Publications by authors named "Louise A Brinton"

303 Publications

Endogenous Progestogens and Colorectal Cancer Risk among Postmenopausal Women.

Cancer Epidemiol Biomarkers Prev 2021 Jun 7;30(6):1100-1105. Epub 2021 Apr 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Background: The role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women.

Methods: The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992-1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)].

Results: High concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40-1.25; progesterone HR, 1.25; 95% CI, 0.71-2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75-1.44; , 0.06).

Conclusions: We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women.

Impact: Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172440PMC
June 2021

Sex Hormones, Insulin, and Insulin-like Growth Factors in Recurrence of High-Stage Endometrial Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Apr 23;30(4):719-726. Epub 2021 Feb 23.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients.

Methods: Stage II-IV patients ( = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of , IGF-binding proteins () and , insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade.

Results: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47-0.95), IR positivity (HR, 0.53; 95% CI, 0.29-0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02-2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02-1.92) were associated with increased recurrence risk.

Conclusions: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer.

Impact: This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026669PMC
April 2021

Associations of fecal microbial profiles with breast cancer and nonmalignant breast disease in the Ghana Breast Health Study.

Int J Cancer 2021 Jun 26;148(11):2712-2723. Epub 2021 Feb 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

The gut microbiota may play a role in breast cancer etiology by regulating hormonal, metabolic and immunologic pathways. We investigated associations of fecal bacteria with breast cancer and nonmalignant breast disease in a case-control study conducted in Ghana, a country with rising breast cancer incidence and mortality. To do this, we sequenced the V4 region of the 16S rRNA gene to characterize bacteria in fecal samples collected at the time of breast biopsy (N = 379 breast cancer cases, N = 102 nonmalignant breast disease cases, N = 414 population-based controls). We estimated associations of alpha diversity (observed amplicon sequence variants [ASVs], Shannon index, and Faith's phylogenetic diversity), beta diversity (Bray-Curtis and unweighted/weighted UniFrac distance), and the presence and relative abundance of select taxa with breast cancer and nonmalignant breast disease using multivariable unconditional polytomous logistic regression. All alpha diversity metrics were strongly, inversely associated with odds of breast cancer and for those in the highest relative to lowest tertile of observed ASVs, the odds ratio (95% confidence interval) was 0.21 (0.13-0.36; P < .001). Alpha diversity associations were similar for nonmalignant breast disease and breast cancer grade/molecular subtype. All beta diversity distance matrices and multiple taxa with possible estrogen-conjugating and immune-related functions were strongly associated with breast cancer (all Ps < .001). There were no statistically significant differences between breast cancer and nonmalignant breast disease cases in any microbiota metric. In conclusion, fecal bacterial characteristics were strongly and similarly associated with breast cancer and nonmalignant breast disease. Our findings provide novel insight into potential microbially-mediated mechanisms of breast disease.
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http://dx.doi.org/10.1002/ijc.33473DOI Listing
June 2021

Fatherhood status in relation to prostate cancer risks in two large U.S.-based prospective cohort studies.

Cancer Med 2021 01 21;10(1):405-415. Epub 2020 Nov 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Background: Despite the high incidence and mortality of prostate cancer (PCa) in the Unites States, few risk factors have been consistently linked with these PCa outcomes. Assessing proxies of reproductive factors may offer insights into PCa pathogenesis. In this study, we examined fatherhood status as a proxy of fertility in relation to total, nonaggressive, aggressive, and fatal PCa.

Methods: We examined participants of two cohorts, the NIH-AARP Diet and Health (NIH-AARP) Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals of associations between fatherhood status and number of children sired in relation to PCa incidence.

Results: Fatherhood status (one or more children vs. childless) was positively associated with total PCa risk in NIH-AARP or PLCO, but was not statistically significant (p = 0.06 and 0.55, respectively). Number of children sired indicated a slightly elevated risk of total PCa, but HRs were rarely significant and were of a fairly constant magnitude with no discernable trend relative to the childless referent group. Associations were similar for nonaggressive and aggressive PCa. The trend test for fatal PCa was statistically significant in NIH-AARP (p  < 0.01), despite none of the individual categorical point estimates reaching this threshold.

Conclusion: This study provides tentative evidence that fathering children is associated with a slightly increased PCa risk. Future research should strive to assess better proxies of reproductive function in relation to aggressive and fatal PCa to provide more specific evidence for this putative relationship.
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http://dx.doi.org/10.1002/cam4.3606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826462PMC
January 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 Jan 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

Int J Cancer 2021 May 17;148(9):2068-2078. Epub 2020 Nov 17.

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
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http://dx.doi.org/10.1002/ijc.33360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969437PMC
May 2021

Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast.

NPJ Breast Cancer 2020 7;6:41. Epub 2020 Sep 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA.

Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts ( = 0.004), but not with acini counts ( = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.
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http://dx.doi.org/10.1038/s41523-020-00184-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477555PMC
September 2020

Association of Circulating Progesterone With Breast Cancer Risk Among Postmenopausal Women.

JAMA Netw Open 2020 04 1;3(4):e203645. Epub 2020 Apr 1.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Importance: The role of endogenous progesterone in the development of breast cancer remains largely unexplored to date, primarily owing to assay sensitivity limitations and low progesterone concentrations in postmenopausal women. Recently identified progesterone metabolites may provide insights as experimental data suggest that 5α-dihydroprogesterone (5αP) concentrations reflect cancer-promoting properties and 3α-dihydroprogesterone (3αHP) concentrations reflect cancer-inhibiting properties.

Objective: To evaluate the association between circulating progesterone and progesterone metabolite levels and breast cancer risk.

Design, Setting, And Participants: Using a sensitive liquid chromatography-tandem mass spectrometry assay, prediagnostic serum levels of progesterone and progesterone metabolites were quantified in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (n = 15 595). Participation was limited to women not receiving exogenous hormone therapy at the time of blood sampling (1992-1993). Incident breast cancer cases (n = 405) were diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within 10-year age and clinical center strata. Progesterone assays were completed in July 2017; subsequent data analyses were conducted between July 15, 2017, and December 20, 2018.

Exposures: Circulating concentrations of pregnenolone, progesterone, and their major metabolites.

Main Outcomes And Measures: Development of breast cancer, with hazard ratios (HRs) and 95% CIs was estimated using Cox proportional hazards regression adjusted for key confounders, including estradiol. Evaluation of hormone ratios and effect modification were planned a priori.

Results: The present study included 405 incident breast cancer cases and a subcohort of 495 postmenopausal women; the mean (SD) age at the time of the blood draw was 67.2 (6.2) years. Progesterone concentrations were a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels were at an increased risk for breast cancer per SD increase in progesterone levels (HR, 1.16; 95% CI, 1.00-1.35; P = .048). The association with progesterone was linear in a 5-knot spline and stronger for invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004). Among women in the lowest quintile (Q1) of circulating estradiol (<6.30 pg/mL) elevated progesterone concentrations were associated with reduced breast cancer risk per SD increase in progesterone levels (HR, 0.38; 95% CI, 0.15-0.95; P = .04) and increased risk among women in higher quintiles of estradiol (Q2-Q5; ≥6.30 pg/mL) (HR, 1.18; 95% CI, 1.04-1.35; P = .01; P = .04 for interaction).

Conclusions And Relevance: In this case-cohort study of postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer. Additional research should be undertaken to assess how postmenopausal breast cancer risk is associated with both endogenous progesterone and progesterone metabolites and their interactions with estradiol.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.3645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182797PMC
April 2020

Endogenous estradiol and inflammation biomarkers: potential interacting mechanisms of obesity-related disease.

Cancer Causes Control 2020 Apr 25;31(4):309-320. Epub 2020 Feb 25.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Purpose: Disentangling the effects of endogenous estrogens and inflammation on obesity-related diseases requires a clearer understanding of how the two biological mechanisms relate to each other.

Methods: We studied 155 healthy postmenopausal women not taking menopausal hormone therapy enrolled in the Prostate Lung Colorectal and Ovarian (PLCO) screening cancer trial. From a baseline blood draw, we measured endogenous estradiol and 69 inflammation biomarkers: cytokines, chemokines, adipokines, angiogenic factors, growth factors, acute phase proteins, and soluble receptors. We evaluated the estradiol-inflammation relationship by assessing associations across different models (linear, ordinal logistic, and binary logistic) using a variety of estradiol classifications. We additionally investigated the estradiol-inflammation relationship stratified by baseline obesity status (BMI < 30 stratum and BMI > 30 stratum).

Results: Associations of estradiol with 7 inflammation biomarkers met p < 0.05 statistical significance in linear and ordinal models: C-reactive protein (CRP), adiponectin, chemokine (C-X-C motif) ligand-6, thymus activation-regulated chemokine, eosinophil chemotactic protein, plasminogen activator inhibitor-1, and serum amyloid A. The positive association between estradiol and CRP was robust to model changes. Each standard deviation increase in endogenous estradiol doubled a woman's odds of having CRP levels higher than the study median (odds ratio 2.29; 95% confidence interval 1.28, 4.09). Estradiol was consistently inversely associated with adiponectin. Other estradiol-inflammation biomarker associations were not robust to model changes.

Conclusions: Endogenous estradiol appears to be associated with CRP and adiponectin; the evidence is limited for other inflammation biomarkers.
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http://dx.doi.org/10.1007/s10552-020-01280-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472689PMC
April 2020

Reproductive factors and risk of breast cancer by tumor subtypes among Ghanaian women: A population-based case-control study.

Int J Cancer 2020 09 13;147(6):1535-1547. Epub 2020 Mar 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Higher proportions of early-onset and estrogen receptor (ER) negative cancers are observed in women of African ancestry than in women of European ancestry. Differences in risk factor distributions and associations by age at diagnosis and ER status may explain this disparity. We analyzed data from 1,126 cases (aged 18-74 years) with invasive breast cancer and 2,106 controls recruited from a population-based case-control study in Ghana. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for menstrual and reproductive factors using polytomous logistic regression models adjusted for potential confounders. Among controls, medians for age at menarche, parity, age at first birth, and breastfeeding/pregnancy were 15 years, 4 births, 20 years and 18 months, respectively. For women ≥50 years, parity and extended breastfeeding were associated with decreased risks: >5 births vs. nulliparous, OR 0.40 (95% CI 0.20-0.83) and 0.71 (95% CI 0.51-0.98) for ≥19 vs. <13 breastfeeding months/pregnancy, which did not differ by ER. In contrast, for earlier onset cases (<50 years) parity was associated with increased risk for ER-negative tumors (p-heterogeneity by ER = 0.02), which was offset by extended breastfeeding. Similar associations were observed by intrinsic-like subtypes. Less consistent relationships were observed with ages at menarche and first birth. Reproductive risk factor distributions are different from European populations but exhibited etiologic heterogeneity by age at diagnosis and ER status similar to other populations. Differences in reproductive patterns and subtype heterogeneity are consistent with racial disparities in subtype distributions.
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http://dx.doi.org/10.1002/ijc.32929DOI Listing
September 2020

Relationship of Serum Progesterone and Progesterone Metabolites with Mammographic Breast Density and Terminal Ductal Lobular Unit Involution among Women Undergoing Diagnostic Breast Biopsy.

J Clin Med 2020 Jan 17;9(1). Epub 2020 Jan 17.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

The association of progesterone/progesterone metabolites with elevated mammographic breast density (MBD) and delayed age-related terminal duct lobular unit (TDLU) involution, strong breast cancer risk factors, has received limited attention. Using a reliable liquid chromatography-tandem mass-spectrometry assay, we quantified serum progesterone/progesterone metabolites and explored cross-sectional relationships with MBD and TDLU involution among women, ages 40-65, undergoing diagnostic breast biopsy. Quantitative MBD measures were estimated in pre-biopsy digital mammograms. TDLU involution was quantified in diagnostic biopsies. Adjusted partial correlations and trends across MBD/TDLU categories were calculated. Pregnenolone was positively associated with percent MBD-area (MBD-A, rho: 0.30; p-trend = 0.01) among premenopausal luteal phase women. Progesterone tended to be positively associated with percent MBD-A among luteal phase (rho: 0.26; p-trend = 0.07) and postmenopausal (rho: 0.17; p-trend = 0.04) women. Consistent with experimental data, implicating an elevated 5α-pregnanes/3α-dihydroprogesterone (5αP/3αHP) metabolite ratio in breast cancer, higher 5αP/3αHP was associated with elevated percent MBD-A among luteal phase (rho: 0.29; p-trend = 0.08), but not postmenopausal women. This exploratory analysis provided some evidence that endogenous progesterone and progesterone metabolites might be correlated with MBD, a strong breast cancer risk factor, in both pre- and postmenopausal women undergoing breast biopsy. Additional studies are needed to understand the role of progesterone/progesterone metabolites in breast tissue composition and breast cancer risk.
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http://dx.doi.org/10.3390/jcm9010245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019918PMC
January 2020

The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles: An Analysis from the Ovarian Cancer Cohort Consortium (OC3).

Cancer Res 2020 03 13;80(5):1210-1218. Epub 2020 Jan 13.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056529PMC
March 2020

Association of Anti-Mullerian Hormone, Follicle-Stimulating Hormone, and Inhibin B with Risk of Ovarian Cancer in the Janus Serum Bank.

Cancer Epidemiol Biomarkers Prev 2020 03 13;29(3):636-642. Epub 2020 Jan 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Background: Reproductive factors, including parity, breastfeeding, and contraceptive use, affect lifetime ovulatory cycles and cumulative exposure to gonadotropins and are associated with ovarian cancer. To understand the role of ovulation-regulating hormones in the etiology of ovarian cancer, we prospectively analyzed the association of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B with ovarian cancer risk.

Methods: Our study included 370 women from the Janus Serum Bank, including 54 type I and 82 type II invasive epithelial ovarian cancers, 49 borderline tumors, and 185 age-matched controls. We used conditional logistic regression to assess the relationship between hormones and risk of ovarian cancer overall and by subtype (types I and II).

Results: Inhibin B was associated with increased risk of ovarian cancer overall [OR, 1.97; 95% confidence interval (CI), 1.14-3.39; = 0.05] and with type I ovarian (OR, 3.10; 95% CI, 1.04-9.23; = 0.06). FSH was not associated with ovarian cancer risk overall, but higher FSH was associated with type II ovarian cancers (OR, 2.78; 95% CI, 1.05-7.38). AMH was not associated with ovarian cancer risk.

Conclusions: FSH and inhibin B may be associated with increased risk in different ovarian cancer subtypes, suggesting that gonadotropin exposure may influence risk of ovarian cancer differently across subtypes.

Impact: Associations between prospectively collected AMH, FSH, and inhibin B levels with risk of ovarian cancer provide novel insight on the influence of premenopausal markers of ovarian reserve and gonadotropin signaling. Heterogeneity of inhibin B and FSH effects in different tumor types may be informative of tumor etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060092PMC
March 2020

Application of convolutional neural networks to breast biopsies to delineate tissue correlates of mammographic breast density.

NPJ Breast Cancer 2019 19;5:43. Epub 2019 Nov 19.

2Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD USA.

Breast density, a breast cancer risk factor, is a radiologic feature that reflects fibroglandular tissue content relative to breast area or volume. Its histology is incompletely characterized. Here we use deep learning approaches to identify histologic correlates in radiologically-guided biopsies that may underlie breast density and distinguish cancer among women with elevated and low density. We evaluated hematoxylin and eosin (H&E)-stained digitized images from image-guided breast biopsies ( = 852 patients). Breast density was assessed as global and localized fibroglandular volume (%). A convolutional neural network characterized H&E composition. In total 37 features were extracted from the network output, describing tissue quantities and morphological structure. A random forest regression model was trained to identify correlates most predictive of fibroglandular volume ( = 588). Correlations between predicted and radiologically quantified fibroglandular volume were assessed in 264 independent patients. A second random forest classifier was trained to predict diagnosis (invasive vs. benign); performance was assessed using area under receiver-operating characteristics curves (AUC). Using extracted features, regression models predicted global ( = 0.94) and localized ( = 0.93) fibroglandular volume, with fat and non-fatty stromal content representing the strongest correlates, followed by epithelial organization rather than quantity. For predicting cancer among high and low fibroglandular volume, the classifier achieved AUCs of 0.92 and 0.84, respectively, with epithelial organizational features ranking most important. These results suggest non-fatty stroma, fat tissue quantities and epithelial region organization predict fibroglandular volume. The model holds promise for identifying histological correlates of cancer risk in patients with high and low density and warrants further evaluation.
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http://dx.doi.org/10.1038/s41523-019-0134-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864056PMC
November 2019

Involution of Breast Lobules, Mammographic Breast Density and Prognosis Among Tamoxifen-Treated Estrogen Receptor-Positive Breast Cancer Patients.

J Clin Med 2019 Nov 4;8(11). Epub 2019 Nov 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Mammographic breast density (MD) reflects breast fibroglandular content. Its decline following adjuvant tamoxifen treated, estrogen receptor (ER)-positive breast cancer has been associated with improved outcomes. Breast cancers arise from structures termed lobules, and lower MD is associated with increased age-related lobule involution. We assessed whether pre-treatment involution influenced associations between MD decline and risk of breast cancer-specific death. ER-positive tamoxifen treated patients diagnosed at Kaiser Permanente Northwest (1990-2008) were defined as cases who died of breast cancer ( = 54) and matched controls (remained alive over similar follow-up; = 180). Lobule involution was assessed by examining terminal duct lobular units (TDLUs) in benign tissues surrounding cancers as TDLU count/mm, median span and acini count/TDLU. MD (%) was measured in the unaffected breast at baseline (median 6-months before) and follow-up (median 12-months after tamoxifen initiation). TDLU measures and baseline MD were positively associated among controls ( < 0.05). In multivariable regression models, MD decline (≥10%) was associated with reduced risk of breast cancer-specific death before (odds ratio (OR): 0.41, 95% CI: 0.18-0.92) and after (OR: 0.41, 95% CI: 0.18-0.94) adjustment for TDLU count/mm, TDLU span (OR: 0.34, 95% CI: 0.14-0.84), and acini count/TDLU (OR: 0.33, 95% CI: 0.13-0.81). MD decline following adjuvant tamoxifen is associated with reduced risk of breast cancer-specific death, irrespective of pre-treatment lobule involution.
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http://dx.doi.org/10.3390/jcm8111868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912285PMC
November 2019

Circulating estrogens and postmenopausal ovarian and endometrial cancer risk among current hormone users in the Women's Health Initiative Observational Study.

Cancer Causes Control 2019 Nov 21;30(11):1201-1211. Epub 2019 Sep 21.

Frederick National Laboratory for Cancer Research, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick, MD, USA.

Purpose: Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users.

Methods: We conducted a nested case-control study among postmenopausal women using MHT at baseline in the Women's Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype.

Results: Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17-7.73); p-trend = 0.03; p-het < 0.01]. Endometrial cancer risk was unrelated to estrogen/estrogen metabolite levels among women who took combined estrogen/progestin therapy (EPT).

Conclusions: These findings provide novel evidence that may support a heterogeneous hormonal etiology across ovarian cancer subtypes. Circulating estrogens did not influence endometrial cancer risk among women with EPT-induced high-estrogen levels. Larger studies are needed to delineate the relationship between ovarian/endometrial cancer subtypes and estrogen levels in the context of MHT use.
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http://dx.doi.org/10.1007/s10552-019-01233-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785392PMC
November 2019

Pre-diagnosis body mass index, physical activity and ovarian cancer mortality.

Gynecol Oncol 2019 10 2;155(1):105-111. Epub 2019 Aug 2.

Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States of America. Electronic address:

Background: Ovarian cancer is the deadliest gynecologic malignancy, yet the effects on survival of modifiable pre-diagnosis lifestyle factors, such as obesity and physical activity, remain largely unexplored. Our objective was to evaluate the effect of pre-diagnosis BMI and physical activity on ovarian cancer mortality using prospectively collected data.

Methods: Data on women who developed ovarian cancer after enrollment into the NIH-AARP Diet and Health Study were analyzed. Cancer incidence was ascertained through linkage state cancer registries and consisted of 741 cases of epithelial ovarian cancer.

Results: Higher pre-diagnosis BMI was associated with increased overall and ovarian cancer-specific mortality. Comparing women with BMI 25-29.9, 30-34.9 and ≥ 35 to normal weight women, the HRs of overall mortality were 1.18 (95%CI 0.96-1.45), 1.05 (0.82-1.36) and 1.59 (1.14-2.18, p-trend = 0.02). The findings were similar for ovarian cancer-specific mortality comparing women with BMI ≥ 35 to normal weight women (BMI <25) with a HR of 1.47 (95%CI 1.03-2.09, p-trend 0.08). Pre-diagnosis physical activity was not associated with mortality, with HRs for overall mortality of 1.06 (95%CI 0.79-1.43), 0.94 (0.72-1.23), 0.98 (0.76-1.25), and 0.98 (0.75-1.28, p-trend = 0.91), comparing women who engaged in vigorous physical activity 1-3 times/month, 1-2 times/week, 3-4 times/week and 5 times/week, respectively, with those who never/rarely engaged in such activity.

Conclusions: Women who were obese before developing ovarian cancer had increased mortality than those who were normal weight, but physical activity before diagnosis was not associated with mortality in this study population. These results suggest that maintaining a healthy weight is a powerful preventative tool.
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http://dx.doi.org/10.1016/j.ygyno.2019.07.025DOI Listing
October 2019

Relationship of circulating insulin-like growth factor-I and binding proteins 1-7 with mammographic density among women undergoing image-guided diagnostic breast biopsy.

Breast Cancer Res 2019 07 23;21(1):81. Epub 2019 Jul 23.

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability. Prior studies have found positive associations between circulating IGF-I and the IGF-I:IGFBP-3 ratio and breast cancer risk. We evaluated the associations of IGF-I, IGFBP-3, and six other IGFBPs with MD.

Methods: Serum IGF measures were quantified in 296 women, ages 40-65, undergoing diagnostic image-guided breast biopsy. Volumetric density measures (MD-V) were assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Area density measures (MD-A) were estimated by computer-assisted thresholding software. Age, body mass index (BMI), and BMI-adjusted linear regression models were used to examine associations of serum IGF measures with MD. Effect modification by BMI was also assessed.

Results: IGF-I and IGFBP-3 were not strongly associated with MD after BMI adjustment. In multivariable analyses among premenopausal women, IGFBP-2 was positively associated with both percent MD-V (β = 1.49, p value = 0.02) and MD-A (β = 1.55, p value = 0.05). Among postmenopausal women, positive relationships between IGFBP-2 and percent MD-V (β = 2.04, p = 0.003) were observed; the positive associations between IGFBP-2 and percent MD-V were stronger among lean women (BMI < 25 kg/m) (β = 5.32, p = 0.0002; p interaction = 0.0003).

Conclusions: In this comprehensive study of IGFBPs and MD, we observed a novel positive association between IGFBP-2 and MD, particularly among women with lower BMI. In concert with in vitro studies suggesting a dual role of IGFBP-2 on breast tissue, promoting cell proliferation as well as inhibiting tumorigenesis, our findings suggest that further studies assessing the role of IGFBP-2 in breast tissue composition, in addition to IGF-1 and IGFBP-3, are warranted.
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http://dx.doi.org/10.1186/s13058-019-1162-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651938PMC
July 2019

Postmenopausal Androgen Metabolism and Endometrial Cancer Risk in the Women's Health Initiative Observational Study.

JNCI Cancer Spectr 2019 Sep 25;3(3):pkz029. Epub 2019 Apr 25.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Background: After menopause, several androgens continue to be produced primarily by the adrenal glands; these can be converted into estrogens via aromatization or into androgen metabolites. It is unclear if androgens are associated with endometrial cancer risk independently of their being precursors to estrogens or if alternative metabolic pathways influence risk.

Methods: We measured prediagnostic serum concentrations of 12 androgens and their metabolites using highly sensitive liquid chromatography-tandem mass spectrometry assays in a nested case-control study of postmenopausal women from the Women's Health Initiative Observational Study (313 endometrial cancer case subjects, 354 matched control subjects). Estrogens were previously assayed. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for endometrial cancer with adjustment for confounders.

Results: Compared to the lowest concentrations, the highest levels of adrenal androgens were associated with increased endometrial cancer risk: dehydroepiandrosterone (5th vs 1st quintile: OR = 1.85, 95% CI = 1.06 to 3.25), androstenedione (OR = 2.36, 95% CI = 1.34 to 4.16), and testosterone (OR = 1.91, 95% CI = 1.12 to 3.24). Downstream androgen metabolites were not associated with endometrial cancer. Although increased risks for the parent androgens were still suggested after adjustment for unconjugated estradiol, the associations attenuated, and with the exception of androstenedione, were no longer statistically significant. We also evaluated ratios of estrogens relative to their androgenic precursors; both higher unconjugated estrone:androstenedione and higher unconjugated estradiol:testosterone were associated with increased endometrial cancer risk.

Conclusions: We identified increased risks for endometrial cancer with the highest levels of adrenal androgens and high levels of estrogens relative to these androgens. As adrenal androgens can be aromatized to estrogens, this suggests androgens likely influence endometrial carcinogenesis via estrogen metabolism.
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http://dx.doi.org/10.1093/jncics/pkz029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620792PMC
September 2019

Molecular Classification of Epithelial Ovarian Cancer Based on Methylation Profiling: Evidence for Survival Heterogeneity.

Clin Cancer Res 2019 Oct 29;25(19):5937-5946. Epub 2019 May 29.

Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Purpose: Ovarian cancer is a heterogeneous disease that can be divided into multiple subtypes with variable etiology, pathogenesis, and prognosis. We analyzed DNA methylation profiling data to identify biologic subgroups of ovarian cancer and study their relationship with histologic subtypes, copy number variation, RNA expression data, and outcomes.

Experimental Design: A total of 162 paraffin-embedded ovarian epithelial tumor tissues, including the five major epithelial ovarian tumor subtypes (high- and low-grade serous, endometrioid, mucinous, and clear cell) and tumors of low malignant potential were selected from two different sources: The Polish Ovarian Cancer study, and the Surveillance, Epidemiology, and End Results Residual Tissue Repository (SEER RTR). Analyses were restricted to Caucasian women. Methylation profiling was conducted using the Illumina 450K methylation array. For 45 tumors array copy number data were available. NanoString gene expression data for 39 genes were available for 61 high-grade serous carcinomas (HGSC).

Results: Consensus nonnegative matrix factorization clustering of the 1,000 most variable CpG sites showed four major clusters among all epithelial ovarian cancers. We observed statistically significant differences in survival (log-rank test, = 9.1 × 10) and genomic instability across these clusters. Within HGSC, clustering showed three subgroups with survival differences (log-rank test, = 0.002). Comparing models with and without methylation subgroups in addition to previously identified gene expression subtypes suggested that the methylation subgroups added significant survival information ( = 0.007).

Conclusions: DNA methylation profiling of ovarian cancer identified novel molecular subgroups that had significant survival difference and provided insights into the molecular underpinnings of ovarian cancer..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774865PMC
October 2019

Recruiting population controls for case-control studies in sub-Saharan Africa: The Ghana Breast Health Study.

PLoS One 2019 16;14(4):e0215347. Epub 2019 Apr 16.

National Cancer Institute, Rockville, MD, United States of America.

Background: In case-control studies, population controls can help ensure generalizability; however, the selection of population controls can be challenging in environments that lack population registries. We developed a population enumeration and sampling strategy to facilitate use of population controls in a breast cancer case-control study conducted in Ghana.

Methods: Household enumeration was conducted in 110 census-defined geographic areas within Ghana's Ashanti, Central, Eastern, and Greater Accra Regions. A pool of potential controls (women aged 18 to 74 years, never diagnosed with breast cancer) was selected from the enumeration using systematic random sampling and frequency-matched to the anticipated distributions of age and residence among cases. Multiple attempts were made to contact potential controls to assess eligibility and arrange for study participation. To increase participation, we implemented a refusal conversion protocol in which initial non-participants were re-approached after several months.

Results: 2,528 women were sampled from the enumeration listing, 2,261 (89%) were successfully contacted, and 2,106 were enrolled (overall recruitment of 83%). 170 women were enrolled through refusal conversion. Compared with women enrolled after being first approached, refusal conversion enrollees were younger and less likely to complete the study interview in the study hospital (13% vs. 23%). The most common reasons for non-participation were lack of interest and lack of time.

Conclusions: Using household enumeration and repeated contacts, we were able to recruit population controls with a high participation rate. Our approach may provide a blue-print for others undertaking epidemiologic studies in populations that lack accessible population registries.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215347PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467449PMC
January 2020

Breast cancer risk prediction in women aged 35-50 years: impact of including sex hormone concentrations in the Gail model.

Breast Cancer Res 2019 03 19;21(1):42. Epub 2019 Mar 19.

Department of Population Health, New York University School of Medicine, 650 First Avenue, New York, NY, 10016, USA.

Background: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.

Methods: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.

Results: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.

Conclusions: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.
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http://dx.doi.org/10.1186/s13058-019-1126-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425605PMC
March 2019

Circulating androgens and postmenopausal ovarian cancer risk in the Women's Health Initiative Observational Study.

Int J Cancer 2019 10 15;145(8):2051-2060. Epub 2019 Feb 15.

Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD.

Our knowledge of epidemiologic risk factors for ovarian cancer supports a role for androgens in the pathogenesis of this disease; however, few studies have examined associations between circulating androgens and ovarian cancer risk. Using highly sensitive LC-MS/MS assays, we evaluated associations between pre-diagnostic serum levels of 12 androgens, including novel androgen metabolites that reflect androgen activity in tissues, and ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS). We frequency-matched 169 ovarian cancer cases to 410 controls from women enrolled in WHI-OS who were not using menopausal hormones at enrollment/blood draw. We estimated associations overall and by subtype (n = 102 serous/67 non-serous) using multivariable adjusted logistic regression. Androgen/androgen metabolite levels were not associated with overall ovarian cancer risk. In analyses by subtype, women with increased levels of androsterone-glucuronide (ADT-G) and total 5-α reduced glucuronide metabolites (markers of tissue-level androgenic activity) were at increased risk of developing non-serous ovarian cancer: ADT-G tertile (T)3 versus T1 odds ratio [OR] (95% confidence interval [CI]) 4.36 (1.68-11.32), p-heterogeneity 0.002; total glucuronide metabolites 3.63 (1.47-8.95), 0.002. Risk of developing serous tumors was unrelated to these markers. ADT-G and total glucuronide metabolites, better markers of tissue-level androgenic activity in women than testosterone, were associated with an increased risk of developing non-serous ovarian cancer. Our work demonstrates that sex steroid metabolism is important in the etiology of non-serous ovarian cancers and supports a heterogeneous hormonal etiology across histologic subtypes of ovarian cancer.
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http://dx.doi.org/10.1002/ijc.32157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660427PMC
October 2019

Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium.

Int J Cancer 2019 07 14;145(1):58-69. Epub 2019 Jan 14.

City of Hope, Duarte, CA.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (p = 0.01), family history of ovarian cancer (p = 0.02), body mass index (BMI; p ≤ 0.04) and smoking (p < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
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http://dx.doi.org/10.1002/ijc.32075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488363PMC
July 2019

Comparability of serum, plasma, and urinary estrogen and estrogen metabolite measurements by sex and menopausal status.

Cancer Causes Control 2019 Jan 1;30(1):75-86. Epub 2018 Dec 1.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Purpose: The comparability between serum, plasma, and urinary measurements of estrogen metabolites via liquid chromatography-tandem mass spectrometry (LC-MS/MS) has not been largely explored, and it is unclear if urinary LC-MS/MS measurements are suitable surrogates of circulating levels.

Methods: Serum, plasma (EDTA and heparin), and urinary estrogen/estrogen metabolite levels were measured via LC-MS/MS in paired samples from 64 healthy volunteers (18 men, 20 premenopausal women, 26 postmenopausal women). Geometric means and Spearman correlation coefficients were used to compare individual and combined pathway levels of estrogens/estrogen metabolites across biologic matrices by sex/menopausal status.

Results: Measured concentrations of estrogens/estrogen metabolites across blood matrices were almost identical (percent differences < 4.8%). Parent estrogen concentrations measured in serum and urine were moderately correlated in postmenopausal women (estrone: r = 0.69, estradiol: r = 0.69). Correlations were similar comparing unconjugated serum estradiol to urinary estrone (r = 0.76) and urinary estradiol (r = 0.65) in postmenopausal women but were moderate to low in premenopausal women (r = 0.60, 0.40, respectively)/men (r = 0.33, 0.53, respectively). Comparing metabolite ratios, proportionally higher concentrations of 16-pathway metabolites were measured in urine versus serum across sex/menopausal status groups (e.g., postmenopausal women: 50.3% 16-pathway metabolites/total in urine versus 35.3% in serum).

Conclusions: There is strong agreement between estrogen/estrogen metabolites measurements in serum, heparin plasma, and EDTA plasma. Individual estrogen metabolite concentrations were moderately correlated between urine and serum, but were not well correlated when evaluating pathway- or relative estrogen concentrations. Differences between serum and urine are likely explained by differences in metabolism and/or excretion.
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http://dx.doi.org/10.1007/s10552-018-1105-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447065PMC
January 2019

Breast cancer risk among women under 55 years of age by joint effects of usage of oral contraceptives and hormone replacement therapy.

Menopause 2018 11;25(11):1195-1200

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Objective: To assess effects on breast cancer risk of exposure to both oral contraceptives and menopausal hormones, an increasingly common exposure.

Design: A case-control study of breast cancer among women under the age of 55 years in Atlanta, GA involving 1,031 cases and 919 population controls was conducted.

Results: Ever use of oral contraceptives was associated with a relative risk of 1.1 (95% 0.9-1.4), whereas the relative risk for hormone replacement therapy was 0.9 (95% CI 0.7-1.2). Seventeen percent of the cases versus 19% of the population controls reported exposure to both agents, resulting in a relative risk of 1.0 (95% CI 0.7-1.4) relative to those unexposed to either preparation. Although there was little variation in risk associated with joint effects by either age or race, there were statistically nonsignificant elevations in risk for this exposure among women who had experienced a natural menopause (relative risk = 2.0, 95% CI 0.7-5.6), were relatively thin (relative risk = 1.5, 0.8-3.0), or who had a first degree relative with breast cancer (relative risk = 2.0, 0.6-7.0). When joint effects of longer term use of both agents were considered, subjects who reported use of oral contraceptives for 10 or more years and hormone replacement for 3 or more years had a relative risk of 3.2 (95% CI 1.4-7.4) compared with nonusers of either preparation.

Conclusions: Although our results must be cautiously interpreted given small numbers within subgroups, they raise concern and emphasize the need for further evaluation on breast cancer risk of the increasingly common exposure to both oral contraceptives and hormone replacement therapy.
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http://dx.doi.org/10.1097/GME.0000000000001217DOI Listing
November 2018

Pooled Analysis of Nine Cohorts Reveals Breast Cancer Risk Factors by Tumor Molecular Subtype.

Cancer Res 2018 10 5;78(20):6011-6021. Epub 2018 Sep 5.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A-like (ER or PR/HER2), 1,368 luminal B-like (ER or PR/HER2), 521 HER2-enriched (ER/PR/HER2), and 1,152 triple-negative (ER/PR/HER2) disease. Ever parous compared with never was associated with lower risk of luminal A-like (HR, 0.78; 95% CI, 0.73-0.83) and luminal B-like (HR, 0.74; 95% CI, 0.64-0.87) as well as a higher risk of triple-negative disease (HR, 1.23; 95% CI, 1.02-1.50; value for overall tumor heterogeneity < 0.001). Direct associations with luminal-like, but not HER2-enriched or triple-negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause ( value for overall tumor heterogeneity < 0.001). Age-specific associations with baseline body mass index differed for risk of luminal A-like and triple-negative breast cancer ( value for tumor heterogeneity = 0.02). These results provide the strongest evidence for etiologic heterogeneity of breast cancer to date from prospective studies. These findings comprise the largest study of prospective data to date and contribute to the accumulating evidence that etiological heterogeneity exists in breast carcinogenesis. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223627PMC
October 2018

Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?

Int J Cancer 2019 02 1;144(4):730-740. Epub 2018 Nov 1.

National Cancer Institute, Bethesda, MD.

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.
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http://dx.doi.org/10.1002/ijc.31851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746113PMC
February 2019

Cancer Progress and Priorities: Uterine Cancer.

Cancer Epidemiol Biomarkers Prev 2018 09;27(9):985-994

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

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http://dx.doi.org/10.1158/1055-9965.EPI-18-0264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504985PMC
September 2018

rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Int J Mol Sci 2018 Aug 21;19(9). Epub 2018 Aug 21.

Department of Gynecology, Jena University Hospital-Friedrich Schiller University, Jena 07743, Germany.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed ( = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa ( = 0.51, = 1.7 × 10), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
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http://dx.doi.org/10.3390/ijms19092473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163881PMC
August 2018