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Few studies have assessed the association between endogenous steroid hormone levels and a subsequent diagnosis of endometriosis. We prospectively evaluated premenopausal plasma sex hormone levels and the risk of laparoscopically confirmed endometriosis in a nested case-control study within Nurses’ Health Study II. Between blood collection (1996–1999) and 2009, we ascertained 446 women with incident endometriosis and matched them to 878 controls through risk-set sampling. We conducted multivariable conditional logistic regression accounting for matching and confounders to estimate relative risks (RRs) and 95% confidence intervals (CIs). Women with greater early follicular-phase total or free estradiol levels had a nonlinear increased risk of endometriosis (early follicular total estradiol: second quartile vs. first, RR = 2.23 (95% CI: 1.44, 3.47); third quartile, RR = 1.83 (95% CI: 1.16, 2.88); fourth quartile, RR = 1.68 (95% CI: 1.05, 2.68); early follicular free estradiol: second quartile vs. first, RR = 1.63 (95% CI: 1.05, 2.54); third quartile, RR = 2.02 (95% CI: 1.31, 3.12); fourth quartile, RR = 1.04 (95% CI: 0.66, 1.65)). Free testosterone assessed in quartile categories was not associated with endometriosis, although a threshold effect was observed, with a positive association among women in the top 2% of free testosterone levels. Levels of mid–luteal-phase total and free estradiol, follicular and luteal estrone, total testosterone, progesterone, and sex hormone binding globulin were not associated with endometriosis risk. These results support the role of sex steroids in endometriosis etiology, although the relationships suggest complex threshold effects.

Supplemental Table 1: Adjusted geometric mean hormone levels by lifetime ovulatory years quartile among postmenopausal women not using hormone therapy at the time of blood draw in the Nurses' Health Study; excluding hysterectomized women whose age at menopause was n=1683

Background:Lifetime ovulatory years (LOY) is estimated by the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influences sex hormone levels in postmenopausal women with at least one intact ovary not using hormones.Methods:Estradiol, estrone, estrone sulfate, total testosterone, dehydroepiandrostendione sulfate, prolactin, and sex hormone binding globulin were measured in 1,976 postmenopausal women from the Nurses’ Health Study. Associations of age, body mass index (BMI), smoking, alcohol use, and other factors on hormones were assessed by t tests and ANOVA. Linear regression was used to assess multivariable adjusted associations between LOY and hormones and trends in hormone levels per 5-year increases in LOY were estimated.Results:Women averaged 61.4 years old, 11.0 years since menopause, with BMI of 25.8 kg/m2. A total of 13.6% had irregular cycles, 17.5% hysterectomy, 6.4% unilateral oophorectomy, and 13.8% were current smokers. Variables associated with one or more hormone levels were included as covariates. Each 5-year increase in LOY was significantly associated with a 5.2% increase in testosterone in women with BMI < 25 kg/m2 and a 7.4% increase in testosterone and 7.3% increase in estradiol in women with above-average BMI.Conclusions:This is the first study to show that greater LOY is associated with higher testosterone in postmenopausal women and higher estradiol in those with elevated BMI, suggesting accumulation of functioning stromal and thecal cells from repeated ovulations and peripheral conversion of testosterone.Impact:A possible explanation for why greater LOY increases risk for breast, endometrial, and ovarian cancer is offered.

Objective Pelvic floor pain, abdominal wall pain, and central nervous system pain amplification can be contributing factors in chronic pelvic pain (CPP), however; limited research has investigated the association of pelvic floor, abdominal, and uterine tenderness with central nervous system pain amplification. We assessed whether pressure pain thresholds on the non-dominant thumbnail, a marker of central nervous system pain amplification, were associated with pelvic floor, abdominal, and uterine tenderness among women with endometriosis or CPP. Study design We conducted a cross-sectional study among 88 females with endometriosis and/or CPP. Abdominal (6 locations), pelvic floor (6 locations) and uterine (1 location) tenderness were assessed via a standardized physical exam. Participants reported their pain levels (0–10 scale) with application of 2 kg of pressure at each area, with a pain rating of ≥4 on the 0–10 scale considered moderate to severe pain. Pain sensitivity was measured on the non-dominant thumbnail by applying discrete pressure stimuli using a previously validated protocol. Results Overall, 50% (44/88), 42% (37/88), and 58% (51/88) of participants reported high pelvic floor, abdominal, and uterine tenderness, respectively. Pressure intensities needed to elicit ‘faint’ and ‘mild’ pain were lower for participants with high vs. low pelvic floor tenderness (median intensity for ‘faint’ pain = 0.50 kgf/cm2(min–max:0.25–3.25) vs. 1.06(0.25–3.00), p-value = 0.006; median intensity for ‘mild’ pain = 2.00(0.63–4.88) vs. 2.63(0.75–6.00), p-value = 0.03). No association was observed between pressure pain sensitivity and abdominal or uterine tenderness (p > 0.11). Participants with endometriosis without pain were less likely to have high pelvic floor (22.2%), abdominal (11.1%), and uterine (25.9%) tenderness compared to participants with endometriosis with pain (63.0%, 50%, 65.2%, respectively) and participants with chronic pelvic pain (60%, 73.3%, 93.3%, respectively). Conclusions These results suggest that high pelvic floor tenderness among women with endometriosis/CPP may be a marker of heightened pain sensitivity suggestive of central nervous system pain amplification and may impact treatment response. Future research should examine whether this clinical phenotype predicts response to medical and behavioral treatments (e.g, anti-convulsants, behavioral therapy, Physical Therapy).

Background: Estimated lifetime ovulatory years (LOY) is the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influence sex-hormone levels in postmenopausal women not using hormone therapy. Methods: Hormones, including estradiol and testosterone, were measured in 1976 postmenopausal women from the Nurses’ Health Study in plasma collected in 1990. Effects of age, years since menopause, body mass index (BMI), smoking status, and hysterectomy on hormone levels were assessed by t-tests and ANOVA. Multivariable linear regression was used to assess associations between LOY and hormones adjusted for potential confounders and the trend in hormone levels per 5-year increases in LOY estimated. Results: Women in the sample averaged: 61.4 years old at blood draw, 11.0 years since menopause, with a BMI of 25.8 kg/m2. 17.5% had a hysterectomy and 13.8% were current smokers. These characteristics were associated with one or more hormone levels and included as adjustment variables. Each 5-year increase in LOY was associated with a 6.0% increase in testosterone (95% CI 3.3%, 8.7%) in all women. In women with above-average BMI, each 5-year increase in LOY was associated with a 7.3% (3.5%, 11.2%) increase in testosterone, a 6.9% (2.7%,11.3%) increase in estradiol, and a 6.9% (2.9%,10.9%) increase in estrone. Conclusion: Greater LOY is associated with higher testosterone in postmenopausal women as well as greater estradiol in those with above-average BMI. This may be due to an accumulation of functioning stromal and thecal cells from repeated ovulation and peripheral conversion of testosterone. Citation Format: Daniel W. Cramer, Allison F. Vitonis, Tianyi Huang, Amy L. Shafrir, Heather Eliassen, Robert L. Barbieri, Susan E. Hankinson. Ovulatory years prior to menopause and postmenopausal endogenous hormone levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB137.

STUDY QUESTION How accurately do women report a diagnosis of endometriosis on self-administered questionnaires? SUMMARY ANSWER Based on the analysis of four international cohorts, women self-report endometriosis fairly accurately with a > 70% confirmation for clinical and surgical records. WHAT IS KNOWN ALREADY The study of complex diseases requires large, diverse population-based samples, and endometriosis is no exception. Due to the difficulty of obtaining medical records for a condition that may have been diagnosed years earlier and for which there is no standardized documentation, reliance on self-report is necessary. Only a few studies have assessed the validity of self-reported endometriosis compared with medical records, with the observed confirmation ranging from 32% to 89%. STUDY DESIGN, SIZE, DURATION We compared questionnaire-reported endometriosis with medical record notation among participants from the Black Women’s Health Study (BWHS; 1995-2013), Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l’Education Nationale (E3N; 1990-2006), Growing Up Today Study (GUTS; 2005–2016), and Nurses’ Health Study II (NHSII; 1989–1993 first wave, 1995–2007 second wave). PARTICIPANTS/MATERIALS, SETTING, METHODS Participants who had reported endometriosis on self-administered questionnaires gave permission to procure and review their clinical, surgical, and pathology medical records, yielding records for 827 women: 225 (BWHS), 168 (E3N), 85 (GUTS), 132 (NHSII first wave), and 217 (NHSII second wave). We abstracted diagnosis confirmation as well as American Fertility Society (AFS) or revised American Society of Reproductive Medicine (rASRM) stage and visualized macro-presentation (e.g. superficial peritoneal, deep endometriosis, endometrioma). For each cohort, we calculated clinical reference to endometriosis, and surgical- and pathologic-confirmation proportions. MAIN RESULTS AND THE ROLE OF CHANCE Confirmation was high—84% overall when combining clinical, surgical, and pathology records (ranging from 72% for BWHS to 95% for GUTS), suggesting that women accurately report if they are told by a physician that they have endometriosis. Among women with self-reported laparoscopic confirmation of their endometriosis diagnosis, confirmation of medical records was extremely high (97% overall, ranging from 95% for NHSII second wave to 100% for NHSII first wave). Importantly, only 42% of medical records included pathology reports, among which histologic confirmation ranged from 76% (GUTS) to 100% (NHSII first wave). Documentation of visualized endometriosis presentation was often absent, and details recorded were inconsistent. AFS or rASRM stage was documented in 44% of NHSII first wave, 13% of NHSII second wave, and 24% of GUTS surgical records. The presence/absence of deep endometriosis was rarely noted in the medical records. LIMITATIONS, REASONS FOR CAUTION Medical record abstraction was conducted separately by cohort-specific investigators, potentially introducing misclassification due to variation in abstraction protocols and interpretation. Additionally, information on the presence/absence of AFS/rASRM stage, deep endometriosis, and histologic findings were not available for all four cohort studies. WIDER IMPLICATIONS OF THE FINDINGS Variation in access to care and differences in disease phenotypes and risk factor distributions among patients with endometriosis necessitates the use of large, diverse population samples to subdivide patients for risk factor, treatment response and discovery of long-term outcomes. Women self-report endometriosis with reasonable accuracy (>70%) and with exceptional accuracy when women are restricted to those who report that their endometriosis had been confirmed by laparoscopic surgery (>94%). Thus, relying on self-reported endometriosis in order to use larger sample sizes of patients with endometriosis appears to be valid, particularly when self-report of laparoscopic confirmation is used as the case definition. However, the paucity of data on histologic findings, AFS/rASRM stage, and endometriosis phenotypic characteristics suggests that a universal requirement for harmonized clinical and surgical data documentation is needed if we hope to obtain the relevant details for subgrouping patients with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by Eunice Kennedy Shriver National Institute of Child Health and Development grants HD48544, HD52473, HD57210, and HD94842, National Cancer Institute grants CA50385, R01CA058420, UM1CA164974, and U01CA176726, and National Heart, Lung, and Blood Institute grant U01HL154386. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. AS, SM, and KT were additionally supported by the J. Willard and Alice S. Marriott Foundation. MK was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (#PIOF-GA-2011-302078) and is grateful to the Philippe Foundation and the Bettencourt-Schueller Foundation for their financial support. Funders had no role in the study design, conduct of the study or data analysis, writing of the report, or decision to submit the article for publication. LA Wise has served as a fibroid consultant for AbbVie, Inc for the last three years and has received in-kind donations (e.g. home pregnancy tests) from Swiss Precision Diagnostics, Sandstone Diagnostics, Kindara.com, and FertilityFriend.com for the PRESTO cohort. SA Missmer serves as an advisory board member for AbbVie and a single working group service for Roche; neither are related to this study. No other authors have a conflict of interest to report. Funders had no role in the study design, conduct of the study or data analysis, writing of the report, or decision to submit the article for publication. TRIAL REGISTRATION NUMBER N/A.

Background: Differential associations between ovarian cancer risk factors and estrogen receptor-α (ERα) ovarian tumor expression have been noted; however, no research has assessed estrogen receptor-β (ERβ) expression. Thus, in exploratory analyses, we assessed the association of several factors with ovarian cancer risk by ERβ tumor status. Methods: We conducted a nested case–control study within the prospective Nurses' Health Study cohorts (NHS/NHSII), with exposures collected through biennial questionnaires. Paraffin-embedded tumor blocks were requested for cases diagnosed from 1976 to 2006 (NHS) and 1989 to 2005 (NHSII) and tissue microarrays were stained for nuclear ERβ (ERβ-nuc) and cytoplasmic ERβ (ERβ-cyto), with any staining considered positive (+). We obtained odds ratios (OR) and 95% confidence intervals (CI) using multivariate polytomous logistic regression. Results: We included 245 cases [43% ERβ-cyto (+) and 71% ERβ-nuc (+)] and 1,050 matched controls. An inverse association was observed between parity and risk of ERβ-nuc (+) (OR, parous vs. nulliparous: 0.46; 95% CI, 0.26–0.81), but not ERβ-nuc (–) tumors (OR, parous vs. nulliparous: 1.51; 95% CI, 0.45–5.04; Pheterogeneity = 0.04). Conversely, parity was inversely associated with ERβ-cyto (–) tumors (OR, parous vs. nulliparous: 0.42; 95% CI, 0.23–0.78), but was not associated with ERβ-cyto (+) tumors (OR, parous vs. nulliparous: 1.08; 95% CI, 0.45–2.63; Pheterogeneity = 0.05). Associations for other exposures, including hormone therapy, did not differ by ERβ-nuc or ERβ-cyto status. Conclusions: Our results suggest that parity may influence ovarian cancer risk, in part, through alterations in ERβ localization within tumor cells. Impact: Alterations in ERβ expression and localization appear to be important for ovarian cancer etiology. Future research should confirm our results and assess potential biologic mechanisms for the observed associations.

Although cells of mushroom-producing fungi typically contain paired haploid nuclei (n + n), most Armillaria gallica vegetative cells are uninucleate. As vegetative nuclei are produced by fusions of paired haploid nuclei, they are thought to be diploid (2n). Here we report finding haploid vegetative nuclei in A. gallica at multiple sites in southeastern Massachusetts, USA. Sequencing multiple clones of a single-copy gene isolated from single hyphal filaments revealed nuclear heterogeneity both among and within hyphae. Cytoplasmic bridges connected hyphae in field-collected and cultured samples, and we propose nuclear migration through bridges maintains this nuclear heterogeneity. Growth studies demonstrate among- and within-hypha phenotypic variation for growth in response to gallic acid, a plant-produced antifungal compound. The existence of both genetic and phenotypic variation within vegetative hyphae suggests that fungal individuals have the potential to evolve within a single generation in response to environmental variation over time and space.

PROBLEM Associations between immune dysfunction conditions (eg, systemic lupus erythematous, rheumatoid arthritis) and endometriosis have been observed in adult women, but not assessed among a younger population. We investigated the association between immune-mediated conditions and endometriosis among young women. METHOD OF STUDY This cross-sectional analysis in the Women's Health Study: From Adolescence to Adulthood included 551 participants with surgically diagnosed endometriosis (median age=19) and 652 controls without endometriosis (median age=24). Participants completed an expanded Endometriosis Phenome and Biobanking Harmonization Project questionnaire. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to investigate the associations between autoimmune/inflammatory, atopic, chronic pain/fatigue, and endocrine disorders with endometriosis, adjusting for confounders. RESULTS Participants with any autoimmune and/or inflammatory condition had an increased odds of co-occurring endometriosis (OR: 1.87; CI: 0.92-3.80), as did participants with allergies (OR: 1.76; CI: 1.32-2.36), asthma (OR: 1.35; CI: 0.97-1.88), chronic fatigue syndrome and/or fibromyalgia (OR: 5.81; CI: 1.89-17.9), or previous mononucleosis (OR: 1.75; CI: 1.14-2.68). Odds of endometriosis were lower among participants with eczema (OR: 0.68; CI: 0.44-1.04). We observed a positive trend between the number of immune-mediated conditions and the odds of endometriosis (p-trend=0.0002). Endocrine disorders were not associated with endometriosis. CONCLUSIONS Among this population of adolescents and adult women, endometriosis was more likely among participants with autoimmune and/or inflammatory diseases, allergies, asthma, previous mononucleosis infection, and chronic fatigue and/or fibromyalgia. We observed that an increasing number of immune-mediated conditions were positively associated with endometriosis risk. It is important for clinicians who care for adolescents and women with these conditions to consider endometriosis as a comorbidity.

Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses’ Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65–0.91]; >10 years of use, 0.43 [0.32–0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41–0.67]) and second-generation progestins (0.43 [0.30–0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50–0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49–0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (

Endometriosis is a painful gynecologic disease affecting one in ten reproductive aged women worldwide. Few studies have correlated this symptomatology with biomarker levels among women with and without endometriosis, and no studies correlating pain with biomarker levels have been performed in young patient populations. The purpose of this study was to examine whether CA125 correlates with different types and severity of pain among adolescents and young women with and without endometriosis and assess its performance as an endometriosis biomarker among those presenting with dysmenorrhea in this young population. Reproductive-aged women with laparoscopically-confirmed endometriosis (n = 282) and controls (n = 293) who participated in The Women's Health Study: From Adolescence to Adulthood (A2A), a cohort of adolescents and young women enrolled from 2012-2018, were included in this cross-sectional analysis. Plasma CA125 values were measured using WERF EPHect compliant blood samples collected at enrollment. Average CA125 were calculated by self-reported pain type (i.e. dysmenorrhea, non-cyclic/general pelvic pain, dyspareunia), severity, and frequency in endometriosis cases and controls. Median age at blood draw was 24 years in controls and 17 years in cases, with 68% and 89% non-Hispanic white, respectively. Most endometriosis cases (95%) were rASRM stage I/II. Average CA125 values were 12.5 U/mL in controls and 12.1 U/mL in cases adjusted for age. CA125 did not differ by pain type, its severity, or frequency in endometriosis cases or controls. Among participants who reported dysmenorrhea, CA125 did not discriminate endometriosis cases from controls using cutoff of 35 U/mL (AUC = 0.51, 95%CI = 0.50-0.53). Among adolescents and young adult women, CA125 did not correlate with pain type. CA125 did not efficiently discriminate endometriosis cases from controls even when accounting for pain symptomatology. Average CA125 values were low in adolescents and young women in both endometriosis cases and controls, suggesting cautious interpretation may be needed when measuring CA125 in this population.

Endometriosis affects approximately 10% of women of reproductive age. Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk. Relationships with other potential characteristics including physical activity, dietary factors, and lactation have been less consistent, partially because of the need for rigorous data collection and a longitudinal study design. Critical methodologic complexities include the need for a clear case definition; valid selection of comparison/control groups; and consideration of diagnostic bias and reverse causation when exploring demographic characteristics, medical history, and lifestyle factors. Reviewers and editors must demand a detailed description of rigorous methods to facilitate comparison and replication to advance our understanding of endometriosis.

Background: One model of ovarian cancer development model divides tumors into two types. Type I tumors are characterized by KRAS and BRAF mutations, which can activate mitogen-activated protein kinase (MAPK). Type II tumors are characterized by tubal precursor lesions with p53 mutations. We evaluated the association between lifestyle and reproductive factors and risk of ovarian cancer defined by p53 and MAPK expression. Methods: Epithelial ovarian cancer cases (n = 274) and controls (n = 1,907) were identified from the Nurses' Health Study and Nurses' Health Study II prospective cohorts, and the population-based New England Case–Control study. Reproductive and lifestyle exposures were assessed by questionnaire/interview. We performed immunohistochemical assays for p53 and MAPK expression. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using polytomous logistic regression. Results: Parity was associated with a decreased risk of p53 wild-type tumors (OR = 0.31; 95% CI, 0.18–0.55), but not p53-mutant tumors (OR = 0.92; 95% CI, 0.54–1.59)(Pheterogeneity < 0.01). Family history of breast or ovarian cancer was associated with risk of MAPK-negative (OR = 2.06; 95% CI, 1.39–3.06), but not MAPK-positive tumors (OR = 0.74; 95% CI, 0.43–1.27; Pheterogeneity< 0.01). In cross-classified analyses, family history of breast or ovarian cancer was most strongly associated with p53-mutant/MAPK-negative tumors (OR = 2.33; 95% CI, 1.44–3.75). Differences by MAPK expression were also observed for estrogen plus progesterone hormone therapy use (Pheterogeneity = 0.03). Conclusions: These findings provide evidence that parity, family history, and estrogen plus progesterone hormone therapy use may be differentially associated with tumor subtypes defined by p53 and MAPK expression. Impact: In future studies, other immunohistochemical markers or gene expression profiles that more clearly define these subtypes should be considered. Cancer Epidemiol Biomarkers Prev; 27(1); 96–102. ©2017 AACR.

Reproductive events, such as ovulation, trigger an inflammatory cascade. Few studies have examined their long-term influence on inflammatory profiles. We included 3,393 premenopausal and 3,915 postmenopausal women with intact ovaries/uterus from the Nurses’ Health studies (Nurses’ Health Study (1989–1990) and Nurses’ Health Study II (1996–1999)) in an analysis of the association between lifetime ovulatory years (LOY) and levels of inflammatory biomarkers. We estimated LOY as age at menopause (age at blood collection for premenopausal women) minus age at menarche, subtracting years of oral contraceptive (OC) use and 1 year per pregnancy. After adjustment for other inflammation-related factors (e.g., body mass index, exercise, diet), every 5-year increase in LOY was associated with lower C-reactive protein (CRP) levels in both premenopausal (difference = −11.5%, 95% confidence interval: −15.0, −8.0; P

In this issue of the American Journal of Epidemiology, Huang et al. (Am J Epidemiol. 2020;189(7):660–670) report an inverse relationship between lifetime ovulatory years (LOY) and circulating levels of C-reactive protein (CRP), counter to their hypothesis. CRP is a nonspecific systemic marker of chronic inflammation, and there is evidence that there are other drivers of systemic inflammation as measured by CRP. There also is a body of evidence supporting the possibility that ovulation may be responsible for a localized inflammatory response. Because ovarian cancer is the fifth most common cause of cancer death in women, preventive strategies are urgently needed. The findings of this report underscore the need for new research initiatives to determine the relationship between incessant ovulation and ovarian cancer risk in order to identify mechanisms of carcinogenesis.

Purpose: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. Experimental Design: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. Results: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Conclusions: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. Clin Cancer Res; 24(6); 1389–401. ©2017 AACR.

Oophorectomy prior to natural menopause reduces breast cancer risk. We evaluated whether timing of oophorectomy (during premenopause vs. postmenopause) or hysterectomy was associated with hormone levels, specifically estradiol, estrone, estrone sulfate, testosterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and prolactin, using data from the Nurses’ Health Study. We included 2,251 postmenopausal women not using hormones who provided blood samples in 1989–1990 and/or 2000–2002, and who were controls in various nested case–control studies. We used multivariate linear mixed-effects models to assess geometric mean hormone levels by surgery status. Bilateral oophorectomy was associated with 25 % lower testosterone levels versus women with natural menopause (20.8 vs. 15.5 ng/dL) (P < 0.0001) with no effect of timing of surgery (P = 0.80). SHBG levels were lower among women with a premenopausal oophorectomy (52.2 nmol/L) versus those with natural menopause (58.1 nmol/L) or a postmenopausal oophorectomy (62.0 nmol/L) (P = 0.02). There was no significant association of oophorectomy with estradiol, estrone, estrone sulfate, DHEAS, or prolactin levels (P ≥ 0.23). A simple hysterectomy was associated with a significant 8 % lower testosterone (P = 0.03) and 14 % lower DHEAS (P = 0.02) levels compared with women with natural menopause but not with other hormone levels. Although limited by small numbers, our findings suggest no differential influence of timing of surgery on sex hormone levels. The reduction of testosterone levels in women with oophorectomy or hysterectomy suggests a possible role of this hormone in postmenopausal breast cancer development.

Oral contraceptives (OCs) have been consistently associated with a reduced ovarian cancer risk; however, most previous studies included women in older birth cohorts using high-dose OC formulations. We assessed OC use, including type and dose, and ovarian cancer risk among women born between 1947 and 1964 using more recent formulations. We included 110,929 Nurses’ Health Study II participants. Women reported duration of OC use and brands used from age 13 to baseline (1989) and every 2 years thereafter through 2009. We categorized brands by estrogen and progestin type, dose, and potency, and used Cox proportional hazards models, adjusted for age, calendar time, reproductive factors, and body mass index, to assess associations with ovarian cancer. Over 2,178,679 person-years of follow-up, we confirmed 281 cases. At baseline, 83% of participants reported ever using OCs. Compared to never use, we observed an increased risk of ovarian cancer with ≤6 months of OC use (HR 1.82; 95% CI 1.13–2.93) but a non-significant 57% (95% CI 0.18–1.03) decreased risk with ≥15 years of OC use. The increased risk among short-term users (≤1 year) was restricted to OCs containing mestranol (HR 1.83; 95% CI 1.16–2.88) and first-generation progestin (HR 1.72; 95% CI 1.11–2.65). The associations between OCs and ovarian cancer observed for this younger birth cohort differ substantially from the results of previous cohort studies, possibly reflecting changes in OC formulations and use patterns over time, although these results could be due to chance. Additional studies should evaluate newer OC formulations and ovarian cancer risk.

Objective We assessed the association between reproductive and hormonal factors and ovarian cancer incidence characterized by estrogen receptor-α (ERα) and progesterone receptor (PR) status. Methods Tissue microarrays were used to assess ERα and PR expression among 197 Nurses' Health Study (NHS), 42 NHSII and 76 New England Case-Control Study (NECC) ovarian cancer cases. NHS/NHSII cases were matched to up to 4 controls (n=954) on diagnosis date and birth year. NECC controls (n=725) were frequency matched on age. Cases were considered receptor positive if ≥1% of tumor cells stained positive. Associations by ERα and PR status were assessed using polytomous logistic regression. p-Value for heterogeneity was calculated using a likelihood ratio test. Results 45% of ovarian tumors were PR(+), 78% were ERα(+) and 45% were ERα(+)/PR(+), while 22% were ERα(–)/PR(–). Postmenopausal status was associated with an increased risk of PR(–) tumors (OR: 2.07; 95%CI: 1.15–3.75; p-heterogeneity=0.01) and age at natural menopause was inversely associated with PR(–) tumors (OR, per 5years: 0.77; 95%CI: 0.61–0.96; p-het=0.01). Increasing duration of postmenopause was differentially associated by PR status (p-het=0.0009). Number of children and tubal ligation were more strongly associated with ERα(–) versus ERα(+) tumors (p-het=0.002 and 0.05, respectively). No differential associations were observed for oral contraceptive or hormone therapy use. Conclusions Postmenopausal women have an increased risk of developing PR(–) ovarian tumors compared to premenopausal women. The associations observed for ovarian cancer differ from those seen for breast cancer suggesting that the biology for tumor development through ERα and PR pathways may differ.

Background: Ovarian cancer survival is poor, particularly for platinum-resistant cases. The previous literature on pre-diagnostic reproductive factors and ovarian cancer survival has been mixed. Therefore, we evaluated pre-diagnostic reproductive and hormonal factors with overall survival and, additionally, platinum-chemotherapy resistance. Methods: We followed 1649 invasive epithelial ovarian cancer cases who were enrolled between 1992 and 2008 for overall mortality within the New England Case-Control Study and abstracted chemotherapy data on a subset (n=449). We assessed pre-diagnostic reproductive and hormonal factors during in-person interviews. We calculated hazard ratios (HRs) using Cox-proportional hazards models. Results: We observed 911 all-cause deaths among 1649 ovarian cancer cases. Self-reported endometriosis and longer duration of hormone therapy use were associated with improved survival (HR: 0.72; 95% confidence interval (CI): 0.54–0.94 and HR, ⩾5 years vs never: 0.70; 95% CI: 0.55–0.90, respectively). Older age at menopause and menarche were associated with worse survival (HR, ⩽50 vs >50 years: 1.23; 95% CI: 1.03–1.46 and HR, 13 vs

Objectives An earlier investigation raised concern that some cancer cases might be linked to work at a semiconductor manufacturing plant. The aim of this study was to describe an update of the cancer incidence and mortality of these workers and assess whether workplace exposures contributed to any increased risk of selected cancers. Methods Standardised mortality ratios and standardised incidence ratios were calculated for cancer site groups of a priori interest in a cohort previously flagged against the National Health Service Central Register, with follow-up extended to the 2007 for deaths and 2006 for cancer registrations. Cases of female breast cancer, lung and stomach cancer, and male brain cancer, and a random sample of control subjects individually age-matched to the breast cancer cases, were identified from within the cohort dataset and invited to participate via General Practitioners. Exposures were estimated using a job exposure matrix developed from a historical hygiene assessment and assigned to job histories obtained from personal interview of subjects (or proxies). Results Though the findings were uncertain, there were no excesses of mortality or cancer incidence, either overall or for specific cancer sites, suggestive of a workplace effect. Logistic regression analyses comparing 20 cases of breast cancer with 83 matched controls showed no consistent evidence of any relationship with occupational exposures. Assessment of commonalities of workplace exposures among case sets for other cancer types was limited by the small numbers. Conclusions These results do not support earlier concerns about occupational cancer risks among this cohort.

BACKGROUND: One recent model of ovarian cancer development divides ovarian cancer into two types. Type II tumors are fast growing, potentially arising from the fallopian tubes, and characterized by tubal precursor lesions with p53 mutations. Type I tumors are slow–growing, arising from the ovary, and characterized by KRAS, BRAF, and PTEN mutations. The purpose of this study was to evaluate the association between selected lifestyle and reproductive risk factors and risk of ovarian cancer defined by expression of p53 (as a marker of Type II disease) and mitogen–activated protein kinase (MAPK), which is upregulated by KRAS and BRAF (as a marker of Type I disease). METHODS: Epithelial ovarian cancer cases with available tumor blocks and cancer–free controls were identified from the Nurses' Health Study (NHS) and NHS II prospective cohorts, and from the population–based New England Case–Control (NECC) study of ovarian cancer. We performed immunohistochemical assays for p53 and MAPK expression. Age– and multivariable–adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between each lifestyle or reproductive risk factor (e.g. parity, oral contraceptive use, tubal ligation, age at menarche, menopausal status, age at menopause, hormone therapy use, and family history of ovarian cancer) and ovarian cancer using polytomous logistic regression. RESULTS: 249 cases and 1051 controls from the NHS/NHS II and 77 cases and 857 controls from the NECC study were included in the analyses. Overall there were few significant differences in lifestyle or reproductive risk factors by p53 or MAPK tumor expression. Increasing parity was associated with a greater decreased risk of p53 negative tumors (OR=0.40; 95% CI=0.26–0.62) than p53 positive tumors (OR=0.85; 95% CI=0.46–1.57) (pheterogeneity=0.03). Family history of ovarian cancer was associated with risk of developing MAPK negative (OR=1.87; 95% CI=1.28–2.74) but not MAPK positive tumors (OR=0.76; 95% CI=0.46–1.23) (pheterogeneity CONCLUSIONS: These findings provide evidence that parity and family history may be associated with tumor subtypes defined by p53 and MAPK expression. However, in future studies other immunohistochemical markers that more clearly define these subtypes should be considered. Citation Format: Holly R. Harris, Megan S. Rice, Amy L. Shafrir, Elizabeth M. Poole, Jonathan L. Hecht, Kathryn L. Terry, Shelley S. Tworoger. LIFESTYLE AND REPRODUCTIVE RISK FACTORS AND OVARIAN CANCER RISK BY p53 AND MAPK EXPRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-008.

We recently reported that high levels of multiple sex and growth hormones were associated with increased postmenopausal breast cancer risk. Limited research has explored the relationship between reproductive, anthropometric, and lifestyle factors and levels of multiple hormones simultaneously.This cross-sectional analysis included 738 postmenopausal Nurses' Health Study participants who were controls in a breast cancer nested case-control study and had measured levels of estrone, estradiol, estrone sulfate, testosterone, androstenedione, dehydroepiandrosterone sulfate, prolactin, and sex hormone binding globulin (SHBG). A score was created by summing the number of hormones a woman had above (below for SHBG) each hormone's age-adjusted geometric mean. The association between lifestyle, anthropometric, and reproductive exposures and the score was assessed using generalized linear models.The hormone score ranged from 0 to 8 with a mean of 4.0 (standard deviation = 2.2). Body mass index (BMI) and alcohol consumption at blood draw were positively associated with the hormone score: a 5 unit increase in BMI was associated with a 0.79 (95%CI: 0.63, 0.95) unit increase in the score (p 0.0001) and each 15 g/day increase in alcohol consumption was associated with a 0.41 (95%CI: 0.18, 0.63) unit increase in the score (p = 0.0004). Family history of breast cancer, age at menarche, and physical activity were not associated with the score.Reproductive breast cancer risk factors were not associated with elevated levels of multiple endogenous hormones, whereas anthropometric and lifestyle factors, particularly BMI and alcohol consumption, tended to be associated with higher levels of multiple hormones.

Background: This study estimates the potential population health burden from exposure to combustion-derived particulate air pollution in domestic settings in Ireland and Scotland. Methods: The study focused on solid fuel combustion used for heating and the use of gas for cooking. PM2.5 (particulate matter with an aerodynamic diameter < 2.5 mu m) was used as the pollutant mixture indicator. Measured PM2.5 concentrations in homes using solid fuels were adjusted for other sources of PM2.5 by subtracting PM2.5 concentrations in homes using gas for cooking but not solid fuel heating. Health burden was estimated for exposure indoors 6 pm - midnight, or all day (24-hour), by combining estimated attributable annual PM2.5 exposures with (i) selected epidemiological functions linking PM2.5 with mortality and morbidity (involving some re-scaling from PM10 to PM2.5, and adjustments 'translating' from concentrations to exposures) and (ii) on the current population exposed and background rates of morbidity and mortality. Results: PM2.5 concentrations in coal and wood burning homes were similar to homes using gas for cooking, used here as a baseline (mean 24-hr PM2.5 concentrations 8.6 mu g/m(3)) and so health impacts were not calculated. Concentrations of PM2.5 in homes using peat were higher (24-hr mean 15.6 mu g/m(3)); however, health impacts were calculated for the exposed population in Ireland only; the proportion exposed in Scotland was very small. The assessment for winter evening exposure (estimated annual average increase of 2.11 mu g/m(3) over baseline) estimated 21 additional annual cases of all-cause mortality, 55 of chronic bronchitis, and 30,100 and 38,000 annual lower respiratory symptom days (including cough) and restricted activity days respectively. Conclusion: New methods for estimating the potential health burden of combustion-generated pollution from solid fuels in Irish and Scottish homes are provided. The methodology involves several approximations and uncertainties but is consistent with a wider movement towards quantifying risks in PM2.5 irrespective of source. Results show an effect of indoor smoke from using peat (but not wood or coal) for heating and cooking; but they do not suggest that this is a major public health issue.

Introduction: Ovarian cancer survival is poor particularly for women with platinum-resistant disease. Therefore evaluating pre-diagnostic risk factors that are associated with ovarian cancer survival and platinum resistance in particular may help identify women who will not benefit from standard therapy. However, limited research has assessed pre-diagnostic reproductive and hormonal factors in relation to ovarian cancer survival and no studies have assessed these factors with platinum resistance. Objective: To evaluate the association of pre-diagnostic reproductive and hormonal factors with both ovarian cancer survival and platinum resistance among ovarian cancer patients. Methods: We included 1,648 cases of invasive epithelial ovarian cancer from a population-based case-control study with cases and controls recruited in Eastern Massachusetts and New Hampshire from 1992-2008. Reproductive and hormonal factors, including oral contraceptive use, parity, tubal ligation and endometriosis, were assessed during in-person interviews. Invasive ovarian cancer cases who received platinum chemotherapy and had medical record follow-up data (n=610) were included in the analyses on platinum resistance, which was defined as a recurrence within the first six months after the end of platinum-based chemotherapy. We used Cox proportional hazards models to calculate overall ovarian cancer survival and platinum resistance controlling for age, enrollment wave, reproductive factors, and tumor histology and stage. The same reproductive and hormonal factors were assessed for ovarian cancer survival and platinum resistance. As the cause of death was not known for all cases, we also restricted follow-up to the first five years when the vast majority of deaths should be from ovarian cancer in a secondary analysis. Results: We observed 906 deaths during 13,920 person-years of follow-up. Self-report of a physician diagnosis of endometriosis was associated with a 28% (95% CI: 0.55-0.95; p=0.02) decreased risk of death from ovarian cancer. We observed no association between oral contraceptive use, parity, age at first birth, and ovulatory years and ovarian cancer survival (p>0.17). Restricting analyses to the first five years did not substantially change the results. In preliminary analyses, 162 of the 610 women with platinum-based therapy had a disease recurrence within six months of ending treatment over 3,216 person-months of follow-up. Ever having a spontaneous or induced abortion was associated with a 44% (95% CI: 1.00-2.07; p=0.05) increased risk of platinum resistance but was not associated with overall ovarian cancer survival (p=0.18). Additionally, there was a suggestion that increasing age at menarche (Hazard ratio (HR): 1.13; 95% CI: 0.99-1.29 per year; p=0.07) and physician-diagnosed endometriosis (HR: 0.45; 95% CI: 0.19-1.05; p=0.06) were associated with platinum resistance. No association was observed for oral contraceptive use, parity, age at first birth, and ovulatory years (p>0.53), although the results were based on a small sample size. Conclusion: Increasing age at menarche and ever having a spontaneous or induced abortion were associated with an increased risk of platinum chemotherapy resistance. Additionally, physician-diagnosed endometriosis was associated with a reduced risk of ovarian cancer death and a suggestion of a reduced risk of platinum-resistance after adjusting for various factors including tumor histology. Although endometriosis increases the risk of endometrioid and clear cell tumors, which tend to have a more favorable prognosis, our data suggest endometriosis may improve survival through pathways other than tumor histology. Citation Format: Amy L. Shafrir, Ana Babic, Rulla M. Tamimi, Bernard A. Rosner, Shelley S. Tworoger, Kathryn L. Terry. Reproductive and hormonal risk factors in relation to ovarian cancer survival and platinum resistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B33.

Objectives To describe an update of the cancer incidence and mortality of workers at a Scottish semiconductor manufacturing facility to assess potential workplace cancer risks. Methods Company records had been used to identify a cohort of 4388 workers employed at the facility between 1970 and 1999. Subjects were flagged against National Health Service records for notification of cancer registrations and deaths. Standardised mortality (to end 2007) and cancer registration (to end 2006) ratios (SMRs and SRRs) were calculated for cancer site groups of a priori interest, comparing with Scottish rates adjusted for local deprivation status. Results There was a substantial deficit of mortality overall, particularly among men, compatible, at least in part, with a healthy work effect: SMR% (males) 45, 95% CI 34 to 57; SMR% (females) 73, 95% CI 58 to 90. Total cancer registrations were consistent with expectation for men (SRR% 90, 95% CI 69 to 116) and women (SRR% 102, 95% CI 85 to 122). SRRs for four cancer sites highlighted in an earlier analysis (lung, stomach and breast cancer in women; and brain cancer in men) were not statistically significantly elevated overall; neither were those for any other cancer site group. Analyses of cohort subgroups (including a group more likely to have worked in areas using carcinogens) by time since first employment, and analyses by duration of employment did not reveal any associations suggestive of a workplace effect on cancer rates. Conclusions This analysis does not support earlier concerns about a possible link between working at the facility and increased risks of cancer.

Objectives HSE9s 2001 report on cancer in a Scottish cohort of semiconductor manufacturing workers showed some statistically significant results, suggestive of increased risks. Recently, the follow-up in the cohort was extended. We report on a case-based study to investigate these suggestions. Methods From the extended follow-up, cases of breast, stomach and lung cancer in women, and of brain cancer in men were identified. It was planned that the lung and breast cancer cases would be interviewed and compared with matched controls, and that the rarer stomach and brain cancers would be examined case-only. A questionnaire was designed to collect detailed employment histories within the factory and elsewhere, information relevant to possible asbestos exposure, and lifestyle and environmental factors. A historical hygiene assessment was carried out at the factory, to inform construction of a job-exposure matrix. Results Attempts to recruit cases (or proxy respondents) were only partially successful; as a result, the lung cancers element was converted to a case-only study. Comparison with controls was possible for only 20 breast cancer cases (including 7 proxy respondents). From an extensive programme of conditional logistic analyses, statistical significance was achieved for exposure to arsenic compounds, antimony trioxide and sulphuric acid mist and to gases in general, but only in a few of the analyses. Examination of proxy responses for stomach, lung and brain cancers did not suggest any common workplace factors for any of these outcomes. Conclusions We interpreted this evidence as not supportive of an occupational risk for any of the cancers.