D.W. Voskuil

Physical activity and breast cancer: a systematic review.

Background: Many epidemiologic studies have found an association between physical activity and breast cancer risk, although this has not been a consistent finding. Methods: Studies were identified through a systematic review of literature available on PubMed through February 2006. We included all cohort and case–control studies that assessed total or leisure time activities in relation to occurrence or mortality of breast cancer. The fully adjusted risk estimates and 95% confidence intervals for the highest versus lowest level of activity were documented for each study as well as evidence for a dose–response relationship. Methodologic quality was also assessed. Due to statistical and methodologic heterogeneity among studies, we did not carry out statistical pooling. To draw conclusions, we performed a best-evidence synthesis taking study quality into account. Results: Nineteen cohort studies and 29 case–control studies were evaluated. There was strong evidence for an inverse association between physical activity and postmenopausal breast cancer with risk reductions ranging from 20% to 80%. For premenopausal breast cancer, however, the evidence was much weaker. For pre- and postmenopausal breast cancer combined, physical activity was associated with a modest (15–20%) decreased risk. Evidence for a dose–response relationship was observed in approximately half of the higher-quality studies that reported a decreased risk. A trend analysis indicated a 6% (95% confidence interval = 3% to 8%) decrease in breast cancer risk for each additional hour of physical activity per week assuming that the level of activity would be sustained. Conclusions: There is evidence for an inverse association between physical activity and breast cancer risk. The evidence is stronger for postmenopausal breast cancer than for premenopausal breast cancer.

Physical Activity and Endometrial Cancer Risk, a Systematic Review of Current Evidence

Objective: To assess the epidemiologic evidence for the association between physical activity and endometrial cancer risk, taking into account the methodologic quality of each study. Design: Systematic review, best evidence synthesis. Data Sources: Studies were identified through a systematic review of literature available on PubMed through December 2006. Review Methods: We included cohort and case-control studies that assessed total and/or leisure time and/or occupational activities in relation to the incidence of endometrial cancer. The methodologic quality of the studies was assessed with a comprehensive scoring system. Results: The included cohort (n = 7) and case-control (n = 13) studies consistently show that physical activity is associated with a decreased risk of endometrial cancer. The best evidence synthesis showed that the majority (80%) of 10 high-quality studies found risk reductions of >20%. Pooling of seven high-quality cohort studies that measured total, leisure time, or occupational activity showed a significantly decreased risk of endometrial cancer (summary estimate: OR, 0.77; 95% CI, 0.70-0.85) for the most active women. Case control studies with relatively unfavorable quality scores reported divergent risk estimates, between 2-fold decreased and 2-fold increased risk. Effect modification by body mass index or menopausal status was not consistently observed. Evidence for an effect of physical activity during childhood or adolescence was limited. Conclusions: Physical activity seems to be associated with a reduction in the risk of endometrial cancer, which is independent of body weight. Further studies, preferably prospective cohort studies, are needed to determine the magnitude of the risk reduction and to assess which aspects of physical activity contribute most strongly to the reduced risk and in which period of life physical activity is most effective. (Cancer Epidemiol Biomarkers Prev 2007;16(4):639–48)

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.

Risk of colorectal adenomas in relation to meat consumption, meat preparation, and genetic susceptibility in a Dutch population.

AbstractObjective: We studied the association between meat consumption and colorectal adenomas, and potential influence of genetic susceptibility to heterocyclic aromatic amines (HCAs) formed during meat cooking at high temperatures. Methods: We studied HCA concentration in relation to preparation habits among 63 volunteers. Associations of meat consumption, meat preparation habits, and genetic susceptibility with colorectal adenoma risk were investigated among 431 adenoma cases and 433 polyp-free controls recruited at endoscopy. Participants completed a meat consumption and preparation questionnaire and provided blood for DNA isolation. Polymorphisms of N-acetyltransferases (NAT) 1 and 2, sulfotransferase (SULT) 1A1, and glutathione-S-transferases (GST) M1 and T1 were determined. Results: HCAs were present in habitually prepared meat, although meat consumption (7 versus5x/week) did not increase the risk of colorectal adenomas (odds ratio (OR) 1.2, 95% confidence interval (CI) 0.8–1.9). Also, presumed unfavorable preparation habits (e.g., use of lid, preference for darkly browned meat) did not increase adenoma risk (OR 0.8 and 0.9, respectively). Only the combination of NAT2 slow acetylation and frequent meat consumption (>5x/week) slightly increased adenoma risk (OR 1.6, 95% CI 1.1–2.3). Conclusions: In this Dutch population, unfavorable meat consumption and preparation habits did not increase colorectal adenoma risk, and these associations were not influenced by relevant genetic polymorphisms.

Dietary determinants of circulating insulin-like growth factor (IGF)-I and IGF binding proteins 1, -2 and -3 in women in the Netherlands

AbstractObjective: Epidemiological studies suggest that individuals with elevated plasma concentrations of insulin-like growth factor (IGF-I) are at increased risk of developing cancer. We assessed whether dietary intake of total energy, protein, alcohol, phytoestrogens and related foods, and tomatoes and lycopene was associated with plasma levels of IGF-I and IGF binding proteins (IGFBPs) in Dutch women. Methods: A cross-sectional study was conducted in 224 premenopausal and 162 postmenopausal women, aged 49-69, participating in the Prospect-EPIC study in the Netherlands. Diet was assessed using a food frequency questionnaire. Results: In postmenopausal women, higher alcohol intake was associated with lower plasma IGFBP-1 concentrations (alcohol 1.4 to 20 g/day: 20% decrease in IGFBP-1; p= 0.04), and higher intake of plant lignans was associated with higher IGFBP-1 concentrations (plant lignans 0 to 1 mg/day: 59% increase in IGFBP-1; p=0.02). Higher soy intake was associated with higher plasma IGFBP-2 concentrations in premenopausal women (soy 0 to 2.5g/day: 3% increase in IGFBP-2; p= 0.04). No independent associations of dietary factors with IGF-I or IGFBP-3 concentrations were observed. However, in premenopausal women alcohol intake was inversely associated with IGF-I and positively associated with IGFBP-3 after mutual adjustment. Conclusions: In this study population, with limited variation in dietary intake, total energy, protein, phytoestrogens and lycopene were not associated with IGF-I and IGFBP-3. Alcohol was inversely, and some measures of phytoestrogen intake were positively associated with plasma IGFBP-1 or -2 concentrations. The roles of IGFBP-1 and -2 in relation to IGF-I bioactivity and cancer deserve further investigation.

Colorectal cancer risk in HNPCC families : Development during lifetime and in successive generations

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. Int. J. Cancer 72:205–209, 1997.

Insulin-Like Growth Factor (IGF)-System mRNA Quantities in Normal and Tumor Breast Tissue of Women with Sporadic and Familial Breast Cancer Risk

The insulin-like growth factor (IGF)-system plays a role in breast cancer susceptibility as well as in growth and progression of breast carcinomas. So far, findings have been based on serum IGF-I levels and semi-quantitative assessment of IGF-system expression levels in model systems and human tissue. Quantitative data on mRNA expression in different types of human breast tissue are lacking. Breast tissue samples (n= 83) were available from 72 women. Messenger RNA expression of IGF-I, IGF-II, and their receptors (IGF-1R and IGF-2R) was assessed by real-time RT-PCR. We found a large variation in mRNA levels. Expression of each gene was significantly higher in normal tissue than in tumor tissue (median for normal and tumor tissue, respectively (arbitrary units); IGF-I: 25.2 and 1.4; IGF-II: 5.9 and 0.6; IGF-1R: 0.18 and 0.07; IGF-2R: 1.8 and 0.9; p < 0.0001, Mann–Whitney test). Interestingly, in tumor tissue from patients with a strong family history of breast cancer, expression of both receptors was higher than in sporadic patients (IGF-1R: 0.13 and 0.05, p= 0.04; IGF-2R: 1.1 and 0.8, p= 0.04). For cancer-free controls, expression of IGF-II and IGF-2R in normal breast tissue was also higher in women with a family history of breast cancer than in women without such a family history (IGF-II: 7.2 and 1.5, p= 0.02; IGF-2R: 2.6 and 1.5, p= 0.09). Our study quantitatively shows that mRNA expression levels of IGF-system components in the breast are generally higher in normal tissue compared with tumor tissue, and higher in tissue from women with a family history of breast cancer. A basis has therefore been created for studies aimed at understanding IGF as a breast cancer risk factor, the relationship between IGF-systems in serum and tissues, and effects of lifestyle factors on the IGF-system.

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.

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. Int. J. Cancer 81:675–681, 1999.

Effects of Lycopene on the Insulin-Like Growth Factor (IGF) System in Premenopausal Breast Cancer Survivors and Women at High Familial Breast Cancer Risk

Insulin-like growth factor-I (IGF-I) is an important growth factor associated with increased risk of premenopausal breast cancer. We conducted a randomized, placebo-controlled, double-blind, crossover trial to evaluate whether tomato-derived lycopene supplementation (30 mg/day for 2 mo) decreases serum levels of total IGF-I in premenopausal women with 1) a history of breast cancer ( n = 24) or 2) a high familial breast cancer risk ( n = 36). Also, IGF binding protein (IGFBP) increasing effects were evaluated. Lycopene supplementation did not significantly alter serum total IGF-I and other IGF system components in the 2 study populations combined. However, statistically significant discordant results were observed between the 2 study populations (i.e., P < 0.05 for total IGF-I, free IGF-I, and IGFBP-3). Total IGF-I and IGFBP-3 were increased in the breast cancer survivor population [total IGF-I = 7.0%, 95% confidence interval (CI) = –0.2 to 14.3%; IGFBP-3 = 3.3%, 95% CI = 0.7–6.0%), and free IGF-I was decreased in the family history population (–7.6%, 95% CI = –14.6 to –0.6%). This randomized controlled trial shows that 2 mo of lycopene supplementation has no effect on serum total IGF-I in the overall study population. However, lycopene effects were discordant between the 2 study populations showing beneficial effects in high-risk healthy women but not in breast cancer survivors.