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1.
Int J Cancer ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33567105

RESUMO

Emerging evidence suggests that normal weight postmenopausal women with a relative excess of body fat are at increased breast cancer risk. However, little is known about the associations between obesity-related blood markers and risk of breast cancer among these individuals. In this prospective study comprising 58 629 normal weight postmenopausal women (body mass index between 18.5 kg/m2 and 24.9 kg/m2 ) who were enrolled in the UK Biobank cohort between 2006 and 2010, we examined the associations of glycated hemoglobin, triglycerides, high-density lipoprotein cholesterol, C-reactive protein (CRP), testosterone and sex hormone-binding globulin (SHBG) with risk of breast cancer. A total of 1268 postmenopausal breast cancer cases were ascertained during a median follow-up period of 7 years. Women with CRP, total testosterone and free testosterone (FT) levels in the highest quintile had increased risk of breast cancer compared to those in the lowest quintile (HRQ5 vs Q1 : 1.35, 95% confidence interval [CI]: 1.12-1.63, HR Q5 vs Q1 : 1.47, 95% CI: 1.20-1.80 and HR Q5 vs Q1 : 1.53, 95% CI: 1.23-1.90, respectively), whereas those with SHBG in the highest quintile had reduced risk (HR Q5 vs Q1 : 0.70, 95% CI: 0.56-0.88). These associations were attenuated but persisted after additional adjustment for BMI, fat mass index (whole body fat mass [kg]/height [m2 ]) or waist circumference and after mutual adjustment for testosterone, CRP and/or SHBG. Our study suggests that the risk of postmenopausal breast cancer among normal weight women is increased in association with relatively high levels of CRP and testosterone and with relatively low levels of SHBG.

2.
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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33563604

RESUMO

Obesity represents one of the most significant public health challenges worldwide. Current clinical practice relies on body mass index (BMI) to define the obesity status of an individual, even though the index has long been recognized for its limitations as a measure of body fat. In normal BMI individuals, increased central adiposity has been associated with worse health outcomes, including increased risks of cardiovascular disease and metabolic disorders. The condition leading to these outcomes has been described as metabolic obesity in the normal weight (MONW). More recent evidence suggests that MONW is associated with increased risk of several obesity-related malignancies, including postmenopausal breast, endometrial, colorectal, and liver cancers. In MONW patients, the false reassurance of a normal range BMI can lead to lost opportunities for implementing preventive interventions that may benefit a substantial number of people. A growing body of literature has documented the increased risk profile of MONW individuals and demonstrated practical uses for body composition and biochemical analyses to identify this at-risk population. In this review, we survey the current literature on MONW and cancer, summarize pathophysiology and oncogenic mechanisms, highlight potential strategies for diagnosis and treatment, and suggest directions for future research.

4.
Breast Cancer Res ; 23(1): 15, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33516237

RESUMO

BACKGROUND: It is well established that tumors are antigenic and can induce an immune response by the host, entailing lymphocytic infiltration of the tumor and surrounding stroma. The extent and composition of the immune response to the tumor, assessed through evaluation of tumor-infiltrating lymphocyte counts, has been shown in many studies to have prognostic and predictive value for invasive breast cancer, but currently, there is little evidence regarding the association between infiltrating immune cell counts (IICCs) in women with benign breast disease (BBD) and risk of subsequent invasive breast cancer. METHODS: Using a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest, we conducted a nested case-control study in which cases were women who developed a subsequent invasive breast cancer during follow-up and controls were individually matched to cases on age at BBD diagnosis. We assessed IICCs in normal tissue and in the BBD lesions, and we used unconditional logistic regression to estimate the multivariable odds ratios (OR) and 95% confidence intervals (CI) for the associations between IICCs and breast cancer risk. RESULTS: There was no association between the IICC in normal tissue (multivariable OR per 5% increase in IICC = 1.05, 95% CI = 0.96-1.16) or in the BBD lesion (OR per 5% increase in IICC = 1.06, 95% CI = 0.96-1.18) and risk of subsequent invasive breast cancer. Also, there were no associations within subgroups defined by menopausal status, BBD histology, BMI, and history of smoking. CONCLUSION: The results of this study suggest that IICCs in BBD tissue are not associated with altered risk of subsequent invasive breast cancer.

5.
Diabetes Care ; 44(3): 672-680, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33431419

RESUMO

OBJECTIVE: To evaluate associations of oily and nonoily fish consumption and fish oil supplements with incident type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We included 392,287 middle-aged and older participants (55.0% women) in the UK Biobank who were free of diabetes, major cardiovascular disease, and cancer and had information on habitual intake of major food groups and use of fish oil supplements at baseline (2006-2010). Of these, 163,706 participated in one to five rounds of 24-h dietary recalls during 2009-2012. RESULTS: During a median 10.1 years of follow-up, 7,262 incident cases of T2D were identified. Compared with participants who reported never consumption of oily fish, the multivariable-adjusted hazard ratios of T2D were 0.84 (95% CI 0.78-0.91), 0.78 (0.72-0.85), and 0.78 (0.71-0.86) for those who reported <1 serving/week, weekly, and ≥2 servings/week of oily fish consumption, respectively (P-trend < 0.001). Consumption of nonoily fish was not associated with risk of T2D (P-trend = 0.45). Participants who reported regular fish oil use at baseline had a 9% (95% CI 4-14%) lower risk of T2D compared with nonusers. Baseline regular users of fish oil who also reported fish oil use during at least one of the 24-h dietary recalls had an 18% (8-27%) lower risk of T2D compared with constant nonusers. CONCLUSIONS: Our findings suggest that consumption of oily fish but not nonoily fish was associated with a lower risk of T2D. Use of fish oil supplements, especially constant use over time, was also associated with a lower risk of T2D.

6.
Am J Epidemiol ; 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33325511

RESUMO

Poor diet quality is a leading risk factor for death in the United States (U.S.). We examined the association between Healthy Eating Index-2015 (HEI-2015) scores and death from all-causes, cardiovascular disease (CVD), cancer, Alzheimer's Disease and Dementia not otherwise specified (NOS) among postmenopausal women in the Women's Health Initiative Observational Study (1993-2017). This analysis included 59,388 participants who completed a food frequency questionnaire and were free of cancer, CVD and diabetes at enrollment. Stratified Cox proportional hazards models were fit using person-years from enrollment as the underlying time metric. We estimated multivariable adjusted hazard ratios and 95% confidence intervals for risk of death associated with HEI-2015 quintiles, with higher scores reflecting more optimal diet quality. Over a median of 18.2 years, 9,679 total deaths 3,303 cancer deaths, 2,362 CVD deaths, and 488 deaths from Alzheimer's Disease and Dementia NOS occurred. Compared to those with lower scores, women with higher HEI-2015 scores had an 18% lower risk of all-cause mortality and 21% lower risk of cancer mortality. HEI-2015 scores were not associated with mortality from CVD, Alzheimer's Disease and dementia NOS. Consuming a diet aligned with 2015-2020 U.S. Dietary Guidelines may have beneficial impacts for preventing death from cancer and overall.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33335021

RESUMO

BACKGROUND: Female hormones may play roles during renal cell carcinoma (RCC) carcinogenesis. The aims of this study were to investigate associations between hysterectomy, oophorectomy, and risk of RCC and to assess whether the associations were modified by exogenous estrogen, commonly used among women who have undergone hysterectomy. METHODS: Postmenopausal women (n = 144,599) ages 50-79 years at enrollment (1993-1998) in the Women's Health Initiative were followed for a mean of 15.9 years. Hysterectomy and oophorectomy were self-reported. Incident RCC cases were confirmed by physician review of medical records and pathology reports. Multivariable Cox proportional hazards modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for potential confounders. RESULTS: A total of 583 women developed RCC during follow-up. We observed that hysterectomy, regardless of oophorectomy status, was significantly associated with an increased risk of RCC (HR, 1.28; 95% CI, 1.03-1.60). The association appeared to be more pronounced in women with age at hysterectomy younger than 40 years (HR, 1.34; 95% CI, 1.01-1.80) or older than 55 years (HR, 1.52; 95% CI, 1.01-2.29). Oophorectomy was not significantly associated with risk of RCC. There was no evidence that exogenous estrogen use modified the association between hysterectomy and risk of RCC. CONCLUSIONS: In this large prospective study, we showed that women with a history of hysterectomy had 28% increased risk of RCC, and this finding was not modified by exogenous hormone use. IMPACT: If our findings are confirmed, women should be made aware of increased risk of RCC when considering hysterectomy.

8.
Cancer Epidemiol ; 70: 101855, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33220638

RESUMO

BACKGROUND: The association of sugar containing beverages (SCBs) with risk of breast, endometrial, ovarian and colorectal cancers is unclear. Therefore, we investigated these associations in the Canadian Study of Diet, Lifestyle, and Health. METHODS: The study population comprised an age-stratified subcohort of 3185 women and 848, 161, 91 and 243 breast, endometrial, ovarian and colorectal cancer cases, respectively. We used Cox proportional hazards regression models modified for the case-cohort design to assess the associations of SCBs with risk of the aforementioned cancers. RESULTS: Compared to SCB intake in the lowest tertile, SCB intake in the highest tertile was positively associated with endometrial cancer risk (HRT3 vs T1 = 1.58, 95 % CI = 1.08-2.33 and 1.78, 95 % CI = 1.12-2.81 for overall and Type 1 endometrial cancer, respectively) and ovarian cancer (HRT3 vs T1 = 1.76, 95 % CI: 1.09-2.83). Fruit juice intake was also positively associated with risk of Type 1endometrial (HRT3 vs T1 = 1.63, 95 % CI = 1.03-2.60). After excluding women with diabetes or cardiovascular diseases, we also observed sugar-sweetened beverages (SSBs) intake in the highest tertile was associated with higher risk of Type 1 endometrial cancer (HR T3 vs T1 = 1.65; 95 % CI: 1.03-2.64). None of the beverages was associated with risk of breast or colorectal cancer. CONCLUSION: We conclude that, in this cohort, relatively high SCB intake was associated with higher risk of endometrial and ovarian cancers, but not of breast or colorectal cancers. Our findings also suggest that relatively high SSB and fruit juice intake are associated with higher risk of Type 1 endometrial cancer.

9.
Int J Cancer ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33105052

RESUMO

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

10.
Eur J Epidemiol ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33128203

RESUMO

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.

11.
Cancer Epidemiol ; 69: 101831, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33038639

RESUMO

BACKGROUND: Experimental studies have suggested a role for sex hormones in the etiology of colorectal cancer (CRC) but epidemiological data are inconclusive. METHODS: We examined the associations of testosterone, estradiol, and sex hormone binding globulin (SHBG), with risk of CRC (n = 3,247) in 206,508 men and 219,106 women enrolled in the UK Biobank. Participants were followed for a median of 7.1 years. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for CRC risk. RESULTS: In men, in multivariable adjusted models testosterone and SHBG were not associated with CRC. Among men in the highest tertile of physical activity, SHBG was inversely associated with risk (HRq5vs. q1 0.75, 0.56-0.99,). In women, testosterone and SHBG were not associated with CRC risk. There were no differences in the associations between testosterone, SHBG and CRC risk in the analyses stratified by menopausal status. We did not observe an association between estradiol and CRC risk; however, given the limited number of individuals with detectable values of estradiol (13.2 % of the total sample) we are unable to draw a firm conclusions regarding this association. CONCLUSION: The results of this study did not provide support for associations of sex hormones and SHBG with CRC risk.

12.
J Natl Cancer Inst ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33010161

RESUMO

BACKGROUND: In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research. METHODS: Among prostate cancer cases diagnosed in 2007 in the U.S. SEER-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV). RESULTS: In our case population (n = 55,900), 3,073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM stage and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of stage T4 or N1 or M1 or Gleason score ≥8 prostate cancer, as this definition had one of the higher PPVs (0.23, 95% confidence interval [CI] 0.22-0.24) and reasonable sensitivity (0.66, 95% CI 0.64-0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses. CONCLUSIONS: We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced stage (T4 or N1 or M1), high grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.

13.
JAMA ; 324(4): 369-380, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32721007

RESUMO

Importance: The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. Objective: To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials. Design, Setting, and Participants: Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017. Interventions: In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration. Main Outcomes and Measures: The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer. Results: Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11). Conclusions and Relevance: In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.


Assuntos
Neoplasias da Mama/epidemiologia , Estrogênios Conjugados (USP)/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversos , Histerectomia , Acetato de Medroxiprogesterona/efeitos adversos , Idoso , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/mortalidade , Neoplasias da Mama/prevenção & controle , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Seguimentos , Humanos , Histerectomia/efeitos adversos , Incidência , Acetato de Medroxiprogesterona/uso terapêutico , Pessoa de Meia-Idade , Pós-Menopausa , Risco
14.
Cancer Epidemiol Biomarkers Prev ; 29(10): 2096-2099, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32699078

RESUMO

BACKGROUND: It is biologically plausible that genotoxic estrogens, namely estrogen DNA adducts (EDA), have a role in breast cancer development. Support comes from three prior studies that reported elevated concentrations of EDA relative to estrogen metabolites and conjugates (EDA:EMC) in women with breast cancer relative to control women. METHODS: In postmenopausal women in the Women's Health Initiative (WHI), EDA:EMC in 191 controls was compared with findings in 194 prediagnosis urine samples from breast cancer cases. EDA:EMC determinations were by mass spectrometry as previously described, and logistic regression was employed to estimate ORs. RESULTS: EDA:EMC did not differ in breast cancer cases compared with controls overall [0.93 (95% confidence interval, 0.71-1.23)], with a mean (SD) of 2.3 (0.8) and 2.4 (1.1) in cases and controls, respectively. Similarly, the ratio did not differ when examined by estrogen receptor or recency of biospecimen collection prior to breast cancer. CONCLUSIONS: Despite the demonstrated genotoxic properties of certain catechol estrogens resulting in EDAs, this analysis did not provide evidence for an increased breast cancer risk in relation to an elevated EDA:EMC. IMPACT: This analysis, conducted prospectively within postmenopausal women in the WHI study, suggests that a strong association between EDA:EMC and breast cancer could be ruled out, as this study was powered to detect an OR of 2.2 or greater.

15.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1832-1836, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581113

RESUMO

BACKGROUND: There is some evidence to suggest that endogenous levels of sex hormones might influence the etiology of cancers of the pancreas, kidney, and brain, but epidemiologic data are lacking. METHODS: We evaluated the association of circulating levels of total and free testosterone, and of sex hormone-binding globulin (SHBG), with the risk of cancers of the pancreas, kidney, and brain, and of total and free estradiol with the risk of kidney cancer, in the UK Biobank cohort study (n = 425,793; 225 pancreatic cancers, 749 kidney cancers, 467 brain cancers). Multivariable Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the associations. RESULTS: Testosterone and SHBG levels were not associated with risk of pancreatic cancer. Most of the associations for the other two anatomic sites were null. There were inverse associations between total testosterone and brain cancer in men and between SHBG and risk of kidney cancer in the total sample and in women. Estradiol was not associated with the risk of kidney cancer. CONCLUSIONS: The results of this study provide little support for associations between sex hormones/SHBG and risk of cancers of the pancreas, kidney, and brain. Larger studies are warranted. IMPACT: Although these results provide little support for roles for sex hormones and SHBG in the etiology of cancers of the pancreas, kidney, and brain, there is a need for studies with larger numbers of cases.

16.
Br J Cancer ; 123(2): 316-324, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32376888

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -ß, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. METHODS: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). RESULTS: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. CONCLUSIONS: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.

17.
J Hepatol ; 73(4): 863-872, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32437829

RESUMO

BACKGROUND & AIMS: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. METHODS: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. RESULTS: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only. CONCLUSION: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. LAY SUMMARY: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

18.
Cancers (Basel) ; 12(4)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244564

RESUMO

Metastasis causes ~90% of breast cancer mortality. However, standard prognostic tests based mostly on proliferation genes do not measure metastatic potential. Tumor MicroEnvironment of Metastasis (TMEM), an immunohistochemical biomarker for doorways on blood vessels that support tumor cell dissemination is prognostic for metastatic outcome in breast cancer patients. Studies quantifying TMEM doorways have involved manual scoring by pathologists utilizing static digital microscopy: a labor-intensive process unsuitable for use in clinical practice. We report here a validation study evaluating a new quantitative digital pathology (QDP) tool (TMEM-DP) for identification and quantification of TMEM doorways that closely mimics pathologists' workflow and reduces pathologists' variability to levels suitable for use in a clinical setting. Blinded to outcome, QDP was applied to a nested case-control study consisting of 259 matched case-control pairs. Sixty subjects of these were manually scored by five pathologists, digitally recorded using whole slide imaging (WSI), and then used for algorithm development and optimization. Validation was performed on the remainder of the cohort. TMEM-DP shows excellent reproducibility and concordance and reduces pathologist time from ~60 min to ~5 min per case. Concordance between manual scoring and TMEM-DP was found to be >0.79. These results show that TMEM-DP is capable of accurately identifying and scoring TMEM doorways (also known as MetaSite score) equivalent to pathologists.

19.
Cancer Epidemiol Biomarkers Prev ; 29(6): 1107-1119, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32179703

RESUMO

BACKGROUND: Evidence suggest that diabetes and glycated hemoglobin (HbA1c) levels are associated with cancer risk. However, previous studies have been limited variably by failure to adjust for cancer-specific risk factors (e.g., body mass index), inattention to diabetes duration and use of antidiabetic medications, and failure to stratify by obesity. METHODS: We examined the association between diabetes, HbA1c, and cancer risk in the UK Biobank, using data from 476,517 participants (54% women), followed for an average period of 7.1 years. Diabetes was defined on the basis of baseline self-reported diagnosis of diabetes and/or use of diabetes medication, while HbA1c measured at baseline was categorized as low (<31 mmol/mol), normal (31-<39 mmol/mol), increased risk (39-<48 mmol/mol), and high risk for diabetes (≥48 mmol/mol). Multivariable Cox proportional hazards models were used to estimate the association of diabetes and cancer at different anatomical sites, with adjustment for cancer-specific risk factors. RESULTS: Diabetes was associated with increased risk of cancers of the stomach, liver, bladder, endometrium, and lung among smokers, and with decreased risk of prostate cancer. Compared with the normal HbA1c category, the increased risk category was positively associated with risk of cancers of the colon, liver, bladder, and lung among smokers, and the high-risk category was associated with increased risk of cancers of the esophagus, liver, pancreas, and bladder, and with decreased risk of prostate cancer. CONCLUSIONS: These results suggest that both diabetes and/or elevated HbA1c are associated with risk of cancer at several anatomic sites. IMPACT: The associations of diabetes and HbA1c levels with cancer suggest their importance in cancer prevention.

20.
Cancer Epidemiol Biomarkers Prev ; 29(5): 1058-1066, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32127398

RESUMO

BACKGROUND: Sex steroid hormones and sex hormone-binding globulin (SHBG) have been implicated in the etiology of invasive breast cancer, but their associations with risk of the precursor lesion, ductal carcinoma in situ (DCIS) of the breast, remain unclear. METHODS: We used Cox proportional hazards regression models to estimate the associations of serum levels of estradiol (premenopausal women only), testosterone, and/or SHBG with DCIS risk among 182,935 women. After a median follow-up of 7.1 years, 186 and 531 DCIS cases were ascertained in premenopausal and postmenopausal women, respectively. RESULTS: Total and free estradiol were positively associated with risk of DCIS among premenopausal women. The HRs for the highest versus the lowest tertiles were 1.54 (1.06-2.23) and 1.72 [95% confidence interval (CI), 1.15-2.57], respectively. Among postmenopausal women, elevated levels of free testosterone (FT), and to a lesser extent, total testosterone, were positively associated with DCIS risk. The HRs for the highest versus the lowest quartiles were 1.42 (95% CI, 1.09-1.85) and 1.16 (95% CI, 0.91-1.48), respectively. Serum SHBG levels were inversely associated with risk of DCIS among postmenopausal women (HRq4 vs. q1: 0.75; 95% CI, 0.56-0.99). CONCLUSIONS: This study suggests that elevated levels of estradiol are associated with increased risk of DCIS among premenopausal women, and that among postmenopausal women, elevated levels of testosterone, and particularly those of FT, are associated with increased DCIS risk, while elevated levels of SHBG are associated with reduced risk. IMPACT: These findings may be helpful in developing prevention strategies aimed at reducing breast cancer risk among premenopausal and postmenopausal women.

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