Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case–control study ...nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone‐binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor‐positive and ‐negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer ORQ4‐Q1 = 1.56 (95% CI 1.15–2.13), ptrend = 0.02 for testosterone and ORQ4‐Q1 = 1.33 (95% CI 0.99–1.79), ptrend = 0.04 for free testosterone, but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor‐positive and ‐negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 ORQ4‐Q1 = 1.32 (95% CI 0.87–2.01), ptrend = 0.05 compared to breast cancer diagnosed at age 50 or above ORQ4‐Q1 = 0.94 (95% CI 0.60–1.47), ptrend = 0.34, phet = 0.04. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen.
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Sex hormones have often been connected with the development of breast cancer, and estrogens have clear pro‐proliferative effects on breast cancer cells. In this large prospective study, the authors underscore a direct association of premenopausal levels of testosterone with subsequent breast cancer risk. By contrast, no direct relationship between premenopausal estrogen and progesterone levels with increased breast cancer risk was observed although a weak association between higher estradiol levels and increased risk for tumors diagnosed before age 50 was noted. The authors point to the possibility that a conversion from androgen to estrogen might take place in the breast that may mechanistically explain the increased risk in breast cancer development when androgens are high.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on ...other complex diseases.
First, to summarize the main design features of a prospective case-control study –nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort– on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles.
Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models.
There were differences among countries in subjects’ characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p’-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.
The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects’ characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.
•There are unique methodological issues for research on environmental causes of human diseases.•Through innovative methods, the study addressed some of such issues.•Analyses assessing disease progression bias suggested it was unlikely in this study.•Exposure to POPs was widespread in the study population, with substantial variability.•Lipids were influenced by differences in study design across participating centres.•Differences across study centres in some design features and participant characteristics are relevant for other multicentre studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exogenous polyunsaturated fatty acids modulate the cytotoxic activity of anti-cancer drugs. In this study, we examined whether lipid peroxidation is a potential mechanism through which fatty acids ...enhance drug cytotoxicity. We measured cell viability in the human breast cancer cell line MDA-MB-231 exposed to doxorubicin in the presence of non-cytotoxic concentrations of various polyunsaturated fatty acids for 6 days. To determine the role of lipid peroxidation, the hydroperoxide level was measured in cell extracts. Among all polyunsaturated fatty acids tested, docosahexaenoic acid (DHA, 22:6n-3) was the most potent in increasing doxorubicin cytotoxicity: cell viability decreased from 54% in the presence of 10(-7) M doxorubicin alone to 21% when cells were incubated with doxorubicin and DHA. After addition of an oxidant system (sodium ascorbate/2-methyl-1,4-naphthoquinone) to cells incubated with doxorubicin and DHA, cell viability further decreased to 12%. Cell hydroperoxides increased commensurately. The effect of DHA on doxorubicin activity and lipid hydroperoxide formation was abolished by a lipid peroxidation inhibitor (dl-alpha-tocopherol) or when oleic acid (a non-peroxidizable fatty acid) was used in place of DHA. No effect was observed with mitoxantrone, a drug with a low peroxidation-generating potential. Thus, DHA may increase the efficacy of oxyradical-producing drugs through a mechanism involving a generation of lipoperoxides. This may lead in vivo to a modulation of tumor cell chemosensitivity by DHA and oxidant agents.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Folate is a nutrient of major health significance, but its dietary intake assessment is particularly complex to quantify through traditional approaches. Attempts have been made to validate dietary ...instruments for assessing folate intake against circulating concentration biomarkers. However, this requires careful attention on various methodological issues. We conducted a qualitative review of 17 recently published validation studies to identify these issues. The majority of the tested instruments were self‐administered food frequency questionnaires while the biomarker most frequently used was serum/plasma folate. Seasonality was not considered in most studies. Little attention was given to using updated food composition databases based on reliable chemical methods and including fortified foods and dietary supplements. Time sequence of the test instrument and the reference biomarker used was often ambiguous, and reference periods did not always match. Correlation coefficient was the metric most commonly used, and correlations between dietary folate intake and blood folate concentration varied from weak to moderate (r = 0.05–0.54). The correlations were stronger when dietary supplement use was considered, and when serum/plasma rather than red blood cell folate was used. This review summarises issues that need to be considered in future studies intending to validate instruments for dietary folate assessment against concentration biomarkers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To assess the part that host fatty-acid supply and tumor-specific fatty-acid utilization contribute to the membrane lipid composition of tumor tissue, intra-individual comparisons of membrane fatty ...acids were carried out between breast-carcinoma tissue and non-tumorous breast tissue adjacent to the tumor and taken as reference. Phospholipids were purified by thin-layer chromatography from tumor biopsies obtained from 59 patients with a localized presentation of breast cancer, and fatty acids analyzed by capillary gas chromatography. Elevated levels of palmitic, palmitoleic and arachidonic acids, along with a low level of linoleic acid, were observed in membrane phospholipids of tumors with poor histoprognostic grade. The level of mono-unsaturated fatty acids was higher, and the level of essential fatty acids was lower in the tumor than in the reference breast tissue. Fatty-acid-desaturating activity was not detectable in tumors. A positive relationship was observed among patients for most of the fatty acids between carcinoma and non-tumorous breast tissue, except for mono-unsaturated and essential fatty-acid levels, which were not correlated between both tissues. These data suggest that mechanisms specifically related to malignant transformation and tumor progression influence the membrane fatty-acid profile of breast carcinoma. Fatty acid supply to the tumor, possibly modified by metabolic conditions related to the host, also seems to play a decisive role in this composition.
Les acides gras trans (AGT) représentent une catégorie de lipides naturellement présents dans les aliments (produits dans l’estomac des ruminants) ou générés par des procédés industriels ...d’hydrogénation partielle des huiles végétales. Leur rôle en tant que facteurs de risque cardiovasculaire a été largement démontré. En revanche, leur implication dans l’étiologie du cancer est suspectée, mais les preuves épidémiologiques restent limitées. L’objectif était d’étudier le risque de cancer (tout cancer, cancers du sein, de la prostate) associé à la consommation d’acides gras trans (apport total, acides gras trans d’origine naturelle ou industrielle et leurs isomères spécifiques) à partir des données de l’étude de cohorte prospective NutriNet-Santé (2009–2020).
Au total, 104 909 participants ont été inclus. Les apports alimentaires en acides gras trans ont été estimés à partir d’enregistrements alimentaires de 24h répétés validés, appariés à une table de composition détaillée. Les associations entre les quartiles de l’apport en AGT et le risque de cancer ont été évaluées à l’aide de modèles de Cox multi-ajustés.
Au total, 3374 cas de cancer sont survenus au cours du suivi, dont 982 cancers du sein et 405 cancers de la prostate. L’apport alimentaire total en acides gras trans était associé à un risque plus élevé de cancer de la prostate (HR pour le quartile 4 par rapport au quartile 1 : 1,27, 1,11–1,77 Ptendance=0,005). Les acides gras trans d’origine naturelle (AGTr) étaient associés à un risque accru de cancer (1,16, 1,02–1,32 Ptendance=0,07), en particulier les isomères de l’acide linoléique conjugué (ALC) (1,19, 1,04-1,36 Ptendance=0,04). Ces associations ont été spécifiquement observées pour le cancer du sein (AGTr : 1,35, 1,06–1,72 Ptendance=0,01 ; ALC : 1,29, 1,00–1,66 Ptendance=0,048), en particulier le cancer du sein préménopausique (AGTr : 1,68, 1,06–2,67 Ptendance=0,02 ; ALC : 2,013, 1,25–3,23 Ptendance=0,003). Plusieurs isomères d’acides gras trans d’origine industrielle étaient également associés à une augmentation du risque de cancer au global (1,18, 1,06–1,31 Ptendance=0,02 pour l’acide transdocosénoïque), de cancer du sein (isomère 18 :2t : 1,30, 1,06–1,58 Ptendance=0,01 ; acide hexadécénoïque : 1,28, 1,05–1,56 Ptendance=0,02) et de cancer de la prostate (acide transdocosénoïque : 1,52, 1,09–2,12 Ptendance=0,07).
Dans cette large étude prospective, plusieurs types d’acides gras trans étaient associés à un risque accru de cancer au global, du sein et de la prostate. Bien que d’autres études soient nécessaires pour mieux appréhender les mécanismes sous-jacents, ces résultats soutiennent l’objectif de l’OMS visant à l’élimination des acides gras trans d’origine industrielle de l’alimentation mondiale d’ici à 2023. En attendant, la consommation de produits alimentaires contenant des huiles partiellement hydrogénées devrait être évitée.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between ...dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC).
A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided.
A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile HRQ5-Q1 = 0.92, 95% CI = 0.83 to 1.01, P trend = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P trend = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P trend = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (>12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P interaction = .035).
Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women.
Pattern analysis has emerged as a tool to depict the role of multiple nutrients/foods in relation to health outcomes. The present study aimed at extracting nutrient patterns with respect to breast ...cancer (BC) aetiology.
Nutrient patterns were derived with treelet transform (TT) and related to BC risk. TT was applied to twenty-three log-transformed nutrient densities from dietary questionnaires. Hazard ratios (HR) and 95 % confidence intervals computed using Cox proportional hazards models quantified the association between quintiles of nutrient pattern scores and risk of overall BC, and by hormonal receptor and menopausal status. Principal component analysis was applied for comparison.
The European Prospective Investigation into Cancer and Nutrition (EPIC).
Women (n 334 850) from the EPIC study.
The first TT component (TC1) highlighted a pattern rich in nutrients found in animal foods loading on cholesterol, protein, retinol, vitamins B12 and D, while the second TT component (TC2) reflected a diet rich in β-carotene, riboflavin, thiamin, vitamins C and B6, fibre, Fe, Ca, K, Mg, P and folate. While TC1 was not associated with BC risk, TC2 was inversely associated with BC risk overall (HRQ5 v. Q1=0·89, 95 % CI 0·83, 0·95, P trend<0·01) and showed a significantly lower risk in oestrogen receptor-positive (HRQ5 v. Q1=0·89, 95 % CI 0·81, 0·98, P trend=0·02) and progesterone receptor-positive tumours (HRQ5 v. Q1=0·87, 95 % CI 0·77, 0·98, P trend<0·01).
TT produces readily interpretable sparse components explaining similar amounts of variation as principal component analysis. Our results suggest that participants with a nutrient pattern high in micronutrients found in vegetables, fruits and cereals had a lower risk of BC.
Few epidemiological studies have examined the association between dietary trans fatty acids and weight gain, and the evidence remains inconsistent. The main objective of the study was to investigate ...the prospective association between biomarker of industrial trans fatty acids and change in weight within the large study European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
Baseline plasma fatty acid concentrations were determined in a representative EPIC sample from the 23 participating EPIC centers. A total of 1,945 individuals were followed for a median of 4.9 years to monitor weight change. The association between elaidic acid level and percent change of weight was investigated using a multinomial logistic regression model, adjusted by length of follow-up, age, energy, alcohol, smoking status, physical activity, and region.
In women, doubling elaidic acid was associated with a decreased risk of weight loss (odds ratio (OR) = 0.69, 95% confidence interval (CI) = 0.55-0.88, p = 0.002) and a trend was observed with an increased risk of weight gain during the 5-year follow-up (OR = 1.23, 95% CI = 0.97-1.56, p = 0.082) (p-trend<.0001). In men, a trend was observed for doubling elaidic acid level and risk of weight loss (OR = 0.82, 95% CI = 0.66-1.01, p = 0.062) while no significant association was found with risk of weight gain during the 5-year follow-up (OR = 1.08, 95% CI = 0.88-1.33, p = 0.454). No association was found for saturated and cis-monounsaturated fatty acids.
These data suggest that a high intake of industrial trans fatty acids may decrease the risk of weight loss, particularly in women. Prevention of obesity should consider limiting the consumption of highly processed foods, the main source of industrially-produced trans fatty acids.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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