The authors propose a novel approach to evaluate the effects of risk factors on disease risks in carriers of high-penetrance alleles in disease susceptibility genes. Most studies to date have utilised data collected on carriers identified through ongoing genetic testing programs. The advantage of this approach is that it allows relatively large numbers of affected and unaffected carriers to be identified rapidly. However, genetic testing is targeted at individuals with a strong family history of disease, so that the selection of carriers is not random with respect to disease status. Risk factors are often analysed by standard cohort analysis methods, but these can be biased in retrospective studies if subjects are selected on the basis of phenotype. To overcome this problem, a weighted cohort approach is proposed, under which individuals are weighted according to certain sampling probabilities in order to mimic a true cohort. The method is illustrated by analyses of data from the International BRCA1/2 Carrier Cohort Study (IBCCS). Simulations demonstrate that the method gives rate ratio estimates that are close to unbiased provided that the absolute disease risks are well estimated. The power to detect associations is, however, reduced compared with an unweighted approach.

The clinical outcome of contralateral prophylactic mastectomy (CPM) in women with a BRCA1 or BRCA2 mutation and a personal history of invasive breast cancer is unknown. We identified a cohort of 148 female BRCA1 or BRCA2 mutation carriers (115 and 33, respectively) who previously were treated for unilateral invasive breast cancer stages I -IIIa. In all, 79 women underwent a CPM, while the other women remained under intensive surveillance. The mean follow-up was 3.5 years and started at the time of CPM or at the date of mutation testing, whichever came last, that is, on average 5 years after diagnosis of the first breast cancer. One woman developed an invasive contralateral primary breast cancer after CPM, whereas six were observed in the surveillance group (Po0.001). Contralateral prophylactic mastectomy reduced the risk of contralateral breast cancer by 91%, independent of the effect of bilateral prophylactic oophorectomy (BPO). At 5 years follow-up, overall survival was 94% for the CPM group vs 77% for the surveillance group (P ¼ 0.03), but this was unexpectedly mostly due to higher mortality related with first breast cancer and ovarian cancer in the surveillance group. After adjustment for BPO in a multivariate Cox analysis, the CPM effect on overall survival was no longer significant. Our data show that CPM markedly reduces the risk of contralateral breast cancer among BRCA1 or BRCA2 mutation carriers with a history of breast cancer. Longer follow-up is needed to study the impact of CPM on contralateral breast cancer-specific survival. The choice for CPM is highly correlated with that for BPO, while only BPO leads to a significant improvement in overall survival so far. Women identified as carriers of a mutation in one of the breast and ovarian cancer-susceptibility genes BRCA1 or BRCA2 have strongly elevated risks of developing breast or ovarian cancer (Ford et al, 1998). A recent meta-analysis (Antoniou et al, 2003) including 22 studies, revealed an average cumulative risk of 65% for breast cancer and 39% for ovarian cancer in BRCA1 mutation carriers by age 70 years. The corresponding estimates for women with a mutation in BRCA2 were 45 and 11%. Once diagnosed with breast cancer, these women are also at high risk of developing breast cancer in the contralateral breast. Early reports of The Breast Cancer Linkage Consortium estimated a contralateral breast cancer cumulative risk of 50 -60% at age 70 years in BRCA1 or BRCA2 mutation carriers (Easton et al, 1995; The Breast Cancer Linkage Consortium, 1999). Later studies estimated even higher incidences of contralateral breast cancer within the first 5 years of follow-up after the primary breast cancer: 12 -33% among BRCA1 or BRCA2 mutation carriers (2.4 -6.5% per year) (Robson et al, 1998;Verhoog et al, 1998Verhoog et al, , 1999) as compared to a 0.4 -1% per year for breast cancer patients in general (Fisher et al, 1984).Owing to the elevated risks and fear of contralateral breast cancer, some women opt for contralateral prophylactic mastectomy (CPM). No stu...

CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.