Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers

It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case–control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20–1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99–1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14–1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03–1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79–1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.     

Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer

BACKGROUND: BRCA1 and BRCA2 are the two major susceptibility genes involved in hereditary breast cancer. This study was undertaken to provide reliable population-based estimates of genetic influence and to characterize the nature and prevalence of BRCA1 and BRCA2 germline mutations in early-onset breast cancer. METHODS: In a series comprising all women diagnosed with breast cancer under the age of 41 years in southern Sweden during 1990 through 1995 (n = 262), family history of cancer was evaluated in 95% (n = 250) of the case subjects and germline mutations in BRCA1 and BRCA2 were analyzed in 89% (n = 234). All statistical tests were two-sided. RESULTS: A total of 97 case subjects had at least one first- or second-degree relative with breast or ovarian cancer; 34 (14%; 95% confidence interval [CI] = 9.6% to 18%) cases had at least two first- or second-degree relatives, 22 (8.8%; 95%CI = 5.3% to 12%) had one first-degree relative, and 41 (16%; 95% CI = 12% to 21%) had one second-degree relative with either cancer. If two females affected with breast or ovarian cancer who were related through an unaffected male were also defined as first-degree relatives, then a higher number of case subjects, 120 (48%; 95% CI = 42% to 54%), had at least one first-degree or second-degree relative with breast or ovarian cancer. Sixteen (6.8%; 95% CI = 4.0% to 11%) BRCA1 mutation carriers and five (2.1%; 95% CI = 0.70% to 4.9%) BRCA2 mutation carriers were identified. Among case subjects with one first- or more than one first- or second-degree relative with breast or ovarian cancer, BRCA mutations were more frequent (P<.001) than among the case subjects without this degree of family history. BRCA mutations were also statistically significantly more common among women with bilateral breast cancer than among women with unilateral breast cancer (P =.002). BRCA mutations were more common among younger case subjects than among older ones (P =.0027). CONCLUSIONS: Almost half (48%) of women in southern Sweden with early-onset breast cancer have some family history of breast or ovarian cancer, and 9.0% of early-onset breast cancer cases are associated with a germline mutation in BRCA1 or BRCA2. Mutation carriers were more prevalent among young women, women with at least one first- or second-degree relative with breast or ovarian cancer, and women with bilateral breast cancer.     

BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50.

BACKGROUND: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. METHODS: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. RESULTS: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. CONCLUSIONS: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.     

Long-term prognosis of early-onset breast cancer in a population-based cohort with a known BRCA1/2 mutation status

All women in the South Sweden Health Care Region with breast cancer diagnosed aged less than 41 during the period between 1990 and 1995 were contacted in 1996 and offered germline mutation analysis of the BRCA1 and BRCA2 genes. Mutation carriers (n = 20) were compared with noncarriers (n = 201) for overall survival (OS) and risk of contralateral breast cancer (CBC). Mutation carriers were younger at diagnosis and more likely to have ER-negative, PgR-negative and grade III tumors. Median follow-up was 19 years. The 5-, 10-, 15-, and 20-year OS were 60, 45, 39, and 39 % for mutation carriers and 82, 70, 59, and 53 % for noncarriers, respectively (5-year log-rank P = 0.013; 10-year P = 0.008; 15-year P = 0.020; and 20-year P = 0.046). In univariable analysis, there was a trend for an inferior OS for mutation carriers (HR 1.8; 95 % CI 1.0–3.3). When stratified for use of (neo)adjuvant chemotherapy, an inferior OS was significant only for the subgroup of patients who did not receive chemotherapy (HR 3.0; 95 % CI 1.2–7.7). In multivarible analysis, BRCA1/2 mutation status was a significant predictor of OS when adjusting for tumor stage, age, and use of chemotherapy, but not when ER status was also included in the model. The 15-year cumulative risk of CBC was 53 % for mutation carriers and 10 % for noncarriers (HR 5.9; 95 % CI 1.9–18.6); among the noncarriers the risks were 5, 22, and 30 % for patients without close relatives having breast cancer, with second-degree relatives having breast cancer, and with firstdegree relatives with breast cancer, respectively. In conclusion, the poor prognosis of young BRCA1/2 mutation carriers with breast cancer is mainly explained by the prevalent occurrence of negative prognostic factors rather than mutation status per se, and can to at least some extent be abrogated by the use of chemotherapy.     

Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study

Breast cancers arising in women with and without a germline mutation in the BRCA1 or BRCA2 gene display different histological features, which suggests unique mechanisms of molecular pathogenesis: We used a molecular pathological analysis to define the genetic abnormalities relevant to these specific pathogeneses. Tumor material was studied from 40 women with breast cancer diagnosed before 40 years of age, sampled from a population-based study and stratified by BRCA1 and BRCA2 germline mutation status. Cases were not selected for family history or ethnic origin, and none were known to be genetically related. Thus, germline mutation itself is likely to impact on the molecular pathogenesis of these tumors, with no substantial influence due to modifying genetic or environmental factors. Breast cancers occurring in BRCA1 mutation carriers had significantly higher levels of p53 expression, including the preinvasive (carcinoma in situ) stage of disease, compared with cancers occurring in BRCA2 mutation carriers or women with no detectable germline mutation. These cancers also had a higher proliferation rate as measured by Ki-67 antibody. Expression of the prognostic factors c-erbB-2, cyclin D1, and estrogen receptor was significantly less common in BRCA1 mutation carriers. Lower levels of cyclin D1 were also found in cancers from BRCA2 mutation carriers compared with non-mutation carriers. Direct p53 mutation analysis revealed mutations in 18% of all of the early-onset breast cancers within the study and included rare insertion and deletional mutations in cancers from BRCA1 mutation carriers. Our data indicate that a BRCA1 breast cancer phenotype may be recognized by an exceptionally high proliferation rate and early and frequent p53 overexpression but infrequent selection for overexpression of several other prognostic factor proteins known to be involved in breast oncogenesis. In contrast, breast cancers arising in BRCA2 mutation carriers have a more heterogeneous phenotypic profile.     

BRCA mutation testing in determining breast cancer therapy

BRCA mutation-associated breast cancer differs from sporadic breast cancer with regard to future cancer risks and sensitivity to systemic therapies. Now that rapid genetic testing for BRCA1 and BRCA2 mutations is available at the time of breast cancer diagnosis, BRCA mutation status can be considered when making treatment and prevention decisions for BRCA mutation carriers with breast cancer. This article reviews surgical options for management of affected BRCA mutation carriers with emphasis on the risks of ipsilateral recurrence and contralateral breast cancer. The roles of breast-conserving surgery, prophylactic mastectomy, and oophorectomy are reviewed. In addition, the sensitivity of BRCA mutation-associated breast cancer to endocrine therapy, platinum chemotherapy, and poly (ADP-ribose) polymerase inhibitors is reviewed.     

Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort and review

Purpose The debate concerning poorer survival for patients with breast cancer (BC) carrying a BRCA1 germline mutation is unresolved, and requires additional data from population-based studies. Patients and methods We followed 232 women with invasive BC under age 46, ascertained prospectively through a French population-based BC registry and tested for BRCA1/2 mutations (median follow-up: 82 months). We compared tumour characteristics and survival rates between 21 BRCA1/2 deleterious mutation carriers and 211 non-carriers. Results As compared to sporadic tumours, BRCA1/2 tumours showed higher grade (P = 0.02), fewer ductal carcinoma in situ (P = 0.02), more frequent medullary histology (P = 0.02), more frequent negative oestrogen and progesterone receptors (P = 0.001 each). At 5 years, BC-specific survival, metastasis-free survival, ipsilateral recurrence-free survival and contralateral BC-free survival rates for BRCA1/2 mutation carriers were 95.0%, 94.7%, 100% and 90.0% respectively, compared with 89.6%, 78.2%, 88.8% and 94.4% respectively, for non-carriers (not significant). Rates for women carrying only a BRCA1 mutation were 93.3%, 93.3%, 100%, 86.7%, respectively. 76% of BRCA1/2 carriers received chemotherapy. Conclusion Despite unfavourable tumour features, we found no evidence for poorer short-term survival in BRCA1 mutation carriers compared to non-carriers in this prospective population-based cohort. The high rate of BRCA1 carriers who received chemotherapy for their BC should question the positive impact of this treatment, as suggested by preclinical studies showing increased chemosensitivity of BRCA1-associated tumours.     

Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations.

BACKGROUND: Recent oral contraceptive use has been associated with a small increase in breast cancer risk and a substantial decrease in ovarian cancer risk. The effects on risks for women with germ line mutations in BRCA1 or BRCA2 are unclear.METHODS: Subjects were population-based samples of Caucasian women that comprised 1,156 incident cases of invasive breast cancer diagnosed before age 40 (including 47 BRCA1 and 36 BRCA2 mutation carriers) and 815 controls from the San Francisco Bay area, California, Ontario, Canada, and Melbourne and Sydney, Australia. Relative risks by carrier status were estimated using unconditional logistic regression, comparing oral contraceptive use in case groups defined by mutation status with that in controls.RESULTS: After adjustment for potential confounders, oral contraceptive use for at least 12 months was associated with decreased breast cancer risk for BRCA1 mutation carriers [odds ratio (OR), 0.22; 95% confidence interval (CI), 0.10-0.49; P < 0.001], but not for BRCA2 mutation carriers (OR, 1.02; 95% CI, 0.34-3.09) or noncarriers (OR, 0.93; 95% CI, 0.69-1.24). First use during or before 1975 was associated with increased risk for noncarriers (OR, 1.52 per year of use before 1976; 95% CI, 1.22-1.91; P < 0.001).CONCLUSIONS: There was no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for mutation carriers, and there may be a reduced risk for BRCA1 mutation carriers. Because current formulations of oral contraceptives may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, they should not be contraindicated for a woman with a germ line mutation in BRCA1 or BRCA2.     

BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark.

PURPOSE: To evaluate the prevalence of BRCA1 and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark. METHODS: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze the BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors. RESULTS: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations in Denmark. We identified several differences between mutation carriers and noncarriers: mutation carriers were diagnosed at a significantly early age (median, 49 and 61 years, respectively; P = 0.0001); the frequency of BRCA1 mutation carriers was 23% for women diagnosed <40 years, 15% for 40 to 49 years, 4% for 50 to 59 years, and 2% for > or =60 years (P = 0.00002); ovarian cancer in carriers was diagnosed at a later stage (P = 0.002) and tumors were of poorer grade (P = 0.0001); and first-degree relatives of mutation carriers had greater relative risks of both ovarian cancer [10.6 (95% confidence interval, 4.2-26.6); P < 0.0001] and breast cancer <60 years [8.7 (95% confidence interval, 3.0-25.0); P < 0.0001]. CONCLUSION: These data may have a significant effect on risk assessment and clinical management of individuals from Denmark who are predisposed to ovarian cancer because they carry a BRCA1 or BRCA2 mutation.     

Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation

Genetic testing for mutations in BRCA1 and BRCA2 is available in Canada for women with a significant family history of breast cancer. For the majority of tested women, a BRCA1 or BRCA2 mutation is not found, and counselling regarding breast cancer risk is based on the review of the pedigree. In this prospective study, we estimate breast cancer risks in women with a family history of breast cancer and for whom the proband tested negative for a mutation in BRCA1 or BRCA2. Families with two or more breast cancers under the age of 50 years, or with three cases of breast cancer at any age, and who tested negative for a BRCA1 or BRCA2 mutation were identified. Follow-up information on cancer status was collected on all first-degree relatives of breast cancer cases. The standardised incidence ratios (SIRs) for breast cancer were calculated by dividing the observed numbers of breast cancer by the expected numbers of breast cancers, based on the rates in the provincial cancer registries. A total of 1492 women from 365 families were included in the analyses. The 1492 first-degree relatives of breast cancer cases contributed 9109 person-years of follow-up. Sixty-five women developed breast cancer, compared to 15.2 expected number (SIR=4.3). The SIR was highest for women under the age of 40 (SIR=14.9) years and decreased with increasing age. However, the absolute risk was higher for women between the age of 50 and 70 (1% per year) years than for women between 30 and 50 (0.4% per year) years of age. There was no elevated risk for ovarian, colon or any other form of cancer. Women with a significant family history of breast cancer (ie, two or more breast cancers under the age of 50 years, or three or more breast cancers at any age), but who test negative for BRCA mutations have approximately a four-fold risk of breast cancer. Women in these families may be candidates for tamoxifen chemoprevention and/or intensified breast screening with an MRI.     

Early oral contraceptive use as a prognostic factor in breast cancer

The survival of 193 premenopausal breast cancer patients was investigated in relation to their history of early use of oral contraceptives. The women were born in 1939 or later and diagnosed in the southern health care region of Sweden. Women, who had started their oral contraceptive use (OC-use) before 20 years of age had a significantly lower survival rate as compared with those who had never used OC and late users (p = 0.02 and = 0.04 respectively, generalized Wilcoxon test). For women who started OC-use between 20 to 25 years of age, a tendency for a shorter survival was seen in comparison with women who had never used OC (p = 0.18). For all patients simultaneously, the relative risk adjusted for age at diagnosis increased for earlier OC-start. When only stages II and III were considered in a stratified multivariate model, a significantly elevated risk was seen for early users of OC irrespective of age or of adjuvant treatment given. The estrogen and progesterone receptor concentrations of the primary tumor were significantly lower among early users (p = 0.001 and p = 0.05 respectively).     

The role of BRCA mutation testing in determining breast cancer therapy

Landmark discoveries in the field of breast cancer research include the identification of germline BRCA mutations as a cause of hereditary disease, and the use of gene-expression profiling to identify distinct subtypes of breast cancer. These findings, coupled with the availability of rapid germline testing, make it possible to identify a BRCA mutation carrier contemporaneous with a diagnosis of breast cancer. For the first time, testing for a germline mutation that predisposes to cancer has the potential to influence the immediate surgical, radiotherapeutic, and drug treatment choices of an individual with a new diagnosis of breast cancer. In this Review, we examine the implications of moving germline BRCA mutation testing from highly specialized family cancer clinics to mainstream settings.     

Characteristics of BRCA1 mutations in a population-based case series of breast and ovarian cancer

Breast and ovarian cancers account for approximately 210000 newly diagnosed cases per year. More than half a million American women are estimated to be carriers of a breast cancer susceptibility gene. The purpose of this study was to assess the association of characteristics such as, age at diagnosis, race/ethnicity and family history of cancer with inherited BRCA1 mutations in a population-based sample of breast and ovarian cancer cases. No selection was made by race, age at diagnosis or positive family history of breast or ovarian cancer. The population under study was all breast cancer cases diagnosed in Orange County, CA, during the 1-year period beginning 1 March 1994 and all ovarian cancer cases diagnosed in Orange County during the 2-year period beginning 1 March 1994. This report focuses on the first consecutively ascertained 802 participating probands enrolled in the study, of which 9 were male breast cancer probands, 673 were female breast cancer probands and 120 were ovarian cancer probands. We observed 11 BRCA1 mutations or 1.6% (95% CI: 0.8-2.9) among the 673 female breast cancer probands and 4 BRCA1 mutations or 3.3% (95% CI: 0.8-8. 3) among the 120 ovarian cancer probands. No BRCA1 mutations were identified among the 98 non-white breast and ovarian cancer probands. The prevalence of BRCA1 mutations in non-Hispanic-white breast cancer cases below the age of 50 years was 2%. Positive family history of breast or ovarian cancers was significantly associated with BRCA1 mutation status among breast cancer probands. Similarly, positive family history of breast or ovarian cancer was significantly associated with BRCA1 mutation status among the ovarian cancer probands. In summary, we present results on the prevalence of BRCA1 mutations in a significantly larger sample of population-based breast and ovarian cancer cases than previously reported. The results indicate that, using a conservative approach to targeted genotyping of BRCA1, the frequency of mutations was consistent with those reported using similar methods of population-based case ascertainment.     

Cancer incidence in first-degree relatives of a population-based set of cases of early-onset breast cancer

Reliable determination of familial risks for cancer is important for clinical counselling, cancer prevention and understanding cancer aetiology. Family-based gene identification efforts may be targeted if the risks are well characterised and the mode of inheritance is identified. Early-onset breast cancer in a family member is a risk indicator for cancer among first-degree relatives; however, the familial risk pattern has not been assessed fully in population-based incidence studies. We estimated the risks for cancers of the breast, ovary and other sites among the first-degree relatives of 8868 patients in whom breast cancer was diagnosed before they reached the age of 50 years (diagnosed during the period 1943-1999). Population registers and parish records were used to identify 31,235 first-degree relatives, who were followed up to 31 December 2002 for occurrence of cancer by linkage to the Danish Cancer Registry. The observed incidence rates were compared with national rates adjusted for age, sex and calendar period. Overall, 39% of the 674 cases of breast cancer and 43% of the 143 cases of ovarian cancer among relatives were associated with a diagnosis of early-onset breast cancer in a family member. Among relatives under 50 years of age, the proportions were 56% and 58%, respectively, and among relatives 50 years or above the proportions were approximately 30% and 10%. In addition, a slightly but significantly increased risk for cancer of the cervix uteri was observed among relatives, and among those under 50 years of age, we found significantly increased risks for cancers of the colon and gall-bladder. In conclusion, the excess risk for breast cancer in first-degree relatives is large and remains sizable in the subgroup of female relatives aged 50 years or older, and that mutations in BRCA1/2 seem to explain only half of breast cancer cases attributable to family history.     

Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group

Estimates of the contribution of BRCA1 and BRCA2 to breast cancer incidence in outbred populations have been based on studies that are either small or have selected for cases diagnosed at an early age. Only one of these has reported an estimate of the breast cancer risk associated with a mutation in these genes, and there is no published ovarian cancer risk estimate derived from a population-based case series. We screened a population-based series of breast cancer cases diagnosed before the age of 55 for mutations in BRCA1 and BRCA2. Pedigree information from the mutation carriers was used to estimate penetrance and the proportion of familial risk of breast cancer due to BRCA1 and BRCA2. We identified eight (0.7%) BRCA1 and 16 (1.3%) BRCA2 mutation carriers in 1220 breast cancer cases (actual sample size 1435 adjusted for 15% polymerase chain reaction failure rate). Mutation prevalence was substantially higher in cases diagnosed before 35 years-of-age and with increasing number of relatives affected with breast or ovarian cancer. However, most mutation carriers were diagnosed in the older age groups, and a minority reported a first-degree relative with breast cancer. Breast cancer penetrance by age 80 was estimated to be 48% (95% CI 7-82%) for BRCA1 mutation carriers and 74% (7-94%) for BRCA2 mutation carriers. Ovarian cancer penetrance for BRCA1 and BRCA2 combined was 22% (6-65%) by age 80. 17% of the familial risk of breast cancer was attributable to BRCA1 and BRCA2. At birth, the estimated prevalence of BRCA1 mutation carriers was 0.07% or 0.09% depending on the penetrance function used for the calculation. For BRCA2, the birth prevalence estimates were 0.14% and 0.22%. Mutations in the genes BRCA1 and BRCA2 are rare in the population and account for a small fraction of all breast cancer in the UK. They account for less than one fifth of the familial risk of breast cancer. Eligibility criteria for BRCA1 and BRCA2 mutation testing based on family history and age of onset will identify only a small proportion of mutation carriers.     

Cancer risk in Jewish BRCA1 and BRCA2 mutation carriers: effects of oral contraceptive use and parental origin of mutation

BRCA1 and BRCA2 germline mutations substantially increase breast and ovarian cancer risk, yet penetrance is incomplete. The effects of oral contraceptives (OC) on breast cancer risk in mutation carriers are unclear, and the putative effect of parental origin of mutation on cancer risk has not been reported. Data on OC use and parental origin of the mutation were obtained at counseling from 888 BRCA1 (n = 638) or BRCA2 (n = 250) Jewish Israeli mutation carriers who were counseled and genotyped in a single medical center. Overall, 403 (45.4%) of participants had breast cancer (age at diagnosis 49.65 ± 12.2 years), 112 (12.6%) ovarian cancer (age at diagnosis 56.8 ± 10.8 years) and the rest (n = 373−42%) were asymptomatic carriers (age at counseling 40.7 ± 10.6 years). Of study participants, 472 (53.15%) ever used OC, and 298 used OC for at least 5 years. In 129 the mutation originated on the paternal side as judged by direct testing or obligate carriership and in 460 the mutation was maternally inherited. Multivariate logistic regression analysis, and stratifying for birth year, age at menarche, breast feeding, and number of births, showed that ever use of OC (Hazards Ratio-HR = 1.84 95% CI 1.465–2.314, P = 0.001) and paternal compared with maternal origin of mutation (OR = 1.55 95% CI 1.14–2.12, P = 0.006) were significantly associated with breast cancer and an earlier age at breast cancer diagnosis. The authors conclude that OC use and paternal origin of mutation affect breast cancer penetrance in Jewish BRCA1 and BRCA2 mutation carriers.     

The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation

Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan–Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5 %, compared to a survival of 88.6 % for women who did not become pregnant (adjusted hazard ratio = 0.76; 95 % CI 0.31–1.91; p = 0.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.     

BRCA1/BRCA2 mutation status and clinical-pathologic features of 108 male breast cancer cases from Tuscany: a population-based study in central Italy

Background Male breast cancer (MBC) is a rare and scarcely investigated disease. The strongest genetic risk factor for MBC is represented by inherited BRCA2 mutations, whereas the association between MBC and BRCA1 mutations is less clear. MBC appears to be biologically similar to breast cancer in females, however the phenotypic characteristics of BRCA1/2-related MBCs are not yet well elucidated. Objective To investigate the genetic and phenotypic characteristics of MBC in a large and well-characterized population-based series of 108 MBCs from Tuscany (Central Italy) and to evaluate associations between BRCA1/BRCA2 mutation status and clinical-pathological features including breast/ovarian cancer first-degree family history, tumor histology and grade, proliferative activity, estrogen/progesterone receptors (ER/PR) and epidermal growth factor receptor 2 (HER2) expression. Results BRCA1/BRCA2 mutations were identified in ten MBCs, in particular, two cases (1.9%) carried BRCA1 and eight cases (7.4%) carried BRCA2 mutations. The same BRCA1 mutation (3347delAG) was detected in two unrelated MBC cases. Three novel BRCA2 pathogenic mutations were found. Statistically significant associations emerged between BRCA2-related tumors and absence of PR expression (P = 0.008), HER2 over-expression (P = 0.002) and high tumor grade (P = 0.005). Conclusions Here, we (i) reported that in our population about 9% of MBC cases are accounted for by BRCA1/BRCA2 mutations; (ii) enlarged the BRCA2 mutational spectrum and (iii) characterized a specific phenotype associated with BRCA2-related MBCs suggestive of aggressive behavior. Overall, our results may have important implications on clinical management for this rare disease.