The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial.

OBJECTIVE: To evaluate the influence of low-dose, enteric-coated aspirin tablets (100 mg/day for 2 years) on colorectal tumour recurrence in Asian patients with single/multiple colorectal tumours excised by endoscopy. DESIGN: A double-blinded, randomised, placebo-controlled multicentre clinical trial was conducted. PARTICIPANTS: 311 subjects with single/multiple colorectal adenomas and adenocarcinomas excised by endoscopy were enrolled in the study (152 patients in the aspirin group and 159 patients in the placebo group). Enrolment began at the hospitals (n=19) in 2007 and was completed in 2009. RESULTS: The subjects treated with aspirin displayed reduced colorectal tumourigenesis and primary endpoints with an adjusted OR of 0.60 (95% CI 0.36 to 0.98) compared with the subjects in the placebo group. Subgroup analysis revealed that subjects who were non-smokers, defined as those who had smoked in the past or who had never smoked, had a marked reduction in the number of recurrent tumours in the aspirin-treated group. The adjusted OR for aspirin treatment in non-smokers was 0.37 (CI 0.21 to 0.68, p<0.05). Interestingly, the use of aspirin in smokers resulted in an increased risk, with an OR of 3.44. In addition, no severe adverse effects were observed in either group. CONCLUSIONS: Low-dose, enteric-coated aspirin tablets reduced colorectal tumour recurrence in an Asian population. The results are consistent with those obtained from other randomised controlled trials in Western countries. THE CLINICAL TRIAL REGISTRY WEBSITE AND THE CLINICAL TRIAL NUMBER: http://www.umin.ac.jp (number UMIN000000697).

The rs6983267 SNP is associated with MYC transcription efficiency, which promotes progression and worsens prognosis of colorectal cancer.

BACKGROUND: The oncogenic single nucleotide polymorphism rs6983267, located on 8q24.21, may affect copy number aberrations and/or expression profiles in colorectal cancer (CRC). We investigated the role of this single nucleotide polymorphism in the clinical outcome of CRC. METHODS: Array comparative genomic hybridization (aCGH) and oligomicroarrays were performed on cancer cells from 157 primary CRC tissues. Expression profiles were analyzed by means of extraction expression module (EEM) analyses. Mutations in TP53, KRAS, and BRAF and microsatellite instability were also examined in 107 of the 157 cases. RESULTS: aCGH analysis revealed two clusters; more frequent genomic copy number alteration (CNA) was observed in the 89 cases in cluster B than in the 18 cases in cluster A. The average CNA was higher in samples containing the major allele (GT/TT) of rs6983267 than in those containing the minor allele (GG). Additionally, MYC expression was the highest in samples containing the GG allele (n = 18), followed by the GT and TT alleles (n = 41 and 48, respectively). EEM analysis revealed dominant up-regulation of MYC in samples containing the minor allele. Moreover, the presence of the minor allele in a MYC-positive, CNA-negative context predicted a poorer prognosis than the presence of the major allele in a MYC-negative, CNA-positive context in CRC. CONCLUSIONS: The presence of the minor allele of rs6983267 at 8q24.21 worsened the prognosis of CRC through up-regulation of MYC transcription. Furthermore, progression of CRC may require global CNA in the presence of the major allele and with lack of MYC transcription.

Obesity/weight gain and breast cancer risk: findings from the Japan collaborative cohort study for the evaluation of cancer risk.

BACKGROUND: We analyzed data from the Japan Collaborative Cohort Study (36 164 women aged 40-79 years at baseline in 1988-1990 with no previous diagnosis of breast cancer and available information on weight and height) to examine the association between baseline body mass index (BMI)/weight gain from age 20 years and breast cancer risk in a non-Western population. METHODS: The participants were followed prospectively from enrollment until 1999-2003 (median follow-up: 12.3 years). During follow-up, breast cancer incidence was mainly confirmed through record linkage to population-based cancer registries. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% CIs for the association between breast cancer risk and body size. RESULTS: In 397 644.1 person-years of follow-up, we identified 234 breast cancer cases. Among postmenopausal women, the adjusted HR increased with BMI, with a significant linear trend (P < 0.0001). Risk was significantly increased among women with a BMI of 24 or higher (HR: 1.50, 95% CI: 1.09-2.08 for BMI of 24-28.9, and 2.13, 1.09-4.16 for BMI ≥ 29) as compared with women with a BMI of 20 to 23.9. Weight gain after age 20 years and consequent overweight/obesity were combined risk factors for postmenopausal breast cancer risk. This combined effect was stronger among women aged 60 years or older. However, the HRs were not significant in premenopausal women. CONCLUSIONS: Our findings support the hypothesis that weight gain and consequent overweight/obesity are combined risk factors for breast cancer among postmenopausal women, particularly those aged 60 years or older.

Relationship of living conditions with dietary patterns among survivors of the great East Japan earthquake.

BACKGROUND: During the year after the Great East Japan Earthquake on March 11, 2011, the health conditions and lifestyles of survivors were extensively surveyed. We examined the relationship between living conditions and dietary pattern among survivors. METHODS: A total of 10 466 survivors aged 18 years or older (25% of the population of that age in the area) participated in a survey of Iwate Prefecture. The average frequency of daily consumption of 8 food groups was determined by questionnaire. After excluding staple foods, which were consumed 3 times a day by 85% of participants, factor analysis was performed on 7 food groups among 9789 people (3795 men, 5994 women). RESULTS: Factor analysis identified 2 dietary patterns-prudent and meat. The prudent dietary pattern is characterized by high intakes of fish and shellfish, soybean products, vegetables, fruit, and dairy products and was more evident among older participants and women. The meat dietary pattern is characterized by high intakes of meat and eggs and was more evident among younger participants and men. Age-adjusted multiple logistic regression analyses showed that male and female current smokers and men and women living in difficult conditions were likely to have a lower prudent dietary pattern score; male current smokers and male daily alcohol drinkers were likely to have a higher meat dietary pattern score. CONCLUSIONS: During the year after the earthquake, the prudent dietary pattern was associated with better living conditions among survivors, whereas the meat dietary pattern was not.

Body mass index and weight change during adulthood are associated with increased mortality from liver cancer: the JACC Study.

BACKGROUND: We investigated the association of baseline body mass index (BMI) and weight change since age 20 years with liver cancer mortality among Japanese. METHODS: The data were obtained from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). A total of 31 018 Japanese men and 41 455 Japanese women aged 40 to 79 years who had no history of cancer were followed from 1988 through 2009. RESULTS: During a median 19-year follow-up, 527 deaths from liver cancer (338 men, 189 women) were documented. There was no association between baseline BMI and liver cancer mortality among men or men with history of liver disease. Men without history of liver disease had multivariable hazard ratios (HR) of 1.95 (95%CI, 1.07-3.54) for BMI less than 18.5 kg/m(2) and 1.65 (1.05-2.60) for BMI of 25 kg/m(2) or higher, as compared with a BMI of 21.0 to 22.9 kg/m(2). BMI was positively associated with liver cancer mortality among women and women with history of liver disease. Weight change since age 20 years was positively associated with liver cancer mortality among women regardless of history of liver disease. Women with history of liver disease had a multivariable HRs of 1.96 (1.05-3.66) for weight gain of 5.0 to 9.9 kg and 2.31 (1.18-4.49) for weight gain of 10 kg or more, as compared with weight change of -4.9 to 4.9 kg. CONCLUSIONS: Both underweight (BMI <18.5 kg/m(2)) and overweight (BMI ≥25 kg/m(2)) among men without history of liver disease, and weight gain after age 20 (weight change ≥5 kg) among women with history of liver disease, were associated with increased mortality from liver cancer.

Cohort profile of the Japan Collaborative Cohort Study at final follow-up.

The Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study) was established in the late 1980s to evaluate the risk impact of lifestyle factors and levels of serum components on human health. During the 20-year follow-up period, the results of the study have been published in almost 200 original articles in peer-reviewed English-language journals. However, continued follow-up of the study subjects became difficult because of the retirements of principal researchers, city mergers throughout Japan in the year 2000, and reduced funding. Thus, we decided to terminate the JACC Study follow-up at the end of 2009. As a final point of interest, we reviewed the population registry information of survivors. A total of 207 (0.19%) subjects were ineligible, leaving 110 585 eligible participants (46 395 men and 64 190 women). Moreover, errors in coding date of birth and sex were found in 356 (0.32%) and 59 (0.05%) cases, respectively, during routine follow-up and final review. Although such errors were unexpected, their impact is believed to be negligible because of the small numbers relative to the large total study population. Here, we describe the final cohort profile at the end of the JACC Study along with selected characteristics of the participants and their status at the final follow-up. Although follow-up of the JACC Study participants is finished, we will continue to analyze and publish study results.

[Validity and reproducibility of a physical activity questionnaire used for health surveying among victims of the Great East Japan Earthquake].

OBJECTIVES: This study was performed to assess the validity and reproducibility of a questionnaire on physical activity status used for health surveying among victims of the Great East Japan Earthquake. METHODS: Seventy-four residents (21 men and 53 women) living in temporary housing in Kamaishi City, Iwate Prefecture, participated in this study. The physical activity status questionnaire was composed of 4 questions regarding the frequency of performing domestic and occupational physical activities, the frequency of leaving their residence, walking duration per day, and sedentary time. The physical activity level for 2 weeks was measured using a tri-accelerometer to validate the responses to the questionnaire. Test-retest reproducibility was examined at 2-week intervals. RESULTS: The physical activity levels were 4,521 +/- 2,266 steps/day for men and 4,533 +/- 2,070 steps/day for women. There was a significant difference in step count between those responding differently to the 3 options in the questionnaire regarding average walking duration per day: those who reported walking for > or = 60 min, 30-60 min, or < or = 30 min had step counts of 5,343 +/- 1,757, 4,760 +/- 1,752, and 3,063 +/- 1,772 steps/day, respectively (P < 0.05). When the response options for 3 questions (excluding those for sedentary time) were given scores (a higher score for a higher physical activity level), there were significant correlations between question score and step count (r = 0.486, P < 0.05) and the amount of moderate to vigorous physical activity (r = 0.342, P < 0.05). The test-retest trial showed a moderate degree of reproducibility, with weighted K coefficients of 0.41-0.65. CONCLUSION: Three questions on physical activity levels may allow assessment of an individual's physical activity level, with a moderate degree of reproducibility.

Increased risk for CRC in diabetic patients with the nonrisk allele of SNPs at 8q24.

BACKGROUND: Colorectal cancer (CRC) oncogenesis was considered to be determined by interactions between genetic and environmental factors. Specific interacting factors that influence CRC morbidity have yet to be fully investigated. METHODS: A multi-institutional collaborative study with 1511 CRC patients and 2098 control subjects was used to compare the odds ratios for the occurrence of polymorphisms at 11 known single nucleotide polymorphisms (SNPs). TaqMan PCR and questionnaires were used to evaluate the effects of environmental exposures. RESULTS: Variants of rs6983267 on 8q24 were the most significant markers of risk for CRC (odds ratio 1.16, 95% confidence interval 1.06-1.27, P = 0.0015). Non-insulin-dependent diabetes mellitus (DM), a higher body mass index at age 20, and meat consumption were environmental risk factors, whereas a tuna-rich diet and vitamin intake were protective factors. The cohort of rs6983267 SNP major (T) allele at 8q24 and DM had a 1.66-fold higher risk ratio than the cohort of major allele patients without DM. CONCLUSIONS: We confirmed that interactions between the genetic background and environmental factors are associated with increased risk for CRC. There is a robust risk of the minor G allele at the 8q24 rs6983267 SNP; however, a major T allele SNP could more clearly reveal a correlation with CRC specifically when DM is present.

Profile of participants and genotype distributions of 108 polymorphisms in a cross-sectional study of associations of genotypes with lifestyle and clinical factors: a project in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study.

BACKGROUND: Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene-environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005. METHODS: We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay. RESULTS: The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35-69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001). CONCLUSIONS: This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene-environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.

Impact of insulin resistance, insulin and adiponectin on kidney stones in the Japanese population.

OBJECTIVES: It has been reported that kidney stones are linked to metabolic syndrome (MetS), which is characterized by insulin resistance. The aim of the present study was to examine the association of insulin resistance, insulin and adiponectin with kidney stones in a Japanese population. METHODS: From February 2007 to March 2008, 1036 (529 men and 507 women) apparently healthy Japanese subjects, aged 35-79 years, were analyzed. Weight, height, waist circumference and blood pressure were measured. Overnight fasting blood was collected to measure insulin and adiponectin levels. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to assess insulin resistance. Logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence intervals for a self-reported history of kidney stones across tertiles of HOMA-IR, insulin and adiponectin. RESULTS: Of the participants, 84 men (15.6%) and 35 women (6.9%) had a history of kidney stones. Age, body mass index, waist circumference, systolic and diastolic blood pressures, HOMA-IR and insulin were significantly higher in women with than in women without kidney stones. There was no difference in adiponectin level between subjects with and without a history of kidney stones in either sex. Furthermore, a significant positive trend was observed in the age-adjusted OR for a history of kidney stones across insulin tertiles (P-value for trend = 0.04) in women. CONCLUSIONS: For Japanese women, HOMA-IR and insulin are associated with a history of kidney stones. The findings suggest that MetS components could increase the risk of kidney stones through subclinical hyperinsulinemia and insulin resistance.

Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles.

BACKGROUND: Oesophageal squamous cell carcinoma (OSCC) is considered a difficult cancer to cure. The detection of environmental and genetic factors is important for prevention on an individual basis. OBJECTIVE: To identify groups at high risk for OSCC by simultaneously analysing both genetic and environmental risk factors. Methods A multistage genome-wide association study of OSCC in Japanese individuals with a total of 1071 cases and 2762 controls was performed. RESULTS: Two associated single-nucleotide polymorphisms (SNPs), as well as smoking and alcohol consumption, were evaluated as genetic and environmental risk factors, respectively, and their interactions were also evaluated. Risk alleles of rs1229984 (ADH1B) and rs671 (ALDH2) were highly associated with OSCC (odds ratio (OR)=4.08, p=4.4×10(-40) and OR=4.13, p=8.4×10(-76), respectively). Also, smoking and alcohol consumption were identified as risk factors for OSCC development. By integrating both genetic and environmental risk factors, it was shown that the combination of rs1229984 and rs671 risk alleles with smoking and alcohol consumption was associated with OSCC. Compared with subjects with no more than one environmental or genetic risk factor, the OR reached 146.4 (95% CI 50.5 to 424.5) when both environmental and genetic risk factors were present. Without the genetic risks, alcohol consumption did not correlate with OSCC. In people with one or two genetic risk factors, the combination of alcohol consumption and smoking increased OSCC risk. CONCLUSIONS: Analysis of ADH1B and ALDH2 variants is valuable for secondary prevention of OSCC in high-risk patients who smoke and drink alcohol. In this study, SNP genotyping demonstrated that the ADH1B and/or ALDH2 risk alleles had an interaction with smoking and, especially, alcohol consumption. These findings, if replicated in other groups, could demonstrate new pathophysiological pathways for the development of OSCC.

Risk factors for colon cancer in Northeastern Thailand: interaction of MTHFR codon 677 and 1298 genotypes with environmental factors.

BACKGROUND: Polymorphisms in methylenetetrahydrofolate reductase (MTHFR), such as MTHFR C677T and A1298C, are associated with several cancers. This study aimed to evaluate the effects of MTHFR polymorphisms on colon cancer risk and possible interactions with environmental factors in a population from northeastern Thailand. METHODS: This hospital-based case-control study was conducted during 2002-2006; 130 colon cancer cases and 130 age- and sex-matched controls were enrolled. Information was collected and blood samples were obtained for assay of MTHFR C677T and A1298C polymorphisms by polymerase chain reaction with restriction fragment length polymorphism techniques. Associations between variables of interest and colon cancer were assessed using conditional logistic regression. RESULTS: Increased risk of colon cancer was associated with alcohol consumption and bowel habits. Alcohol drinkers who consumed < or = 0.50 or >0.50 units of alcohol per day had elevated risks (OR(adj) = 3.5; 95% CI: 1.19-10.25 and OR(adj) = 1.71; 95% CI: 0.74-3.96, respectively). The risk was also higher in subjects with frequent constipation (11.69; 2.18-62.79) and occasional constipation (3.43; 1.72-6.82). An interaction was observed between the MTHFR C677T polymorphism and freshwater fish consumption on colon cancer risk (P value for interaction = 0.031). Interactions were observed between the MTHFR A1298C polymorphism and bowel habits, family history of cancer, alcohol consumption, and beef consumption on colon cancer risk (P-value for interaction = 0.0005, 0.007, 0.067, 0.003, respectively). CONCLUSIONS: In a Thai population, colon cancer risk was associated with alcohol and beef consumption, bowel habits, and family history of cancer. Interactions between MTHFR polymorphisms and environmental factors were also observed.

Alcohol drinking may not be a major risk factor for fatty liver in Japanese undergoing a health checkup.

The question of whether alcohol drinking is a risk factor for fatty liver as shown by ultrasonography was investigated by both cross-sectional and longitudinal approaches in Japanese undergoing a health checkup. In this cross-sectional study, 32,438 males (49.0 +/- 11.9 years old) and 31,009 females (48.2 +/- 11.6 years old) receiving a health checkup from 2000 to 2005 were included. Longitudinally, 5,444 males (49.8 +/- 10.7 years old) and 4,980 females (50.4 +/- 9.3 years old) participating in both 2000 and 2005 were included. Multiple logistic regression analyses were performed for both sexes, adjusted for age, BMI, and smoking. The prevalence of fatty liver in non-, occasional, daily moderate, and daily heavy drinkers was 28.5, 27.5, 18.7, and 19.1% in men and 12.4, 7.7, 5.4, and 6.7% in women, respectively (inverse association, P < or = 0.05 for both). Occasional, daily moderate, and daily heavy drinking in men and occasional and daily moderate drinking in women were inversely associated with fatty liver in the cross-sectional study. Daily moderate and heavy drinking appeared protective in men in the longitudinal study. Alcohol drinking may not be a major risk for fatty liver in Japanese undergoing a health checkup.

Abdominal circumference should not be a required criterion for the diagnosis of metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is an established concept. However, it is characterized by a number of different definitions as well as different cut-off points (COPs) for waist circumference (WC) and different modes for incorporating WC into the diagnostic criteria. METHODS: Abdominal ultrasonography was performed in 2,333 subjects who also underwent comprehensive medical examinations between April and July 2006. The odds ratios for the number of MetS components were calculated by taking central obesity status into account and considering concurrent fatty liver as an independent variable. We compared the areas under the receiver operating characteristic (ROC) curves for fatty liver and MetS using several MetS criteria. RESULTS: Regardless of the WC criterion selected, we observed a strong linear trend for an association (trend P < 0.0001) between MetS and the number of components. The odds ratio (OR) of subjects without central obesity but with all three MetS components was 9.69 (95% confidence interval 3.11-30.2) in men and 55.3 (6.34-483) in women. The COP for the largest area under the curve in men and women was ≥82 cm (OR 0.701) and ≥77 cm (OR 0.699), respectively, when WC was considered as a component. When WC distribution is taken into consideration, practical and appropriate COPs should be ≥85 cm for men and ≥80 cm for women. CONCLUSION: We suggest that a WC of ≥85 cm for men and ≥80 cm for women would be optimal COPs for the central obesity criteria in the Japanese population. In addition, central obesity should be incorporated as a component of MetS rather than an essential requirement for the diagnosis of MetS.

Changes in thioredoxin concentrations: an observation in an ultra-marathon race.

OBJECTIVES: Changes in plasma thioredoxin (TRX) concentrations before, during, and after a 130-km endurance race were measured with the aim of elucidating the relationship between exercise and oxidative stress (OS). METHODS: Blood samples were taken from 18 runners participating in a 2-day-long 130-km ultra-marathon during the 2 days of the race and for 1 week thereafter. There were six sampling time points: at baseline, after the goal had been reached on the first and second day of the endurance race, respectively, and on 1, 3, and 5/6 days post-endurance race. The samples were analyzed for plasma TRX concentrations, platelet count, and blood lipid profiles. RESULTS: Concentrations of plasma TRX increased from 17.9 ± 1.2 ng/mL (mean ± standard error of the mean) at baseline to 57.3 ± 5.0 ng/mL after the first day's goal had been reached and to 70.1 ± 6.9 ng/mL after the second day's goal had been reached; it then returned to the baseline level 1 day after the race. Platelet counts of 21.3 ± 1.2 × 10(4) cell/µL at baseline increased to 23.9 ± 1.5 × 10(4) cells/µL on Day 1 and to 26.1 ± 1.0 × 10(4) cells/µL on Day 2. On Day 7, the platelet counts had fallen to 22.1 ± 1.2 × 10(4) cell/µL. There was a significant positive correlation between plasma TRX and platelet count. CONCLUSIONS: These data suggest that plasma TRX is an OS marker during physical exercise. Further studies are needed to determine the appropriate level of exercise for the promotion of health.

Meta- and pooled analysis of GSTP1 polymorphism and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.

Effect of physical activity on breast cancer risk: findings of the Japan collaborative cohort study.

PURPOSE: This study aimed to examine prospectively the association between physical activity and breast cancer risk in a non-Western population. METHODS: We analyzed data from the Japan Collaborative Cohort Study, which included 30,157 women, ages 40 to 69 years at baseline (1988-1990), who reported no previous history of breast cancer, and provided information on their walking and exercise habits. The subjects were followed prospectively from enrollment until 2001 (median follow-up period, 12.4 years). Breast cancer incidence during this period was confirmed using records held at population-based cancer registries. The Cox proportional hazards model was used to estimate the hazard ratio (HR) for the association of breast cancer incidence with physical activity. RESULTS: During the 340,055 person-years of follow-up, we identified 207 incident cases of breast cancer. The most physically active group (who walked for > or = 1 hour per day and exercised for > or = 1 hour per week) had a lower risk of breast cancer (HR, 0.45; 95% confidence interval, 0.25-0.78) compared with the least active group after adjusting for potential confounding factors. The inverse association of exercise on breast cancer was stronger among those who walked for > or = 1 hour per day than those who walked for <1 hour per day (P = 0.042). These results were not significantly modified by menopausal status or body mass index (BMI). CONCLUSIONS: Our analysis provided evidence that physical activity decreased the risk of breast cancer. Walking for 1 hour per day and undertaking additional weekly exercise both seemed to be protective against breast cancer, regardless of menopausal status or BMI.