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Background: Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age.Methods: We used the Prospective Family Cohort Study of 14 657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk models when using the alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were 2-sided.Results: Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff < .001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or older, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA.Conclusions: Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years. [ABSTRACT FROM AUTHOR]

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%-56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models. [ABSTRACT FROM AUTHOR]

There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17 917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7 years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR = 0.68, 95% CI = 0.32 to 1.47, HR = 0.94, 95% CI = 0.70 to 1.26, and HR = 1.10, 95% CI = 0.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Having a family history of breast cancer, particularly if it involves early-onset disease, is a risk factor for breast cancer, but little is known about specific causes of this association. Consequently, we studied mothers, sisters, and aunts of an age-stratified sample of 1567 unselected case patients diagnosed with breast cancer before age 60 years, recruited to a population-based, case-controlfamily study, in which case patients, control subjects, and their relatives were administered the same questionnaire. Methods: Extensive BRCA1 and BRCA2 mutation testing was carried out for 788 case patients diagnosed before age 40 years, including manual sequencing of DNA from 72 patients with two or more affected relatives. Standardized morbidity ratios, age-specific cumulative risks, and hazard ratios were calculated for groupings of relatives. Results: Cumulative risks of breast cancer to age 50 years in the sisters, mothers, and aunts of the case patients, respectively, were 6, 3, and 2 times the population risk if the case patient was younger than age 40 years at diagnosis but were considerably lower if the case patient was older at diagnosis. When relatives of the case patients with a BRCA1 or BRCA2 mutation were excluded, these risks fell by, at most, 20%. Sisters and aunts, but not mothers, who had an additional first-degree relative with breast cancer were at increased risk, and the risk was greater when that relative was younger at diagnosis. Hazard ratios were 10.7 (95% confidence interval [CI] = 4.2 to 26.8) for sisters and 4.2 (95% CI = 2.2 to 8.1) for aunts, if the relative was aged 40 years at diagnosis. Fewer than one-third of the excess of breast cancers in relatives of case patients diagnosed before age 40 years that are attributed to familial factors are BRCA1- or BRCA2-related. Conclusion: Mutations in genes other than BRCA1 and BRCA2 may be associated with a high risk of breast cancer, especially in young women. [ABSTRACT FROM AUTHOR]

Background: We conducted a population-based, case-control-family study to determine whether androgen receptor (AR) exon 1 polymorphic CAG repeat length (CAGn) was a risk factor for early-onset breast cancer in the Australian population.Methods: Case subjects under 40 years of age at diagnosis of a first primary breast cancer and age-matched control subjects were interviewed to assess family history and other risk factors. AR CAGn length was determined for 368 case subjects and 284 control subjects. Distributions in the two groups were compared by linear and logistic regression, allowing adjustment for measured risk factors. All statistical tests were two-tailed.Results: When analyzed as either a continuous or a dichotomous variable, there was no association between CAG, length and breast cancer risk, before or after adjustment for risk factors. Mean (95% confidence interval [CI]) CAGn lengths were 22.0 (21.8-22.2) for case subjects and 22.0 (21.7-22.3) for control subjects (P = .9). The frequency (95% CI) of alleles with 22 or more CAGn repeats was 0.531 (0.494-0.568) for case subjects and 0.507 (0.465-0.549) for control subjects (P = .4). After adjustment, the average effect on log OR (odds ratio) per allele was 0.16 (95% CI = -0.03 to 0.40; P = .2), and the effect of any allele was equivalent to an OR of 1.40 (95% CI = 0.94-2.09; P = .1). Stratification by family history also failed to reveal any association. Similar results were obtained when alleles were defined by other cutoff points.Conclusion: We found no evidence for an association between AR exon 1 CAGn length and breast cancer risk in women under the age of 40, despite having 80% power to detect modest effects. [ABSTRACT FROM AUTHOR]