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Background: Treatment with tamoxifen or chemotherapy reduces the risk of contralateral breast cancer (CBC). However, it is uncertain how long the protection lasts and whether the protective effect is modified by patient, tumor, or treatment characteristics.Methods: The population-based WECARE Study included 1521 cases with CBC and 2212 age- and year of first diagnosis-matched controls with unilateral breast cancer recruited during two phases in the USA, Canada, and Denmark. Women were diagnosed with a first breast cancer before age 55 years during 1985-2008. Abstraction of medical records provided detailed treatment information, while information on risk factors was obtained during telephone interviews. Risk ratios (RRs) and 95 % confidence intervals (CIs) for CBC were obtained from multivariable conditional logistic regression models.Results: Compared with never users of tamoxifen, the RR of CBC was lower for current users of tamoxifen (RR = 0.73; 95 % CI = 0.55-0.97) and for past users within 3 years of last use (RR = 0.73; 95 % CI = 0.53-1.00). There was no evidence of an increased risk of estrogen receptor-negative CBC associated with ever use of tamoxifen or use for 4.5 or more years. Use of chemotherapy (ever versus never use) was associated with a significantly reduced RR of developing CBC 1-4 years (RR = 0.59; 95 % CI = 0.45-0.77) and 5-9 years (RR = 0.73; 95 % CI = 0.56-0.95) after first breast cancer diagnosis. RRs of CBC associated with tamoxifen or with chemotherapy use were independent of age, family history of breast cancer, body mass index and tumor characteristics of the first breast cancer with the exception that the RR of CBC was lower for lobular histology compared with other histologies.Conclusion: Our findings are consistent with previous studies showing that treatment with tamoxifen or chemotherapy is associated with a lower risk of CBC although the risk reduction appears to last for a limited time period after treatment is completed. [ABSTRACT FROM AUTHOR]

Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.

Background: While certain inherited syndromes (e.g. Neurofibromatosis or Li-Fraumeni) are associated with an increased risk of glioma, most familial gliomas are non-syndromic. This study describes the demographic and clinical characteristics of the largest series of non-syndromic glioma families ascertained from 14 centres in the United States (US), Europe and Israel as part of the Gliogene Consortium., Methods: Families with 2 or more verified gliomas were recruited between January 2007 and February 2011. Distributions of demographic characteristics and clinical variables of gliomas in the families were described based on information derived from personal questionnaires., Findings: The study population comprised 841 glioma patients identified in 376 families (9797 individuals). There were more cases of glioma among males, with a male to female ratio of 1.25. In most families (83%), 2 gliomas were reported, with 3 and 4 gliomas in 13% and 3% of the families, respectively. For families with 2 gliomas, 57% were among 1st-degree relatives, and 31.5% among 2nd-degree relatives. Overall, the mean (±standard deviation [SD]) diagnosis age was 49.4 (±18.7) years. In 48% of families with 2 gliomas, at least one was diagnosed at <40y, and in 12% both were diagnosed under 40y of age. Most of these families (76%) had at least one grade IV glioblastoma multiforme (GBM), and in 32% both cases were grade IV gliomas. The most common glioma subtype was GBM (55%), followed by anaplastic astrocytoma (10%) and oligodendroglioma (8%). Individuals with grades I-II were on average 17y younger than those with grades III-IV., Interpretation: Familial glioma cases are similar to sporadic cases in terms of gender distribution, age, morphology and grade. Most familial gliomas appear to comprise clusters of two cases suggesting low penetrance, and that the risk of developing additional gliomas is probably low. These results should be useful in the counselling and clinical management of individuals with a family history of glioma., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutations in BRCA1 and BRCA2, it is critical to determine the effectiveness of standard adjuvant therapies in preventing CBC in mutation carriers. The WECARE study is a matched, case-control study of 708 women with CBC as cases and 1,399 women with unilateral breast cancer (UBC) as controls, including 181 BRCA1/BRCA2 mutation carriers. Interviews and medical record reviews provided detailed information on risk factors and breast cancer therapy. All study participants were screened for BRCA1 and BRCA2 mutations using denaturing high-performance liquid chromatography (DHPLC) to detect genetic variants in the coding and flanking regions of the genes. Conditional logistic regression was used to compare the risk of CBC associated with chemotherapy and tamoxifen in BRCA1/BRCA2 mutation carriers and non-carriers. Chemotherapy was associated with lower CBC risk both in non-carriers (RR = 0.6 [95% CI: 0.5-0.7]) and carriers (RR = 0.5 [95% CI: 0.2-1.0]; P value = 0.04). Tamoxifen was associated with a reduced CBC risk in non-carriers (RR = 0.7 [95% CI: 0.6-1.0]; P value = 0.03). We observed a similar but non-significant reduction associated with tamoxifen in mutation carriers (RR = 0.7 [95% CI: 0.3-1.8]). The tests of heterogeneity comparing carriers to non-carriers did not provide evidence for a difference in the associations with chemotherapy (P value = 0.51) nor with tamoxifen (P value = 0.15). Overall, we did not observe a difference in the relative risk reduction associated with adjuvant treatment between BRCA1/BRCA2 mutation carriers and non-carriers. However, given the higher absolute CBC risk in mutation carriers, the potentially greater impact of adjuvant therapy in reducing CBC risk among mutation carriers should be considered when developing treatment plans for these patients.

Purpose: Women with breast cancer diagnosed early in life comprise a substantial portion of those tested for BRCA1/BRCA2 mutations; however, little information is available on the subsequent risks of contralateral breast cancer in mutation carriers. This study assessed the risk of subsequent contralateral breast cancer associated with carrying a BRCA1 or BRCA2 mutation., Patients and Methods: In this nested case-control study, patients with contralateral breast cancer diagnosed 1 year or more after a first primary breast cancer (n = 705) and controls with unilateral breast cancer (n = 1,398) were ascertained from an underlying population-based cohort of 52,536 women diagnosed with a first invasive breast cancer before age 55 years. Interviews and medical record reviews were used to collect risk factor and treatment histories. All women were tested for BRCA1/BRCA2 mutations. Relative (rate ratios) and absolute (5- and 10-year cumulative) risks of developing contralateral breast cancer following a first invasive breast cancer were computed., Results: Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance., Conclusion: The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.

Purpose: To quantify the risk of second primary breast cancer in the contralateral breast (CB) after radiotherapy (RT) for first breast cancer., Methods and Materials: The study population included participants in the Women's Environmental, Cancer, and Radiation Epidemiology study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were <55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using multivariable-adjusted conditional logistic regression models., Results: Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women <40 years of age who received >1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR = 2.5, 95% CI 1.4-4.5). No excess risk was observed in women >40 years of age. Women <40 years of age with follow-up periods >5 years had a RR of 3.0 (95% CI 1.1-8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI 0.1-3.0)., Conclusions: Women <40 years of age who received a radiation dose >1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent.

Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women's Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). In this study, 708 women with asynchronous CBC served as cases and 1,397 women with unilateral breast cancer served as controls. ATM, a serine-threonine kinase, controls the cellular response to DNA double-strand breaks, and has been implicated in breast cancer risk. Complete mutation screening of the ATM gene in all 2,105 study participants identified 240 distinct sequence variants; only 15 were observed in >1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. In contrast, carriers of common variants had a statistically significant reduction in risk of CBC. Four of these 15 variants were individually associated with a significantly decreased risk of second primary breast cancer [c.1899-55T>G, rate ratio (RR), 0.5; 95% confidence interval (CI), 0.3-0.8; c.3161C>G, RR, 0.5; 95% CI, 0.3-0.9; c.5558A>T, RR, 0.2; 95% CI, 0.1-0.6; c.6348-54T>C RR, 0.2; 95% CI, 0.1-0.8]. These data suggest that some alleles of ATM may exert an antineoplastic effect, perhaps by altering the activity of ATM as an initiator of DNA damage responses or a regulator of p53.

Purpose: To investigate whether oral contraceptive (OC) use and postmenopausal hormones (PMH) are associated with an increased risk of developing asynchronous bilateral breast cancer among women diagnosed with breast cancer younger than 55 years., Patients and Methods: The WECARE (Women's Environment, Cancer, and Radiation Epidemiology) study is a population-based, multicenter, case-control study of 708 women with asynchronous bilateral breast cancer and 1,395 women with unilateral breast cancer. Risk factor information collected during a telephone interview focused on exposures before and after the first breast cancer diagnosis. Treatment and tumor characteristics were abstracted from medical records. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% CIs., Results: OC use before the first breast cancer diagnosis was not associated with risk of asynchronous bilateral breast cancer (RR = 0.88; 95% CI, 0.67 to 1.16). OC use after breast cancer diagnosis was also not significantly associated with risk (RR = 1.56; 95% CI, 0.71 to 3.45). Risk did not increase with longer duration of use or among women who had begun using OCs at a younger age. No evidence of an increased risk of asynchronous bilateral breast cancer was observed with PMH use before (RR = 1.21; 95% CI, 0.90 to 1.61) or after breast cancer diagnosis (RR = 1.10; 95% CI, 0.67 to 1.77). Neither duration nor type of PMH were associated with risk. Age at and time since first breast cancer diagnosis did not substantially affect these results., Conclusion: This study provides no strong evidence that OC or PMH use increases the risk of a second cancer in the contralateral breast.

Background: Women with an initial breast cancer diagnosis are at elevated risk of developing subsequent cancer in the contralateral breast. Studies of reproductive factors and contralateral breast cancer (CBC) have provided inconsistent results., Methods: We employed a case-control study nested within five population-based cancer registries in the United States and Denmark to examine associations between reproductive history and CBC risk. Cases were women with asynchronous CBC who had their first primary invasive breast cancer before age 55 years. Two controls, who had only one primary breast cancer diagnosis, were individually matched to each case on age and year of diagnosis, race, and registry. A total of 694 case-control triplets and 11 case-control pairs were enrolled. Information regarding possible CBC risk factors was obtained via telephone interviews. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% confidence intervals (95% CI) associated with risk factors of interest., Results: Increasing number of full-term pregnancies (FTP) was inversely associated with CBC risk (P trend, 0.001). Women who reported menarche before age 13 years had an increased risk of CBC (RR, 1.26; 95% CI, 1.01-1.58). Age at first FTP, breastfeeding history, and age at menopause were not significantly associated with CBC risk., Conclusions: These results suggest age at menarche and parity, which are established risk factors for first primary breast cancer, are associated with CBC, whereas other reproductive risk factors associated with first primary breast cancer, such as age at first FTP, are less important factors in the development of CBC.

Epidemiologic studies of breast and other cancers are increasingly turning toward large, multi-center designs in order to obtain adequate power to detect low-penetrance susceptibility alleles. The size of such studies often makes it necessary to distribute the genetic screening efforts to multiple sites. Careful standardization of screening methodology and quality control across sites is required for such multi-center screening designs to be efficient. In this report, we illustrate our approach to these challenges in the context of the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study, a multi-center population-based genetic epidemiologic study of women with unilateral and bilateral breast cancer. We provide optimized conditions for screening the ataxia-telangiectasia gene (ATM) for variation by denaturing high-performance liquid chromatography (DHPLC) and describe the results of two independent quality control studies at four international centers employing these conditions. Finally, we report novel mutations in the ATM gene identified both in patients with ataxia-telangiectasia and in patients with unilateral or bilateral breast cancer., (Copyright 2003 Wiley-Liss, Inc.)