Annekatrin Lukanova

Meat consumption and colorectal cancer risk: Dose‐response meta‐analysis of epidemiological studies

The hypothesis that consumption of red and processed meat increases colorectal cancer risk is reassessed in a meta‐analysis of articles published during 1973–99. The mean relative risk (RR) for the highest quantile of intake vs. the lowest was calculated and the RR per gram of intake was computed through log‐linear models. Attributable fractions and preventable fractions for hypothetical reductions in red meat consumption in different geographical areas were derived using the RR log‐linear estimates and prevalence of red meat consumption from FAO data and national dietary surveys. High intake of red meat, and particularly of processed meat, was associated with a moderate but significant increase in colorectal cancer risk. Average RRs and 95% confidence intervals (CI) for the highest quantile of consumption of red meat were 1.35 (CI: 1.21–1.51) and of processed meat, 1.31 (CI: 1.13–1.51). The RRs estimated by log‐linear dose‐response analysis were 1.24 (CI: 1.08–1.41) for an increase of 120 g/day of red meat and 1.36 (CI: 1.15–1.61) for 30 g/day of processed meat. Total meat consumption was not significantly associated with colorectal cancer risk. The risk fraction attributable to current levels of red meat intake was in the range of 10–25% in regions where red meat intake is high. If average red meat intake is reduced to 70 g/week in these regions, colorectal cancer risk would hypothetically decrease by 7–24%.

Serum insulin-like growth factor-I and breast cancer

Insulin‐like growth factor I (IGF‐I) is a systemic hormone with potent mitogenic and anti‐apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre‐menopausal ages. In a prospective case‐control study nested within a cohort of New York City women, IGF‐I, IGF‐binding protein 3 (IGFBP‐3) and C peptide were measured in frozen serum samples from 172 pre‐menopausal and 115 post‐menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post‐menopausal breast cancer was not associated with serum IGF‐I, IGFBP‐3 or C‐peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF‐I in pre‐menopausal women. The odds ratio (OR) for the highest quartile of IGF‐I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91–2.81]. The OR decreased to 1.49 (95% CI 0.80–2.79) after adjustment for IGFBP‐3. In analyses restricted to subjects who were pre‐menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07–4.94). Adjustment for IGFBP‐3 reduced the OR to 1.90 (95% CI 0.82–4.42). There was no association between pre‐menopausal breast cancer and IGFBP‐3, IGF‐I:IGFBP‐3 ratio or non‐fasting levels of C peptide. Elevated circulating levels of IGF‐I may be an indicator of increased risk of breast cancer occurring before age 50. Int. J. Cancer 88:828–832, 2000.

Obesity and colon cancer: Does leptin provide a link?

Obesity, a risk factor for colorectal cancer, is associated with elevated serum levels of leptin, the adipocyte‐derived hormone, and insulin. Experimental and epidemiologic studies have indicated a role for insulin in the pathogenesis of colon cancer, and recent experimental studies have suggested a similar role for leptin. In a case‐control study nested in the Janus Biobank, Norway, we measured serum levels of leptin and C‐peptide (a marker of pancreatic insulin secretion) in cryopreserved prediagnostic sera from men (median age, 45 years) who were diagnosed with cancer of the colon (n = 235) or rectum (n = 143) after blood collection (median time, 17 years), and among 378 controls matched for age and date of blood collection. Conditional logistic regression analyses showed an approximately 3‐fold increase in colon cancer risk with increasing concentrations of leptin up to an odds ratio (OR) of 2.72 (95% CI = 1.44–5.12) for top vs. bottom quartile (ptrend = 0.008). The corresponding OR for C‐peptide was 1.81 (95% CI = 0.67–4.86; ptrend = 0.19). The risk estimates remained unchanged after mutual adjustment. No association of hormone levels with rectal cancer risk was found. Reproducibility of hormone measurements assessed by intraclass coefficients (ICCs) for paired samples taken 1 year apart was high for leptin (ICC = 0.82) but lower for C‐peptide (ICC = 0.30). Our results suggest that leptin is a risk factor for colon cancer, and that leptin may provide a link between obesity and colon cancer. Leptin may be directly involved in colon tumorigenesis or it may serve as a sensitive and robust marker of an obesity‐induced adverse endocrine environment. Only weak support for an association of insulin with colon cancer was found.

Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women

Experimental and epidemiological data support a role for sex steroid hormones in the pathogenesis of endometrial cancer. The associations of pre‐diagnostic blood concentrations of estradiol, estrone, testosterone, androstenedione, DHEAS and SHBG with endometrial cancer risk were investigated. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Cases were 124 postmenopausal women with invasive endometrial cancer. For each case, 2 controls were selected, matching the case on cohort, age and date of recruitment. Only postmenopausal women who did not use exogenous hormones at the time of blood donation were included. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated by conditional logistic regression. ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels, relative to the lowest were as follows: 4.13 (1.76–9.72), ptrend = 0.0008 for estradiol, 3.67 (1.71–7.88), ptrend = 0.0007 for estrone, 2.15 (1.05–4.40), ptrend = 0.04 for androstenedione, 1.74 (0.88–3.46), ptrend = 0.06 for testosterone, 2.90 (1.42–5.90), ptrend = 0.002 for DHEAS and 0.46 (0.20–1.05), ptrend = 0.01 for SHBG after adjustment for body mass index, use of oral contraceptives and hormone replacement therapy. The results of our multicenter prospective study showed a strong direct association of circulating estrogens, androgens and an inverse association of SHBG levels with endometrial cancer in postmenopausal women. The effect of elevated androstenedione and testosterone levels on disease risk seems to be mediated mainly through their conversion to estrogens, although an independent effect of androgens on tumor growth cannot be ruled out, in particular in the years close to diagnosis.

Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer†

Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF‐I and decreased levels of IGF‐binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre‐diagnostic blood concentrations of C‐peptide (a marker of pancreatic insulin production), IGF‐I, IGFBP‐1, ‐2 and ‐3 with endometrial cancer risk. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C‐peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91–11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65–11.7)]. IGFBP‐1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15–0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22–1.07)]. Risk was unrelated to levels of IGF‐I, IGFBP‐2 and IGFBP‐3. Chronic hyperinsulinemia, as reflected by increased circulating C‐peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer.

Body mass index and cancer : Results from the Northern Sweden Health and Disease Cohort

Excess weight has been associated with increased risk of cancer. The effect of body mass index (BMI, kg/m2) on overall cancer risk and on risk of developing several common cancer types was examined in a population‐based cohort study. Height and weight measurements were available for 35,362 women and 33,424 men recruited in the Northern Sweden Health and Disease Cohort between 1985 and 2003. Among cohort members, 2,691 incident cancer cases were identified. The association of BMI with cancer risk was examined using Poisson regression. Women with BMI > 27.1 (top quartile) had a 29% higher risk of developing any malignancy compared to women with BMI of 18.5–22.2 (lowest quartile), which increased to 47% in analysis limited to nonsmokers. Analyses according to WHO cut‐off points showed that obese women (BMI ≥ 30) had a 36% higher risk of cancer than women with BMI in the normal range (18.5–25). Individual cancer sites most strongly related to obesity were endometrium (risk for top quartile = 3.53, 95% confidence interval 1.86–7.43), ovary (2.09, 1.13–4.13) and colon (2.05, 1.04–4.41). BMI was inversely related to breast cancer occurring before age 49 (0.58, 0.29–1.11, ptrend < 0.04). In men, there was no association of BMI with overall cancer risk. Obese men (BMI ≥ 30), however, were at increased risk of developing kidney cancer (3.63, 1.23–10.7) and, after exclusion of cases diagnosed within 1 year of recruitment, colon cancer (1.77, 1.04–2.95). Our study provides further evidence that BMI is positively associated with cancer risk. In women from northern Sweden, up to 7% of all cancers were attributable to overweight and obesity and could be avoided by keeping BMI within the recommended range.

Anthropometric factors and risk of endometrial cancer: the European prospective investigation into cancer and nutrition

ObjectiveTo examine the association between anthropometry and endometrial cancer, particularly by menopausal status and exogenous hormone use subgroups.MethodsAmong 223,008 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, there were 567 incident endometrial cancer cases during 6.4 years of follow-up. The analysis was performed with Cox proportional hazards modeling.ResultsWeight, body mass index (BMI), waist and hip circumferences and waist–hip ratio (WHR) were strongly associated with increased risk of endometrial cancer. The relative risk (RR) for obese (BMI 30– < 40 kg/m2) compared to normal weight (BMI < 25) women was 1.78, 95% CI = 1.41–2.26, and for morbidly obese women (BMI ≥ 40) was 3.02, 95% CI = 1.66–5.52. The RR for women with a waist circumference of ≥88 cm vs. <80 cm was 1.76, 95% CI = 1.42–2.19. Adult weight gain of ≥20 kg compared with stable weight (±3 kg) increased risk independent of body weight at age 20 (RR = 1.75, 95% CI = 1.11–2.77). These associations were generally stronger for postmenopausal than premenopausal women, and oral contraceptives never-users than ever-users, and much stronger among never-users of hormone replacement therapy compared to ever-users.ConclusionObesity, abdominal adiposity, and adult weight gain were strongly associated with endometrial cancer risk. These associations were particularly evident among never-users of hormone replacement therapy.

Fruits and vegetables and lung cancer: Findings from the European prospective investigation into cancer and nutrition

Intake of fruits and vegetables is thought to protect against the development of lung cancer. However, some recent cohort and case‐control studies have shown no protective effect. We have assessed the relation between fruit and vegetable intake and lung cancer incidence in the large prospective investigation on diet and cancer, the European Prospective Investigation Into Cancer and Nutrition (EPIC). We studied data from 478,021 individuals that took part in the EPIC study, who were recruited from 10 European countries and who completed a dietary questionnaire during 1992–1998. Follow‐up was to December 1998 or 1999, but for some centres with active follow‐up to June 2002. During follow‐up, 1,074 participants were reported to have developed lung cancer, of whom 860 were eligible for our analysis. We used the Cox proportional hazard model to determine the effect of fruit and vegetable intake on the incidence of lung cancer. We paid particular attention to adjustment for smoking. Relative risk estimates were obtained using fruit and vegetable intake categorised by sex‐specific, cohort‐wide quintiles. After adjustment for age, smoking, height, weight and gender, there was a significant inverse association between fruit consumption and lung cancer risk: the hazard ratio for the highest quintile of consumption relative to the lowest being 0.60 (95% Confidence Interval 0.46–0.78), p for trend 0.0099. The association was strongest in the Northern Europe centres, and among current smokers at baseline, and was strengthened when the 293 lung cancers diagnosed in the first 2 years of follow‐up were excluded from the analysis. There was no association between vegetable consumption or vegetable subtypes and lung cancer risk. The findings from this analysis can be regarded as re‐enforcing recommendations with regard to enhanced fruit consumption for populations. However, the effect is likely to be small compared to smoking cessation.

Height, Body Mass Index, and Ovarian Cancer: A Pooled Analysis of 12 Cohort Studies

Background: Although many studies have investigated the association between anthropometry and ovarian cancer risk, results have been inconsistent. Methods: The associations of height, body mass index (BMI), and ovarian cancer risk were examined in a pooled analysis of primary data from 12 prospective cohort studies from North America and Europe. The study population consisted of 531,583 women among whom 2,036 epithelial ovarian cancer cases were identified. To summarize associations, study-specific relative risks (RR) were estimated using the Cox proportional hazards model and then combined using a random-effects model. Results: Women with height ≥1.70 m had a pooled multivariate RR of 1.38 [95% confidence interval (95% CI), 1.16-1.65] compared with those with height <1.60 m. For the same comparison, multivariate RRs were 1.79 (95% CI, 1.07-3.00) for premenopausal and 1.25 (95% CI, 1.04-1.49) for postmenopausal ovarian cancer (Pinteraction = 0.14). The multivariate RR for women with a BMI ≥30 kg/m2 was 1.03 (95% CI, 0.86-1.22) compared with women with a BMI from 18.5 to 23 kg/m2. For the same comparison, multivariate RRs were 1.72 (95% CI, 1.02-2.89) for premenopausal and 1.07 (95% CI, 0.87-1.33) for postmenopausal women (Pinteraction = 0.07). There was no statistically significant heterogeneity between studies with respect to height or BMI. BMI in early adulthood was not associated with ovarian cancer risk. Conclusion: Height was associated with an increased ovarian cancer risk, especially in premenopausal women. BMI was not associated with ovarian cancer risk in postmenopausal women but was positively associated with risk in premenopausal women. (Cancer Epidemiol Biomarkers Prev 2008;17(4):902–12)

Components of the metabolic syndrome and colorectal cancer risk : a prospective study

Objective:To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer.Methods:We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m−2), hypertension (blood pressure ⩾140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose ⩾6.1 mmol l−1 or post-load glucose in capillary plasma ⩾8.9 mmol l−1).Results:None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20–5.52; P trend=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1–9 were 1.56 (95% CI 0.93–2.62; P=0.090), 1.83 (95% CI 1.00–3.36; P=0.051) and 1.50 (95% CI 0.83–2.71; P=0.18), respectively.Conclusions:Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.