Kaoru Hirose

Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58 515 women with invasive breast cancer and 95 067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, womens age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19–1.45, P<0.00001) for an intake of 35–44 g per day alcohol, and 1.46 (1.33–1.61, P<0.00001) for ⩾45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5–8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98–1.07, and for current smokers=0.99, 0.92–1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58 515 women with invasive breast cancer and 95 067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, womens age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19–1.45, P<0.00001) for an intake of 35–44 g per day alcohol, and 1.46 (1.33–1.61, P<0.00001) for ⩾45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5–8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98–1.07, and for current smokers=0.99, 0.92–1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.

A Large-scale, Hospital-based Case-Control Study of Risk Factors of Breast Cancer According to Menopausal Status

We conducted a large‐scale, hospital‐based case‐control study to evaluate differences and similarities in the risk factors of female breast cancer according to menopausal status. This study is based on a questionnaire survey on life style routinely obtained from outpatients who first visited the Aichi Cancer Center Hospital between January 1, 1988 and December 31, 1992. Among 36,944 outpatients, 1,186 women with breast cancer detected by histological examination were taken as the case group (607 premenopausal women and 445 postmenopausal women) and 23,163 women confirmed to be free of cancer were selected as the control group. New findings and reconfirmed factors of breast cancer were as follows. 1) The risk of at least one breast cancer history among subjects’ first‐degree relatives was relatively high among pre‐ as well as post‐menopausal women. 2) A protective effect of physical activity against breast cancer was observed among both pre‐ and post‐menopausal women. 3) Dietary control decreased the risk of premenopausal breast cancer. 4) Current smoking and drinking elevated the risk of breast cancer in premenopausal women. 5) Decreasing trends of breast cancer risk were associated with intake of bean curd, green‐yellow vegetables, potato or sweet potato, chicken and ham or sausage in premenopausal women, while in postmenopausal women a risk reduction was associated with a more frequent intake of boiled, broiled and/or raw fish (sashimi). Further study will be needed to clarify the age group‐ and/or birth cohort‐specific risk factors for breast cancer among the young generation in Japan.

Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan

Objectives: The purpose of this study was to examine the hypothesis that tea and coffee consumption have a protective effect against development of digestive tract cancers. Methods: A comparative case-referent study was conducted using Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) data from 1990 to 1995 in Nagoya, Japan. This study comprised 1,706 histologically diagnosed cases of digestive tract cancers (185 esophagus, 893 stomach, 362 colon, 266 rectum) and a total of 21,128 non-cancer outpatients aged 40 years and over. Logistic regression was used to analyze the data, adjusting for gender; age; year and season at hospital-visit; habitual smoking and alcohol drinking; regular physical exercise; fruit, rice, and beef intake; and beverage intake. Results: The odds ratio (OR) of stomach cancer decreased to 0.69 (95 percent confidence interval [CI] = 0.48-1.00) with high intake of green tea (seven cups or more per day). A decreased risk was also observed for rectal cancer with three cups or more daily intake of coffee (OR = 0.46, CI = 0.26-0.81). Conclusions: The results suggest the potential for protective effect against site-specific digestive tract cancer by consumption of green tea and coffee, although most associations are limited only to the upper category of intake and have no clear explanation for site-specificity.

Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan

Experimental studies suggest various features of anticancer activity of green tea including inhibitory effect of tumor invasion and metastasis. This study was conducted to examine the association between regular green tea consumption prior to diagnosis and subsequent risk of breast cancer recurrence. The Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) was started in 1988, in which information on lifestyle has routinely been collected from all first-visit outpatients by questionnaire. A total of 1160 new surgical cases of female invasive breast cancers with HERPACC information diagnosed between June 1990 and August 1998 were followed up through December 1999, and the risk (hazard ratio: HR) of recurrence was assessed with reference to daily green tea consumption using a Cox proportional hazard model. During 5264 person-years of follow-up, 133 subjects (12%) were documented to suffer recurrence of breast cancer. A decreased HR for recurrence adjusted for stage was observed with consumption of three or more daily cups of green tea (HR=0.69, 95% confidence interval (95%CI)=0.47-1.00). Particularly in stage I, the HR was decreased statistically significantly (HR=0.43, 95%CI=0.22-0.84). A similar tendency was observed for stage II subjects, but was not present among more advanced stages. Although careful interpretation is needed, these results suggest the possibility that regular green tea consumption may be preventive against recurrence of breast cancer in early stage cases.

Epidemiological features of first-visit outpatients in Japan: Comparison with general population and variation by sex, age, and season

To evaluate the methodological issues in using first-visit outpatients as controls in epidemiological studies, the features of general lifestyles of non-cancer outpatients at Aichi Cancer Center Hospital (ACCH) were compared with those of the general population, and their variation by sex, age, and season was determined by using a self-administered questionnaire. The study included 1231 subjects randomly selected from the Nagoya electoral roll (CRG), and three groups of non-cancer ACCH outpatients living in Nagoya; 800 from the period September to December 1992 (OPG1), 2326 from January to December 1992 (OPG2), and 12,243 from January 1991 to December 1992 (OPG3). In the younger age group, the proportion of current smokers was higher in the CRG than in the OPGs. In the older age groups, the proportion of those who consumed fresh vegetables and fruit everyday was higher in the OPGs than in the CRG. For other items, the features of the OPGs were not significantly different from those of the CRG. Among the OPG3, there were differences in the features of general lifestyles between sexes and consumption of several food items varied with age. Seasonal variation, however, was only observed in the specific food items where supply varied seasonally. It was concluded that, with due consideration of age, sex, and season in the analysis, it is feasible to use non-cancer outpatients as controls in epidemiological studies.

Subsite-specific risk factors for colorectal cancer: a hospital-based case-control study in Japan.

To investigate the subsite-specific risk factors for colorectal cancer, we conducted a case-control study, using a common questionnaire which inquired about general lifestyles over the past five years (1988–92), at the Aichi Cancer Center Hospital, Nagoya, Japan. This study compared 432 patients with histopathologically diagnosed colorectal cancer (94 proximal colon [cecum, ascending colon, transverse colon]; 137 distal colon [descending colon, sigmoid colon]; 201 rectum [rectosigmoid, rectum]); and 31,782 first-visit outpatient controls who were free from cancer. In both genders, habitual smoking selectively increased the risk for rectum cancer. Soft or loose feces increased the risk for all subsites of colorectal cancer, particularly in female cancer (odds ratio [OR]=4.5). Among female dietary habits, Japanese-style foods decreased the risk factors for distal colon cancer, but increased the risk for proximal colon cancer. These results suggested that the risk factors for colorectal cancer differ by subsite among such a low-risk population as the Japanese. It is suggested also that ‘irritable bowel’ (soft or loose feces) might be associated with distal subsites of colorectal cancer, independently or combined with habitual smoking. Cancer Causes and Control 1995, 6, 14–22.

One-carbon metabolism-related gene polymorphisms and risk of breast cancer.

Environmental exposures and/or genetic background in Japanese population, which might contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in detail. Folate plays an essential role in DNA methylation and synthesis, and thus may be involved in the development of breast cancer. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS), influence folate metabolism, but epidemiological studies have yielded inconsistent findings. We therefore conducted a case-control study to clarify their associations with breast cancer risk. A total of 456 breast cancer cases and 912 age-matched and menopausal status-matched non-cancer controls were genotyped for the polymorphisms. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic models adjusted for potential confounders and gene-environment interactions between the polymorphisms and folate consumption were also evaluated. We observed an increased risk of postmenopausal breast cancer with the MTHFR 677TT genotype (OR = 1.83, 95% CI: 1.08-3.11) with a menopausal status-based analysis. In combination analysis, a significantly elevated OR was found among postmenopausal women with the MTHFR 677TT genotype and lower intake of dietary folate compared with those with 677CC genotype and adequate folate consumption (OR = 2.80, 95% CI: 1.11-7.07). In addition, interaction between the MTRR A66G polymorphism and folate intake for risk of postmenopausal breast cancer was observed (interaction P = 0.008). Our findings indicated that the MTHFR and MTRR polymorphisms were associated with individual susceptibility to breast cancer among postmenopausal women.

Subsite (cervix/endometrium)-specific risk and protective factors in uterus cancer

In Japan the incidence of cervical cancer has been high, but has recently been decreasing gradually, while the incidence of endometrial cancer is running at lower levels but is gradually increasing. To clarify the common and/or specific risk and/or protective factors of cervical cancer (CC) in contrast with endometrial cancer (EC), a comparative case‐control study was conducted at the Aichi Cancer Center Hospital, Japan. In total, 556 CC cases and 145 EC cases were included and 26,751 women, confirmed as free of cancer, were chosen as the common control group. Odds ratio and its 95% confidence interval (95%CI) for each exposure variable were estimated by using an unconditional logistic regression model adjusted for age and first‐visit year. Habitual smoking and experience of pregnancy increased the risk of CC, while decreasing the risk of EC. Greater body mass index (>20), daily intake of fruit and more frequent intake of boiled or broiled fish (>1–2 times/week) decreased the risk of CC, whereas they increased the risk of EC. Daily intake of milk decreased the risk of CC. The results obtained from this study suggest that several EC‐increasing risk factors are in fact CC‐decreasing determinants. The observed risk reduction in both CC and EC by physical exercise and dietary control for health is noteworthy from the public health standpoint and warrants further investigation.

Dietary factors protective against breast cancer in Japanese premenopausal and postmenopausal women

Since components of the Japanese diet that might be responsible for the relatively low breast cancer incidence rates observed in Japan have not been clarified in detail, a case‐referent study with reference to menopausal status was conducted using data from the hospital‐based epidemiologic research program at Aichi Cancer Center (HERPACC). In total, 2,385 breast cancer cases were included, and 19,013 women, confirmed as free of cancer, were recruited as the reference group. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined by multiple logistic regression analysis. There were reductions in risk associated with high intake of milk and green–yellow vegetables (green leafy vegetables, carrots and pumpkins) among both pre‐ and postmenopausal women. The protective effects of the Japanese diet were more prominent among postmenopausal than premenopausal women. The adjusted OR of fish consumption (5 or more times per week vs. fewer than 3 times per month) was 0.75 (95% CI 0.57–0.98, ptrend = 0.01) for postmenopausal breast cancer. A significant decrease in postmenopausal breast cancer risk was also observed for increasing intake of fruit (OR = 0.61, 95% CI 0.41–0.91). Thus, traditional Japanese dietary factors may protect against breast cancer development, especially among postmenopausal women.

Association of p53 Codon Arg72Pro and p73 G4C14-to-A4T14 at Exon 2 Genetic Polymorphisms with the Risk of Japanese Breast Cancer

BackgroundThe association between breast cancer risk and genetic polymorphisms ofp53 at codon 72 (Arg72Pro) has been investigated by several studies, but the results are not consistent. The aim of this case-control study conducted in Nagoya, Japan, was to reconfirm the results of prior studies of polymorphisms ofp53 Arg72Pro, and to test if polymorphisms ofp73 G4C14-to-A4T14 at exon 2 (G4A) were also associated with breast cancer risk.MethodsThe cases were 200 breast cancer patients who visited Aichi Cancer Center Hospital. The controls were 282 local citizens who underwent a health check-up. All cases and controls were recruited from Chubu Japan. Genotyping was carried out by Polymerase chain reaction with confronting two-pair primers.ResultsThep53 genotype distribution was 40.4% forArg72 homozygous, 48.9% for heterozygous, and 10.7% forPro72 homozygous in controls, and 32.0%, 50.0%, and 18.0% in cases, respectively. A comparison between cases and controls indicated a significantly increased risk forPro72 homozygosity in cases (odds ratio = 2.14; 95% confidence interval = 1.21-3.79). The genotypic frequencies forp73 G4A were 54.3% forGIG, 39.7% forG/A, and 6.0% forAI A in controls; and 59.0%, 32.0%, and 9.0% in cases, respectively. There were no significant differences inp73 G4A frequency between cases and controls.ConclusionsThis study implies an association of breast cancer risk with thep53 polymorphismArg72Pro, but not withp 73 G4A.