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Mammographic dense area (MDA) is an established predictor of future breast cancer risk. Recent studies have found that risk prediction might be improved by redefining MDA in effect at higher‐than‐conventional intensity thresholds. We assessed whether such higher‐intensity MDA measures gave stronger prediction of subsequent contralateral breast cancer (CBC) risk using the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population‐based CBC case‐control study of ≥1 year survivors of unilateral breast cancer diagnosed between 1990 and 2008. Three measures of MDA for the unaffected contralateral breast were made at the conventional intensity threshold ("Cumulus") and at two sequentially higher‐intensity thresholds ("Altocumulus" and "Cirrocumulus") using the CUMULUS software and mammograms taken up to 3 years prior to the first breast cancer diagnosis. The measures were fitted separately and together in multivariable‐adjusted logistic regression models of CBC (252 CBC cases and 271 unilateral breast cancer controls). The strongest association with CBC was MDA defined using the highest intensity threshold, Cirrocumulus (odds ratio per adjusted SD [OPERA] 1.40, 95% CI 1.13‐1.73); and the weakest association was MDA defined at the conventional threshold, Cumulus (1.32, 95% CI 1.05‐1.66). In a model fitting the three measures together, the association of CBC with Cirrocumulus was unchanged (1.40, 95% CI 0.97‐2.05), and the lower brightness measures did not contribute to the CBC model fit. These results suggest that MDA defined at a high‐intensity threshold is a better predictor of CBC risk and has the potential to improve CBC risk stratification beyond conventional MDA measures. [ABSTRACT FROM AUTHOR]

Breast cancer survivors have a high risk of a second primary contralateral breast cancer (CBC), but there are few studies of CBC risk in racial/ethnic minority populations. We examined whether the incidence and risk factors for CBC differed by race/ethnicity in the United States. Women with a first invasive Stage I‐IIB breast cancer diagnosis at ages 20‐74 years between 2000 and 2015 in the Surveillance, Epidemiology, and End Results Program (SEER) 18 registries were followed through 2016 for a diagnosis of invasive CBC ≥1 year after the first breast cancer diagnosis. We used cause‐specific Cox proportional hazards models to test the association between race/ethnicity and CBC, adjusting for age, hormone receptor status, radiation therapy, chemotherapy and stage at first diagnosis, and evaluated the impact of contralateral prophylactic mastectomy, socioeconomic status, and insurance status on the association. After a median follow‐up of 5.9 years, 9247 women (2.0%) were diagnosed with CBC. Relative to non‐Hispanic (NH) White women, CBC risk was increased in NH Black women (hazard ratio = 1.44, 95% CI 1.35‐1.54) and Hispanic women (1.11, 95% CI 1.02‐1.20), with the largest differences among women diagnosed at younger ages. Adjustment for contralateral prophylactic mastectomy, socioeconomic status and health insurance did not explain the associations. Therefore, non‐Hispanic Black and Hispanic women have an increased risk of CBC that is not explained by clinical or socioeconomic factors collected in SEER. Large studies of diverse breast cancer survivors with detailed data on treatment delivery and adherence are needed to inform interventions to reduce this disparity. What's new? Breast‐cancer survivors have an increased risk of developing a second primary, contralateral breast cancer (CBC). Does race or ethnicity influence this risk? In this study, the authors found that Black women do have a higher risk than non‐Hispanic white women. However, this increase was not explained by age at diagnosis, receipt of chemotherapy or radiation therapy, socioeconomic or insurance status, or hormone‐receptor status of the first breast cancer. Further studies of diverse cohorts are needed to identify modifiable predictors of CBC, in order to develop interventions to reduce this disparity. [ABSTRACT FROM AUTHOR]

Glioma incidence is highest in non‐Hispanic Whites, and to date, glioma genome‐wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case–Control Study and GliomaSE Case–Control Study previously estimated to have <80% EA, or self‐identify as non‐White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR≥0.4), and ≥15% NAA (AMR≥0.15), genome‐wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10−4; 11p11.12, p = 7.0 × 10−4) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR≥0.4. In addition, we identified a peak at rs1620291 (p = 4.36 × 10−6) in 7q21.3. Among AMR≥0.15, we found an association between increased EA in one region (12q24.21, p = 8.38 × 10−4), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10−4). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies. What's new? Glioma is rare in non‐White populations, and most glioma genome‐wide association studies have included only primarily European ancestry populations. Here, the authors assess whether variation in European ancestry is associated with glioma risk in populations with a combination of European, African and Native American ancestry. Based on African American and Hispanic cases from two large glioma case–control studies, this analysis shows that increased European ancestry in admixed populations may be associated with increased glioma risk. The associations between glioma and two chromosomal regions previously identified in European ancestry populations, and four novel regions, may guide future studies. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age‐at‐diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age‐at‐diagnosis has been explored, genome‐wide association studies (GWAS) have not previously been stratified by age. Potential age‐specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age‐stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta‐analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54–63 = 1.50x10−9, OR54–63 = 1.28, 95%CI54–63 = 1.18–1.39; p64+ = 2.14x10−11, OR64+ = 1.32, 95%CI64+ = 1.21–1.43] and rs11979158 [p54–63 = 6.13x10−8, OR54–63 = 1.35, 95%CI54–63 = 1.21–1.50; p64+ = 2.18x10−10, OR64+ = 1.42, 95%CI64+ = 1.27–1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p18–53 = 9.30 × 10−11, OR18–53 = 1.76, 95%CI18–53 = 1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'‐like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p = 0.0005). Age‐specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with 'secondary glioblastoma.' What's new? The authors performed the first genome‐wide association analysis examining age‐at‐diagnosis and germline risk variants in glioblastoma. They report a higher frequency of germline variants associated with lower grade gliomas (LGG) in the younger cohort (age 18–53), as well as high frequency of LGG‐like somatic variants in The Cancer Genome Atlas Glioblastoma cohort. This could indicate that glioblastoma at a younger age might more often evolve from an LGG (secondary glioblastoma) than at an older age and should be taken into consideration when molecular classification is not available. [ABSTRACT FROM AUTHOR]

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast‐enhanced magnetic resonance imaging (MRI). MRI‐density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of our study was to examine the relationship between BPE and MRI‐density and serum hormone concentrations in postmenopausal women. This was a study of cancer‐free postmenopausal women undergoing contrast‐enhanced breast MRI (N = 118). At the time of MRI all women completed a self‐administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI‐density. Compared to women with “minimal” BPE, those who had “marked” BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, ptrend across all categories = 0.001; 150% increase, ptrend = 0.001; and 158% increase, ptrend = 0.001, respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI‐density and serum E1, E2 and bioavailable E2 were observed. Serum estrogen concentrations were significantly positively associated with BPE. Our study provides further evidence of the hormone‐sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast. [ABSTRACT FROM AUTHOR]

A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer. We examined the tumor archives at Memorial Sloan Kettering Cancer Center for the period 1995-2006 to identify cases of contralateral breast cancer where surgery for both tumors was performed at the Center. We report results from 49 patients successfully analyzed by a targeted massively parallel sequencing assay. Somatic mutations and copy number alterations were defined by state-of-the-art algorithms. Clonal relatedness was evaluated by statistical tests specifically designed for this purpose. We found evidence that the tumors in contralateral breasts were clonally related in three cases (6%) on the basis of matching mutations at codons where somatic mutations are rare. Clinical data and the presence of similar patterns of gene copy number alterations were consistent with metastasis for all three cases. In three additional cases, there was a solitary matching mutation at a common PIK3CA locus. The results suggest that a subset of contralateral breast cancers represent metastases rather than independent primary tumors. Massively parallel sequencing analysis can provide important evidence to clarify the diagnosis. However, given the inter-tumor mutational heterogeneity in breast cancer, sufficiently large gene panels need to be employed to define clonality convincingly in all cases. [ABSTRACT FROM AUTHOR]

Alcohol drinking and, to a lesser extent, cigarette smoking are risk factors for a first primary breast cancer. Information on these behaviours at diagnosis may contribute to risk prediction of contralateral breast cancer (CBC) and they are potentially modifiable. The WECARE Study is a large population-based case-control study of women with breast cancer where cases ( N = 1,521) had asynchronous CBC and controls ( N = 2,212), matched on survival time and other factors, had unilateral breast cancer (UBC). Using multivariable conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CI), we examined the risk of CBC in relation to drinking and smoking history at and following first diagnosis. We adjusted for treatment, disease characteristics and other factors. There was some evidence for an association between CBC risk and current drinking or current smoking at the time of first breast cancer diagnosis, but the increased risk occurred primarily among women exposed to both (RR = 1.62, 95% CI 1.24-2.11). CBC risk was also elevated in women who both smoked and drank alcohol after diagnosis (RR = 1.54, 95% CI 1.18-1.99). In the subset of women with detailed information on amount consumed, smoking an average of ≥10 cigarettes per day following diagnosis was also associated with increased CBC risk (RR = 1.50, 95% CI 1.08-2.08; p-trend = 0.03). Among women with a diagnosis of breast cancer, information on current drinking and smoking could contribute to the prediction of CBC risk. Women who both drink and smoke may represent a group who merit targeted lifestyle intervention to modify their risk of CBC. [ABSTRACT FROM AUTHOR]

Studies examining the relationship between body mass index ( BMI) and risk of contralateral breast cancer ( CBC) have reported mixed findings. We previously showed that obese postmenopausal women with estrogen receptor ( ER)-negative breast cancer have a fivefold higher risk of CBC compared with normal weight women. In the current analysis, we reexamined this relationship in the expanded Women's Environmental Cancer and Radiation Epidemiology ( WECARE) Study, focusing on the impact of menopausal status and ER status of the first breast cancer. The WECARE Study is a population-based case-control study of young women with CBC (cases, N = 1386) and with unilateral breast cancer (controls, N = 2045). Rate ratios ( RR) and 95% confidence intervals ( CI) were calculated to assess the relationship between BMI and risk of CBC stratified by menopausal and ER status. Positive associations with obesity and weight gain were limited to women who became postmenopausal following their first primary breast cancer. Among those with an ER-negative first breast cancer, obesity (vs. normal weight) at first diagnosis was associated with an increased risk of CBC ( RR = 1.9, 95% CI: 1.02, 3.4). Also, weight gain of ≥10 kg after first diagnosis was associated with an almost twofold increased risk of CBC ( RR = 1.9, 95% CI: 0.99, 3.8). These results suggest that women with an ER-negative first primary cancer who are obese at first primary diagnosis or who experience a large weight gain afterward may benefit from heightened surveillance. Future studies are needed to address the impact of weight loss interventions on risk of CBC. [ABSTRACT FROM AUTHOR]

Varicella zoster virus ( VZV) is a neurotropic α-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study ( GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals ( CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted. [ABSTRACT FROM AUTHOR]

With the advent of increasingly detailed molecular portraits of tumor specimens, much attention has been directed toward identifying clinically distinct subtypes of cancer. Subtyping of tumors can also be accomplished with the goal of identifying distinct etiologies. We demonstrate the use of new methodologies to identify genes that distinguish etiologically heterogeneous subtypes of breast cancer using data from the case-control Cancer and Steroid Hormone Study. Tumor specimens were evaluated using a breast cancer expression panel of 196 genes. Using a statistical measure that distinguishes the degree of etiologic heterogeneity in tumor subtypes, each gene is ranked on the basis of its ability to distinguish etiologically distinct subtypes. This is accomplished independently using case-control comparisons and by examining the concordance odds ratios in double primaries. The estrogen receptor gene, and others in this pathway with expression levels that correlated strongly with estrogen receptor levels, demonstrate high degrees of etiologic heterogeneity in both methods. Our results are consistent with a growing literature that confirms the distinct etiologies of breast cancers classified on the basis of estrogen receptor expression levels. This proof-of-principle project demonstrates the viability of new strategies to identify genomic features that distinguish subtypes of cancer from an etiologic perspective. [ABSTRACT FROM AUTHOR]

Cancer has traditionally been studied using the disease site of origin as the organizing framework. However, recent advances in molecular genetics have begun to challenge this taxonomy, as detailed molecular profiling of tumors has led to discoveries of subsets of tumors that have profiles that possess distinct clinical and biological characteristics. This is increasingly leading to research that seeks to investigate whether these subtypes of tumors have distinct etiologies. However, research in this field has been opportunistic and anecdotal, typically involving the comparison of distributions of individual risk factors between tumors classified on the basis of candidate tumor characteristics. The purpose of this article is to place this area of investigation within a more general conceptual and analytic framework, with a view to providing more efficient and practical strategies for designing and analyzing epidemiologic studies to investigate etiologic heterogeneity. We propose a formal definition of etiologic heterogeneity and show how classifications of tumor subtypes with larger etiologic heterogeneities inevitably possess greater disease risk predictability overall. We outline analytic strategies for estimating the degree of etiologic heterogeneity among a set of subtypes and for choosing subtypes that optimize the heterogeneity, and we discuss technical challenges that require further methodologic research. We illustrate the ideas by using a pooled case-control study of breast cancer classified by expression patterns of genes known to define distinct tumor subtypes. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Medical record abstraction (MRA) and self‐report questionnaires are two methods frequently used to ascertain cancer treatment information. Prior studies have shown excellent agreement between MRA and self‐report, but it is unknown how a recall window longer than 3 years may affect this agreement.The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population‐based case‐control study of controls with unilateral breast cancer individually matched to cases with contralateral breast cancer. Participants who were diagnosed with a first primary breast cancer from 1985 to 2008 before the age of 55 years completed a questionnaire that included questions on treatment. First primary breast cancer treatment information was abstracted from the medical record from radiation oncology clinic notes for radiation treatment and from systemic adjuvant treatment reports for hormone therapy and chemotherapy. Agreement between MRA and self‐reported treatment was assessed with the kappa statistic and corresponding 95% confidence intervals (CIs).A total of 2808 participants with MRA and self‐reported chemotherapy treatment information, 2733 participants with MRA and self‐reported hormone therapy information, and 2905 participants with MRA and self‐reported radiation treatment information were identified. The median recall window was 12.5 years (range, 2.8–22.2 years). MRA and self‐reported treatment agreement was excellent across treatment modalities (kappachemo, 98.5; 95% CI, 97.9–99.2; kappahorm, 87.7; 95% CI, 85.9–89.5; kapparad, 97.9; 95% CI, 97.0–98.7). There was no heterogeneity across recall windows (pchemo = .46; phorm = .40; prad = .61).Agreement between self‐reported and MRA primary breast cancer treatment modality information was excellent for young women diagnosed with breast cancer and was maintained even among women whose recall window was more than 20 years after diagnosis. [ABSTRACT FROM AUTHOR]