Quality of life in relation to tamoxifen or exemestane treatment in postmenopausal breast cancer patients: a Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial side study.

Tamoxifen and aromatase inhibitors are associated with side effects which can significantly impact quality of life (QoL). We assessed QoL in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial and compared these data with reported adverse events in the main database. 2,754 Dutch postmenopausal early breast cancer patients were randomized between 5 years of exemestane, or tamoxifen (2.5-3 years) followed by exemestane (2.5-2 years). 742 patients were invited to participate in the QoL side study and complete questionnaires at 1 (T1) and 2 (T2) years after start of endocrine treatment. Questionnaires comprised the EORTC QLQ-C30 and BR23 questionnaires, supplemented with FACT-ES questions. 543 patients completed questionnaires at T1 and 454 patients (84%) at T2. Overall QoL and most functioning scales improved over time. The only clinically relevant and statistically significant difference between treatment types concerned insomnia; exemestane-treated patients reported more insomnia than tamoxifen-treated patients. Discrepancy was observed between QoL issue scores reported by the patients and adverse events reported by physicians. Certain QoL issues are treatment- and/or time-specific and deserve attention by health care providers. There is a need for careful inquiry into QoL issues by those prescribing endocrine treatment to optimize QoL and treatment adherence.

Maintenance of physical activity and body weight in relation to subsequent quality of life in postmenopausal breast cancer patients.

BACKGROUND: We prospectively examined the association between physical activity, body weight and quality of life in Dutch postmenopausal early breast cancer patients treated with adjuvant endocrine therapy. PATIENTS AND METHODS: In this side study of a large clinical trial, lifestyle and quality-of-life questionnaires were filled out 1 and 2 years after the start of endocrine therapy (T1 and T2, respectively) and included a pre-diagnosis lifestyle assessment (T0). A total of 435 breast cancer patients returned both questionnaires. RESULTS: Individuals with a physical activity level above the median who maintained this level from T0 to T1 reported the best global quality of life and physical functioning and the least fatigue at T2, as compared with individuals with low levels of physical activity which further decreased after diagnosis (difference of +16, +14, and -22 points on a 0-100 quality-of-life scale, respectively; P < 0.01). Overweight or obese women who gained body weight after diagnosis reported worst quality of life and most fatigue as compared with women who maintained a stable body weight (difference of -8, -10 and +2 points, respectively; P < 0.01). CONCLUSION: Maintaining high pre-diagnosis physical activity levels and a healthy body weight is associated with better quality of life after breast cancer.

The frequency, magnitude and timing of post-diagnosis body weight gain in Dutch breast cancer survivors.

To evaluate the association between systemic treatments and post-diagnosis weight gain in breast cancer patients during longer follow-up periods, we conducted a retrospective cohort study (n=271). Information on adjuvant systemic treatments and repeated body weight measurements was obtained from medical records, and analysed using multi-level regressions. During the first year, a mean weight change of +2.0kg (SD 4.9) was observed. Overall, 29% of all breast cancer patients had gained 5kg or more in body weight during total follow-up (median: 3 years). In multi-level analyses, women who received combined systemic treatment gained significantly more weight as compared with women who received no systemic treatment (4.5kg versus 2.0kg at 5 years post-diagnosis, p<0.05). Significant weight gain occurs in breast cancer patients in the Netherlands during the first year post-diagnosis. After the first year, further weight gain mainly occurs in women who receive chemotherapy in combination with endocrine therapy.

Meat consumption and meat preparation in relation to colorectal adenomas among sporadic and HNPCC family patients in The Netherlands.

Meat consumption and meat preparation methods are thought to be associated with the risk of sporadic colorectal cancer, and possibly adenomas. As the same somatic mutations occur in sporadic adenomas and hereditary non-polyposis colorectal cancer (HNPCC)-related adenomas, similar exogenous factors may play a role in the development of both types of adenoma. In a case control study among 57 sporadic colorectal adenoma cases and 62 adenoma cases from HNPCC families (and 148 adenoma-free controls) from the Netherlands, we examined whether meat consumption and preparation are similarly associated with sporadic and suspected HNPCC colorectal adenomas. Frequency of meat consumption was not significantly associated with adenoma risk in our population of sporadic and HNPCC family cases and controls (Odds Ratios (OR) for high versus low consumption were 1.0 and 0.6, respectively). Interestingly, consumption of red meat and specific preparation methods (i.e., "not adding any water" and " closed lid with most meat types") slightly, but non-significantly, increased the risk of adenomas in the sporadic group only (OR, 95% Confidence Interval (CI): 4.1, 0.7-23.0, 2.0, 0.6-6.5 and 2.6, 0.9-7.2, respectively). This is the first study to examine possible differences or similarities in risk factors for sporadic and HNPCC colorectal carcinogenesis. Our results do not provide support for meat consumption as a risk factor for adenoma formation in HNPCC family members. Some characteristics of habitual meat preparation in the Netherlands may, however, increase the risk of sporadic adenomas.

Determinants of circulating insulin-like growth factor (IGF)-I and IGF binding proteins 1-3 in premenopausal women: physical activity and anthropometry (Netherlands).

OBJECTIVE: Epidemiologic studies suggest that subjects with elevated plasma concentrations of insulin-like growth factor (IGF)-I are at increased risk of developing cancer. The objective of our study was to assess whether cancer risk factors such as lack of physical activity, obesity, and central body fat distribution are associated with plasma levels of IGF-I and related proteins (i.e. IGF binding proteins 1-3 and C-peptide). METHODS: A cross-sectional study was conducted in a population of 225 premenopausal women, aged 49-57, participating in the Prospect-EPIC study in the Netherlands. Plasma concentrations of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were determined. On the day of blood collection height, weight, and waist and hip circumference were measured. Habitual physical activity was assessed using a validated self-administered questionnaire. RESULTS: Mean concentrations of plasma IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were 156.1, 14.3, 434.4, 3062, and 2.86 ng/ml, respectively. Women in the highest tertile for physical activity had lower plasma concentrations of IGF-I, IGFBP-3, and C-peptide, and higher concentrations of IGFBP-1 and IGFBP-2, as compared to women in the lowest tertile. However, these differences were not statistically significant. BMI and related measures were significantly inversely associated with IGFBP-1 and IGFBP-2, and positively with IGFBP-3 and C-peptide. Linear regression analyses showed that the non-significant association of physical activity with components of the plasma IGF system was further attenuated by adjusting for obesity and central body fat distribution. CONCLUSIONS: Our data suggest that an active lifestyle is not independently associated with the plasma IGF system. We did confirm that a lean body shape is associated with higher concentrations of IGFBP-1 and IGFBP-2, and possibly also with lower concentrations of IGF-I and IGFBP-3.

Animal products and K-ras codon 12 and 13 mutations in colon carcinomas.

K-ras gene mutations (codons 12 and 13) were determined by PCR-based mutant allele-specific amplification (MASA) in tumour tissue of 185 colon cancer patients: 36% harboured mutations, of which 82% were located in codon 12. High intakes of animal protein, calcium and poultry were differently associated with codon 12 and 13 mutations: odds ratios (OR) and 95% confidence intervals (95% CI) for codon 12 versus codon 13 were 9.0 (2.0-42), 4.1 (1.4-12) and 15 (1.4-160), respectively. In case-control comparisons, high intakes of animal protein and calcium were positively associated with colon tumours harbouring codon 12 mutations [for animal protein per 17 g, OR (95% CI) = 1.5 (1.0-2.1); for calcium per 459 mg, 1.2 (0.9-1.6)], while inverse associations were observed for tumours with K-ras mutations in codon 13 [for animal protein 0.4 (0.2-1.0); for calcium 0.6 (0. 3-1.2)]. Transition and transversion mutations were not differently associated with these dietary factors. These data suggest a different dietary aetiology of colon tumours harbouring K-ras codon 12 and 13 mutations.

No major difference in K-ras and p53 abnormalities in sporadic and hereditary nonpolyposis colorectal adenomas.

K-ras and p53 gene mutations are known to occur in high frequencies in sporadic colorectal cancers, but findings are inconsistent in hereditary nonpolyposis colorectal cancer (HNPCC). We compared K-ras codon 12 and 13 gene mutations and p53 protein overexpression in 48 HNPCC (positive for Amsterdam criteria) and 59 sporadic colorectal adenomas, to examine whether they may represent similar or different molecular pathways to cancer. In sporadic adenomas K-ras mutations were detected in 32% and p53 overexpression in 31% of the cases. Similarly, K-ras mutations and p53 overexpression were both found in 25% of HNPCC adenomas. The frequencies of these abnormalities were not significantly different between HNPCC and sporadic adenomas. When taking differences in adenoma size into account, the frequencies were even more similar. In conclusion, these results suggest a similar molecular pathway to adenomas in HNPCC and sporadic carcinogenesis, with respect to involvement of K-ras and p53.

Assessing the human intake of heterocyclic amines: limited loss of information using reduced sets of questions.

The aim of this study was to evaluate loss of information from a reduced food frequency questionnaire as compared with an extensive reference method developed to assess the intake of heterocyclic amines (HCAs). Food frequency data were linked to concentrations of HCAs in cooked foods to estimate the individual daily exposure to a combination of five HCAs. The number of food items in the questionnaire was reduced and selected in three ways: (a) according to the contribution to the estimated total intake; (b) the between-person variance; or (c) dishes included in other studies. The effect on sensitivity, specificity, concordance, the correlation coefficient, kappa, and simulated relative risks was determined using information from a population-based study conducted in Stockholm. Only a limited amount of misclassification was introduced when the number of dishes was reduced from 39 to 15 or 20, and no major difference was seen when dishes were selected according to the total intake or the between-person variance. Our data indicate that for a specific exposure, such as HCAs, the loss of accuracy in an analytical epidemiological study is small and may not be relevant when the number of dishes in a food frequency questionnaire is decreased, if the initially chosen dishes are carefully selected and cover a reasonable part of the total intake or between-person variance.

p53 over-expression and p53 mutations in colon carcinomas: relation to dietary risk factors.

Epidemiological studies have suggested that dietary factors may differently affect p53-dependent and p53-independent pathways to colon cancer. Results of such studies may depend on the method used to assess p53 status. This case-control study of 185 colon-cancer cases and 259 controls examines this relation, using both immunohistochemistry and SSCP(exons 5-8)/sequencing to detect p53 abnormalities. Of 185 carcinomas analyzed using immunohistochemistry, 81 (44%) were categorized as p53 over-expression. p53 mutations were detected in 59 tumors (32%). A slight increase in risk observed for intake of saturated fat was largely due to an increased risk in cases without p53 over-expression (OR per 16.1 g/day, 1.46; 95% CI, 1.08-1.97), and no association in cases with p53 over-expression (OR, 1.07, 95% CI, 0.78-1.47). However, findings were less pronounced when cases were classified by mutation analysis (wild-type OR, 1.33; 95% CI, 1.01-1.75; mutated OR, 1.16; 95% CI, 0.81-1.65). Similar results were observed for total fat intake. For other nutrients and for vegetable and meat food groups no differences in risk for either p53 pathway were observed, independent of the laboratory technique used. Interestingly, in cases with transversion mutations in the p53 gene, an increased risk was observed for saturated fat (OR, 2.00; 95% CI, 0.97-4.14), in contrast to those with mutations at CpG sites (OR, 0.93; 95% CI, 0.55-1.57). An increase in colon-cancer risk for the p53-independent pathway due to fat intake, is more pronounced when using immunohistochemistry. However, mutation analysis is needed to study the possible association with a small group of tumors with transversion mutations.

Colorectal cancer risk in HNPCC families: development during lifetime and in successive generations. National Collaborative Group on HNPCC.

Members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at a much higher rate, and at a much younger age, than the general population. To quantify lifetime colorectal cancer risk in HNPCC family members, we calculated the cumulative incidence (CI) in different age categories, and compared this to the general population. Furthermore, we investigated whether successive generations of HNPCC families had earlier onset of disease. In 51 HNPCC families, selected according to the "Amsterdam criteria", the CI of colorectal cancer at age 75 was 40%, compared to only 4% in the general population. The CI ratio (CIR) of HNPCC family members relative to the general population was 148 at age 40, 79 at age 50 and 11 at age 75. Comparing successive generations of HNPCC families, the CI at age 75 increases from 19% in the ancestors to 32% in the first generation and 55% in the second generation. However, Cox proportional hazard analysis showed that this generation effect (RR per generation: 1.8, 95% CL = 1.4-2.2) largely disappears after adjustment for year of birth. In summary, at young ages, HNPCC family members experience an up-to-150 times higher risk for colorectal cancer than the general population. This risk difference declines from age 60 onwards. The earlier age of onset in successive HNPCC generations does not appear to be a biological feature of HNPCC, but reflects a secular time trend in cancer occurrence in these families, similar to that in the general population.

Meat consumption and preparation, and genetic susceptibility in relation to colorectal adenomas.

Epidemiological evidence suggests that a high meat consumption and/or animal fat intake may increase the risk of colorectal cancer. The objective of this study is to examine the role of dietary factors, in particular meat preparation and consumption, in relation to colorectal adenomas, the pattern of DNA-mutations (e.g. K-ras and p53), and genetic susceptibility (NAT2, HNPCC). In a case control study on diet and colorectal adenomas (sporadic and HNPCC), acetylator status (NAT2) of cases and controls as well as K-ras and p53 mutations in adenomas will be assessed. Consumption and preparation of meat, the primary interest of this study, will be assessed by a food frequency questionnaire designed especially for this purpose.

Intake and sources of alpha-linolenic acid in Dutch elderly men.

OBJECTIVE: Intake of alpha-linolenic acid may have a beneficial effect on coronary heart disease, but little information is available on the intake and sources of alpha-linolenic acid (C18:3 n-3) in populations. We therefore assessed intake and sources of alpha-linolenic acid in Dutch elderly men. DESIGN AND SUBJECTS: Dietary histories were obtained from participants of the Zutphen Elderly Study, a Dutch cohort study. Food consumption data were available from 876 men in 1985 and from 541 of the same men in 1990. Daily intakes of alpha-linolenic acid were assessed using a food table developed for this purpose. Alpha-linolenic acid content of edible fats, seafood and some commonly eaten dishes were mainly derived from chemical analyses of Dutch foods, and other values were obtained from published food tables. RESULTS: Alpha-linolenic acid provided 0.5 +/- 0.1% of energy intake (mean +/- s.d.) or 1.30 +/- 0.46 g/day in 1985, and 1.21 +/- 0.52 g/day in 1990. The Pearson correlation coefficient for intake of alpha-linolenic acid in 1985 and 1990 was 0.34. Margarines were the main source (25.4%), followed by meat and the fats used in cooking meat (10.8%), bread (9.8%) and vegetables (7.8%). CONCLUSIONS: An increase in intake of alpha-linolenic acid, is most easily realized by the use of unhydrogenated oils rich in alpha-linolenic acid such as rapeseed and soybean oil, and of margarines and other fats containing such oils.