 for trend). We observed an almost twofold risk increase for exposure to more than four radiographs before age 30 (1.83, 0.84 to 4.00, P=0.012 for trend) and for more than four radiographs at ages 30-39 (2.04, 0.85 to 4.90, P=0.101 for trend; data not shown), though this latter category included only six cases. We found no other associations between exposure at ages 30-39 and risk of breast cancer.
Table 5 Analyses on different types of diagnostic procedures by age period and risk of breast cancer for subcohort of 1122 BRCA1/2 mutation carriers
The risk estimates presented in tables 4 and 5 were not materially affected by inclusion of the estimates for each age period (that is, <20, 20-29, and 30-39 years) in the same model or by adjustment for occupational exposure. The results of the procedure specific analyses did not change when we included different exposure types in one model. The results did not differ by country (data not shown). Use of a two or 10 year time lag did not materially affect the results (data not shown).
A strong family history of breast cancer could be an indication for mammographic screening at a young age. We investigated this potential bias away from the null by a subgroup analysis of the cumulative breast dose in carriers who never had a mammogram before age 30 (table 6). This resulted in a similar association compared with the complete model (table 4).
Table 6 Analyses of estimated cumulative breast dose of diagnostic radiation before age 30 and risk of breast cancer for BRCA1/2 mutation carriers who had never undergone mammography
We investigated whether there was a difference in the association between exposure to diagnostic radiation and risk of breast cancer for BRCA1 and BRCA2 carriers. Among BRCA1 carriers, any exposure before age 30 was associated with an increased risk (hazard ratio 2.83, 95% confidence interval 1.59 to 5.04) and the following pattern of dose-response emerged: risks for cumulative dose estimates of <0.0020 Gy, ≥0.0020-0.0065 Gy, ≥0.0066-0.0173 Gy, and ≥0.0174 Gy were 2.46 (1.27 to 4.77), 2.45 (1.02 to 5.90), 2.72 (0.99 to 7.44), and 5.00 (1.96 to 12.74), respectively. For BRCA2 carriers we did not observe an association in the subcohort, but this analysis was limited because of the small number of cases. The P value for interaction between gene and ever versus never exposure before age 30 was 0.631. We also evaluated risk associated with exposure before the age of 30 by attained age below and above the median of 40 to examine the effect of time since exposure. We observed a non-significant higher risk for the younger attained age group compared with the older age group (1.87 (1.13 to 3.10) v 1.64 (1.00 to 2.68), respectively). We observed no effect modification by birth cohort (P>0.05 for interaction; data not shown).
In the entire cohort, a history of any exposure before age 30 was also associated with a significantly increased risk (hazard 1.39, 1.12 to 1.73) but no dose-response emerged (supplementary table B). The association with exposure before age 20 was similar (1.37, 1.11 to 1.68), with some indication of a dose-response. There was no evidence of an increased risk of breast cancer associated with exposure at ages 30-39. The unweighted excess relative risks per Gy for exposures before ages 40 and 30 were 3.90 (P=0.121) and 5.54 (P=0.107). In the analysis of specific diagnostic procedures we found no significant associations between specific procedures and risk of breast cancer (supplementary table C). Based on only a few cases, exposure to computed tomography before age 30 seemed to be associated with increased risk of breast cancer (2.36, 0.71 to 7.88).