Publications by authors named "Kathryn L Terry"

179 Publications

Common Analgesic Use for Menstrual Pain and Ovarian Cancer Risk.

Cancer Prev Res (Phila) 2021 Aug 9;14(8):795-802. Epub 2021 Jul 9.

Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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 ( ≤ 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.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0090DOI Listing
August 2021

Identification of a Locus Near Associated With Progression-Free Survival in Ovarian Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Jun 23. Epub 2021 Jun 23.

Gynecologic Oncology Center, Kiel, Germany.

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.

Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.

Results: We found seven SNPs at 12q24.33 associated with PFS ( < 5 × 10), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; = 1.47 × 10). High expression of a nearby gene, , is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin .

Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. is a plausible candidate for the target of this association.

Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1817DOI Listing
June 2021

Cardiovascular medications and survival in people with ovarian cancer: A population-based cohort study from British Columbia, Canada.

Gynecol Oncol 2021 Aug 3;162(2):461-468. Epub 2021 Jun 3.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States.

Objectives: Research examining survival among people with ovarian cancer following use of statins or β-blockers has been conflicting. Many studies to date have suffered from immortal time bias and/or had limited power. To address these limitations, we used time-dependent analyses to study the association between statin or β-blocker use among all people diagnosed with an epithelial ovarian cancer in British Columbia, Canada between 1997 and 2015.

Methods: Population-based administrative data were linked for 4207 people with ovarian cancer. Statin or β-blocker use was examined using time-dependent variables for any use, cumulative duration of use and by user-group according to whether use was initiated before or after their ovarian cancer diagnosis. Cox proportional hazards models were run to estimate the association between statin or β-blocker use and survival.

Results: Any postdiagnosis use of statins was associated with better ovarian cancer survival in the full cohort (adjusted hazard ratio (aHR) = 0.76, 95% CI 0.64, 0.89) and among women with serous cancers (aHR = 0.80, 95%CI 0.67-0.96). This was primarily driven by new use post-diagnosis (aHR = 0.67, 95%CI, 0.51-0.89), but there was a trend towards better survival among those who continued use from before diagnosis (aHR 0.83, 95%CI, 0.68-1.00). There was no statistically significant association between β-blocker use and survival.

Conclusion: Postdiagnosis statin use was associated with improved survival among people with ovarian cancer. Given the consistency of this finding in the literature, we recommend a randomized clinical trial of statin use in people with ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2021.05.021DOI Listing
August 2021

Prediagnosis and postdiagnosis leisure time physical activity and survival following diagnosis with ovarian cancer.

Int J Cancer 2021 Sep 21;149(5):1067-1075. Epub 2021 May 21.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

Little is known about the influence of prediagnosis and postdiagnosis physical activity on ovarian cancer survival. We investigated this association in two large cohorts, the Nurses' Health Study (NHS) and NHSII. Analyses included 1461 women with confirmed invasive, epithelial ovarian cancer and data on physical activity. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality. Ovarian cancer-specific mortality was not associated with physical activity reported 1-8 years before diagnosis overall (≥7.5 vs <1.5 MET-hours/week, HR = 0.96), for high-grade serous/ poorly differentiated tumors, or non-serous/ low-grade serous tumors (P-heterogeneity = .45). An inverse association was observed for activity 1-4 years after diagnosis (≥7.5 vs <1.5 MET-hours/week, HR = 0.67, 95%CI: 0.48-0.94), with similar results by histotype (P-heterogeneity = .53). Women who decreased their activity from ≥7.5 MET-hours/week 1-8 years before diagnosis to <7.5 MET-hours/week 1-4 years after diagnosis, compared to those with <7.5 MET-hours/week across periods, had a 49% increased risk of death (HR = 1.49, 95%CI: 1.07-2.08). Physical activity after, but not before, ovarian cancer diagnosis was associated with better prognosis.
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http://dx.doi.org/10.1002/ijc.33676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282739PMC
September 2021

Self-reported infertility diagnoses and treatment history approximately 20 years after fertility treatment initiation.

Fertil Res Pract 2021 Mar 12;7(1). Epub 2021 Mar 12.

Mel and Enid Zuckerman College of Public Health, University of Arizona, 1295 N. Martin Avenue, Tucson, AZ, 85724, USA.

Background: Infertility history may have important implications for clinical practice and scientific discovery. Previous research on the validity of self-reported infertility measurements has been limited in scope and duration (< 5 years). In this study, we validated self-reported infertility history measures 15-23 years after fertility treatment initiation among women who utilized assisted reproductive technology (ART).

Methods: Women who received ART treatments from three Boston infertility clinics and who enrolled in a prior study (1994-2003) were re-contacted in 2018 for the AfteR Treatment Follow-up Study (ART-FS). Infertility history was collected from clinical records and two self-report questionnaires (at ART initiation and at ART-FS enrollment). Treatment history included specific details (fresh or frozen embryo transfers, number of cycles) and treatment recall prior to ART initiation. Self-reported infertility diagnoses included polycystic ovary syndrome (PCOS), endometriosis, uterine factor infertility, tubal factor infertility, diminished ovarian reserve/advanced maternal age, male factor infertility, and other/unknown. We compared self-reported measures from 2018 to self-reported and clinical data from prior study initiation, using Cohen's kappa, sensitivity, specificity, and 95% confidence intervals.

Results: Of 2644 women we attempted to recontact, 808 completed the ART-FS, with an average follow-up of 19.6 years (standard deviation: 2.7). Recall of fertility treatment usage had moderate sensitivity (IVF = 0.85, Clomiphene/Gonadotropin = 0.81) but low specificity across different infertility treatment modalities (IVF = 0.63, Clomiphene/Gonadotropin = 0.55). Specific IVF details had low to moderate validity and reliability with clinical records. Reliability of recalled infertility diagnosis was higher when compared to self-report at ART initiation (PCOS K = 0.66, Endometriosis K = 0.76, Tubal K = 0.73) than when compared to clinical records (PCOS K = 0.31, Endometriosis K = 0.48, Tubal K = 0.62) and varied by diagnosis.

Conclusions: The ability of women to recall specific IVF treatment details was moderately accurate and recall of self-reported infertility diagnosis varied by diagnosis and measurement method.
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http://dx.doi.org/10.1186/s40738-021-00099-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953690PMC
March 2021

Prospective Analyses of Lifestyle Factors Related to Energy Balance and Ovarian Cancer Risk by Infiltration of Tumor-Associated Macrophages.

Cancer Epidemiol Biomarkers Prev 2021 May 2;30(5):920-926. Epub 2021 Mar 2.

Division of Public Health Sciences, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Lifestyle factors related to energy balance have been associated with ovarian cancer risk and influence the tumor immune microenvironment, including tumor-associated macrophages (TAM). However, no studies have assessed whether these factors differentially impact ovarian cancer risk by TAM densities.

Methods: We conducted a prospective analysis in the Nurses' Health Studies to examine the associations of physical activity, sitting time, and a food-based empirical dietary inflammatory pattern (EDIP) score with invasive epithelial ovarian cancer risk by TAM density assessed by immunohistochemistry. We considered density of CD68 (marker of total TAMs) and CD163 (marker of pro-carcinogenic M2-type TAMs), and their ratios. We used multivariable Cox proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) of exposures with risk of ovarian tumors with high versus low TAMs, including analyses stratified by body mass index.

Results: Analyses included 312 incident ovarian cancer cases with TAM measurements. Physical activity, sitting time, and EDIP score were not differentially associated with ovarian cancer risk by TAM densities ( > 0.05). Among overweight and obese women, higher EDIP score was associated with increased risk of CD163 low-density tumors (HR comparing extreme tertiles, 1.57; 95% CI, 0.88-2.80; = 0.01), but not CD163 high-density tumors (comparable HR, 1.16; 95% CI, 0.73-1.86; = 0.24), though this difference was not statistically significant ( = 0.22).

Conclusions: We did not observe differential associations between lifestyle factors and ovarian cancer risk by TAM densities.

Impact: Future investigations examining the interplay between other ovarian cancer risk factors and the tumor immune microenvironment may help provide insight into ovarian cancer etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102357PMC
May 2021

Intrauterine device use and risk of ovarian cancer: Results from the New England Case-Control study and Nurses' Health Studies.

Int J Cancer 2021 Jul 17;149(1):75-83. Epub 2021 Mar 17.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1002/ijc.33531DOI Listing
July 2021

Depot-Medroxyprogesterone Acetate Use Is Associated with Decreased Risk of Ovarian Cancer: The Mounting Evidence of a Protective Role of Progestins.

Cancer Epidemiol Biomarkers Prev 2021 May 22;30(5):927-935. Epub 2021 Feb 22.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.

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 ( < 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.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1355DOI Listing
May 2021

Co-occurrence of immune-mediated conditions and endometriosis among adolescents and adult women.

Am J Reprod Immunol 2021 Jul 25;86(1):e13404. Epub 2021 Feb 25.

Division of Adolescent and Young Adult Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.1111/aji.13404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243788PMC
July 2021

IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Nature 2021 Mar 3;591(7850):464-470. Epub 2021 Feb 3.

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells, yet exhibit low response rates to immune checkpoint inhibitors. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.
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http://dx.doi.org/10.1038/s41586-020-03144-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969354PMC
March 2021

Racial/ethnic differences in average CA125 and CA15.3 values and its correlates among postmenopausal women in the USA.

Cancer Causes Control 2021 Mar 18;32(3):299-309. Epub 2021 Jan 18.

Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA.

Purpose: Among healthy postmenopausal women, levels of CA125 and CA15.3 are influenced by demographic and reproductive factors, including race/ethnicity. In this study, we sought to examine the interaction between race/ethnicity and other correlates of these biomarkers and whether the racial differences observed are simply determined by other correlates with racial differences.

Methods: In archived sera from 946 postmenopausal women who participated in the 2001-2002 cycle of the National Health and Nutrition Examination Survey, we measured CA125 and CA15.3 and examined their associations with health survey and examination data available in this cohort. We used multivariable linear regression to examine the association between CA125 and CA15.3 and race/ethnicity. We then calculated geometric means of these markers by demographic and reproductive factors stratified by race/ethnicity and used likelihood ratio tests to evaluate heterogeneity.

Results: Non-white race was associated with lower CA125, with Non-Hispanic Black women being associated with - 29.0% (95% CI - 42.5%, - 12.2%) difference and Mexican American women being associated with - 6.4% (95% CI - 18.1%, 6.9%) difference on average compared to Non-Hispanic White women. Associations between CA125 and age and parity varied by race/ethnicity. Non-Hispanic Black women were associated with higher CA15.3 compared to Non-Hispanic White women, with 17.3% (95% CI - 0.5%, 38.3%) differences on average. Associations between CA15.3 and age, number of births, and age at natural menopause varied by race/ethnicity.

Conclusions: Among postmenopausal women, Non-Hispanic Black women were associated with lower CA125 and higher CA15.3 levels compared to Non-Hispanic White women. Our results support that race/ethnicity should be considered when assigning thresholds for these biomarkers being tested for diagnostic or screening purposes.
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http://dx.doi.org/10.1007/s10552-020-01384-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887701PMC
March 2021

A Clinical and Pathologic Exploration of Suspected Peritoneal Endometriotic Lesions.

Int J Gynecol Pathol 2020 Dec 14. Epub 2020 Dec 14.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (J.C.W.) Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital (A.D.D.V., A.F.V., M.R.L., K.L.T., S.A.M.) Departments of Obstetrics and Gynecology (A.F.V., M.R.L., K.L.T.) Pathology (C.P.C.), Brigham and Women's Hospital and Harvard Medical School Department of Medicine, Division of Adolescent and Young Adult Medicine, Boston Children's Hospital and Harvard Medical School (A.D.D.V., S.A.M.) Department of Surgery, Division of Gynecology, Boston Children's Hospital (M.R.L.) Center for Infertility and Reproductive Surgery, Brigham and Women's Hospital (M.R.L.) Department of Epidemiology, Harvard T. H. Chan School of Public Health (K.L.T., S.A.M.), Boston, Massachusetts Department of Pathology, School of Medicine, Stanford University, Stanford, California (B.E.H.) Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan (S.A.M.).

Endometriosis is generally histopathologically defined as the presence of at least 2 of the following: endometrial stroma, Müllerian epithelium, and/or hemosiderin-laden macrophages (HLM). Despite clinically evident endometriotic lesions, biopsies are frequently nondiagnostic. In this study, we conducted a large-scale review of biopsies of lesions clinically thought to represent endometriosis and correlate the histologic findings with clinical appearance to expand sensitivity of the pathologic definition of endometriosis, particularly in patients on hormonal therapy. In all, 112 biopsies from 78 patients (mean age=25, range 18-39 yr) were reviewed for histopathologic features suggestive of or diagnostic for endometriosis including the presence of endometrial stroma, Müllerian epithelium, dystrophic calcifications, HLM, chronic inflammation, adhesions, and vascular proliferation. Endometriosis was confirmed by pathologic criteria in 37 of 78 patients (47%). Biopsies from patients on hormonal therapy (n=62, 80%) were significantly less likely to meet pathologic criteria for endometriosis (P=0.01). Nondiagnostic biopsies (70/112; 63%) frequently displayed HLM (20%), chronic inflammation (29%), dystrophic calcifications (26%), vascular proliferation (20%), or adhesions (20%) and were significantly more likely to have a vascular clinical appearance (P=0.01). Diagnostic biopsies (42/112; 38%) were more likely to have a blue/black clinical appearance (P=0.03), demonstrate HLM (P=0.004), and display pseudodecidualization (P=0.05). Patients with a high clinical suspicion of endometriosis have a range of histologic findings, with less than half meeting the current histopathologic criteria for diagnosing endometriosis. Given the heterogeneous histopathologic appearance, revision of the histologic criteria may be warranted with further exploration, particularly for lesions with predominantly vascular features.
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http://dx.doi.org/10.1097/PGP.0000000000000743DOI Listing
December 2020

Endometriosis and cancer: a systematic review and meta-analysis.

Hum Reprod Update 2021 Feb;27(2):393-420

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Endometriosis is an often chronic, inflammatory gynaecologic condition affecting 190 million women worldwide. Studies have reported an elevated cancer risk among patients with endometriosis. However, prior research has included methodologic issues that impede valid and robust interpretation.

Objective And Rationale: We conducted a meta-analysis of studies investigating the association between endometriosis and cancer risk and analysed the results by methodologic characteristics. We discuss the implications of cancer screening in patients and management challenges faced by clinicians.

Search Methods: We searched PubMed and Embase databases for eligible studies from inception through 24 October 2019. We included cohort and case-control studies examining the association between endometriosis and cancer risk; cross-sectional studies and case reports were excluded. Publications had to present risk/rate/odds estimates with 95% CI. Random effects meta-analysis was used to estimate summary relative risks (SRR) and CIs. Heterogeneity across studies was assessed by the Q test and I2 statistics, and publication bias using Egger's and Begg's tests. Risk of bias and quality of the included studies were assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool.

Outcomes: Forty-nine population-based case-control and cohort studies were included. Twenty-six studies were scored as having a 'serious'/'critical' risk of bias, and the remaining 23 'low'/'moderate'. Cancer-specific analyses showed a positive association between endometriosis and ovarian cancer risk (SRR = 1.93, 95% CI = 1.68-2.22; n = 24 studies) that was strongest for clear cell (SRR = 3.44, 95% CI = 2.82-4.42; n = 5 studies) and endometrioid (SRR = 2.33, 95% CI = 1.82-2.98; n = 5 studies) histotypes (Pheterogeneity < 0.0001), although with significant evidence of both heterogeneity across studies and publication bias (Egger's and Begg's P-values < 0.01). A robust association was observed between endometriosis and thyroid cancer (SRR = 1.39, 95% CI =1.24-1.57; n = 5 studies), a very small association with breast cancer (SRR = 1.04, 95% CI =1.00-1.09; n = 20 studies) and no association with colorectal cancer (SRR = 1.00, 95% CI =0.87-1.16; n = 5 studies). The association with endometrial cancer was not statistically significant (SRR = 1.23, 95% CI =0.97-1.57; n = 17 studies) overall and wholly null when restricted to prospective cohort studies (SRR = 0.99, 95% CI =0.72-1.37; n = 5 studies). The association with cutaneous melanoma was also non-significant (SRR = 1.17, 95% CI =0.97-1.41; n = 7 studies) but increased in magnitude and was statistically significant when restricted to studies with low/moderate risk of bias (SRR = 1.71, 95% CI = 1.24-2.36, n = 2 studies). The most robust finding both in terms of statistical significance and magnitude of effect was an inverse association with cervical cancer (SRR = 0.68, 95% CI =0.56-0.82; n = 4 studies); however, this result has a high potential to reflect heightened access to detection of dysplasia for women who reached an endometriosis diagnosis and is thus likely not causal. Several additional cancer types were explored based on <4 studies.

Wider Implications: Endometriosis was associated with a higher risk of ovarian and thyroid, and minimally (only 4% greater risk) with breast cancer, and with a lower risk of cervical cancer. However, this meta-analysis confirms that: a majority of studies had severe/critical risk of bias; there is impactful heterogeneity across studies-and for ovarian cancer, publication bias; and causal inference requires temporality, which in many studies was not considered. We discuss the implications of these potential associations from the perspectives of patients with endometriosis, clinicians involved in their care, and scientists investigating their long-term health risks.
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http://dx.doi.org/10.1093/humupd/dmaa045DOI Listing
February 2021

Evaluation of CA125 in relation to pain symptoms among adolescents and young adult women with and without surgically-confirmed endometriosis.

PLoS One 2020 24;15(8):e0238043. Epub 2020 Aug 24.

Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, Massachusetts, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238043PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444809PMC
October 2020

Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies.

J Natl Cancer Inst 2021 Mar;113(3):301-308

Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Parity 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.

Methods: A 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.

Results: Ever 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 < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.

Conclusions: Incomplete 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.
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http://dx.doi.org/10.1093/jnci/djaa099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936053PMC
March 2021

In utero and early life exposures in relation to endometriosis in adolescents and young adults.

Eur J Obstet Gynecol Reprod Biol 2020 Sep 15;252:393-398. Epub 2020 Jul 15.

Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA, 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA; Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MA, 49503, USA.

Objective: Endometriosis is a common gynecologic disorder often associated with severe pelvic pain and infertility with few known modifiable risk factors. We investigated whether in utero and early life exposures are associated with surgically diagnosed endometriosis among adolescents and young adults.

Study Design: This case-control study, including 295 laparoscopically-confirmed endometriosis cases and 309 population-based controls aged <25 years, was conducted using data from The Women's Health Study: From Adolescence to Adulthood which enrolled participants from 2012 to 2018. Information on in utero and early life factors were collected using a modified WERF EPHect questionnaire at enrollment, including their mother's age at delivery, birthweight, gestation length, exposure to smoking in utero and secondhand smoke during childhood up to age 13, and if the participant was breastfed.

Results: Median age at enrollment was 17 years (range 12-24) in cases and 22 years (range 7-24) in controls, with 83 % and 68 % non-Hispanic whites, respectively. The majority of cases (95 %) were rASRM stage I or II at diagnostic surgery. Exposure to breastfeeding in early life was associated with lower odds of endometriosis diagnosis (OR = 0.39, 95 % CI = 0.21-0.74). Exposure to secondhand smoke during childhood due to maternal smoking was associated with increased odds of endometriosis diagnosis (OR = 2.70, 95 % CI = 1.11-6.60).

Conclusions: Among adolescents and young adults, our data suggest exposures to breastfeeding in early life and secondhand smoke during childhood may be associated with endometriosis risk, providing insight into etiologic pathways to be explored in this young population.
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http://dx.doi.org/10.1016/j.ejogrb.2020.07.014DOI Listing
September 2020

Dietary fat intake, erythrocyte fatty acids, and risk of uterine fibroids.

Fertil Steril 2020 10 14;114(4):837-847. Epub 2020 Jul 14.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Division of Adolescent and Young Adult Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan.

Objective: To prospectively evaluate the association between dietary fat intake and risk of uterine fibroids; and to evaluate the association between erythrocyte membrane fatty acid (FA) levels and fibroid risk.

Design: Prospective cohort study. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence interval (CI). In a subset of participants 34 individual FAs were measured and logistic regression analysis was used to estimate odds ratios (ORs) and 95% CI for the association between FA tertiles and fibroids.

Setting: Not applicable.

Patient(s): Premenopausal US women (81,590) in the Nurses' Health Study II, aged 25-42 years at enrollment in 1989 for whom diet was assessed by a food frequency questionnaire. A total of 553 participants with erythrocyte FA measurements.

Intervention(s): Not applicable.

Main Outcome Measure(s): Cases of fibroids were defined on the basis of self-reported ultrasound or hysterectomy confirmation.

Result(s): A total of 8,142 cases of ultrasound-confirmed or hysterectomy-confirmed were diagnosed during an 18-year period (1991-2009). No associations were observed between intake of any dietary fats and fibroids in the multivariable models. However, when erythrocyte FAs were examined, an inverse association was observed between total n-3 polyunsaturated FAs and likelihood of fibroids (OR for third versus first tertile, 0.41; 95% CI 0.19-0.89). In addition, total trans FAs were associated with more odds of fibroids (OR for third tertile, 3.33; 95% CI 1.50-7.38).

Conclusion(s): Our findings provide preliminary suggestions that n-3 polyunsaturated FAs and trans FAs may play a role in fibroid etiology; however, these results should be confirmed in future studies.
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http://dx.doi.org/10.1016/j.fertnstert.2020.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554115PMC
October 2020

Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival.

Gynecol Oncol 2020 09 6;158(3):702-709. Epub 2020 Jul 6.

Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Purpose: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival.

Methods: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery.

Results: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival.

Conclusions: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.
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http://dx.doi.org/10.1016/j.ygyno.2020.06.481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487048PMC
September 2020

Peripheral Blood Leukocyte Telomere Length and Endometriosis.

Reprod Sci 2020 10 23;27(10):1951-1959. Epub 2020 Jun 23.

Department of Obstetrics and Gynecology, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.

Endometriosis is a common gynecologic disease defined by the presence of endometrial-like tissue outside the uterine cavity. While its etiology is largely unknown, accumulating evidence suggests that inflammation plays a major role. Our objective was to investigate the association between peripheral blood leukocyte telomere length (LTL) and endometriosis using data from two large population-based studies, the New England Case-Control Study (NEC; n = 877) and the National Health and Nutrition Examination Survey (NHANES; n = 2268). NEC control participants were identified through a combination of random digit dialing, drivers' license lists, and town resident lists. In NHANES, selection algorithms were used to identify a nationally representative sample. Blood samples and demographic, reproductive, and health-related information were available from both data sources. Endometriosis was defined as self-reported of physician-diagnosed endometriosis. LTL was measured using quantitative polymerase chain reaction. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between LTL and endometriosis. Shorter LTL was associated with greater odds of history of endometriosis. In NEC, women with the shortest LTL tertile compared with the longest had a 2.5-fold greater odds of endometriosis (OR = 2.56, 95% CI = 1.16-5.63; p value, test for linear trend = 0.02). The association was stronger among women who usually experienced moderate or severe menstrual pain (OR  = 3.50, 95% CI = 1.12-10.97). In NHANES, the data suggested a similar but attenuated association (OR = 1.29, 95% CI = 0.85-1.96). The observed associations in NEC suggest that shorter LTL may be associated with greater odds of endometriosis. A better understanding of how LTL influences endometriosis risk could elucidate novel disease pathophysiology.
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http://dx.doi.org/10.1007/s43032-020-00214-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483746PMC
October 2020

Association Between Breastfeeding and Ovarian Cancer Risk.

JAMA Oncol 2020 06 11;6(6):e200421. Epub 2020 Jun 11.

Women's Cancer Research Center, Magee-Womens Research Institute, Hillman Cancer Center, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Importance: Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent.

Objective: To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype.

Design, Setting, And Participants: A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019.

Exposures: Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies.

Main Outcomes And Measures: Diagnosis of epithelial ovarian cancer.

Results: A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02).

Conclusions And Relevance: Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.
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http://dx.doi.org/10.1001/jamaoncol.2020.0421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118668PMC
June 2020

Estrogen Plus Progestin Hormone Therapy and Ovarian Cancer: A Complicated Relationship Explored.

Epidemiology 2020 05;31(3):402-408

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.

Background: Menopausal estrogen-alone therapy is a risk factor for endometrial and ovarian cancers. When a progestin is included with the estrogen daily (continuous estrogen-progestin combined therapy), there is no increased risk of endometrial cancer. However, the effect of continuous estrogen-progestin combined therapy on risk of ovarian cancer is less clear.

Methods: We pooled primary data from five population-based case-control studies in the Ovarian Cancer Association Consortium, including 1509 postmenopausal ovarian cancer cases and 2295 postmenopausal controls. Information on previous menopausal hormonal therapy use, as well as ovarian cancer risk factors, was collected using in-person interviews. Logistic regression was used to assess the association between use of continuous estrogen-progestin combined therapy and risk of ovarian cancer by duration and recency of use and disease histotype.

Results: Ever postmenopausal use of continuous estrogen-progestin combined therapy was not associated with increased risk of ovarian cancer overall (OR = 0.85, 95% CI = 0.72, 1.0). A decreased risk was observed for mucinous ovarian cancer (OR = 0.40, 95% CI = 0.18, 0.91). The other main ovarian cancer histotypes did not show an association (endometrioid: OR = 0.86, 95% CI = 0.57, 1.3, clear cell: OR = 0.68, 95% CI = 0.40, 1.2; serous: OR = 0.98, 95% CI = 0.80, 1.2).

Conclusions: Given that estrogen-alone therapy has been shown to be associated with increased risk of ovarian cancer, these findings are consistent with the hypothesis that adding a progestin each day ameliorates the carcinogenic effects of estrogen on the cells of origin for all histotypes of ovarian cancer.
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http://dx.doi.org/10.1097/EDE.0000000000001175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584395PMC
May 2020

The association between abuse history in childhood and salivary rhythms of cortisol and DHEA in postmenopausal women.

Psychoneuroendocrinology 2020 02 14;112:104515. Epub 2019 Nov 14.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States.

A history of child abuse (CA) is associated with morbidity and mortality in adulthood, and one proposed mechanism is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Therefore, we evaluated whether a history of physical and sexual CA was associated with daily rhythms of HPA hormones (cortisol and dehydroepiandrosterone (DHEA)) among postmenopausal women (mean age: 60.6 years). In 2013, 233 participants from the Nurses' Health Study II provided up to 5-timed saliva samples over the course of a day: immediately upon awakening, 45 min, 4 h, and 10 h after waking, and prior to going to sleep. Among these 233 participants, 217 provided ≥4 timed saliva samples. Assessment of physical and sexual CA history occurred in 2001 using the Revised Conflict Tactics Scale. Cumulative CA history was derived by combining reports of physical and sexual abuse prior to age 18. Piecewise linear mixed models compared diurnal rhythms of cortisol and DHEA between participants with none-to-moderate CA (n = 104, reference group) versus high-to-severe CA (n = 113). Models adjusted for characteristics at each saliva collection, health status, sleep quality, medications, and hormone use. Compared to those with none-to-moderate CA, women with high-to-severe CA had different diurnal rhythms in the early and evening hours, including blunted (less steep) early declines in DHEA (% difference (%D) = 10.7, 95 % Confidence Interval (CI) 4.3, 17.5), and steeper late declines in both cortisol and DHEA (cortisol %D = -2.5, 95 % CI -4.8, -0.1, and DHEA %D= -3.9, 95 % CI -6.0, -1.8). In conclusion, high-to-severe abuse history prior to age 18 was more strongly associated with differences in DHEA rather than cortisol, suggesting that early life abuse may be related to dysregulation of stress-response mechanisms later in life.
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http://dx.doi.org/10.1016/j.psyneuen.2019.104515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935398PMC
February 2020

Development and validation of circulating CA125 prediction models in postmenopausal women.

J Ovarian Res 2019 Nov 26;12(1):116. Epub 2019 Nov 26.

CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: Cancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker.

Methods: We developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses' Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC.

Result: The linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset.

Conclusions: The linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 levels, which may contribute to reducing false positive tests using CA125 as screening biomarker.
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http://dx.doi.org/10.1186/s13048-019-0591-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878636PMC
November 2019

Prediagnosis and postdiagnosis smoking and survival following diagnosis with ovarian cancer.

Int J Cancer 2020 08 2;147(3):736-746. Epub 2019 Dec 2.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Little is known about the influence of prediagnosis and postdiagnosis smoking and smoking cessation on ovarian cancer survival. We investigated this relationship in two prospective cohort studies, the Nurses' Health Study (NHS) and NHSII. Analyses included 1,279 women with confirmed invasive, Stage I-III epithelial ovarian cancer. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality by smoking status, adjusting for age and year of diagnosis, tumor stage, histologic subtype, body mass index and nonsteroidal anti-inflammatory use (postdiagnosis models only). When examining prediagnosis smoking status (assessed a median of 12 months before diagnosis), risk of death was significantly increased for former smokers (HR = 1.19, 95% CI: 1.02-1.39), and suggestively for current smokers (HR = 1.21, 95% CI: 0.96-1.51) vs. never smokers. Longer smoking duration (≥20 years vs. never, HR = 1.23, 95% CI: 1.05-1.45) and higher pack-years (≥20 pack-years vs. never, HR = 1.28, 95% CI: 1.07-1.52) were also associated with worse outcome. With respect to postdiagnosis exposure, women who smoked ≥15 cigarettes per day after diagnosis (assessed a median of 11 months after diagnosis) had increased mortality compared to never smokers (HR = 2.34, 95% CI: 1.63-3.37). Those who continued smoking after diagnosis had 40% higher mortality (HR = 1.40, 95% CI: 1.05-1.87) compared to never smokers. Overall, our results suggest both prediagnosis and postdiagnosis smoking are associated with worse ovarian cancer outcomes.
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http://dx.doi.org/10.1002/ijc.32773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758910PMC
August 2020

Urinary PGE-M Levels and Risk of Ovarian Cancer.

Cancer Epidemiol Biomarkers Prev 2019 11 6;28(11):1845-1852. Epub 2019 Aug 6.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Regular aspirin use may lower ovarian cancer risk by blocking the cyclooxygenase enzymes, resulting in lower expression of prostaglandins, including prostaglandin E2 (PGE2). We evaluated whether higher prediagnosis PGE-M (a urinary biomarker of PGE2) was associated with increased ovarian cancer risk in three prospective cohorts.

Methods: We conducted a case-control study nested in the Nurses' Health Study (NHS), NHSII, and Shanghai Women's Health Study. Our analyses included 304 cases of epithelial ovarian cancer diagnosed from 1996 to 2015 and 600 matched controls. We measured urinary PGE-M using LC/MS with normalization to creatinine. Measures from each study were recalibrated to a common standard. We estimated ORs and 95% confidence intervals (CI) using conditional logistic regression, with PGE-M levels modeled in quartiles. Multivariable models were adjusted for ovarian cancer risk factors.

Results: There was no evidence of an association between urinary PGE-M levels and ovarian cancer risk for women with PGE-M levels in the top versus bottom quartile (OR = 0.80; 95% CI, 0.51-1.27; = 0.37). We did not observe heterogeneity by histotype ( = 0.53), and there was no evidence of effect modification by body mass index ( = 0.82), aspirin use ( = 0.59), or smoking ( = 0.14).

Conclusions: Prediagnosis urinary PGE-M levels were not significantly associated with ovarian cancer risk. Larger sample sizes are needed to consider a more modest association and to evaluate associations for specific tumor subtypes.

Impact: Systemic prostaglandin levels do not appear strongly associated with ovarian cancer risk. Future research into aspirin use and ovarian cancer risk should consider local prostaglandins and prostaglandin-independent mechanisms.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825569PMC
November 2019

Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study.

Int J Epidemiol 2019 06;48(3):822-830

Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Background: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer.

Methods: Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls).

Results: An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations.

Conclusion: Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.
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http://dx.doi.org/10.1093/ije/dyz113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659359PMC
June 2019

Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women.

Cancer Med 2019 05 18;8(5):2503-2513. Epub 2019 Apr 18.

Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York.

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.
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http://dx.doi.org/10.1002/cam4.1996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536963PMC
May 2019

Predicting Circulating CA125 Levels among Healthy Premenopausal Women.

Cancer Epidemiol Biomarkers Prev 2019 06 4;28(6):1076-1085. Epub 2019 Apr 4.

Public Health Direction and Biodonostia Research Institute and Ciberesp, Basque Regional Health Department, San Sebastian, Spain.

Background: Cancer antigen 125 (CA125) is the most promising ovarian cancer screening biomarker to date. Multiple studies reported CA125 levels vary by personal characteristics, which could inform personalized CA125 thresholds. However, this has not been well described in premenopausal women.

Methods: We evaluated predictors of CA125 levels among 815 premenopausal women from the New England Case Control Study (NEC). We developed linear and dichotomous (≥35 U/mL) CA125 prediction models and externally validated an abridged model restricting to available predictors among 473 premenopausal women in the European Prospective Investigation into Cancer and Nutrition Study (EPIC).

Results: The final linear CA125 prediction model included age, race, tubal ligation, endometriosis, menstrual phase at blood draw, and fibroids, which explained 7% of the total variance of CA125. The correlation between observed and predicted CA125 levels based on the abridged model (including age, race, and menstrual phase at blood draw) had similar correlation coefficients in NEC ( = 0.22) and in EPIC ( = 0.22). The dichotomous CA125 prediction model included age, tubal ligation, endometriosis, prior personal cancer diagnosis, family history of ovarian cancer, number of miscarriages, menstrual phase at blood draw, and smoking status with AUC of 0.83. The abridged dichotomous model (including age, number of miscarriages, menstrual phase at blood draw, and smoking status) showed similar AUCs in NEC (0.73) and in EPIC (0.78).

Conclusions: We identified a combination of factors associated with CA125 levels in premenopausal women.

Impact: Our model could be valuable in identifying healthy women likely to have elevated CA125 and consequently improve its specificity for ovarian cancer screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548604PMC
June 2019

Joint exposure to smoking, excessive weight, and physical inactivity and survival of ovarian cancer patients, evidence from the Ovarian Cancer Association Consortium.

Cancer Causes Control 2019 May 23;30(5):537-547. Epub 2019 Mar 23.

Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.

Purpose: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated.

Methods: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors.

Results: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS.

Conclusions: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.
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http://dx.doi.org/10.1007/s10552-019-01157-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614876PMC
May 2019
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