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Supplementary Table S1 shows characteristics among ovarian cancer cases, Supplementary Table S2 shows the association between duration of analgesic use and ovarian cancer risk, Supplementary Table S3 shows the association between frequency of analgesic use and ovarian cancer risk, Supplementary Table S4 shows the association between age at first use of analgesics and ovarian cancer risk, Supplementary Table S5 shows the associations between analgesic use and ovarian cancer risk stratified by oral contraceptive use and history of endometriosis

Menstrual pain has been associated with increased ovarian cancer risk, presumably through increased inflammation, which is known to play a critical role in ovarian carcinogenesis. Analgesic medications are frequently used to treat menstrual pain, some of which lower ovarian cancer risk. In this study, we examined the association between analgesic use for menstrual pain during the premenopausal period and ovarian cancer risk among women with history of menstrual pain. We used data from the New England Case-Control Study, including 1,187 epithelial ovarian cancer cases and 1,225 population-based controls enrolled between 1998 and 2008 with detailed information on analgesic use for their menstrual pain. We used unconditional logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between analgesic use (i.e., aspirin, ibuprofen, acetaminophen) for menstrual pain and ovarian cancer risk. We further conducted a stratified analysis by intensity of menstrual pain (mild/moderate, severe). Among women with menstrual pain during their 20s and 30s, ever use of analgesics for menstrual pain was not significantly associated with ovarian cancer risk. However, among women with severe menstrual pain, ever use of aspirin or acetaminophen for menstrual pain was inversely associated with risk (OR, 0.41; 95% CI, 0.18–0.94 and OR, 0.43; 95% CI, 0.21–0.88 compared with never users, respectively). No significant association was observed between analgesic use and ovarian cancer risk among women with mild/moderate menstrual pain (Pinteraction ≤ 0.03). Our results suggest that use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer.Prevention Relevance:This study investigates whether analgesic use specifically for menstrual pain during the premenopausal period influences ovarian cancer risk. Our results suggest use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer among women with severe menstrual pain.

Supplementary Methods, Tables 1-5, Figures 1-4. Contains additional Methods and Materials on the coding of variables in the risk model, recruitment of cases to the Leeds Case-Control study, imputation, comparing self reported and nurse derived mole counts and calculations for estimating absolute risk. Contains Tables 1-5 on missingness of pooled data, risk assessment for the Leeds dataset including imputed cases, comparisons of self classification and nurse classification of mole count/freckling in the Leeds controls. Contains Figures 1-4 showing the distribution of risk scores in the pooled and Leeds data, a bland-altman plot comparing nurse and self assessment of mole count on the back in Leeds controls and a cartoon used in the Leeds Case-Control study to determine mole count.

Supplementary Methods and Materials from Replication and Functional Genomic Analyses of the Breast Cancer Susceptibility Locus at 6q25.1 Generalize Its Importance in Women of Chinese, Japanese, and European Ancestry

Biological and epidemiologic evidence suggest that androgen or its receptor may play a role in ovarian cancer pathogenesis. The most notable genetic factor influencing androgen receptor (AR) activity is the functional cytosine, adenine, guanine (CAG) repeat in which length is inversely proportional to its transactivational activity. Additional genetic variation due to single nucleotide polymorphisms in the AR gene may be captured through haplotypes. We genotyped the CAG microsatellite and six haplotype-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082) of the androgen receptor gene in 987 ovarian cancer cases and 1,034 controls from a study conducted in New Hampshire and eastern Massachusetts between May 1992 and July 2003. We estimated haplotype frequencies and calculated odds ratios with 95% confidence intervals to evaluate the association between the haplotypes and the AR CAG microsatellite with ovarian cancer risk. We observed that carriage of two alleles with ≥22 CAG repeats was associated with an increased risk of ovarian cancer compared with carriage of two alleles with AR gene were identified, but no association between these and ovarian cancer risk was observed. Our results suggest that possession of two long AR alleles (≥22 CAG repeats) may be associated with increased risk of ovarian cancer compared with women with two short AR alleles (

Supplementary Table 1 from Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk

Supplementary Table 2 from Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk

We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of more than 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95% CI) = 1.30 (1.22–1.38) and 1.64 (1.50–1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10−30], Japanese women [ORs (95% CI) = 1.31 (1.13–1.52) and 1.37 (1.06–1.76), P for trend = 2.51 × 10−4], and European-ancestry American women [ORs (95% CI) = 1.07 (0.99–1.16) and 1.18 (1.04–1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95% CI) = 0.81 (0.63–1.06) and 0.85 (0.65–1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027]. In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high linkage disequilibrium with rs2046210 in Chinese (r2 = 0.91) and European-ancestry (r2 = 0.83) populations, but not in Africans (r2 = 0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region. Cancer Res; 71(4); 1344–55. ©2011 AACR.

This review summarizes key findings from the US National Cancer Institute (NCI) diethylstilbestrol (DES) Combined Cohort Study with a focus on the results of the NCI Third Generation Study, a cohort of DES-exposed and -unexposed granddaughters. Findings to date from the Third Generation Study are discussed in the context of other research efforts and case reports, suggesting an intergenerational heritability of DES-related effects. The DES story serves as a model for the influence of endocrine disrupting chemicals on human health. It also serves as a warning of the special hazards of pregnancy exposures, and more broadly, of the potential for invisible health consequences arising from new or changing exposures. Summary sentence Diethylstilbestrol is associated with adverse health outcomes in women exposed during pregnancy and in prenatally exposed offspring, particularly daughters; evidence suggests that exposure health effects may extend to the next generation.

Background: The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure to DES before birth impacts overall cancer risk, and risk of site-specific cancers. Methods: Men (mean age in 2016 = 62.0 years) who were or were not prenatally DES exposed were identified between 1953 and 1994 and followed for cancer primarily via questionnaire approximately every 5 years between 1994 and 2016. The overall and site-specific cancer rates of the two groups were compared using Poisson regression and proportional hazards modeling with adjustment for age. Results: DES exposure was not associated with either overall cancer [hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.77–1.15] or total prostate cancer rates (HR, 0.95; 95% CI, 0.68–1.33), but was inversely associated with urinary tract cancer incidence (HR, 0.48; 95% CI, 0.23–1.00). Conclusions: There was no increase in either overall or prostate cancer rates among men prenatally DES exposed relative to those unexposed. An unexpected risk reduction was observed for urinary system cancers among the exposed relative to those unexposed. These findings suggest that prenatal DES exposure is unlikely to be an important contributor to cancer development in middle-aged men. Impact: The results of this study could lend reassurance to middle-aged men who were prenatally DES exposed that their exposure does not adversely influence their overall cancer risk.

Background: Combined oral contraceptive use is associated with a decreased risk of invasive epithelial ovarian cancer (ovarian cancer). There is suggestive evidence of an inverse association between progestin-only contraceptive use and ovarian cancer risk, but previous studies have been underpowered. Methods: The current study used primary data from 7,977 women with ovarian cancer and 11,820 control women in seven case–control studies from the Ovarian Cancer Association Consortium to evaluate the association between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestin-only contraceptive, and ovarian cancer risk. Logistic models were fit to determine the association between ever use of DMPA and ovarian cancer risk overall and by histotype. A systematic review of the association between DMPA use and ovarian cancer risk was conducted. Results: Ever use of DMPA was associated with a 35% decreased risk of ovarian cancer overall (OR, 0.65; 95% confidence interval, 0.50–0.85). There was a statistically significant trend of decreasing risk with increasing duration of use (Ptrend < 0.001). The systematic review yielded six studies, four of which showed an inverse association and two showed increased risk. Conclusions: DMPA use appears to be associated with a decreased risk of ovarian cancer in a duration-dependent manner based on the preponderance of evidence. Further study of the mechanism through which DMPA use is associated with ovarian cancer is warranted. Impact: The results of this study are of particular interest given the rise in popularity of progestin-releasing intrauterine devices that have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.

Menstrual pain has been associated with increased ovarian cancer risk, presumably through increased inflammation, which is known to play a critical role in ovarian carcinogenesis. Analgesic medications are frequently used to treat menstrual pain, some of which lower ovarian cancer risk. In this study, we examined the association between analgesic use for menstrual pain during the premenopausal period and ovarian cancer risk among women with history of menstrual pain. We used data from the New England Case-Control Study, including 1,187 epithelial ovarian cancer cases and 1,225 population-based controls enrolled between 1998 and 2008 with detailed information on analgesic use for their menstrual pain. We used unconditional logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between analgesic use (i.e., aspirin, ibuprofen, acetaminophen) for menstrual pain and ovarian cancer risk. We further conducted a stratified analysis by intensity of menstrual pain (mild/moderate, severe). Among women with menstrual pain during their 20s and 30s, ever use of analgesics for menstrual pain was not significantly associated with ovarian cancer risk. However, among women with severe menstrual pain, ever use of aspirin or acetaminophen for menstrual pain was inversely associated with risk (OR, 0.41; 95% CI, 0.18–0.94 and OR, 0.43; 95% CI, 0.21–0.88 compared with never users, respectively). No significant association was observed between analgesic use and ovarian cancer risk among women with mild/moderate menstrual pain (Pinteraction ≤ 0.03). Our results suggest that use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer. Prevention Relevance: This study investigates whether analgesic use specifically for menstrual pain during the premenopausal period influences ovarian cancer risk. Our results suggest use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer among women with severe menstrual pain.

Author(s): Lee, Alice W; Rosenzweig, Stacey; Wiensch, Ashley; Australian Ovarian Cancer Study Group; Ramus, Susan J; Menon, Usha; Gentry-Maharaj, Aleksandra; Ziogas, Argyrios; Anton-Culver, Hoda; Whittemore, Alice S; Sieh, Weiva; Rothstein, Joseph H; McGuire, Valerie; Wentzensen, Nicolas; Bandera, Elisa V; Qin, Bo; Terry, Kathryn L; Cramer, Daniel W; Titus, Linda; Schildkraut, Joellen M; Berchuck, Andrew; Goode, Ellen L; Kjaer, Susanne K; Jensen, Allan; Jordan, Susan J; Ness, Roberta B; Modugno, Francesmary; Moysich, Kirsten; Thompson, Pamela J; Goodman, Marc T; Carney, Michael E; Chang-Claude, Jenny; Rossing, Mary Anne; Harris, Holly R; Doherty, Jennifer Anne; Risch, Harvey A; Khoja, Lilah; Alimujiang, Aliya; Phung, Minh Tung; Brieger, Katharine; Mukherjee, Bhramar; Pharoah, Paul DP; Wu, Anna H; Pike, Malcolm C; Webb, Penelope M; Pearce, Celeste Leigh | Abstract: BackgroundParity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.MethodsA pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.ResultsEver having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend l .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.ConclusionsIncomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

Results of studies assessing intrauterine device (IUD) use and ovarian cancer risk are inconsistent. We examined the association between IUD use, including duration, type and timing of use, and ovarian cancer risk using three population-based studies. Data from the New England Case-Control Study (NEC) and two prospective cohort studies, the Nurses' Health Studies (NHS/NHSII), were included in the analysis. Information on IUD use was collected by in-person interview in NEC and by biennial questionnaire in NHS/NHSII. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) in NEC and Cox regression to calculate hazard ratios (HR) and 95% CI in NHS/NHSII. We used meta-analysis to combine the NEC and the pooled NHS/NHSII results. Overall, IUD use was not associated with epithelial ovarian cancer risk (OR = 0.96, 95% CI: 0.81-1.14 in NEC; HR = 0.89, 95% CI: 0.69-1.15 in NHS/NHSII; combined RR = 0.94, 95% CI: 0.81-1.08). Among IUD users, older age at first use was associated with increased ovarian cancer risk (P-trend = .03). We did not observe significant associations by IUD type or duration of use. In conclusion, IUD use was not associated with ovarian cancer risk in our study.

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 (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). 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.

Background: An estimated 38 million American women currently use contraception, a critical key to women’s health with respect to preventing unwanted pregnancies and reducing maternal morbidity and mortality. Additionally, oral contraceptives (OC) reduce ovarian cancer risk by an estimated 15-30% and are credited with the decreasing ovarian cancer incidence over recent decades. However, contraceptive patterns are changing, with OC use decreasing in favor of intrauterine devices (IUDs). Studies regarding IUD use and ovarian cancer risk are inconsistent, with most reporting decrease in risk or no association. Differences between these studies could be attributable to IUD type, duration of use, age at first use, or type of ovarian cancer. Here we examined the association between IUD use, including duration, type, and timing of use, and ovarian cancer risk using three population-based studies. Methods: In the New England Case-Control Study, a population-based study enrolling participants in New Hampshire and Eastern Massachusetts from 1992 to 2008, 2,323 ovarian cancer cases and 2,339 frequency-matched population-based controls were included in the analysis. Information on IUD use was collected using questionnaire data at time of enrollment. Unconditional logistic regression adjusted for potential confounders including age, body mass index, smoking status, age at menarche, parity, OC use, tubal ligation, genital powder use, endometriosis, family history of ovarian cancer, center, and study phase was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). In the Nurses’ Health Studies (NHS/NHSII), prospective cohort studies established in 1976 and 1989 enrolling 121,700 and 116,429 registered nurses residing in 11 and 14 US states, 1,761 ovarian cancer cases were confirmed through 2015. Information on IUD use was collected in biennial questionnaires from 1976 to 1982. Cox regression adjusted for potential confounders listed above was used to calculate the hazard ratios (HRs) and 95% CIs. NHS and NHSII cohorts were pooled and models were adjusted for cohort. Polytomous logistic regression was used to evaluate the association by histotypes. Results: Overall, IUD use was not associated with ovarian cancer risk (OR=0.99, 95%CI: 0.83-1.17 in NEC; HR=0.89, 95%CI: 0.69-1.15 in NHS/NHSII). While histotype specific associations were not significantly different, IUD use was suggestively associated with increased risk of serous borderline tumors (OR=1.42, 95% CI: 1.00-2.02 in NEC). There was no significant difference by IUD type, duration, or age at first IUD use. The association between IUD use and ovarian cancer risk did not differ when stratified by parity. Conclusion: IUD use was not significantly associated with ovarian cancer risk, although the current study was limited by small sample size to investigate the association between detailed IUD use and risk. Larger studies are warranted to further investigate the association between patterns of IUD use and ovarian cancer risk. Citation Format: Naoko Sasamoto, Jiaxi Yang, Ana Babic, Allison F. Vitonis, Daniel W. Cramer, Linda J. Titus, Shelley S. Tworoger, Kathryn L. Terry. Intrauterine device use and ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B42.

Statins are widely used to lower blood cholesterol and reduce risk for cardiovascular diseases, but attention has recently focused on a role in cancer prevention or therapy. Here we present data from a large case-control study addressing whether statin use can lower the risk for epithelial ovarian cancer (EOC). Between 1992 and 2008, data including medications used for at least six months were collected from 2040 cases with EOC and 2100 frequency-matched controls without the disease who participated in the New England Case Control study. We used unconditional logistic regression controlling for matching factors and potential confounders to examine the association between statin use and the risk for EOC. Overall, women who used statins had 32% lower risk of ovarian cancer compared to non-users (Odds ratio (OR) 0.68, 95% Confidence Interval (CI): 0.54 – 0.85), adjusting for the matching factors and other covariates. The reduced risk was most apparent in women taking a lipophilic statin who began use after age 49, and who had used them 2 – 4.9 years. Statin use was associated with lower risks for both serous and non-serous histologic subtypes with strongest effect seen for mucinous and mixed epithelial subtypes. The association became apparent about a decade after the introduction of statins and did not appear to be confounded by indications for use of statins or medications used concomitantly. In this case-control study, statins were found to lower the risk for both serous and non-serous EOC and especially mucinous EOC.

Background: Ovarian cancer is the fifth leading cause of cancer deaths in US women with few modifiable risk factors. Breastfeeding has been observed to be associated with reduced risk of ovarian cancer in multiple studies. However, prior studies reporting the association between breastfeeding pattern and ovarian cancer risk by histologic subtypes have reported inconsistent findings, likely due to small sample size and lack of details on breastfeeding patterns. The objective of this study is to evaluate the association between breastfeeding patterns and ovarian cancer risk by histologic subtypes using individual questionnaire data from the Ovarian Cancer Association Consortium (OCAC). Method: We evaluated breastfeeding patterns in relation to invasive ovarian cancer risk in 9,807 cases and 12, 971 controls from 13 studies in the OCAC. We performed pooled unconditional logistic regression to evaluate the association between breastfeeding and ovarian cancer risk and used multinomial logistic regression to evaluate the association by histologic subtype. We restricted the analysis to parous women and adjusted for study site, age, body mass index, race, education, oral contraceptive use, number of full-term births, family history of ovarian cancer, and birth decade (to account for change in breastfeeding practice over time). We additionally adjusted for age at first and last births simultaneously when examining the association between first and last age at breastfeeding and ovarian cancer risk. Results: Women who reported ever breastfeeding had a 24% decreased risk of overall invasive ovarian cancer compared to women who never breastfed (OR=0.76, 95%CI: 0.71-0.81) and this association did not differ significantly by histologic subtypes (p-heterogeneity=0.09). Considering only episodes when women breastfed, we observed lower risk of ovarian cancer in women who had longer average duration per episode compared to women who breastfed < 6 months on average per episode (OR=0.85, 95%CI: 0.77-0.93 for 6-12 months; OR=0.77, 95%CI: 0.66-0.89 for > 12 months; p-trend 30 years at first breastfeeding; OR=0.60, 95%CI: 0.53-0.69 for age >35 years at last breastfeeding). Compared to women who never breastfed, women who last breastfed < 10 years ago had 54% reduction of risk (OR= 0.46, 95%CI: 0.39-0.56) while women who last breastfed ≥ 30 years ago had 19% reduction of risk (OR=0.81, 95%CI: 0.74-0.88). Conclusion: Breastfeeding regardless of age or duration was associated with reduced risk of ovarian cancer. Our findings support the benefit of breastfeeding as modifiable risk factor for ovarian cancer regardless of histologic subtypes, which has the potential for reducing the incidence this deadly disease. Citation Format: Naoko Sasamoto, Ana Babic, Susan Jordan, Harvey Risch, Holly Harris, Mary Anne Rossing, Jennifer Doherty, Marc Goodman, Pamela Thompson, Susanne K. Kjær, Allan Jensen, Joellen Schildkraut, Linda Titus, Daniel Cramer, Elisa Bandera, Weiva Sieh, Valerie McGuire, Rebecca Sutphen, Celeste L. Pearce, Anna H. Wu, Malcolm Pike, Penelope Webb, Francesmary Modugno, Kathryn Terry. Breastfeeding pattern and ovarian cancer risk: Results from the Ovarian Cancer Association Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 640.

Background: Telomeres protect chromosomal ends, shorten with cellular division, and signal cellular senescence, but unchecked telomere attrition can lead to telomere dysfunction, upregulation of telomerase, and carcinogenesis. Shorter telomeres in peripheral blood leukocytes (PBL) have been associated with elevated cancer risk. Furthermore, genetic variants in and around the TERT gene have been implicated in carcinogenesis. Methods: We measured relative telomere length (RTL) in PBLs of 911 cases and 948 controls from the New England case–control (NECC) study, a population-based study of ovarian cancer. In addition, we assessed germ line genetic variation in five telomere maintenance genes among 2,112 cases and 2,456 controls from the NECC study and the Nurses' Health Study, a prospective cohort study. ORs and 95% CIs were estimated by logistic regression. Results: Overall, we observed no differences in telomere length between cases and controls. Compared with women with RTL in the longest tertile, women with RTL in the shortest tertile had no increase in risk (OR = 1.01, 95% CI: 0.80–1.28). However, several SNPs in the TERT gene, including rs2736122, rs4246742, rs4975605, rs10069690, rs2736100, rs2853676, and rs7726159, were significantly associated with ovarian cancer risk. We observed a significant gene-level association between TERT and ovarian cancer risk (P = 0.00008). Conclusion: Our observations suggest that genetic variation in the TERT gene may influence ovarian cancer risk, but the association between average telomere length in PBLs and ovarian cancer remains unclear. Impact: The role of telomeres in ovarian carcinogenesis remains unsettled and warrants further investigation. Cancer Epidemiol Biomarkers Prev; 21(3); 504–12. ©2012 AACR.

In utero diethylstilbestrol (DES) exposure is a risk factor for rare development of vaginal and cervical cancer and may potentially be a risk factor for breast cancer. Mammography use in this population is relatively unknown; therefore, this study aims to determine if in utero DES exposure is associated with the frequency of mammography screening examinations while considering demographic and clinical factors.Using combined DES cohort questionnaire data, self-reported mammography screening over the past 5 years (2001-2006) was analyzed in women aged ≥45 years. Binary logistic regression assessed if DES exposure was associated with mammography use after adjustment for benign breast disease (BBD), previous cancer diagnosis, and whether insurance access influenced screening use.Overall, the frequency of mammography examinations was similar for both DES-exposed and unexposed women. DES-exposed (n=2986) and unexposed women (n=1397) over the age of 44 reported receiving ≥3 mammography examinations in the past 5 years (73.8% and 74.0%, respectively). After adjustment, DES exposure was not associated with ≥3 mammograms in the past 5 years compared to ≤2 examinations (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.86-1.17), p=0.99).In utero DES exposure was not associated with mammography use, nor was health insurance status or a BBD or cancer diagnosis. Because of the potential elevated risk for breast cancer in women exposed prenatally to DES, continued monitoring of standard mammography recommendations is recommended for this group, which is predominantly over the age of 45.

Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood.We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero.Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes.In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

To develop a risk-factor score that may provide additional guidance to women and their physicians regarding elective bilateral salpingo-oophorectomy at the time of hysterectomy.From a case-control study conducted from 1992 to 2008 in women residing in eastern Massachusetts or New Hampshire, we selected 1,098 women with invasive ovarian cancer (case group) and 1,363 for the control group who were older than 40 years and had neither hysterectomy nor a personal or family history of breast or ovarian cancer. Using logistic regression, we identified key risk factors and built a risk score. The score was separately assessed in 126 women in the case group and 156 in the control group with excluded prior hysterectomy to determine whether women who developed ovarian cancer could have been distinguished.Summing eight conditions found to be associated with ovarian cancer (Jewish ethnicity, less than 1 year of oral contraceptive use, nulliparity, no breastfeeding, no tubal ligation, painful periods or endometriosis, polycystic ovary syndrome or obesity, talc use), we created a five-level score. Assigning average risk to those with a score of 2, the odds ratios varied from 0.56 (95% confidence interval [CI] 0.42-0.74) for a score of 0-1 to 3.30 (95% CI 2.50-4.35) for a score of 5 or greater (P trend.001). The risk score was higher for women who developed ovarian cancer after hysterectomy than those who did not (P=.01). Lifetime risks for ovarian cancer for a woman at age 40 years are changed from 1.2% with a 0-1 score to 6.6% with a score of 5 or higher.We developed a risk-assessment tool that can quantify women's risk for ovarian cancer and should be validated in other data sets.

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2) = 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 x 10 25]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P = 6.7 x 10 23) and lobular histology (case-only P = 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.

Little is known about the effects of diet after breast cancer diagnosis on survival. We prospectively examined the relation between post-diagnosis dietary factors and breast cancer and all-cause survival in women with a history of invasive breast cancer diagnosed between 1987 and 1999 (at ages 20–79 years). Diet after breast cancer diagnosis was measured using a 126-item food frequency questionnaire. Among 4,441 women without a history of breast cancer recurrence prior to completing the questionnaire, 137 subsequently died from breast cancer within 7 years of enrollment. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for intake of macronutrients as well as selected micronutrients and food groups from Cox proportional hazards regression models. After adjustment for factors at diagnosis (age, state of residence, menopausal status, smoking, breast cancer stage, alcohol, history of hormone replacement therapy), interval between diagnosis and diet assessment, and at follow-up (energy intake, breast cancer treatment, body mass index, and physical activity), women in the highest compared to lowest quintile of intake of saturated fat and trans fat had a significantly higher risk of dying from any cause (HR = 1.41, 95% CI = 1.06 to 1.87, P-trend = 0.03) for saturated fat; (HR = 1.78, 95% CI = 1.35 to 2.32, P-trend = 0.01) for trans fat intake. Associations were similar, though did not achieve statistical significance, for breast cancer survival. This study suggests that lower intake of saturated and trans fat in the post-diagnosis diet is associated with improved survival after breast cancer diagnosis.

Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) can reduce breast cancer incidence by up to 50%, but less is known about its effects on breast cancer-specific and total mortality. Ovarian suppression is an accepted treatment for premenopausal breast cancer that may improve disease-free and overall survival. Prediagnosis TAHBSO may similarly reduce breast cancer mortality rates. However, all-cause mortality among women with breast cancer could be adversely affected by increases in deaths due to heart disease, stroke, or bone fracture that may be associated with TAHBSO. To examine associations between prediagnosis TAHBSO, estrogen therapy, and mortality after breast cancer, we analyzed data from a cohort of 9,215 women ages 50-79 who were diagnosed with invasive breast cancer during 1989-2003 in Wisconsin, Massachusetts, or New Hampshire. Causes and dates of death through 2006 were obtained from the National Death Index. To account for non-breast cancer deaths as competing events, we fit proportional cumulative incidence associated subhazards regression models for breast cancer-specific mortality. Cox proportional hazards regression was used to calculate multivariate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality. Cox regression models were stratified on study center, year of interview, and age at diagnosis and adjusted for body mass index, smoking status, family history of breast cancer and stage at diagnosis as potential confounders. Over an average 8.3 years of follow-up, 2,715 deaths were observed, including 1,507 breast cancer deaths. In total, 1,718 women (18.6%) reported TAHBSO prior to breast cancer diagnosis; while 5,937 women (64.4%) had an intact uterus and ovaries at diagnosis. Compared to women with an intact uterus and ovaries who never used postmenopausal hormones, the subhazard ratio for breast cancer-specific mortality was 0.92 for women who had intact uterus and ovaries and reported using estrogen therapy (95% CI: 0.66, 1.28), 0.71 for women who reported TAHBSO and never used hormones (95% CI: 0.54, 0.95), and 0.93 for women who reported TAHBSO and estrogen use (95% CI: 0.75, 1.16). In contrast, a reduction in all-cause mortality associated with TAHBSO was observed for women who reported estrogen therapy use. Compared to women with an intact uterus and ovaries who never used estrogens, the HR for all-cause mortality among estrogen users who had not undergone TAHBSO was 0.92 (95% CI: 0.73, 1.16), 0.87 for women who reported TAHBSO but no hormone use (95% CI: 0.74, 1.04), and 0.77 among women who reported TAHBSO and estrogen use (95% CI: 0.64, 0.92). Limitations to this analysis included missing information on hormone receptor status and treatment regimens. In these data, prediagnosis TAHBSO was associated with reduced breast cancer-specific mortality among women who never used hormones, and reduced all-cause mortality among estrogen users. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-04.

Folate has been hypothesized to influence carcinogenesis due to its dual role in DNA methylation, which regulates gene expression, and synthesis of purine and thymidylate, which is vital for DNA repair. Thus, we examined ovarian cancer risk in relation to two functional polymorphisms (C677T and A1298C) in the MTHFR gene.We genotyped the C677T (rs1801133) and A1298C (rs1801131) MTHFR polymorphisms in 1642 cases and 2068 controls from three studies, the New England Case Control Study (NEC), Nurses' Health Study (NHS), and Mayo Clinic Ovarian Cancer Case Control Study (MAY).Overall, we observed no association between either SNP and ovarian cancer risk (pooled C677T p(trend)=0.59 and A1298C p(trend)=0.58). Significant associations (C677T p(trend)=0.001, A1298C p(trend)=0.02) between these MTHFR SNPs and serous ovarian cancer risk were observed in the NEC study, but were not replicated in the NHS and MAY studies.MTHFR SNPs C677T and A1298C are not associated with ovarian cancer risk. Our results highlight the need for validation of genetic findings.

Evidence has been inconsistent regarding the impact of social networks on survival after breast cancer diagnosis. We prospectively examined the relation between components of social integration and survival in a large cohort of breast cancer survivors.Women (N=4,589) diagnosed with invasive breast cancer were recruited from a population-based, multi-center, case-control study. A median of 5.6 years (Interquartile Range 2.7-8.7) after breast cancer diagnosis, women completed a questionnaire on recent post-diagnosis social networks and other lifestyle factors. Social networks were measured using components of the Berkman-Syme Social Networks Index to create a measure of social connectedness. Based on a search of the National Death Index, 552 deaths (146 related to breast cancer) were identified. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression.Higher scores on a composite measure of social connectedness as determined by the frequency of contacts with family and friends, attendance of religious services, and participation in community activities was associated with a 15-28% reduced risk of death from any cause (p-trend=0.02). Inverse trends were observed between all-cause mortality and frequency of attendance at religious services (p-trend=0.0001) and hours per week engaged in community activities (p-trend=0.0005). No material associations were identified between social networks and breast cancer-specific mortality.Engagement in activities outside the home was associated with lower overall mortality after breast cancer diagnosis.

Conflicting reports regarding the relationship between breast-feeding and ovarian cancer risk suggest a possible influence of patterns of breast-feeding. We used logistic regression to examine breast-feeding in a large population of parous women who participated in a case-control study of ovarian cancer in New Hampshire and MA, USA. Risk of ovarian cancer was reduced in parous women who ever breast-fed (OR: 0.75; 95% CI: 0.62, 0.92), but evidence was limited for an influence of duration of breast-feeding and the number of children breast-fed. Compared to never breast-feeding, inverse associations were seen for breast-feeding all children (OR: 0.72; 95% CI: 0.58, 0.91) and for breast-feeding some children when the last born child was breast-fed (OR: 0.58; 95% CI: 0.37, 0.91). There was little evidence of reduced risk for those who breast-fed some children when the last born child was not breast-fed (OR: 0.91; 95% CI: 0.66, 1.26). Similar findings were noted in women with exactly two children and in those with two or more children. The protective influence of breast-feeding on ovarian cancer risk may be limited to women who breast-feed their last born child. These findings, which require confirmation by future studies, imply that breast-feeding resets pregnancy-related states that mediate ovarian cancer risk.

The recent decline in US breast cancer incidence rates has been attributed to the marked reduction in use of postmenopausal hormone therapy (HT). An alternative explanation is that women who are not routinely seeking medical care to renew HT prescriptions may be less adherent to recommendations for mammographic screening. To investigate the latter possibility, we compared mammographic intervals according to HT use.Using data (1995-2007) from the New Hampshire Mammography Network (NHMN), a state-based mammography registry, we assessed mammographic intervals corresponding to HT use or nonuse among postmenopausal women. We used linear mixed effects models to assess whether the length of screening mammogram intervals differed according to HT use.A total of 310,185 mammograms, representing 76,192 postmenopausal women and 319,353 person-years of screening, were included in the analysis. The median screening interval corresponding to HT use overall was 13.0 months (interquartile range: 12.4-15.1) and for nonuse was 13.1 (interquartile range: 12.4-15.8). Virtually, all screening mammograms occurred within a 2-year interval regardless of HT use or nonuse (98.5 and 98.1%, respectively).Our findings indicate that screening mammography intervals are similar whether or not women are using HT. Thus, reduced utilization of screening mammography is unlikely to account for the decrease in breast cancer incidence seen soon after the WHI report.

Certain classes of vitamins and nutrients found in fruits and vegetables have been of particular interest in relation to cancer prevention, owing to their potential anticarcinogenic properties. We examined the association between certain fruits, vegetables, carotenoids, and vitamin A and breast cancer risk in a large population-based case-control study of women residing in the states of Massachusetts, New Hampshire and Wisconsin. The study was comprised of 5,707 women with incident invasive breast cancer (2,363 premenopausal women and 3,516 postmenopausal women) and 6,389 population controls (2,594 premenopausal women and 3,516 postmenopausal women). In an interview, women were asked about their intake of carotenoid rich fruits and vegetables 5 years prior to a referent date. An inverse association observed among premenopausal women was for high levels of vitamin A (OR: 0.82, 95% CI: 0.68-0.98, p for trend = 0.01), beta-carotene (OR: 0.81, 95% CI 0.68-0.98, p for trend = 0.009), alpha-carotene (OR: 0.82, 95% CI: 0.68-0.98, p for trend = 0.07) and lutein/zeaxanthin (OR: 0.83, 95% CI 0.68-0.99, p for trend = 0.02). An inverse association was not observed among postmenopausal women. Among premenopausal women who reported ever smoking, these results were stronger than among never smokers, although tests for interaction were not statistically significant. Results from this study are comparable to previous prospective studies, and suggest that a high consumption of carotenoids may reduce the risk of premenopausal but not postmenopausal breast cancer, particularly among smokers.

Several recent studies have evaluated the association between dietary flavonoid intake and ovarian cancer risk, and all reported significant or suggestive inverse associations with certain flavonoids or flavonoid subclasses; however, most of these studies were small to moderate in size. We, therefore, examined this association in a large, population-based case-control study. We calculated intake of 5 common dietary flavonoids (myricetin, kaempferol, quercetin, luteolin, and apigenin), as well as total intake of these flavonoids, for 1,141 cases and 1,183 frequency-matched controls. We used unconditional logistic regression to estimate the relative risk (RR) of ovarian cancer for each quintile of flavonoid intake when compared with the lowest quintile. We did not observe an association between total flavonoid intake and ovarian cancer risk. The multivariable-adjusted RR for the highest versus lowest quintile of total flavonoid intake was 1.06 (95% confidence interval [CI] = 0.78-1.45). In analyses of each individual flavonoid, only intake of apigenin was associated with a borderline significant decrease in risk (RR, highest vs. lowest quintile = 0.79, 95% CI = 0.59-1.06; p-trend = 0.26), and this association was significant after adjustment for intake of the other 4 individual flavonoids (comparable RR = 0.72, 95% CI = 0.53-0.98; p-trend = 0.09). These results provide limited support for an association between flavonoid intake and ovarian cancer risk. However, given the findings of previous studies and the biologic plausibility of this association, additional studies are warranted.

Background Melanoma risk is related to sun exposure; we have investigated risk variation by tumour site and latitude. Methods We performed a pooled analysis of 15 case-control studies (5700 melanoma cases and 7216 controls), correlating patterns of sun exposure, sunburn and solar keratoses (three studies) with melanoma risk. Pooled odds ratios (pORs) and 95% Bayesian confidence intervals (CIs) were estimated using Bayesian unconditional polytomous logistic random-coefficients models. Results Recreational sun exposure was a risk factor for melanoma on the trunk (pOR 1.7; 95% CI: 1.4-2.2) and limbs (pOR 1.4; 95% CI: 1.1-1.7), but not head and neck (pOR 1.1; 95% CI: 0.8-1.4), across latitudes. Occupational sun exposure was associated with risk of melanoma on the head and neck at low latitudes (pOR 1.7; 95% CI: 1.0-3.0). Total sun exposure was associated with increased risk of melanoma on the limbs at low latitudes (pOR 1.5; 95% CI: 1.0-2.2), but not at other body sites or other latitudes. The pORs for sunburn in childhood were 1.5 (95% CI: 1.3-1.7), 1.5 (95% CI: 1.3-1.7) and 1.4 (95% CI: 1.1-1.7) for melanoma on the trunk, limbs, and head and neck, respectively, showing little variation across latitudes. The presence of head and neck solar keratoses was associated with increased risk of melanoma on the head and neck (pOR 4.0; 95% CI: 1.7-9.1) and limbs (pOR 4.0; 95% CI: 1.9-8.4). Conclusion Melanoma risk at different body sites is associated with different amounts and patterns of sun exposure. Recreational sun exposure and sunburn are strong predictors of melanoma at all latitudes, whereas measures of occupational and total sun exposure appear to predict melanoma predominately at low latitudes. Keywords Melanoma, recreational sun exposure, occupational sun exposure, total sun exposure, sunburn, solar keratoses

To determine if women exposed in utero to diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.1994 Diethylstilbestrol-Adenosis (DESAD) cohort data are used to assess the degree of recommended compliance of breast cancer screenings found in 3140 DES-exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data that included reported frequency over the preceding 5 years (1990-1994) of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms.DES-exposed women exceeded annual recommendations for CBEs (aOR 2.20, 95% CI, 1.04-4.67) among women without a history of benign breast disease (BBD) compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (40 years of age), and mammographies, regardless of BBD history.The majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, but over two thirds do not perform monthly BSEs. Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.

Epidemiologic studies have reported an increased risk of breast cancer among women who drink alcohol, including wine ([1][1], [2][2]) Two meta-analyses estimated a ∼10% [95% confidence interval (CI), 5-15%] increased risk of breast cancer with each additional 10 grams (∼1 drink) of alcohol/day

Prior studies have suggested that vitamin D may reduce ovarian cancer risk. Thus, we examined whether three single nucleotide polymorphisms (SNP) in the vitamin D receptor (VDR) gene (Fok1, Bsm1, Cdx2) were associated with risk of epithelial ovarian cancer in a retrospective case-control study (New England Case-Control study, NECC) and a nested case-control study of three prospective cohort studies: the Nurses' Health Study (NHS), NHSII, and the Women's Health Study. Data from the cohort studies were combined and analyzed using conditional logistic regression and pooled with the results from the NECC, which were analyzed using unconditional logistic regression, using a random effects model. We obtained genotype data for 1,473 cases and 2,006 controls. We observed a significant positive association between the number of Fok1 f alleles and ovarian cancer risk in the pooled analysis (Ptrend = 0.03). The odds ratio (OR) for the ff versus FF genotype was 1.26 [95% confidence interval (CI) = 1.01–1.57]. Neither the Bsm1 (Ptrend = 0.96) or Cdx2 (Ptrend = 0.13) SNPs were significantly associated with ovarian cancer risk. Among the prospective studies, the risk of ovarian cancer by plasma vitamin D levels did not clearly vary by any of the genotypes. For example, among women with the Fok1 FF genotype, the OR comparing plasma 25-hydroxyvitamin D ≥32 ng/mL versus

Objective: The purpose of our study was to examine the association of regular tea consumption with the risk of breast cancer in a large population-based case-control study from the United States. Methods: Five thousand and eighty-two women with incident breast cancer between the ages of 20 and 74 years old from population-based cancer registries in Wisconsin, Massachusetts, and New Hampshire and 4,501 age-matched controls from lists of licensed drivers and Medicare beneficiaries completed a structured telephone interview that included information on usual tea consumption 5 years prior to the interview and other breast cancer risk factors. Logistic regression was used to obtain covariate-adjusted odds ratios and 95% confidence intervals associated with quantities of tea consumed. Results: Tea consumption was not related to breast cancer risk overall (P for trend = 0.18). However, when stratified by age, an inverse association was observed among women less than 50 years: those consuming three or more cups per day had a 37% reduced breast cancer risk when compared with women reporting no tea consumption (age and study site–adjusted odds ratios, 0.63; 95% confidence intervals, 0.44-0.89; P = 0.01) with a significant test for trend (P = 0.01). The inverse association noted among younger women was consistent for in situ and invasive breast cancer, and for ductal and lobular breast cancer. All results were unchanged after adjustment for established risk factors. Conclusion: We observed evidence to support a potential beneficial influence for breast cancer associated with moderate levels of tea consumption (three or more cups per day) among younger women. Further research is needed to confirm this association. (Cancer Epidemiol Biomarkers Prev 2009;18(1):341–5)

Meat consumption and heterocyclic amine (HCA) intake have been inconsistently associated with breast cancer risk in epidemiologic studies. Genetic variation in N-acetyltransferase2 (NAT2) has been suggested to modify the association of meat intake with breast cancer through its influence on metabolism of HCAs. We examined associations between meat intake, HCA exposure, acetylator genotype, and breast cancer risk in a case-control study of 2,686 case women and 3,508 controls. Women were asked to report their usual intake, cooking method, and preferred doneness of specific meats. We observed no association between total meat, red meat, or chicken with breast cancer risk. Women who consumed 5 or more servings of meat per week had no increased risk of breast cancer compared to women consuming fewer than 2 servings per week (OR = 0.99, 95% CI 0.84–1.15). No statistically significant associations with breast cancer were found for individual HCAs or for total estimated mutagenic activity of meat. Results varied modestly according to menopausal status. There were no statistically significant interactions with NAT2 genotype. Results do not support an important association of HCAs with breast cancer risk, although potential biases in case-control studies should be considered.

Background: A few studies have observed reduced breast cancer mortality in women who used hormone therapy before diagnosis. Due to the high prevalence of past and current hormone use, it is important to investigate whether these preparations are related to breast cancer mortality. Methods: To evaluate the influence of prediagnostic use of hormone therapy on breast cancer mortality, a prospective cohort of 12,269 women ages 50 years or more diagnosed with incident invasive breast cancer and residents of Wisconsin, Massachusetts, or New Hampshire were enrolled in three phases beginning in 1988. They were followed for death until December 31, 2005, using the National Death Index. Cumulative mortality and multivariable adjusted hazard rate ratios for breast cancer and other mortality causes were calculated for women according to any hormone therapy use, and for exclusive use of estrogen or estrogen-progestin (EP). Results: During an average 10.3 years of follow-up, 1,690 deaths from breast cancer were documented. Cumulative mortality from breast cancer was lower among hormone therapy users, specifically current users at the time of diagnosis, and EP users, compared with nonusers. Adjusted survival varied by type and duration of hormone therapy before diagnosis. A reduced risk of death from breast cancer was associated with EP preparations (hazard rate ratio, 0.73; 0.59-0.91) and with ≥5 years of EP use (0.60; 0.43-0.84). No association was observed for women who were former or current users of E-alone preparations. Conclusions: Although use of combined EP preparations increases breast cancer risk, in this study, use of these hormones before diagnosis was associated with reduced risk of death after a breast cancer diagnosis. The better survival among users, particularly of EP, persisted after adjustment of screening, stage, and measured confounders. (Cancer Epidemiol Biomarkers Prev 2008;17(4):864–71)

BACKGROUND. Previous studies showed an association between viewing of smoking in movies and initiation of smoking among adolescents. However, all studies except one were cross-sectional, and none updated movie smoking exposure prospectively or assessed its influence on children. METHODS. We enrolled elementary school students, 9 to 12 years of age, in a longitudinal study to assess the influence of movie smoking exposure on smoking initiation among children. Movie smoking content was coded for the most popular movie releases; exposure was assessed by asking children which movies they had seen, on the basis of unique lists of 50 movies sampled randomly from top box office hits and video rentals. Data collection occurred in 3 waves (the baseline survey and 2 follow-up surveys), ∼1 year apart. Movie lists were updated for each data collection wave, to reflect recent releases. Movie smoking exposure was analyzed in relation to smoking initiation by the end of the study period. RESULTS. Approximately 80% of the children's smoking exposure occurred through movies rated G, PG, or PG-13. Children's movie smoking exposure predicted smoking initiation significantly, after adjustment for multiple covariates including child and parent characteristics. The relative risks were 1.09, 1.09, and 1.07 for a 1-decile increase of movie smoking exposure measured at the baseline, second, and third data collection waves, respectively. The adjusted attributable risk of smoking initiation attributable to movie smoking exposure was 0.35. CONCLUSION. Our study, which is the first to enroll children in elementary school and to update movie smoking exposure longitudinally, indicates that early exposure has as much influence on smoking risk as does exposure nearer the outcome. Overall, movie smoking may be responsible for at least one third of smoking initiation for children in this age group.

Diethylstilbestrol (DES) is a synthetic estrogen that was prescribed to > 2 million pregnant women in the mid-1900s. In later years, it was discovered to be associated with the occurrence of vaginal clear cell adenocarcinoma (Herbst et al. 1971), anatomic abnormalities of the reproductive tract (Stillman 1982), and poor reproductive outcomes in daughters (Beral and Colwell 1981; Kaufman et al. 2000; Palmer et al. 2001). DES exposure in utero may also exert long-term effects on female endocrine function, possibly leading to permanent dysregulation of the hypothalamic–pituitary–ovarian axis and alterations in hormone biosynthesis in adult women (Assies 1991; Peress et al. 1982; Wu et al. 1980). Although the effect of DES on plasma sex hormones has not been well studied, elevated levels of serum testosterone (Wu et al. 1980), but not luteinizing hormone (LH) (Peress et al. 1982; Wu et al. 1980), progesterone (Wu et al. 1980), or estrogens (Peress et al. 1982; Wu et al. 1980), have been documented in DES daughters. Levels of follicle-stimulating hormone (FSH) were elevated in DES-exposed women in one study, but no differences were found in LH or the ratio of FSH to LH (Peress et al. 1982); another study found no difference in FSH levels (Wu et al. 1980). Animal data show that in vitro production of testosterone, total estrogen, and progesterone by ovarian tissue was significantly greater in female mice exposed prenatally to DES, at all ages studied (Haney et al. 1984). Secondary sex ratio (proportion of male births)—a prevalence measure that reflects both sex programming at the time of conception and survival until birth—may be influenced by exposure to endocrine disruptors such as DES. In humans, several studies have examined the relation between preconceptual exposure to endocrine-disrupting compounds and secondary sex ratio, but most associations were observed in men and were mixed in direction (James 2006). With respect to maternal exposure, a significant decrease in sex ratio was found in studies of polychlorinated biphenyls (PCBs) (Weisskopf et al. 2003) and mercury (Sakamoto et al. 2001), but the majority of studies have been null, including those that examined maternal exposure to dioxin (Mocarelli et al. 2000; Rogan et al. 1999; Ryan et al. 2002; Yoshimura et al. 2001), PCBs (del rio Gomez et al. 2002; Karmaus et al. 2002; Taylor et al. 2006; Taylor et al. 1989), lead (Jarrell et al. 2006), and dichlorodiphenyltrichloroethane (DDT) (Cocco et al. 2006; Karmaus et al. 2002). Moreover, dose and timing of exposure have been incompletely characterized in many studies, and little is known about the relation of these chemicals to the maternal endogenous hormonal milieu. For instance, PCBs have estrogenic, antiestrogenic, and androgenic properties (Bonefeld-Jorgensen et al. 2001), making the direction and magnitude of their effects difficult to predict. In a small study of preconception maternal PCB concentrations that stratified by hormonal activity of the PCB, Taylor et al. (2006) found that the odds of a male birth were elevated among women exposed to estrogenic but not antiestrogenic PCBs. Although not statistically significant, these results suggest that PCBs have different biologic effects depending on their underlying hormonal activity. A prevailing hypothesis is that endocrine disruptors such as DES may affect secondary sex ratio through changes in hormonal concentrations around the time of conception (James 1987). In women, high levels of gonadotropins (FSH and LH) and progesterone are hypothesized to change the ratio toward more girls, whereas high testosterone and estrogen levels change the ratio toward more boys (James 1987). Another hypothesis, the “over-ripeness ovopathy” theory (Jongbloet 2004), postulates that sex ratio is influenced by both oocyte maturation and the quality of cervical mucus, with nonoptimal hormonal modulation favoring male-biased progeny. Nonoptimal liquefaction of cervical mucus may facilitate differential migration of sperm, with increased fertilization by Y-bearing sperm because the head, length, perimeter, and area are significantly smaller and the neck and tail are shorter in Y-bearing sperm than in X-bearing sperm (Cui 1997). Because concurrence of both oocyte maturation and cervical mucus liquefaction is modulated by estrogens before the midcycle, any perturbations to the endogenous estrogenic milieu caused by endocrine disruptors may theoretically affect sex ratio (Jongbloet 2004). To our knowledge, there are no studies of secondary sex ratio in women exposed to DES, either prenatally or preconceptually, and most animal studies of this association are null. Specifically, studies in female mice (Honma et al. 2002; Suzuki et al. 2002), rats (Odum et al. 2002), and Chinese rare minnows (Zhong et al. 2005) have found no association between prenatal DES exposure and secondary sex ratio, whereas studies in rats exposed pre-conceptually to DES had an increased proportion of male offspring (Sharpe et al. 1995). We evaluated the association between in utero DES exposure in women and the secondary sex ratio of their offspring in a large collaborative study of participants with and without documented exposure to DES. Based on previous studies of sex steroid hormone levels in women exposed in utero to DES and the possible influence of these hormones on sex ratio (James 1987), we hypothesized that DES-exposed women would have a higher proportion of male offspring than unexposed women.

To examine the association between breast density and risk of breast ductal carcinoma in situ (DCIS).We assessed breast density in relation to DCIS risk using combined data from statewide mammography registries in NH and VT. The prospective analyses were based on 572 DCIS cases arising in 154,936 women (58,496 premenopausal and 96,440 postmenopausal). Women in the study were followed on average 4.1 years. Breast density was scored by community radiologists using BIRADS categories (fatty, scattered density, heterogeneous density, extreme density).In premenopausal women, based on 157 cases, the RR for DCIS risk were 0.29 (95% CI: 0.0.04, 2.24) for fatty breasts, 2.06 (95% CI: 1.39, 3.05) for heterogeneous density, and 2.40 (95% CI: 1.47, 3.91) for extreme density, relative to scattered density. In postmenopausal women, based on 369 cases, the RR for DCIS risk were 0.58 (95% CI: 0.37, 0.93) for fatty breasts, 1.41 (95% CI: 1.12, 1.78) for heterogeneous density, and 1.49 (95% CI: 0.93, 2.37) for extreme density, relative to scattered density. The possible interaction between breast density and menopausal status in relation to DCIS risk was not statistically significant.We observed an association between breast density and DCIS risk. Although the association seemed stronger in premenopausal women, there was no evidence of an interaction involving breast density and menopausal status.