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Purpose: To evaluate the long-term risk of subsequent breast cancer and mortality among women diagnosed with carcinoma in situ of the breast. Patients and Methods: Using the population-based Swedish Multi-Generation and Cancer Registers we selected 8,111 women diagnosed with in situ breast cancer between 1980 and 2004. We estimated the relative risks of subsequent ipsi- and contralateral invasive breast cancer or a contalateral in situ expressed as standardized incidence ratios (SIRs), in relation to age, year, time since diagnosis and family history (1st degree relative) for breast cancer. The relative risk of death was expressed as standardized mortality ratio, (SMR). Results: Of 8,111 women identified with first in situ, 859 had a family history for breast cancer. The overall risk of a subsequent invasive breast cancer is over four fold and the risk for contralateral in situ breasts cancer was almost seven fold, compared with the risk in healthy women. Women with a family history had almost a 50% increased risk for a contralateral invasive breast cancer, IRR 1.49 (95% CI 1.06-2.09) compared to women without, but had no increased risk for a contralateral in situ cancer or ipsilateral invasive breast cancer. The risk for subsequent breast cancer decreased over time after diagnosis, but still 15 years after first in situ diagnosis the risk was over three times higher compared to the general population. Women below 40 years at diagnosis had the highest risk for a subsequent breast event, SIR 8.54 (95% CI 6.07-11.67). The overall mortality for women with no second invasive event was the same as for women in the general population, SIR 1.01 (95% CI 0.95-1.08). Women below 50 years at first in situ diagnosis, with a second invasive cancer, had a higher mortality compare to women above 50 years, SIR 8.3 (95% CI 5.38-11.54) and SIR 1.70 (95% CI 1.39-2.06) respectively. Conclusion: The risk for a subsequent invasive breast cancer, as well as mortality was substantially higher in younger women, which should be taken into account when planning their treatment and follow-up. Family history did not increase the risk for a subsequent ipsilateral invasive cancer. [ABSTRACT FROM AUTHOR]

Introduction: Survival after breast cancer has improved substantially over the past decades. As a result, an increasing number of breast cancer survivors is starting or extending their family post-diagnosis. We evaluated mortality risks of offspring from women with a history of breast cancer. Methods: From the Swedish Multi-Generation Register and the Cancer Register we identified all 63,205 children whose mother had ever been diagnosed with invasive breast cancer. For these children, we calculated relative mortality risks as compared to the background population (Standardized Mortality Ratios [SMRs]). We compared SMRs according to the mother's parity status at diagnosis and timing of birth in relation to time of diagnosis, i.e. before (>1 year before), around (between 1 year before and 1 year after) and after (>1 year after) diagnosis. Results: Children born around their mother's breast cancer diagnosis had an increased mortality risk as compared to the background population (SMR 2.70 95% CI [1.64-.44]). This risk was particularly high for first-born children (SMR 11.07 (95% CI [2.09-27.13]), who had an absolute excess risk of 6.4% to die before the age of 5 years. Children born more than one year before or after their mother's breast cancer diagnosis had similar mortality risks as the background population. Conclusion: Children born around their mother's breast cancer diagnosis have significantly increased mortality risks. Offspring of nulliparous women have a particularly high relative mortality risk, suggesting that pregnant breast cancer patients may be keen to keep their first child in spite of potential treatment toxicity. [ABSTRACT FROM AUTHOR]

Clinical guidelines have recommended patients with high-risk breast cancer to extend adjuvant hormone therapy beyond 5 years. However, the prevalence, predictors, and outcomes of extended adjuvant hormone therapy in the real world remain unknown. By linking six Swedish health registries, we prospectively followed 13,168 patients with breast cancer (2005-2020) from their first prescription of tamoxifen or aromatase inhibitors and categorized them as extending or not extending adjuvant hormone therapy. Cox regression analysis was used to investigate whether extended therapy was associated with breast cancer outcomes. Among patients with breast cancer who were recommended to extend adjuvant hormone therapy by the national guidelines, the proportion of women who extended therapy increased 5 folds during the past 10 years, reaching 80.9% during 2018 to 2020. Patients were more likely to extend therapy after completing 5-year adjuvant hormone therapy if they were young [40 vs. ≥65 years: OR, 1.71; 95% confidence interval (CI), 1.13-2.58], had positive lymph nodes (OR, 2.25; 95% CI, 1.85-2.73), had high tumor grade (grade 3 vs. 1: OR, 1.79; 95% CI, 1.34-2.39), received chemotherapy (OR, 5.22; 95% CI, 4.19-6.50), had first-degree relatives who died from breast cancer (OR, 1.84; 95% CI, 1.21-2.81), or had a high income (OR, 1.23; 95% CI, 1.01-1.49). Extended use of adjuvant hormone therapy was statistically significantly associated with improved disease-free survival (HR, 0.72; 95 CI%, 0.55-0.95). This study provides real-world evidence showing the use and improved breast cancer outcomes of extended adjuvant hormone therapy beyond 5 years., Significance: The proportion of patients with breast cancer extending adjuvant hormone therapy beyond 5 years has increased dramatically in recent years, which is associated with improved patient outcomes., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this., Methods: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test., Results: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (P GXE =4.44×10 -6 )., Conclusion: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk., Impact: Our study suggests a limited role of gene-environment interactions in breast cancer risk., Competing Interests: Conflict of interest disclosure statement: The authors declare no potential conflicts of interest.

Background: In recent years, biologically motivated continuous tumor growth models have been introduced for breast cancer screening data. These provide a novel framework from which mammography screening effectiveness can be studied., Methods: We use a newly developed natural history model, which is unique in that it includes a carcinogenesis model for tumor onset, to analyze data from a large Swedish mammography cohort consisting of 65,536 participants, followed for periods of up to 6.5 years. Using patient data on age at diagnosis, tumor size, and mode of detection, as well as screening histories, we estimate distributions of patient's age at onset, (inverse) tumor growth rates, symptomatic detection rates, and screening sensitivities. We also allow the growth rate distribution to depend on the age at onset., Results: We estimate that by the age of 75, 13.4% of women have experienced onset. On the basis of a model that accounts for the role of mammographic density in screening sensitivity, we estimated median tumor doubling times of 167 days for tumors with onset occurring at age 40, and 207 days for tumors with onset occurring at age 60., Conclusions: With breast cancer natural history models and population screening data, we can estimate latent processes of tumor onset, tumor growth, and mammography screening sensitivity. We can also study the relationship between the age at onset and tumor growth rates., Impact: Quantifying the underlying processes of breast cancer progression is important in the era of individualized screening., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype., Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype., Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m 2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking., Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype., Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care., (©2021 American Association for Cancer Research.)

Mammographic features influence breast cancer risk and are used in risk prediction models. Understanding how genetics influence mammographic features is important because the mechanisms through which they are associated with breast cancer are not well known. Here, using mammographic screening history and detailed questionnaire data from 56,820 women from the KARMA prospective cohort study, we investigated the association between a genetic predisposition to breast cancer and mammographic features among women with a family history of breast cancer ( N = 49,674) and a polygenic risk score (PRS, N = 9,365). The heritability of mammographic features such as dense area (MD), microcalcifications, masses, and density change (MDC, cm 2 /year) was estimated using 1,940 sister pairs. Heritability was estimated at 58% [95% confidence interval (CI), 48%-67%) for MD, 23% (2%-45%) for microcalcifications, and 13% (1%-25%)] for masses. The estimated heritability for MDC was essentially null (2%; 95% CI, -8% to 12%). The association between a genetic predisposition to breast cancer (using PRS) and MD and microcalcifications was positive, while for masses this was borderline significant. In addition, for MDC, having a family history of breast cancer was associated with slightly greater MD reduction. In summary, we have confirmed previous findings of heritability in MD, and also established heritability of the number of microcalcifications and masses at baseline. Because these features are associated with breast cancer risk and can improve detecting women at short-term risk of breast cancer, further investigation of common loci associated with mammographic features is warranted to better understand the etiology of breast cancer. SIGNIFICANCE: These findings provide novel data on the heritability of microcalcifications, masses, and density change, which are all associated with breast cancer risk and can indicate women at short-term risk., (©2020 American Association for Cancer Research.)

Background: Endogenous hormones and mammographic density are risk factors for breast cancer. Joint analyses of the two may improve the ability to identify high-risk women., Methods: This study within the KARMA cohort included prediagnostic measures of plasma hormone levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and mammographic density in 629 cases and 1,223 controls, not using menopausal hormones. We evaluated the area under the receiver-operating curve (AUC) for risk of breast cancer by adding DHEA, DHEAS, and mammographic density to the Gail or Tyrer-Cuzick 5-year risk scores or the CAD2Y 2-year risk score., Results: DHEAS and percentage density were independently and positively associated with breast cancer risk ( P = 0.007 and P < 0.001, respectively) for postmenopausal, but not premenopausal, women. No significant association was seen for DHEA. In postmenopausal women, those in the highest tertiles of both DHEAS and density were at greatest risk of breast cancer (OR, 3.5; 95% confidence interval, 1.9-6.3) compared with the lowest tertiles. Adding DHEAS significantly improved the AUC for the Gail (+2.1 units, P = 0.008) and Tyrer-Cuzick (+1.3 units, P = 0.007) risk models. Adding DHEAS to the Gail and Tyrer-Cuzick models already including mammographic density further increased the AUC by 1.2 units ( P = 0.006) and 0.4 units ( P = 0.007), respectively, compared with only including density., Conclusions: DHEAS and mammographic density are independent risk factors for breast cancer and improve risk discrimination for postmenopausal breast cancer., Impact: Combining DHEAS and mammographic density could help identify women at high risk who may benefit from individualized breast cancer screening and/or preventive measures among postmenopausal women., (©2020 American Association for Cancer Research.)

Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes - or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer-specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers ( n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16-2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21-2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (<25%), non- BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12-3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64-0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection. Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329-38. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Subtype heterogeneity for breast cancer risk factors has been suspected, potentially reflecting etiologic differences and implicating risk prediction. However, reports are conflicting regarding the presence of heterogeneity for many exposures. To examine subtype heterogeneity across known breast cancer risk factors, we conducted a case-control analysis of 2,632 breast cancers and 15,945 controls in Sweden. Molecular subtype was predicted from pathology record-derived IHC markers by a classifier trained on PAM50 subtyping. Multinomial logistic regression estimated separate ORs for each subtype by the exposures parity, age at first birth, breastfeeding, menarche, hormone replacement therapy use, somatotype at age 18, benign breast disease, mammographic density, polygenic risk score, family history of breast cancer, and BRCA mutations. We found clear subtype heterogeneity for genetic factors and breastfeeding. Polygenic risk score was associated with all subtypes except for the basal-like ( P heterogeneity < 0.0001). "Never breastfeeding" was associated with increased risk of basal-like subtype [OR 4.17; 95% confidence interval (CI) 1.89-9.21] compared with both nulliparity (reference) and breastfeeding. Breastfeeding was not associated with risk of HER2-overexpressing type, but protective for all other subtypes. The observed heterogeneity in risk of distinct breast cancer subtypes for germline variants supports heterogeneity in etiology and has implications for their use in risk prediction. The association between basal-like subtype and breastfeeding merits more research into potential causal mechanisms and confounders. Cancer Res; 77(13); 3708-17. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls., Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable., Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10 -17 ). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m 2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m 2 ). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10 -4 ). There was evidence of directional pleiotropy (P = 1.5 × 10 -4 ). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10 -4 ), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS., Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI., Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR., Competing Interests: Statement: No potential conflicts of interest were disclosed by the other authors., (©2016 American Association for Cancer Research.)

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.)

Unlabelled: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis., Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)

Background: Family history is an established risk factor for breast cancer. Although some important genetic factors have been identified, the extent to which familial risk can be attributed to genetic factors versus common environment remains unclear., Methods: We estimated the familial concordance and heritability of breast cancer among 21,054 monozygotic and 30,939 dizygotic female twin pairs from the Nordic Twin Study of Cancer, the largest twin study of cancer in the world. We accounted for left-censoring, right-censoring, as well as the competing risk of death., Results: From 1943 through 2010, 3,933 twins were diagnosed with breast cancer. The cumulative lifetime incidence of breast cancer taking competing risk of death into account was 8.1% for both zygosities, although the cumulative risk for twins whose co-twins had breast cancer was 28% among monozygotic and 20% among dizygotic twins. The heritability of liability to breast cancer was 31% [95% confidence interval (CI), 10%-51%] and the common environmental component was 16% (95% CI, 10%-32%). For premenopausal breast cancer these estimates were 27% and 12%, respectively, and for postmenopausal breast cancer 22% and 16%, respectively. The relative contributions of genetic and environmental factors were constant between ages 50 and 96. Our results are compatible with the Peto-Mack hypothesis., Conclusion: Our findings indicate that familial factors explain almost half of the variation in liability to develop breast cancer, and results were similar for pre- and postmenopausal breast cancer, Impact: We estimate heritability of breast cancer, taking until now ignored sources of bias into account., (©2015 American Association for Cancer Research.)

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored., Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium., Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue., Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2., Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk., (©2015 American Association for Cancer Research.)

Background: Increasing evidence shows that some cancers originate in utero. It is hypothesized that elevated exposure to some steroid hormones might increase cancer risk and that hormone transfer between twin fetuses could result in different prenatal exposure to testosterone., Methods: This large-scale prospective twin study compared opposite-sex (OS) and same-sex (SS) twins to test the impact of intrauterine exposures on cancer risk. On the basis of the Danish and Swedish twin and cancer registries, we calculated incidence rate ratios for OS and SS twins, whereas standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated for OS/SS twins compared with the general population., Results: A total of 18,001 cancers were identified during 1943-2009. No significant differences were observed between OS and SS twins, neither for the sex-specific cancers nor for cancer at all sites. All-cause cancer was slightly reduced for OS and SS twins compared with the general population, significant for OS males (SIR, 0.95; 95% CI, 0.92-0.98) and for SS males and females (SIR, 0.97; 95% CI, 0.94-0.99)., Conclusions: Our data suggest that having a male co-twin-which may entail higher exposure to prenatal testosterone-does not increase the risk of sex-specific cancers in OS females. Furthermore, the study supports that twinning per se is not a risk factor of cancer., Impact: Findings are reassuring, as they fail to provide evidence for the hypothesis that endocrine or other difference in the in utero milieu affects the risk of sex-specific cancers., (©2015 American Association for Cancer Research.)

Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10(-5)). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk., (©2015 American Association for Cancer Research.)

Background: Mammographic percent density is an established marker of breast cancer risk. In a study of screen film mammograms, we recently reported a novel feature from the pectoral muscle region to be associated with breast cancer risk independently of area percent density (APD). We now investigate whether our novel feature is associated with risk in a study based on full-field digital mammography (FFDM)., Methods: We carried out a breast cancer risk analysis using a data set of 3,552 healthy controls and 278 cases. We included three image-based measures in our analyses: volumetric percent density (VPD), APD, and the mean intensity of the pectoral muscle (MIP). The datasets comprised different machine vendors and models. In addition, the controls dataset was used to test for the association of our measures against rs10995190, in the ZNF365 gene, a genetic variant known to be associated with mammography density and breast cancer risk., Results: MIP was associated with breast cancer risk [per SD OR, 0.811; 95% confidence interval (CI), 0.707-0.930; P = 0.0028] after adjusting for conventional covariates and VPD. It was also associated with the genetic variant rs10995190 after adjusting for VPD and other covariates (per allele effect = 0.111; 95% CI, 0.053-0.170; P = 1.8 × 10(-4)). Results were similar when adjusting for APD instead of VPD., Conclusion: MIP is a novel mammographic marker, which is associated with breast cancer risk and the genetic variant rs10995190 independently of PD measures., Impact: Inclusion of MIP in risk models should be considered for studies using PD from FFDM., (©2015 American Association for Cancer Research.)

Background: Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age., Methods: To address this question, we undertook the world's largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic (MZ) and 30,054 dizygotic (DZ) same-sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability., Results: The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median, 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability [heritability = 58% (95% confidence interval, 52%-63%)] of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary., Conclusions: Results from the population-based twin cohort indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age., Impact: Findings affect the search for genetic and epigenetic markers and frame prevention efforts., (©2014 American Association for Cancer Research.)

Introduction: Mammographic density is a strong risk factor for breast cancer and an important determinant of screening sensitivity, but its clinical utility is hampered due to the lack of objective and automated measures. We evaluated the performance of a fully automated volumetric method (Volpara)., Methods: A prospective cohort study included 41,102 women attending mammography screening, of whom 206 were diagnosed with breast cancer after a median follow-up of 15.2 months. Percent and absolute dense volumes were estimated from raw digital mammograms. Genotyping was performed in a subset of the cohort (N = 2,122). We examined the agreement by side and view and compared density distributions across different mammography systems. We also studied associations with established density determinants and breast cancer risk., Results: The method showed good agreement by side and view, and distributions of percent and absolute dense volume were similar across mammography systems. Volumetric density was positively associated with nulliparity, age at first birth, hormone use, benign breast disease, and family history of breast cancer, and negatively with age and postmenopausal status. Associations were also observed with rs10995190 in the ZNF365 gene (P < 1.0 × 10(-6)) and breast cancer risk [HR for the highest vs. lowest quartile, 2.93; 95% confidence interval, 1.73-4.96 and 1.63 (1.10-2.42) for percent and absolute dense volume, respectively]., Conclusions: In a high-throughput setting, Volpara performs well and in accordance with the behavior of established density measures., Impact: Automated measurement of volumetric mammographic density is a promising tool for widespread breast cancer risk assessment., (©2014 American Association for Cancer Research.)

Background: Mammographic density is a strong risk factor for breast cancer., Methods: We present a novel approach to enhance area density measures that takes advantage of the relative density of the pectoral muscle that appears in lateral mammographic views. We hypothesized that the grey scale of film mammograms is normalized to volume breast density but not pectoral density and thus pectoral density becomes an independent marker of volumetric density., Results: From analysis of data from a Swedish case-control study (1,286 breast cancer cases and 1,391 control subjects, ages 50-75 years), we found that the mean intensity of the pectoral muscle (MIP) was highly associated with breast cancer risk [per SD: OR = 0.82; 95% confidence interval (CI), 0.75-0.88; P = 6 × 10(-7)] after adjusting for a validated computer-assisted measure of percent density (PD), Cumulus. The area under curve (AUC) changed from 0.600 to 0.618 due to using PD with the pectoral muscle as reference instead of a standard area-based PD measure. We showed that MIP is associated with a genetic variant known to be associated with mammographic density and breast cancer risk, rs10995190, in a subset of women with genetic data. We further replicated the association between MIP and rs10995190 in an additional cohort of 2,655 breast cancer cases (combined P = 0.0002)., Conclusions: MIP is a marker of volumetric density that can be used to complement area PD in mammographic density studies and breast cancer risk assessment., Impact: Inclusion of MIP in risk models should be considered for studies using area PD from analog films., Competing Interests: of Potential Conflicts of Interest No potential conflicts of interest were disclosed., (©2014 American Association for Cancer Research.)

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686)., Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls)., Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors., Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer., Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype., (2012 AACR)

Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures., Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status., Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07)., Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland., Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association., (©2012 AACR)

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways., (©2012 AACR.)

Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of single-nucleotide polymorphisms (SNP) were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case-control status as the outcome. This analysis was repeated using 10 different cutoff points for the most significant density SNPs (1%-10% representing 5,222-50,899 SNPs). Permutation analysis was also conducted across all 10 cutoff points. The association between risk score and breast cancer was significant for all cutoff points from 3% to 10% of top density SNPs, being most significant for the 6% (2-sided P = 0.002) to 10% (P = 0.001) cutoff points (overall permutation P = 0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR = 1.31; 95% confidence interval (CI), 1.08-1.59] compared with women in the bottom 10%. Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants.

Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious., Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium., Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P(trend) = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P(trend) = 0.02)., Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer., Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility., ((c) 2010 AACR.)

Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent.

A family history of non-Hodgkin's lymphoma (NHL) confers increased risk of NHL, but it is unknown whether the excess risk in males and females varies by the sex or kinship of the affected relative. We linked nationwide Swedish registries to identify parents and siblings of NHL patients who developed NHL between January 1, 1961 and December 31, 2002. In males, parental risks were approximately the same from fathers and mothers, whereas sibling risks were higher from brothers [standardized incidence ratio (SIR), 1.8; 95% confidence interval (95% CI), 1.0-2.9] than sisters (SIR, 0.9; 95% CI, 0.2-1.9). In females, parental and sibling risks were higher from same-sex relatives (SIR from mothers, 1.9; 95% CI, 1.2-2.7; SIR from sisters, 6.3; 95% CI, 4.0-9.3) than from opposite-sex relatives (SIR from fathers, 1.2; 95% CI, 0.7-1.9; SIR from brothers, 0.7; 95% CI, 0.2-1.6). These findings did not vary substantially by the age of diagnosis of the offspring. Risk of NHL in offspring was also increased among those with a parent diagnosed with multiple myeloma or leukemia. The relative risk of NHL among those with a parent diagnosed with any hematopoietic cancer was 1.5 (95% CI, 1.4-1.7) and that for having a sibling with any hematopoietic cancer was also 1.5 (95% CI, 1.2-1.9). Our results suggest that part of the familial risk of NHL may be attributable to shared environmental exposures, particularly between same-sex siblings.

Background: Melanoma and squamous cell carcinoma of the skin (SCC) have been previously shown to coaggregate in families. To shed light on the etiology, we estimated the relative contributions of genetic and environmental factors on the occurrence of each disease, in addition to their influence on coaggregation of the two diseases. Because the malignancies are dependent on UV radiation, we did separate analyses for sun-covered and sun-exposed sites., Methods: Our Swedish population-based data included 11 million individuals in 3 million families. We used an extended generalized linear mixed model to estimate the genetic and environmental contribution., Results: In melanoma, the genetic contribution was 18% [95% confidence interval (95% CI), 13-22%] in the all-sites analysis, whereas the family-shared contribution was slightly higher in the sun-covered compared with sun-exposed sites analysis. SCC revealed very similar estimates in all analyses for both the genetic effects estimated to 8% (95% CI, 4-12%) and family-shared environmental factors at 18% (95% CI, 16-19%), respectively. In the coaggregation analysis, genetic and family-shared environmental components were estimated at 47% (95% CI, 43-51%) and 36% (95% CI, 33-39%), respectively., Conclusions: Genetic factors are important in familial aggregation of melanoma and the higher sun-covered compared with sun-exposed site estimate of family-shared environment may convey benefit from cautious sunbathing. In SCC, we observed the highest contribution of family-shared environmental effects in cancer to date, implicating the importance of familial habits. Moreover, we elucidate the potential involvement of genetic variability in the familial coaggregation of melanoma and SCC.

Population attributable faction (PAF) shows the proportion of the disease that could be prevented if the cause could be removed. PAFs for most types of familial cancer have not been determined. We used the Swedish Family-Cancer Database on 10.2 million individuals and 688,537 parental and 116,741 offspring cancers to calculate familial risks, proportions of affected individuals, and familial PAFs for 28 neoplasms among 0-66-year-old offspring. The data were calculated by an exact proband status in the nuclear families. The familial risks for offspring cancer were increased at 23 of 28 sites from the same cancer in only the parent, at 17 sites from a sibling proband and at 12 sites from a parent and sibling proband. The highest PAFs by parent were for prostate (9.01%), breast (3.67%), and colorectal (5.15%) cancer. However, considering that in gender-specific cancers, the familial effect may originate from grandparents, the PAFs for prostate and breast cancer could be multiplied by 2. The PAFs for the sibling history of prostate, breast, and colorectal cancers were 1.55, 2.85, and 1.23% and for the parent and sibling history 0.99, 0.42, and 0.48%, respectively. Because of mutually exclusive proband definition, the PAFs were additive, giving a total PAF of 20.55% for prostate, 10.61% for breast, and 6.87% for colorectal cancer. The present PAF values give an estimate of the heritable single locus or additive effects for cancer in nuclear families. The data show that the familial PAF of prostate cancer was 20.55%, and breast cancer 10.61%, but for most other sites, it was between 1 and 3%.

Propylene oxide (PO), a simple alkylating agent used in the chemical industry, is weakly genotoxic and induces nasal cavity tumors in rodents on inhalation at high air concentrations. DNA adducts, hemoglobin adducts, and sister chromatid exchanges (SCE) were analyzed as biomarkers of exposure in a group of eight PO-exposed workers and eight nonexposed subjects. 1-2-Hydroxypropyladenine (1-HP-adenine) in DNA of WBCs was analyzed using a hypersensitive (32)P-postlabeling assay. HP-valine in hemoglobin was measured using gas chromatography/tandem mass spectrometry. Air measurements indicated PO levels in the range of 1-7 ppm. All three biomarkers showed significantly increased levels in the exposed workers. 1-HP-adenine was recorded in seven of the exposed workers (mean 0.66 mol/10(9) mol nucleotides) but was not detected in any of the control subjects. HP-valine was found in all subjects (means of 2.7 and 0.006 pmol/mg globin in exposed workers and controls, respectively). The average frequencies of SCE were 3.7/cell in exposed workers and 2.0/cell in controls, respectively. DNA and hemoglobin adducts were correlated (r = 0.887), as well as DNA adducts and SCE (r = 0.792) and hemoglobin adducts and SCE (r = 0.762). The present study is the first demonstrating PO-DNA adducts in human individuals. It is also the first study indicating cytogenetic effects in humans from PO exposure, although confounding effects from other sources cannot be excluded.