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Introduction: Physical activity (PA) promotes significant physical and psychosocial benefits for breast cancer survivors. While evidence exists regarding recommendations for the frequency, duration and intensity of exercise that optimise PA benefits for cancer survivors, the role of the environment in achieving optimal outcomes has yet to be determined. This paper presents a protocol for a clinical trial to evaluate the feasibility of a 3-month nature-based walking programme for breast cancer survivors. Secondary outcomes assessed include the impact of the intervention on fitness, quality of life outcomes, and biomarkers of ageing and inflammation., Methods and Analysis: The trial is a 12-week single-arm pilot study. Twenty female breast cancer survivors will engage in a supervised moderate intensity walking intervention in small groups in a nature reserve for 50 minutes three times per week. Data will be collected at baseline and end of study, and include assessment of inflammatory cytokines and anti-inflammatory myokines (TNF-α, IL-1ß, IL-6, CRP, TGF-ß, IL-10, IL-13), as well as ageing (DNA methylation, ageing genes) biomarkers; surveys (Patient-Reported Outcomes Measurement Information System-29, Functional Assessment of Cancer Therapy-General, Post-Traumatic Growth Inventory); and fitness assessments (6 min Walk Test, Grip-Strength, One Repetition-Maximum Leg Press). Participants will also complete weekly surveys assessing social support and participate in an exit interview. This is an important first step for future research on the influence of exercise environment on cancer survivor PA outcomes., Ethics and Dissemination: This study was approved by the Cedars Sinai Medical Center Institutional Review Board (IIT2020-20). Findings will be disseminated through academic manuscripts, conferences, and community presentations., Trial Registration Number: NCT04896580., Competing Interests: Competing interests: All the authors declare that they have not received any payments, gifts, or services or have any competing financial or non-financial interests or personal relationships and activities that could have appeared to influence the work reported in this paper., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Radiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood., Objective: To determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer., Design, Setting, and Participants: This case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women's Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019., Exposures: Stray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median., Main Outcomes and Measures: The main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency., Results: A total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%., Conclusions and Relevance: This study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.

Background: Metabolomics is emerging as an important tool for detecting differences between diseased and non-diseased individuals. However, prospective studies are limited., Methods: We examined the detectability, reliability, and distribution of metabolites measured in pre-diagnostic plasma samples in a pilot study of women enrolled in the Northern California site of the Breast Cancer Family Registry. The study included 45 cases diagnosed with breast cancer at least one year after the blood draw, and 45 controls. Controls were matched on age (within 5 years), family status, BRCA status, and menopausal status. Duplicate samples were included for reliability assessment. We used a liquid chromatography/gas chromatography mass spectrometer platform to measure metabolites. We calculated intraclass correlations (ICCs) among duplicate samples, and coefficients of variation (CVs) across metabolites., Results: Of the 661 named metabolites detected, 338 (51%) were found in all samples, and 490 (74%) in more than 80% of samples. The median ICC between duplicates was 0.96 (25th - 75th percentile: 0.82-0.99). We observed a greater than 20% case-control difference in 24 metabolites (p < 0.05), although these associations were not significant after adjusting for multiple comparisons., Conclusions: These data show that assays are reproducible for many metabolites, there is a minimal laboratory variation for the same sample, and a large between-person variation. Despite small sample size, differences between cases and controls in some metabolites suggest that a well-powered large-scale study is likely to detect biological meaningful differences to provide a better understanding of breast cancer etiology.

Background: Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown., Methods: Participants were breast cancer cases from the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP's contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates., Results: Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CI = 6.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CI = 1.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history., Conclusions: Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history., Methods: The Women's Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations., Results: Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0-1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1-1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0-9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen., Conclusions: Having a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC.

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest: Dr. David Nickle is a full time employee at Merck & Co. No potential conflicts of interest were disclosed by other authors., (©2016 American Association for Cancer Research.)

Background: Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers., Methods: A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records., Findings: Among women treated with radiation, the mean radiation dose was 1.1 Gy (range = 0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR = 4.5, confidence interval, CI = 3.0-6.8), and also among those treated with RT (RR = 1.2, CI = 1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant., Interpretation: Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harbouring deleterious BRCA1/BRCA2 mutations., Funding: All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178]., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: Women who receive chemotherapy for a first primary breast cancer have been observed to have a reduced risk of contralateral breast cancer (CBC), however, whether the genetic profile of a patient modifies this protective effect is currently not understood. The purpose of this study is to investigate the impact of germline genetic variation in genes coding for drug metabolizing enzymes, transporters, and targets on the association between chemotherapy and risk of CBC., Methods: From the population-based Women's Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 636 Caucasian women with CBC (cases) and 1,224 women with unilateral breast cancer (controls). The association between common chemotherapeutic regimens, CMF and FAC/FEC, and risk of CBC stratified by genotype of 180 single nucleotide polymorphisms in 14 genes selected for their known involvement in metabolism, action, and transport of breast cancer chemotherapeutic agents, were determined using conditional logistic regression., Results: CMF (RR = 0.5, 95 % CI 0.4, 0.7) and FAC/FEC (RR = 0.7, 95 % CI 0.4, 1.0) are associated with lower CBC risk relative to no chemotherapy in multivariable-adjusted models. Here we show that genotype of selected genes involved in the metabolism and uptake of these therapeutic agents does not significantly alter the protective effect of either CMF or FAC/FEC on risk of CBC., Conclusion: The results of this study show that germline genetic variation in selected gene does not significantly alter the protective effect of CMF, FAC, and FEC on risk of CBC.

Purpose: To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations., Patients and Methods: From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history-specific 10-year cumulative absolute risks of CBC were estimated., Results: Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%., Conclusion: Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.

Background: Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation, and altered levels of adipose-derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight, and weight change are associated with CBC risk., Methods: Variants in 20 genes [182 single-nucleotide polymorphisms (SNP)] involved in adipose tissue metabolism, energy balance, insulin resistance, and inflammation, as well as those identified through genome-wide association studies (GWAS) of BMI and type II-diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants [643 cases with CBC and 1,271 controls with unilateral breast cancer (UBC)] in the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression., Results: After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor (ER) status did not alter these findings., Conclusion: Among women with early-onset disease who survive a first breast cancer diagnosis, there was no association between variation in obesity-related genes and risk of CBC., Impact: Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer.

Purpose: Our study examined whether reproductive and hormonal factors before, at the time of, or after radiation treatment for a first primary breast cancer modify the risk of radiation-induced second primary breast cancer., Methods and Materials: The Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1399 women (controls) with unilateral breast cancer. Radiotherapy (RT) records, coupled with anthropomorphic phantom simulations, were used to estimate quadrant-specific radiation dose to the contralateral breast for each patient. Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive factors and risk of CBC., Results: Women who were nulliparous at diagnosis and exposed to ≥1 Gy to the contralateral breast had a greater risk for CBC than did matched unexposed nulliparous women (RR=2.2; 95% CI, 1.2-4.0). No increased risk was seen in RT-exposed parous women (RR=1.1; 95% CI, 0.8-1.4). Women treated with RT who later became pregnant (8 cases and 9 controls) had a greater risk for CBC (RR=6.0; 95% CI, 1.3-28.4) than unexposed women (4 cases and 7 controls) who also became pregnant. The association of radiation with risk of CBC did not vary by number of pregnancies, history of breastfeeding, or menopausal status at the time of first breast cancer diagnosis., Conclusion: Nulliparous women treated with RT were at an increased risk for CBC. Although based on small numbers, women who become pregnant after first diagnosis also seem to be at an increased risk for radiation-induced CBC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers., Methods: We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population., Results: Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97)., Conclusion: Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.

The identification of potentially modifiable risk factors, such as body size, could allow for interventions that could help reduce the burden of contralateral breast cancer (CBC) among breast cancer survivors. Studies examining the relationship between body mass index (BMI) and CBC have yielded mixed results. From the population-based, case-control, Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study, we included 511 women with CBC (cases) and 999 women with unilateral breast cancer (controls) who had never used postmenopausal hormone therapy. Rate ratios (RR) and 95% confidence intervals (CI) were used to assess the relationship between BMI and CBC risk. No associations between BMI at first diagnosis or weight-change between first diagnosis and date of CBC diagnosis (or corresponding date in matched controls) and CBC risk were seen. However, obese (BMI ≥ 30 kg/m(2)) postmenopausal women with estrogen receptor (ER)-negative first primary tumors (n = 12 cases and 9 controls) were at an increased risk of CBC compared with normal weight women (BMI < 25 kg/m(2)) (n = 43 cases and 98 controls) (RR = 5.64 (95% CI 1.76, 18.1)). No association between BMI and CBC risk was seen in premenopausal or postmenopausal women with ER-positive first primaries. Overall, BMI is not associated with CBC risk in this population of young breast cancer survivors. Our finding of an over five-fold higher risk of CBC in a small subgroup of obese postmenopausal women with an ER-negative first primary breast cancer is based on limited numbers and requires confirmation in a larger study.

Ionizing radiation (IR) is a breast carcinogen that induces DNA double-strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a population-based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1 gray (Gy) had an increased risk of CBC compared with unexposed carriers (Rate ratios [RR] = 4.31 [95% confidence intervals [CI] 1.93-9.62]); with an excess relative risk (ERR) per Gy = 2.13 [95% CI 0.61-5.33]). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation had a greater CBC risk than unexposed carriers. This suggests that carriers of this haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer., (© 2011 Wiley Periodicals, Inc.)

Differences in incidence, prognosis, and treatment response suggest gene expression patterns may discern breast cancer subtypes with unique risk factor profiles; however, previous results were based predominantly on older women. In this study, we examined similar relationships in women ≤ 56 years, classified by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 for 890 breast cancer cases and 3,432 frequency-matched population-based controls. Odds ratios (OR) and 95% confidence intervals (CI) for tumor subtypes were calculated using multivariate polytomous regression models. A total of 455 (51.1%) tumors were considered luminal A, 72 (8.1%) luminal B, 117 (13.1%) non-luminal HER-2/neu+, and 246 (27.6%) triple negative. Triple negative tumors were associated with breast feeding duration (per 6 months: OR = 0.76, 95% CI 0.64-0.90). Among premenopausal women, increasing body size was more strongly associated with luminal B (OR = 1.73, 95% CI 1.07-2.77) and triple negative tumors (OR = 1.67, 95% CI 1.22-2.28). A history of benign breast disease was associated only with increased risk of luminal A tumors (OR = 1.89, 95% CI 1.43-2.50). A family history of breast cancer was a risk factor for luminal A tumors (OR = 1.93, 95% CI 1.38-2.70) regardless of age, and triple negative tumors with higher risks for women <45 (OR = 5.02, 95% CI 2.82-8.92; P for age interaction = 0.005). We found that little-to-no breastfeeding and high BMI were associated with increased risk of triple negative breast cancer. That some risk factors differ by molecular subtypes suggests etiologic heterogeneity in breast carcinogenesis among young women.

Current evidence suggests that the genetic risk of breast cancer may be caused primarily by rare variants. However, while classification of protein-truncating mutations as deleterious is relatively straightforward, distinguishing as deleterious or neutral the large number of rare missense variants is a difficult on-going task. In this article, we present one approach to this problem, hierarchical statistical modeling of data observed in a case-control study of contralateral breast cancer (CBC) in which all the participants were genotyped for variants in BRCA1 and BRCA2. Hierarchical modeling permits leverage of information from observed correlations of characteristics of groups of variants with case-control status to infer with greater precision the risks of individual rare variants. A total of 181 distinct rare missense variants were identified among the 705 cases with CBC and the 1,398 controls with unilateral breast cancer. The model identified three bioinformatic hierarchical covariates, align-GV, align-GD, and SIFT scores, each of which was modestly associated with risk. Collectively, the 11 variants that were classified as adverse on the basis of all the three bioinformatic predictors demonstrated a stronger risk signal. This group included five of six missense variants that were classified as deleterious at the outset by conventional criteria. The remaining six variants can be considered as plausibly deleterious, and deserving of further investigation (BRCA1 R866C; BRCA2 G1529R, D2665G, W2626C, E2663V, and R3052W). Hierarchical modeling is a strategy that has promise for interpreting the evidence from future association studies that involve sequencing of known or suspected cancer genes., (© 2011 Wiley-Liss, Inc.)

Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous contralateral breast cancer (CBC, cases) and 1,221 women with unilateral breast cancer (UBC, controls) from the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study. BRCA1 and BRCA2 deleterious mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing, yielding including 88 BRCA1 and 60 BRCA2 deleterious mutation carriers. We also genotyped samples on the Illumina Omni1-Quad platform. We assessed the association between CBC risk and common (minor allele frequency (MAF) > 0.05) single-nucleotide polymorphisms (SNPs) in BRCA1 (n SNPs = 22) and BRCA2 (n SNPs = 30) and haplotypes using conditional logistic regression accounting for BRCA1/BRCA2 mutation status. We found no significant associations between any single-SNPs or haplotypes of BRCA1 or BRCA2 and risk of CBC among all women. When we stratified by BRCA1 and BRCA2 mutation carrier status, we found suggestive evidence that risk estimates for selected SNPs in BRCA1 (rs8176318, rs1060915, and rs16940) and BRCA2 (rs11571686, rs206115, and rs206117) may differ in non-carriers and carriers of deleterious mutations in BRCA1 and BRCA2. One common haplotype on BRCA1 was inversely significantly associated with risk only among non-BRCA1 and BRCA2 carriers. The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status.

Introduction: Genome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status., Methods: We genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods., Results: Multiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant., Conclusions: Our results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor.

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.

Objective: Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers., Methods: The WECARE Study is a population-based multi-center case-control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers., Results: None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65-2.65 and 0.53, 95% CI 0.19-1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers., Conclusion: For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers.

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.

Background: Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women., Methods: The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case-control study nested within a cohort of 52,536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided., Results: Among women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01-0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; > or =1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01-0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; > or =1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; P(trend) = .044)., Conclusions: Women who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers.

Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families., Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing., Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor-negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups., Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking., (Copyright 2010 AACR.)

BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC., ((c) 2010 Wiley-Liss, Inc.)

The potential effects of oral contraceptive (OC) and postmenopausal hormone (PMH) use are not well understood among BRCA1 or BRCA2 (BRCA1/2) deleterious mutation carriers with a history of breast cancer. We investigated the association between OC and PMH use and risk of contralateral breast cancer (CBC) in the WECARE (Women's Environment, Cancer, and Radiation Epidemiology) Study. The WECARE Study is a population-based case-control study of 705 women with asynchronous CBC and 1,398 women with unilateral breast cancer, including 181 BRCA1/2 mutation carriers. Risk-factor information was assessed by telephone interview. Mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing in all participants. Outcomes, treatment, and tumor characteristics were abstracted from medical records. Ever use of OCs was not associated with risk among noncarriers (RR = 0.87; 95% CI = 0.66-1.15) or BRCA2 carriers (RR = 0.82; 95% CI = 0.21-3.13). BRCA1 carriers who used OCs had a nonsignificant greater risk than nonusers (RR = 2.38; 95% CI = 0.72-7.83). Total duration of OC use and at least 5 years of use before age 30 were associated with a nonsignificant increased risk among mutation carriers but not among noncarriers. Few women had ever used PMH and we found no significant associations between lifetime use and CBC risk among carriers and noncarriers. In conclusion, the association between OC/PMH use and risk of CBC does not differ significantly between carriers and noncarriers; however, because carriers have a higher baseline risk of second primaries, even a potential small increase in risk as a result of OC use may be clinically relevant.

Women with primary breast cancer are at increased risk of developing second primary breast cancer. Few studies have evaluated risk factors for the development of asynchronous contralateral breast cancer in women with breast cancer. In the Women's Environmental Cancer and Radiation Epidemiology Study (1985-2001), the roles of alcohol and smoking were examined in 708 women with asynchronous contralateral breast cancer (cases) compared with 1,399 women with unilateral breast cancer (controls). Cases and controls aged less than 55 years at first breast cancer diagnosis were identified from 5 population-based cancer registries in the United States and Denmark. Controls were matched to cases on birth year, diagnosis year, registry region, and race and countermatched on radiation treatment. Risk factor information was collected by telephone interview. Rate ratios and 95% confidence intervals were estimated by using conditional logistic regression. Ever regular drinking was associated with an increased risk of asynchronous contralateral breast cancer (rate ratio = 1.3, 95% confidence interval: 1.0, 1.6), and the risk increased with increasing duration (P = 0.03). Smoking was not related to asynchronous contralateral breast cancer. In this, the largest study of asynchronous contralateral breast cancer to date, alcohol is a risk factor for the disease, as it is for a first primary breast cancer.

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.

Context: The risk of breast cancer in BRCA1 and BRCA2 mutation carriers has been examined in many studies, but relatively little attention has been paid to the degree to which the risk may vary among carriers., Objectives: To determine the extent to which risks for BRCA1 and BRCA2 carriers vary with respect to observable and unobservable characteristics., Design, Setting, and Participants: Probands were identified from a population-based, case-control study (Women's Environmental Cancer and Radiation Epidemiology [WECARE]) of asynchronous contralateral breast cancer conducted during the period of January 2000 to July 2004. Participants previously diagnosed with contralateral breast cancer or unilateral breast cancer were genotyped for mutations in BRCA1 and BRCA2. All participants had their initial breast cancer diagnosed during the period of January 1985 to December 2000, before the age of 55 years., Main Outcome Measure: Incidence of breast cancer in first-degree female relatives of the probands was examined and compared on the basis of proband characteristics and on the basis of variation between families., Results: Among the 1394 participants with unilateral breast cancer, 73 (5.2%) were identified as carriers of deleterious mutations (42 with BRCA1 and 31 with BRCA2). Among the 704 participants with contralateral breast cancer, 108 (15.3%) were identified as carriers of deleterious mutations (67 with BRCA1 and 41 with BRCA2). Among relatives of carriers, risk was significantly associated with younger age at diagnosis in the proband (P = .04), and there was a trend toward higher risk for relatives of contralateral breast cancer vs unilateral breast cancer participants (odds ratio, 1.4 [95% confidence interval, 0.8-2.4]; P = .28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics., Conclusion: There exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations.

Background: Results from randomized trials indicate that treatment with tamoxifen or chemotherapy for primary breast cancer reduces the risk for contralateral breast cancer. However, less is known about how long the risk is reduced and the impact of factors such as age and menopausal status., Methods: The study included 634 women with contralateral breast cancer (case patients) and 1158 women with unilateral breast cancer (control subjects) from the Women's Environment, Cancer and Radiation Epidemiology Study. The women were younger than age 55 when they were first diagnosed with breast cancer during 1985-1999. Rate ratios (RRs) and 95% confidence intervals (CIs) for contralateral breast cancer after treatment with chemotherapy or tamoxifen were assessed by multivariable adjusted conditional logistic regression analyses., Results: Chemotherapy was associated with a lower risk for contralateral breast cancer (RR = 0.57, 95% CI = 0.42 to 0.75) than no chemotherapy. A statistically significant association between chemotherapy and reduced risk for contralateral breast cancer persisted up to 10 years after the first breast cancer diagnosis and was stronger among women who became postmenopausal within 1 year of the first breast cancer diagnosis (RR = 0.28, 95% CI = 0.11 to 0.76). Tamoxifen use was also associated with reduced risk for contralateral breast cancer (RR = 0.66, 95% CI = 0.50 to 0.88) compared with no use, and the association was statistically significant for 5 years after the first diagnosis., Conclusion: The associations between chemotherapy and tamoxifen treatment and reduced risk for contralateral breast cancer appear to continue for 10 and 5 years, respectively, after the initial breast cancer is diagnosed. Ovarian suppression may have a role in the association between chemotherapy and reduced risk for contralateral breast cancer.

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.

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.

We have recently proposed a common mechanistic pathway by which obesity and hypertension lead to increased renal cell cancer risk. Our hypothesis posits lipid peroxidation, which is a principal mechanism in rodent renal carcinogenesis, as an intermediate step that leads to a final common pathway shared by numerous observed risks (including obesity, hypertension, smoking, oophorectomy/hysterectomy, parity, preeclampsia, diabetes, and analgesics) or protective factors (including oral contraceptive use and alcohol) for renal cell cancer [Cancer Causes Control 2002;13:287-93]. During this exercise, we have noticed how certain risk factors for renal cell carcinoma are protective for breast cancer and how certain protective factors for renal cell carcinoma increase risk for breast cancer. Parity and oophorectomy, for example, are positively associated with renal cell carcinoma but are negatively associated with breast cancer. Similarly, obesity and hypertension are positively associated with renal cell carcinoma, but obesity is negatively associated with breast cancer in premenopausal women and hypertension during pregnancy is negatively associated with breast cancer. Furthermore, alcohol intake, negatively associated with renal cell carcinoma, is also positively associated with breast cancer. We propose here the possibility that lipid peroxidation may represent a protective mechanism in breast cancer. Although this runs counter to the conventional view that lipid peroxidation is a process that is harmful and carcinogenic, we present here the chemical and biological rationale, based on epidemiologic and biochemical data, which may deserve further consideration and investigation.

Introduction: Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated., Design: To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses., Conclusions: Our study design improves the potential for detecting gene-environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case-control sets and enhanced our ability to detect radiation-genotype interactions.

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.)