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ObjectiveWe developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma.MethodsTo select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data.ResultsAnalyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8years post-enrollment (Hazard Ratio [HR]=2.6, p

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

PurposeCancer screening procedures have brought great benefit to the public's health. However, the science of cancer screening and the evidence arising from research in this field as it is applied to policy is complex and has been difficult to communicate, especially on the national stage. We explore how epidemiologists have contributed to this evidence base and to its translation into policy.MethodsOur essay focuses on breast and lung cancer screening to identify commonalities of experience by epidemiologists across two different cancer sites and describe how epidemiologists interact with evolving scientific and policy environments.ResultsWe describe the roles and challenges that epidemiologists encounter according to the maturity of the data, stakeholders, and the related political context. We also explore the unique position of cancer screening as influenced by the legislative landscape where, due to recent healthcare reform, cancer screening research plays directly into national policy.ConclusionsIn the complex landscape for cancer screening policy, epidemiologists can increase their impact by learning from past experiences, being well prepared and communicating effectively.

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95).Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases. [ABSTRACT FROM AUTHOR]

Approximately 15–30% of all breast cancer tumors are estrogen receptor negative (ER−). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5×10−8) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER− cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3×10−4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a “pleiotropic approach”. [ABSTRACT FROM AUTHOR]

Background Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites. Methods We conducted a prospective case–control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55–74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography–tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided. Results Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol. Conclusions More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer. [ABSTRACT FROM PUBLISHER]

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10?10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10?9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10?9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. [ABSTRACT FROM AUTHOR]

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 × 10−10 adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor–positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 × 10−7) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1. [ABSTRACT FROM AUTHOR]

BRCA mutation carriers are recommended to start mammographic screening for breast cancer as early as age 25-30 years. We used an excess relative risk model (based on a pooled analysis of three cohorts with 7600 subjects who received radiation exposure) to estimate the lifetime risk of radiation-induced breast cancer from five annual mammographic screenings in young (<40 years) BRCA mutation carriers. We then estimated the reduction in breast cancer mortality required to out- weigh the radiation risk. Breast cancer rates for mutation carriers were based on a pooled analysis of 22 pedigree studies with 8139 subjects. For BRCAI mutation carriers, the estimated lifetime risk of radiation-induced breast cancer mortality per 10000 women resulting from annual mammography was 26 (95% confidence interval [li = 14 to 49) for screening at age 25-29 years, 20 (95% Cl = 11 to 39) for screening at age 30-34 years. and 13 (95% Cl = 7 to 23) for screening at age 35-39 years. To outweigh these risks, screening would have to reduce breast cancer mortality by 51% (95% Cl = 27% to 96%) at age 25-29 years, by 12% (95% Cl = 6% to 23%) at age 30-34 years, and by 4% (95% Cl = 2% to 7%) at age 35-39 years; estimates were similar for BRCA2 mutation carriers. If we assume that the mortality reduction from mammography is 15%-25% or less for young women, these results suggest that there would be no net benefit from annual mammographic screening of BRCA mutation carriers at age 25-29 years; the net benefit would be zero or small at age 30-34 years, but there should be some net benefit at age 35 or older. These results depend on a number of assumptions due to the absence of empiric data. The impact of varying these assumptions was therefore examined. [ABSTRACT FROM AUTHOR]

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP (rs1219648) = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci. [ABSTRACT FROM AUTHOR]

Approximately 15–30% of all breast cancer tumors are estrogen receptor negative (ER−). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5×10−8) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER− cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3×10−4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a “pleiotropic approach”.

The article offers information on an updated final recommendation released by the U.S. Preventive Services Task Force for breast cancer screening which confirmed that regular screening mammography is effective in reducing breast cancer mortality for women aged 40 to 74 years. Topics include the general guidance on how a woman or her clinician determine her risk level and the need for analyses that evaluate the benefits and harms when receiving imaging such as tomosynthesis.

Background: Genomewide association studies have identified multiple genetic variants associated with breast cancer. The extent to which these variants add to existing risk-assessment models is unknown. Methods: We used information on traditional risk factors and 10 common genetic variants associated with breast cancer in 5590 case subjects and 5998 control subjects, 50 to 79 years of age, from four U.S. cohort studies and one case–control study from Poland to fit models of the absolute risk of breast cancer. With the use of receiver-operating-characteristic curve analysis, we calculated the area under the curve (AUC) as a measure of discrimination. By definition, random classification of case and control subjects provides an AUC of 50%; perfect classification provides an AUC of 100%. We calculated the fraction of case subjects in quintiles of estimated absolute risk after the addition of genetic variants to the traditional risk model. Results: The AUC for a risk model with age, study and entry year, and four traditional risk factors was 58.0%; with the addition of 10 genetic variants, the AUC was 61.8%. About half the case subjects (47.2%) were in the same quintile of risk as in a model without genetic variants; 32.5% were in a higher quintile, and 20.4% were in a lower quintile. Conclusions: The inclusion of newly discovered genetic factors modestly improved the performance of risk models for breast cancer. The level of predicted breast-cancer risk among most women changed little after the addition of currently available genetic information. N Engl J Med 2010;362:986-93. [ABSTRACT FROM AUTHOR]

An initial analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries shows that the age-adjusted incidence rate of breast cancer in women in the United States fell sharply (by 6.7%) in 2003, as compared with the rate in 2002. Data from 2004 showed a leveling off relative to the 2003 rate, with little additional decrease. Regression analysis showed that the decrease began in mid-2002 and had begun to level off by mid-2003. A comparison of incidence rates in 2001 with those in 2004 (omitting the years in which the incidence was changing) showed that the decrease in annual age-adjusted incidence was 8.6% (95% confidence interval [CI], 6.8 to 10.4). The decrease was evident only in women who were 50 years of age or older and was more evident in cancers that were estrogen-receptor — positive than in those that were estrogen-receptor — negative. The decrease in breast-cancer incidence seems to be temporally related to the first report of the Women's Health Initiative and the ensuing drop in the use of hormone-replacement therapy among postmenopausal women in the United States. The contributions of other causes to the change in incidence seem less likely to have played a major role but have not been excluded. [ABSTRACT FROM AUTHOR]

The article evaluates positive predictive values of CA 125 or transvaginal ultrasonography screening for ovarian cancer according to family history of breast or ovarian cancer. Results indicate that probabilities of abnormal annual CA 125 and transvaginal ultrasonography screens are similar across groups based on family history of breast or ovarian cancer.