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1.
Artigo em Inglês | MEDLINE | ID: mdl-33622671

RESUMO

BACKGROUND: The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. METHODS: Stage II-IV patients (N=816) were included in this study. Pre-treatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and immunohistochemistry. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone and sex hormone binding globulin were measured. Hazard ratios (HR) and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage and grade. RESULTS: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER-positivity (HR 0.67, 95% CI 0.47-0.95), IR-positivity (HR 0.53, 95% CI 0.29-0.98) and circulating IGF-I (highest versus lowest quartile, HR 0.66, 95% CI 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest versus lowest tertile, HR 1.55, 95% CI 1.02-2.36) and pIGF1R/pIR positivity (HR 1.40, 95% CI 1.02-1.92) were associated with increased recurrence risk. CONCLUSIONS: Circulating estradiol and tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in endometrial cancer patients. IMPACT: This study may inform future clinical trials of endocrine-targeted adjuvant therapies in endometrial cancer patients that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.

2.
Cancer Epidemiol Biomarkers Prev ; 29(10): 2019-2025, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32732248

RESUMO

BACKGROUND: Incidence rates of epithelial ovarian cancer (EOC) vary across racial/ethnic groups, yet little is known about the impact of hormone-related EOC risk factors in non-Whites. METHODS: Among 91,625 female Multiethnic Cohort Study participants, 155 incident EOC cases were diagnosed in Whites, 93 in African Americans, 57 in Native Hawaiians, 161 in Japanese Americans, and 141 in Latinas. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between race/ethnicity and EOC risk and between hormone-related factors and EOC risk across racial/ethnic groups. RESULTS: Compared with Whites, African Americans and Japanese Americans had a lower multivariable-adjusted EOC risk; Native Hawaiians had a suggestive higher risk. Parity and oral contraceptive (OC) use were inversely associated with EOC risk (P int race/ethnicity ≥ 0.43); associations were strongest among Japanese Americans (e.g., ≥4 vs. 0 children; HR = 0.45; CI, 0.26-0.79). Age at natural menopause and postmenopausal hormone (PMH) use were not associated with EOC risk in the overall population, but were positively associated with risk in Latinas (e.g., ≥5 years vs. never PMH use; HR = 2.13; CI, 1.30-3.49). CONCLUSIONS: We observed strong associations with EOC risk for parity and OC use in Japanese Americans and PMH use and age at natural menopause in Latinas. However, differences in EOC risk among racial/ethnic groups were not fully explained by established hormone-related risk factors. IMPACT: Our study indicates there are racial/ethnic differences in EOC risk and risk factors, and could help improve prevention strategies for non-White women.

3.
Cancer Epidemiol Biomarkers Prev ; 29(10): 2010-2018, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32732252

RESUMO

BACKGROUND: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites. METHODS: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests. RESULTS: Most associations did not vary by tumor site (P het ≥ 0.05). Associations between first pregnancy (P het = 0.04), tubal ligation (P het = 0.01), and early-adult (age 18-21 years) body mass index (BMI; P het = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer (P het = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases. CONCLUSIONS: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site. IMPACT: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.

4.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1739-1749, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32616494

RESUMO

BACKGROUND: Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case-control analysis. RESULTS: A positive association was found between ovarian cancer and intake of industrial trans elaidic acid [HR comparing fifth with first quintileQ5-Q1 = 1.29; 95% confidence interval (CI) = 1.03-1.62; P trend = 0.02, q-value = 0.06]. Dietary intakes of n-6 linoleic acid (HRQ5-Q1 = 1.10; 95% CI = 1.01-1.21; P trend = 0.03) and n-3 α-linolenic acid (HRQ5-Q1 = 1.18; 95% CI = 1.05-1.34; P trend = 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertileT3-T1 = 1.39; 95% CI = 0.99-1.94; P trend = 0.06) and α-linolenic acids (ORT3-T1 = 1.30; 95% CI = 0.98-1.72; P trend = 0.06). CONCLUSIONS: Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer. IMPACT: If causal, eliminating industrial trans-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.

5.
Cancer Epidemiol Biomarkers Prev ; 29(2): 509-519, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31871106

RESUMO

BACKGROUND: Recent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures. METHODS: Gene signatures of tumor and stroma were developed using paired microdissected tissue from two independent studies. Stromal genes were investigated in two molecular subtype classifications and 61 published gene signatures. Prognostic performance of gene signatures of stromal admixture was evaluated in 2,527 ovarian tumors (16 studies). Computational simulations of increasing stromal cell proportion were performed by mixing gene-expression profiles of paired microdissected ovarian tumor and stroma. RESULTS: Recently described ovarian cancer molecular subtypes are strongly associated with the cell admixture. Tumors were classified as different molecular subtypes in simulations where the percentage of stromal cells increased. Stromal gene expression in bulk tumors was associated with overall survival (hazard ratio, 1.17; 95% confidence interval, 1.11-1.23), and in one data set, increased stroma was associated with anatomic sampling location. Five published prognostic gene signatures were no longer prognostic in a multivariate model that adjusted for stromal content. CONCLUSIONS: Cell admixture affects the interpretation and reproduction of ovarian cancer molecular subtypes and gene signatures derived from bulk tissue. Elucidating the role of stroma in the tumor microenvironment and in prognosis is important. IMPACT: Single-cell analyses may be required to refine the molecular subtypes of high-grade serous ovarian cancer.

6.
Cancer Res ; 79(20): 5442-5451, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31462430

RESUMO

Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient characteristics has not been adequately explored. In this study, we pooled data from case-control studies nested within six cohorts in the Ovarian Cancer Cohort Consortium (OC3) to examine the association between CRP and epithelial ovarian cancer risk overall, by histologic subtype and by participant characteristics. CRP concentrations were measured from prediagnosis serum or plasma in 1,091 cases and 1,951 controls. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI). When CRP was evaluated using tertiles, no associations with ovarian cancer risk were observed. A 67% increased ovarian cancer risk was found for women with CRP concentrations >10 mg/L compared with <1 mg/L (OR = 1.67; 95% CI = 1.12-2.48). A CRP concentration >10 mg/L was positively associated with risk of mucinous (OR = 9.67; 95% CI = 1.10-84.80) and endometrioid carcinoma (OR = 3.41; 95% CI = 1.07-10.92), and suggestively positive, although not statistically significant, for serous (OR = 1.43; 95% CI = 0.82-2.49) and clear cell carcinoma (OR = 2.05; 95% CI = 0.36-11.57; P heterogeneity = 0.20). Heterogeneity was observed with oral contraceptive use (P interaction = 0.03), where the increased risk was present only among ever users (OR = 3.24; 95% CI = 1.62-6.47). This study adds to the existing evidence that CRP plays a role in ovarian carcinogenesis and suggests that inflammation may be particularly implicated in the etiology of endometrioid and mucinous carcinoma. SIGNIFICANCE: C-reactive protein is involved in ovarian carcinogenesis, and chronic inflammation may be particularly implicated in the etiology of mucinous and endometrioid carcinomas.


Assuntos
Biomarcadores Tumorais/sangue , Proteína C-Reativa/análise , Carcinoma/sangue , Proteínas de Neoplasias/sangue , Neoplasias Ovarianas/sangue , Idoso , Carcinogênese , Carcinoma/classificação , Carcinoma/epidemiologia , Estudos de Casos e Controles , Intervalos de Confiança , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Inflamação , Pessoa de Meia-Idade , Razão de Chances , Neoplasias Ovarianas/epidemiologia , Estudos Prospectivos , Risco , Fatores de Risco , Sensibilidade e Especificidade , Estados Unidos/epidemiologia
7.
Ann Intern Med ; 170(1): 22-30, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30534999

RESUMO

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated. Objective: To characterize breast cancer risk in relation to recent childbirth. Design: Pooled analysis of individual-level data from 15 prospective cohort studies. Setting: The international Premenopausal Breast Cancer Collaborative Group. Participants: Women younger than 55 years. Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression. Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns. Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited. Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women. Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.


Assuntos
Neoplasias da Mama/epidemiologia , Parto , Adolescente , Adulto , Aleitamento Materno , Neoplasias da Mama/diagnóstico , Feminino , Predisposição Genética para Doença , Humanos , Idade Materna , Pessoa de Meia-Idade , Paridade , Gravidez , Pré-Menopausa , Modelos de Riscos Proporcionais , Estudos Prospectivos , Receptores Estrogênicos/análise , Fatores de Risco , Adulto Jovem
8.
Eur J Clin Nutr ; 73(8): 1122-1132, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30337714

RESUMO

BACKGROUND: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available. RESULTS: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00-1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02-1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case-control subset. CONCLUSIONS: Greater haem iron intake may be modestly associated with lung cancer risk.


Assuntos
Heme/administração & dosagem , Heme/metabolismo , Ferro na Dieta/administração & dosagem , Ferro na Dieta/sangue , Neoplasias Pulmonares/epidemiologia , Avaliação Nutricional , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco
9.
Int J Cancer ; 145(1): 58-69, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561796

RESUMO

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.


Assuntos
Carcinoma Epitelial do Ovário/epidemiologia , Carcinoma Epitelial do Ovário/patologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Paridade , Gravidez , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fumar/epidemiologia
11.
Lancet Oncol ; 19(8): 1107-1116, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30029888

RESUMO

BACKGROUND: Ovarian cancer is the fifth most common cause of cancer death among women in the USA. In this study, our objective was to determine whether modifiable exposures to common analgesics outside of standard treatment influence prognosis in patients with ovarian cancer. METHODS: The Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) are ongoing prospective studies of 121 700 and 116 429 US nurses who have completed biennial questionnaires since 1976 and 1989, respectively. We retrieved information from medical records, death certificates, or linkage to a state or Surveillance, Epidemiology, and End Results (SEER) cancer registry on ovarian cancer cases. Eligible participants had confirmed invasive, stage I-III epithelial ovarian cancer, and had data available on analgesic use. The primary objective was to determine whether self-reported regular use (≥2 days per week) of aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), or paracetamol before and after ovarian cancer diagnosis, was associated with ovarian cancer-specific survival. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for these associations, adjusting for age and year of diagnosis, disease stage, and histology. FINDINGS: Between June 1, 1976, and May 31, 2012, for the NHS and between June 1, 1989, and May 31, 2013, for NHSII, 1789 participants of the NHS and NHSII studies were diagnosed with epithelial ovarian cancer and 1143 (64%) were eligible to be included in this study; 1031 (90%) of 1143 cases were included in the pre-diagnosis exposure analysis and 964 cases (84%) in the post-diagnosis exposure analysis. Compared with never-users, participants who reported recent (current use in the past 2 years) post-diagnosis use of aspirin (HR 0·68 [95% CI 0·52-0·89]) and non-aspirin NSAIDs (HR 0·67 [95% CI 0·51-0·87]) had an improved ovarian cancer-specific survival. Any type of analgesic use pre-diagnosis, and post-diagnosis use of paracetamol, were not positively associated with ovarian cancer-specific survival. In analyses of change in analgesic use from pre-diagnosis to post-diagnosis, those participants who became recent users of aspirin (HR 0·44 [95% CI 0·26-0·74]) or became recent users of non-aspirin NSAIDs (HR 0·46 [95% CI 0·29-0·73]) post-diagnosis had a lower risk of ovarian cancer-specific death than never-users. INTERPRETATION: Recent use of aspirin or non-aspirin NSAIDs, defined as current use in the past 2 years, after diagnosis appears to improve ovarian cancer-specific survival. If these results are confirmed in further studies, further research should explore potential synergistic effects of anti-inflammatory medications used in combination with standard ovarian cancer therapies to improve the prognosis for patients diagnosed with ovarian cancer. FUNDING: National Institutes of Health, National Cancer Institute, The Marsha Rivkin Center for Ovarian Cancer Research.


Assuntos
Acetaminofen , Analgésicos , Anti-Inflamatórios não Esteroides , Aspirina , Carcinoma Epitelial do Ovário/mortalidade , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais
12.
JAMA Oncol ; 4(11): e181771, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931120

RESUMO

Importance: The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation. Objective: To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics. Design, Setting, and Participants: This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017. Exposures: Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years. Main Outcomes and Measures: Invasive or in situ premenopausal breast cancer. Results: Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 [5.0-U] difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs <17.0) at ages 18 to 24 years (HR, 0.24; 95% CI, 0.14-0.40). Hazard ratios did not appreciably vary by attained age or between strata of other breast cancer risk factors. Associations were stronger for estrogen receptor-positive and/or progesterone receptor-positive than for hormone receptor-negative breast cancer for BMI at every age group (eg, for BMI at age 18 to 24 years: HR per 5.0-U difference for estrogen receptor-positive and progesterone receptor-positive tumors, 0.76 [95% CI, 0.70-0.81] vs hormone receptor-negative tumors, 0.85 [95% CI: 0.76-0.95]); BMI at ages 25 to 54 years was not consistently associated with triple-negative or hormone receptor-negative breast cancer overall. Conclusions and Relevance: The results of this study suggest that increased adiposity is associated with a reduced risk of premenopausal breast cancer at a greater magnitude than previously shown and across the entire distribution of BMI. The strongest associations of risk were observed for BMI in early adulthood. Understanding the biological mechanisms underlying these associations could have important preventive potential.


Assuntos
Fatores Etários , Índice de Massa Corporal , Neoplasias da Mama/etiologia , Adolescente , Adulto , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Fatores de Risco , Adulto Jovem
13.
Cancer Epidemiol Biomarkers Prev ; 27(7): 790-804, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29661801

RESUMO

Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (EOC) risk has not been fully defined.Methods: CA15.3, CA125, and IgG1 antibodies against them were measured in 806 women who developed EOC and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression.Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower anti-CA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA125 antibodies were associated with higher risk for mucinous EOC occurring ≥ 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both.Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC. Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types.Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC. Cancer Epidemiol Biomarkers Prev; 27(7); 790-804. ©2018 AACR.


Assuntos
Biomarcadores Tumorais/genética , Antígeno Ca-125/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Fatores de Risco
14.
Int J Cancer ; 142(2): 262-270, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28921520

RESUMO

Animal and experimental data suggest that anti-Müllerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case-control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable-adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59-1.67) (Ptrend : 0.91). The association did not differ by age at blood draw or oral contraceptive use (all Pheterogeneity : ≥0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all Pheterogeneity : ≥0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer.


Assuntos
Adenocarcinoma de Células Claras/etiologia , Adenocarcinoma Mucinoso/etiologia , Biomarcadores/sangue , Cistadenocarcinoma Seroso/etiologia , Neoplasias do Endométrio/etiologia , Neoplasias Ovarianas/etiologia , Adenocarcinoma de Células Claras/sangue , Adenocarcinoma de Células Claras/epidemiologia , Adenocarcinoma Mucinoso/sangue , Adenocarcinoma Mucinoso/epidemiologia , Adulto , Hormônio Antimülleriano/sangue , Estudos de Casos e Controles , Estudos de Coortes , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/epidemiologia , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/epidemiologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/epidemiologia , Pré-Menopausa , Prognóstico , Adulto Jovem
15.
Int J Cancer ; 142(7): 1355-1360, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29159934

RESUMO

CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; phet = 0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection.


Assuntos
Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Antígeno Ca-125/imunologia , Detecção Precoce de Câncer/métodos , Proteínas de Membrana/imunologia , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/imunologia , Antígeno Ca-125/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade
16.
Br J Cancer ; 117(9): 1412-1418, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-28873086

RESUMO

BACKGROUND: The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk. METHODS: We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. Anti-Mullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics. RESULTS: Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog2: 1.07 (0.99-1.17)), or with any of the examined subgroups. CONCLUSIONS: Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer.


Assuntos
Adenocarcinoma/sangue , Hormônio Antimülleriano/sangue , Biomarcadores Tumorais/sangue , Neoplasias do Endométrio/sangue , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Estudos de Casos e Controles , China/epidemiologia , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/patologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Estados Unidos/epidemiologia
17.
Cancer Epidemiol Biomarkers Prev ; 26(9): 1360-1369, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28600297

RESUMO

Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individual-level data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations. Cancer Epidemiol Biomarkers Prev; 26(9); 1360-9. ©2017 AACR.


Assuntos
Neoplasias da Mama , Adulto , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Pré-Menopausa , Estados Unidos
18.
Cancer Res ; 77(14): 3951-3960, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28381542

RESUMO

Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on prediagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case-control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens [testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)], sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e., histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, ORlog2 = 1.12; 95% confidence interval 1.02-1.24); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors [e.g., testosterone, endometrioid tumors, ORlog2 = 1.40 (1.03-1.91)], but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors [ORlog2 = 0.76 (0.60-0.96)]. Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC. Cancer Res; 77(14); 3951-60. ©2017 AACR.


Assuntos
Androgênios/metabolismo , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/metabolismo , Estudos de Coortes , Feminino , Humanos , Neoplasias Ovarianas/patologia , Fatores de Risco
19.
PLoS One ; 12(3): e0173117, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28257491

RESUMO

Adult height and sitting height may reflect genetic and environmental factors, including early life nutrition, physical and social environments. Previous studies have reported divergent associations for height and chronic disease mortality, with positive associations observed for cancer mortality but inverse associations for circulatory disease mortality. Sitting height might be more strongly associated with insulin resistance; however, data on sitting height and mortality is sparse. Using the European Prospective Investigation into Cancer and Nutrition study, a prospective cohort of 409,748 individuals, we examined adult height and sitting height in relation to all-cause and cause-specific mortality. Height was measured in the majority of participants; sitting height was measured in ~253,000 participants. During an average of 12.5 years of follow-up, 29,810 deaths (11,931 from cancer and 7,346 from circulatory disease) were identified. Hazard ratios (HR) with 95% confidence intervals (CI) for death were calculated using multivariable Cox regression within quintiles of height. Height was positively associated with cancer mortality (men: HRQ5 vs. Q1 = 1.11, 95%CI = 1.00-1.24; women: HRQ5 vs. Q1 = 1.17, 95%CI = 1.07-1.28). In contrast, height was inversely associated with circulatory disease mortality (men: HRQ5 vs. Q1 = 0.63, 95%CI = 0.56-0.71; women: HRQ5 vs. Q1 = 0.81, 95%CI = 0.70-0.93). Although sitting height was not associated with cancer mortality, it was inversely associated with circulatory disease (men: HRQ5 vs. Q1 = 0.64, 95%CI = 0.55-0.75; women: HRQ5 vs. Q1 = 0.60, 95%CI = 0.49-0.74) and respiratory disease mortality (men: HRQ5 vs. Q1 = 0.45, 95%CI = 0.28-0.71; women: HRQ5 vs. Q1 = 0.60, 95%CI = 0.40-0.89). We observed opposing effects of height on cancer and circulatory disease mortality. Sitting height was inversely associated with circulatory disease and respiratory disease mortality.


Assuntos
Estatura , Doenças Cardiovasculares/diagnóstico , Neoplasias/diagnóstico , Doenças Respiratórias/diagnóstico , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/patologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/mortalidade , Neoplasias/patologia , Prognóstico , Estudos Prospectivos , Doenças Respiratórias/epidemiologia , Doenças Respiratórias/mortalidade , Doenças Respiratórias/patologia , Análise de Sobrevida
20.
J Ovarian Res ; 10(1): 20, 2017 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-28320479

RESUMO

BACKGROUND: Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening. METHODS: We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression. RESULTS: CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination. CONCLUSIONS: This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors.


Assuntos
Biomarcadores Tumorais , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Área Sob a Curva , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Detecção Precoce de Câncer , Europa (Continente)/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/terapia , Vigilância da População , Fatores de Risco
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