P<0.05). Compared to those who had their first menstrual periods at 11 or before, women experiencing menarche at 15 or after had an RR of 0.66 (95% CI 0.45–0.97) in the premenopausal group. Age at first full-term pregnancy had an effect on both pre- and postmenopausal breast cancer risk, with significant tests showing increasing risk per year of increasing age (P=0.001 and P<0.05 respectively). A first full-term pregnancy above age 30 conveyed a risk of 1.63 (95% CI 1.12–2.38) and 1.35 (95% CI 1.02–1.78) in the pre- and postmenopausal groups respectively. A protective effect of high parity was observed only for postmenopausal breast cancer risk (P for trend test =0.001), with point estimates of 0.79 (95% CI 0.60–1.04), 0.69 (95% CI 0.54–0.88), 0.66 (95% CI 0.51–0.85) and 0.64 (95% CI 0.48–0.86) associated to a one, two, three and four or more full-term pregnancies. A history of spontaneous abortion had no significant effect on the risk of breast cancer diagnosed before or after menopause. Our results suggest that reproductive events have complex effects on the risk of breast cancer.The aim of this study was to obtain a better understanding of the role of hormonal factors in breast cancer risk and to determine whether the effect of reproductive events differs according to age at diagnosis. It analysed the effect of age at menarche, age at first full-term pregnancy, number of full-term pregnancies and number of spontaneous abortions both on the overall risk of breast cancer and on its pre- or postmenopausal onset, using the data on 1718 breast cancer cases, obtained from a large sample of around 100 000 French women participating in the E3N cohort study. The results provide further evidence that the overall risk of breast cancer increases with decreasing age at menarche, increasing age at first pregnancy and low parity. No overall effect of spontaneous abortions was observed. The effect of these reproductive factors differed according to menopausal status. Age at menarche had an effect on premenopausal breast cancer risk, with a decrease in risk with increasing age of 7% per year  86, 723–727. DOI: 10.1038/sj/bjc/6600124 www.bjcancer.comCancer Research UK© 2002  There is a considerable body of evidence that reproductive factors play a role in the aetiology of breast cancer risk  had a greater effect on the risk of breast cancers diagnosed early (i.e. at an early age or before menopause) than on the risk of those diagnosed late (i.e. after 55 or after menopause). In contrast, it has been shown that the protective effect of multiparity is greater on late breast cancers . EpidemiWe report here on the effects of age at menarche, age at FFTP, number of full-term pregnancies (FTP) and number of spontaneous abortions both on the overall risk of breast cancer and on its pre- or postmenopausal onset, using data obtained from a large sample of French women participating in the E3N cohort study.E3N is a prospective cohort study on cancer risk factors, conducted in France . Part ofThe cohort consists of 100 000 women living in France who are insured with the Mutuelle Générale de l'Education Nationale, a national health insurance scheme primarily covering teachers. They were aged 40–65 at baseline. The main objective of the study was to investigate risk factors for cancer and other diseases . Participants were enrolled in the study between June 1990 and November 1991 after replying to a baseline questionnaire containing questions on lifestyle, i.e. reproductive factors, body build, smoking, past medical history and family history of cancer. Follow-up questionnaires were sent out at approximately 24-month intervals until April 1997.Age at menarche, age at FFTP, overall number of spontaneous abortions and number of FTP were recorded in the two first questionnaires. Menopausal status was recorded in each questionnaire. Postmenopause was defined as the cessation of periods for natural reasons or due to surgery . Women with undefined menopausal status  were considered in the premenopausal group up to 42 years of age, and in the postmenopausal one after 58. They were not considered in the analysis by subgroup between these limits (i.e. (42–58) years of age, defined as the mean age at menopause in our population ±2 s.d.), as were women who never menstruated.n=39). Only 1815 women could not be traced in the MGEN file . Among these, non respondents were considered lost to follow-up.All questionnaires asked participants whether breast cancer had been diagnosed, requesting the addresses of their physicians and permission to contact them. Deaths in the cohort were detected from reports by family members or by the postal service and by a search on the insurance company (MGEN) file, which contains information on vital status. Information on the cause of death was obtained from the National Service on Causes of Deaths (INSERM). Information on non-respondents was obtained from the MGEN file on reimbursement of hospital fees. In this case, the subject's physician was contacted for diagnostic information. The procedure made it possible to find additional breast cancer cases  of the fifth questionnaire (sent out in April 1997) had been returned. Participants contributed person-time up to the date of any diagnosis of breast cancer, date of death, date of last questionnaire returned or December 1997 (for replies to the April 1997 questionnaire received after December 1997), whichever occurred first. Women whose menopause occurred during the period of follow-up contributed person-time in the premenopausal group until the date of menopause and in the postmenopausal group thereafter.n=2044) of cases. Of these, 94.5% confirmed the self-reported diagnosis of breast cancer. After exclusion of the 112 cases whose diagnosis was rejected as a result of the pathology report and 270 cases of carcinoma in situ, 1718 cases of invasive breast cancer were available for analysis, including the 56 cases whose diagnosis was based on the self-report only, as self-reporting proved to be extremely accurate. Histologic types were coded by a pathologist blinded to data on risk factors. Women who had reported a cancer other than a basal cell carcinoma at enrolment were excluded.A total of 2100 breast cancer cases were reported by participants. Pathology reports were obtained for 97% . Breast cancer risk increased with increasing age at FFTP by 3% per year . Each FTP reduced the risk by 8% . All estimates of the relationship between breast cancer risk and spontaneous abortions were non-significant.Menstrual and reproductive factors are considered in Table 2P<0.05) for breast cancers diagnosed before menopause and by 3%  for those diagnosed later. An increase in age at FFTP increased the risk by 4%  per year for breast cancer diagnosed in premenopausal women and by 2%  per year for breast cancer diagnosed in postmenopausal women. The protective effect of an increasing number of FTPs was apparent only among postmenopausal women . A history of spontaneous abortion had no significant effect on the risk of breast cancer diagnosed before or after menopause.Table 3The results provide further evidence that the overall risk of breast cancer increases with decreasing age at menarche, increasing age at first pregnancy and low parity. No overall effect of spontaneous abortions was observed. However, the effect of these reproductive factors differed according to menopausal status. Age at menarche had a significant effect on premenopausal breast cancer risk. Age at FFTP had a significant effect on the risk in both subgroups, the effect being slightly greater before menopause. Parity had a significant protective effect in the postmenopausal subgroup. A history of spontaneous abortions had no effect on the risk.Consideration must be given to the validity of the data on reproductive factors. In a substudy of 751 women in the E3N study who completed the same self-administered questionnaire twice, we found a high rate of reproducibility for answers on age at menarche, age at first pregnancy, number of live births and duration of first pregnancy, with 71, 64, 98 and 80% respectively of identical answers. Nevertheless, even if assessment problems cannot be excluded, there should be no difference between cases and non-cases, given the prospective nature of the study. The reliability of the menopausal status and of age at menopause was assessed in a validation study . AgreemeIndeed, our results are remarkably close to those from the literature , though On 21 studies, we showed that breast cancer risk decreased by about 9% (95% CI 7–11%) for each additional year in age at menarche for breast cancers diagnosed early or before menopause and by about 4% (95% CI 2–5%) for those diagnosed later. The hormonal levels to which girls are exposed increase continuously with age until menarche  and it hIn our previous analysis of 18 studies on age at FFTP, we found that each additional year led to an increased risk of 1.05 for early breast cancer and 1.03 for late breast cancer. According to the proposed multi-step process of carcinogenesis  reduction in the risk of breast cancer diagnosed early or before menopause for each FTP, whereas the reduction rose to 12% (95% CI 10–14%) for breast cancers diagnosed later. The protective effect of multiparity is thus greater for cancers emerging late in life, and this agrees with recent studies that have found a transient increase in breast cancer risk immediately after each pregnancy (Recent reviews on the relationship between breast cancer and spontaneous abortion (Spontaneous abortions result in the lack of differentiation of the breast cells that occurs at the end of FTP. Spontaneous abortions that result from abnormally low production of progesterone by the corpus luteum may affect breast cancer risk as a consequence of low progesterone production. Whether the indication of a transient protection observed in our study on early breast cancer risk is due to the abrogation of the transient increase attributed to the final months of pregnancy, or is linked to the hormonal milieu, or is merely attributable to chance requires further investigation.


The relationship between body mass index ) and post-menopausal breast cancer risk was considered in age-specific strata on the basis of a pooled analysis of three Italian case-control studies, including a total of 3108 post-menopausal breast cancer patients aged 50 years or over and 2664 control subjects. Overall, there was a moderate, but significant, association between BMI and post-menopausal breast cancer: the odds ratios (ORs) were around 1.3 for the three intermediate quintiles compared with the lowest one, and 1.4 for the highest one. The association was moderate among women aged 50-59 years and 60-69 years, with ORs around 1.3 for the highest BMI quintiles, but stronger among elderly women, with ORs of 1.6 for the fourth and 2.1 for the fifth quintile. An 8-unit increase in BMI involved an OR of 1.18 at age 50-59 years, of 1.14 at age 60-69 years and of 1.59 above age 70 years. This pattern of risk is similar to that observed for post-menopausal hormone replacement treatment and is consistent with a duration-risk relationship in the exposure to high oestrogen levels and with a greater differential in oestrogen levels in overweight elderly women. In terms of population attributable risk, 19.6% of all post-menopausal breast cancer patients and 27.1% of those in women above age 70 years were attributable to overweight and obesity in this population. This has, therefore, major preventive implications as to reduce breast cancer risk late in life, it is essentially important to control weight gain in elderly women.


P-trend=0.02), stearate , oleate , saturated FAs , and monounsaturated FAs , when comparing the highest quartile of intake to the lowest. Significant interactions were detected between body mass index and both saturated and monounsaturated FAs, with a markedly reduced risk associated with intake of stearate , oleate , saturated FAs , and monounsaturated FAs  among subjects who are obese. The results suggest that substituting polyunsaturated FAs with saturated or monounsaturated FAs may reduce pancreatic cancer risk, independently of total energy intake, particularly among obese subjects.The possible association of specific fatty acid (FA) intake and pancreatic cancer risk was investigated in a population-based case–control study of 462 histologically confirmed cases and 4721 frequency-matched controls in eight Canadian provinces between 1994 and 1997. Dietary intake was assessed by means of a self-administered food frequency questionnaire. Unconditional logistic regression was used to assess associations between dietary FAs and pancreatic cancer risk. After adjustment for age, province, body mass index, smoking, educational attainment, fat and total energy intake, statistically significant inverse associations were observed between pancreatic cancer risk and palmitate (odds ratios (ORs)=0.73; 95% confidence intervals (CIs) 0.56–0.96;  Pancreatic cancer represents the fourth leading cause of cancer-related deaths in Canada , and is per se does not cause pancreatic cancer  interviews. The study population has been described in detail elsewhere . Like moThe NECSS used frequency matching in selecting the control population to achieve age and gender distributions similar to those of all cancer cases combined. Based on the projected number of incident cancer cases by province, the questionnaires were mailed to 8117 subjects during the 1996 calendar year using the same protocol as for cases. Questionnaires were not returned for 573 controls (7.4%) because of incorrect or changed addresses. Strategies for control selection varied by province, depending on data accessibility. In Prince Edward Island, Nova Scotia, Manitoba, Saskatchewan, and British Columbia, provincial health insurance plans were tapped to obtain a random sample of the provincial population stratified by age and gender. In each of these provinces, more than 95% of residents are covered by public health care plans. Active military personnel and their families as well as indigenous peoples were excluded because they were covered by other plans. In Ontario, Ministry of Finance data were used to derive a stratified random sample, while Newfoundland and Alberta adopted a random digit-dialling method to enrol a population-based sample of controls. A total of 5039 controls were selected to serve as a common control group for all types of cancer. Response rates of 65 and 71% were achieved from the respective male and female control populations.Questionnaires, with telephone follow-up for clarification when necessary, were mailed to subjects to obtain information on residential and occupational history and other risk factors for cancer. The NECSS questionnaire included questions on smoking history, height, weight, physical activity, and educational attainment.Food consumption data were obtained via a semi-quantitative food frequency questionnaire (FFQ) developed after two instruments that have been widely validated previously: the short Block questionnaire . Subtle Data were collected on 475 cases  and 4802 controls . We excluded subjects with daily energy intake <500 kcal (10 cases and 54 controls) or >5000 kcal (three cases and 27 controls) because such intakes are unrealistic and hence of questionable validity. Finally, a total of 462 cases  and 4721 frequency-matched controls  were eligible for analysis.−2), educational attainment (years), total fat intake (g day−1), and total energy intake. To evaluate effect modification by BMI, age, educational attainment, smoking, and physical activity, the P-value for a multiplicative interaction term added to the fully adjusted model was examined – and when it was statistically significant, the analysis was stratified on that variable. Tests for linear trend in the variables included in logistic regression models were performed with scores derived from the median values of categorised variables, and entered into the model as successive integers. All tests of statistical significance were two-sided. Data analysis was performed using SPSS for WINDOWS .Food intake among the cases and controls was converted to specific FA intake based on the CNF. To determine the associations between dietary FA intakes and pancreatic cancer risk, the study subjects were divided into four categories according to quartiles of calorie-adjusted FA intake in the control population. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated based on unconditional logistic regression. Risk estimates were adjusted for matching variables (age group and province), lifetime cigarette consumption , body mass index (BMI) , stearate , oleate , total saturated FAs , and monounsaturated FAs , when comparing the highest quartile of intake to the lowest.P=0.04) as well as oleic acid (P=0.04), and both total saturated and monounsaturated FAs (P=0.05). The risk of pancreatic cancer in relation to intake of stearate, oleate, total saturated and monounsaturated FAs is presented in P-trend=0.001), oleic acid , saturated FAs , and monounsaturated FAs  and pancreatic cancer risk, when comparing the highest to the lowest quartile of intakes. There was no evidence of effect modification by age, educational attainment, smoking, and physical activity .There was a significant interaction between BMI and stearic acid  for intakes in the highest as compared to the lowest quartiles , 0.3 (95% CI 0.1–1.0), 0.2 (95% CI 0.1–0.2), and 0.9  release, which, in rodents, increases susceptibility to carcinogens and causes acinar cell hyperplasia, followed by the development of pancreatic carcinomas (P-trend=0.02) with higher monounsaturated fat intake. Another case–control study  risk reduction related to oleate intake, with monounsaturated FA intake associated with a 28% decrease in pancreatic cancer risk. One case–control study , with 65 and 68% risk reductions, respectively. A cohort study of pancreatic cancer indicated that dietary glycaemic load and the glycaemic index are associated with increased risk of pancreatic cancer among women who were overweight, and among obese women with low physical activity (The major strengths of our study included the large number of pancreatic cancer cases, histological diagnosis, and general population sampling of controls. The large sample size permitted subgroup analyses. Histological confirmation of diagnosis reduced the possibility of disease misclassification, while a population-based approach facilitates extrapolation of results to the general population.Our study is also subject to certain limitations. Since the assessment of dietary exposure was retrospective, recall bias cannot be completely excluded. A prospective cohort approach has several advantages when studying associations between nutritional factors and cancer risk. However, because of the relatively low incidence of pancreatic cancer, the largest cohort to date examining diet and pancreatic cancer risk confirmed only 178 pancreatic cancer cases in 18 years of follow-up (We could not adjust OR estimates for the potentially confounding effects of diabetes mellitus and family history of pancreatic cancer, since this information was not collected at baseline. Nevertheless, we expected that diabetes did not confound the association between specific FA intakes and pancreatic cancer risk because of the likelihood that diet represents the initial risk factor for both chronic diseases, rather than lying on the causal pathway. In addition, it has been suggested that diabetes might be one of the early manifestations of pancreatic cancer, and the significance of diabetes is much weaker if cases of recent onset are excluded . As wellIn conclusion, our current analyses suggest that, independently of total energy intake, substituting polyunsaturated FAs with saturated or monounsaturated FAs may reduce pancreatic cancer risk, particularly in subjects who are obese. Further epidemiological studies assessing the role of specific dietary FA intakes in the aetiology of pancreatic cancer are warranted.


We examined the use of antibiotics among 2728 women with a first diagnosis of breast cancer during 1994–2003, and 27 280 population controls in North Jutland County, Denmark, based on hospital discharge diagnoses, prescription use from 1989 to 2002, and population registry data. We found no increased relative risk of breast cancer associated with use compared with nonuse. The odds ratio for breast cancer associated with more than 10 prescriptions for antibiotics was 1.00 (95% CI 0.86 –1.15). Relative risks were similar for different classes of antibiotics. A subanalysis based on cases and controls younger than 70 years of age, with data on first birth and number of children, showed similar risk estimates even after adjustment for age at first birth and parity. In our study, use of antibiotics was not associated with an increased risk of breast cancer. Breast cancer is the most commonly occurring cancer in women, but we have only limited knowledge about nonhormonal risk factors for this malignancy . Recent To further evaluate this association, we conducted a population-based case–control study of breast cancer in Denmark, a country with one of the highest incidences of breast cancer worldwide .The National Health Service in each Danish county provides health care for all residents, with free access to general practitioners and hospitals, and also refunding a variable proportion of the costs of prescribed drugs. All services are registered by use of the unique 10-digit civil registry number that is assigned to all Danish citizens shortly after birth. Its use allows valid linkage between population-based registries and the creation of a complete hospital discharge and prescription history for each individual.The Hospital Discharge Registry of North Jutland County retains key information on all patients discharged from nonpsychiatric hospitals in the county since 1977 (n=2728) using the Hospital Discharge Registry.All patients with an incident diagnosis of breast cancer  were identified in the period 1 January, 1994–31 March, 2003  and controls (n=19 170) less than 70 years of age. Wald tests were used to test for homogeneity.We used conditional logistic regression to estimate odds ratios (OR)s and associated 95% confidence intervals (CIs) for breast cancer according to the number of prescriptions of antibiotics and different types of antibiotics, adjusted for postmenopausal hormone replacement therapy in the overall analysis. We adjusted for age at first birth, parity, and use of postmenopausal hormone replacement therapy in cases .In this large population-based case–control study, we found no increased risk of breast cancer in association with antibiotic use. Our study thus does not confirm findings from the Seattle case–control study of 2266 women with breast cancer and 7953 controls (Several issues are relevant to the interpretation of our data. The main strengths of this study are its large size, the population-based design based on the Danish health-care system, and the use of exposure data collected before hospitalisation for breast cancer. These data sources have been extensively used in previous pharmacoepidemiological studies (In conclusion, the present data showed no increased breast cancer risk among antibiotic users in a population characterised by one of the highest breast cancer incidence rates worldwide , althoug


Inherited susceptibility to breast cancer is associated with an early onset and bilateral disease. The extent of familial risks has not, however, been fully assessed in population-based incidence studies. The purpose of the study was to quantify the risks for cancers of the breast, ovary and other sites of close relatives of women in whom breast cancer was diagnosed at an early age. Records collected between 1943 and 1990 at the Danish Cancer Registry were searched, and 2860 women were found in whom breast cancer was diagnosed before age 40. Population registers and parish records were used to identify 14 973 parents, siblings and offspring of these women. Cancer occurrence through to 31 December 1993 was determined within the Cancer Registry's files and compared with national incidence rates. Women with early-onset breast cancer were at a nearly fourfold increased risk of developing a new cancer later in life (268 observed vs 68.9 expected). The excess risk was most evident for second cancer of the breast (181 vs 24.5) and for ovarian cancer (20 vs 3.3). For mothers and sisters, risks for cancers of the breast and ovary were significantly increased by two- to threefold. Bilateral breast cancer and breast–ovarian cancer were very strong predictors of familial risks, with one in four female relatives predicted to develop breast and/or ovarian cancer by age 75. Mothers had a slightly increased risk of colon cancer, but not endometrial cancer. The risk for breast cancer was also increased among fathers  and especially brothers , although based on small numbers. The risk for prostatic cancer was unremarkable. In this large population-based survey, the first-degree relatives of women who developed breast cancer before age 40 were prone to ovarian cancer as well as male and female breast cancer, but not other tumours that may share susceptibility genes with breast cancer. © 1999 Cancer Research Campaign


A cohort of 63 090 Norwegian women born 1886–1928 was followed more than 38 years, and relations between reproductive factors and risk of pancreatic cancer were explored; 449 cases were recorded at ages 50–89 years. Age at menopause showed a moderately positive association with risk (rate ratio (RR)=1.08 per 2 years delay in menopause; 95% confidence interval (CI)=1.00–1.17). Neither parity nor duration of breastfeeding showed significant associations with risk after adjusting only for demographic factors. With mutual adjustment, however, parity became positively associated  while duration of breastfeeding was inversely associated . These associations lessened in magnitude with increasing age, and were essentially absent above age 80 years. Risk was raised among women reporting at least one abortion, but no trend was seen with number of abortions. Together with previous studies, the findings raise questions about the role of chance, but do not exclude hormonal factors related to breastfeeding and pregnancy from affecting pancreatic cancer risk. Among Norwegian women, only cancers of lung, breast, colon and ovary cause more deaths than pancreatic cancer . Female Lower incidence rates of pancreatic cancer in women than men, particularly at premenopausal ages, have suggested that sex hormones may be protective in women , while tSome studies have indicated overall positive  were recorded, among them 231 were histologically verified. Among the remaining cases, the diagnosis was based on surgical reports in 99 cases, X-ray examinations in 60 cases, clinical examinations in 31 cases, autopsy in 4 cases and death certificates in 24 cases.Incidence rates were assessed by log-linear Poisson regression analysis , defined as weight/(height)Information on individuals' smoking habits, a potential confounder, was not available. Absolute age-specific incidence rates of lung cancer , during follow-up, were used to assess the extent of smoking. To compare birth cohorts, only the age intervals 60–64, 65–69, 70–74 and 75–79 years were considered, with a total of 393 cancer cases.Pancreatic cancer showed only minor variation in incidence over birth cohorts after accurate adjustment for age  but diffNo association was found between age at menarche and risk . Age at P=0.55). Age at menopause was only weakly associated with parity and breastfeeding in this cohort  and duration of breastfeeding . For age at menopause, a slightly stronger estimate was found . Body mass index showed no association with risk, and adjusting for it did not influence relations with age at menopause, parity or breastfeeding, and nor materially did occupational category.Absolute incidences per 100 000 person-years of lung cancer for the birth cohort 1886–1900 were 6, 10, 16 and 28 for the age intervals 60–64, 65–69, 70–74 and 75–79 years, respectively. For the birth cohort 1901–1910, the corresponding rates were 10, 15, 20 and 39; and for the birth cohort 1911–1928, 38, 65, 72 and 90.In this cohort study, the risk of pancreatic cancer was influenced by age at menopause and, after mutual adjustment, by parity and duration of breastfeeding. The study design, with a complete and lengthy follow-up, essentially eliminated selection bias. Data on risk factors were collected before follow-up, and incomplete information on reproductive variables, possibly affecting women born after 1910, should mostly attenuate risks. Women with early menopause were overrepresented, but after accurate adjustment for age, this did not affect the risk estimates.The lack of association with age at menarche is consistent with certain previous studies . An inveNo significant relation with breastfeeding was found in a cohort study of younger women with shorter overall breastfeeding times (A positive association with parity, seen only after adjustment for breastfeeding, implied that multiparous women who never breastfed carry an elevated risk. Multiparity and prolonged breastfeeding may be associated with a lower risk than in nulliparous women. Failure to take breastfeeding into account may partly explain previous disparate results. It was not possible to adjust for cigarette smoking, a risk factor for pancreatic cancer. Among Norwegian women born in 1890–1894, the maximum proportion of smokers at any time was 10%, but this increased to about 40% among those born in 1925–1929 , particuSmoking is associated with earlier menopause by 1–2 years . This isWe found a higher risk among women reporting an abortion but no trend in risk with the number. Possibly those with several abortions reflected a tendency to miscarry early in pregnancy, whereas factors associated with full-term pregnancy also applied to the occasional later abortion. One early study  showed aThe lack of association with age at first birth is consistent with several studies (The variety of findings in epidemiological studies of pancreatic cancer must raise the role of chance, although larger studies taking into account hormonal levels in different age groups might still be revealing.


The relationship between bowel movement (BM) frequency and the risk of colorectal cancer was examined in a large cohort of 25 731 men and 37 198 women living in 24 communities in Japan. At enrolment, each participant completed a self-administrated questionnaire on BM frequency and laxative use. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were estimated using Cox's proportional-hazard model. During the follow-up period (average length 7.6 years), 649 cases of colorectal cancer, including 429 cases of colon cancer, were identified. Among women, subjects who reported a BM every 2–3 days had the lowest risk of developing colorectal  and colon cancer , whereas those reporting a BM every 6 days or less had an increased risk of developing colorectal  and colon cancer  compared with those reporting ⩾1 BM per day. A similar, but nonsignificant, association between the frequency of BM and cancer risk was observed in men. There was no association between colorectal or colon cancer risk and laxative use. Regulating BM frequency might therefore have a role in the prevention of colorectal cancer. An association between constipation and the risk of colorectal cancer has long been noted. Prolonged intestinal transit time might not only increase the duration of contact between carcinogens in the stools and the gut wall, but could also concentrate carcinogens by increasing colonic water absorption . A meta-Since bowel habits might be influenced by the presence of colorectal cancer, retrospective studies cannot exclude the effects of the cancer itself, as well as recall bias, on their results. However, few prospective studies have addressed this issue. The only cohort study, which had a 12-year follow-up period involving 84 577 women, of colorectal cancer incidence and BM frequency or laxative use reported negative results  Study, the methods of which have been described in detail elsewhere . BrieflyAnalyses were restricted to data from the 65 184 participants who lived in the 24 study areas in which cancer registries were available. A further 58 subjects with a previous history of colorectal cancer, and 2197 subjects for whom information about bowel habits was not available, were excluded. Therefore, a total of 62 929 individuals (25 731 men and 37 198 women) were involved in this analysis.All participants completed a self-administered questionnaire on enrolment. This covered demographic characteristics and lifestyle factors such as diet, tobacco smoking, alcohol consumption, physical activity, BM frequency, susceptibility to diarrhoea and laxative use over the past year. The alternative answers provided on the questionnaire for the frequency of BM were: ‘daily’, ‘every 2–3 days’, ‘every 4–5 days’ and ‘every 6 days or less’. With regard to laxative use, the questionnaire asked only whether the participants used laxatives in the past one year at the time of enrolment; additional data on the type of laxative, the reason for use and the duration of use were not collected. Participants also provided information about susceptibility to diarrhoea by answering ‘yes’, ‘no’ or ‘neutral’ in response to the question: do you often have diarrhoea?Population registries in the municipalities were used to determine the vital and residential status of subjects. Registration of death is required under the Family Registration Law in Japan, which applies throughout the country. Incidences of cancer were confirmed using records from the population-based cancer registries, which were supplemented by a systematic review of death certificates ; in someThe follow-up period ran from the time of the baseline survey through to the end of 1997 in all but three areas . The end point of the study was defined as the incidence of colorectal cancer  or colon cancer (ICD-10: C18). The risk of rectal cancer was not analysed separately because of the relatively small number of cases observed. Subjects who moved out of the study area or died from causes other than colorectal cancer were treated as censored cases. During the study period, only 3.3% (2071) of the participants were lost from the follow-up as a result of a change of residence.χ2) test or one-way analysis of variance (ANOVA). The follow-up period for each participant was calculated as the time between completing the questionnaire and either the diagnosis of colon or rectal cancer, death, moving out of the study area or the end of the study – whichever occurred first.All analyses were carried out by sex using the SAS statistical package release 8.2 . Differences in baseline characteristics between categories of BM frequency were tested using the chi-squared (The incidence rate ratios (IRR) and 95% confidence intervals (CI) for colorectal and colon cancer were estimated, by sex, using Cox's proportional-hazard model according to the levels of BM frequency, laxative use and susceptibility to diarrhoea. The categories of ‘every day’ for BM, ‘nonuse’ for laxative use and ‘no’ or ‘neutral’ for susceptibility to diarrhoea were used as reference groups.−2 and categorised as ‘⩾25 kg m−2’ or ‘<25 kg m−2’; intake frequency of green leafy vegetables (‘daily’ or ‘not daily’); intake frequency of alcohol (‘⩾5 days per week’ or ‘<5 days per week’); current smoking status (‘smoker’ or ‘nonsmoker’); time spent walking per day (‘⩽30 min or ‘>30 min’); history of colorectal cancer in parents or siblings (‘yes’ or ‘no’); and age at leaving full-time education (‘⩾20 years’ or ‘<20 years’). For each covariate, missing values were treated as an additional category and were included in the model. To determine the influence of symptoms of colorectal cancer on bowel habits, analyses were repeated excluding the first 3 years of follow-up. In all cases, two-sided P-values <0.05 were considered to be statistically significant.Analyses were adjusted for the following potential confounding factors: age (continuous variable); body mass index (BMI) calculated as weight (kg) [height (m)]Within the study group, 1.1% of men and 4.0% of women reported infrequent BMs (every 4 days or less). The use of laxatives was more common among women (14.7%) than men (6.9%), whereas men were more likely to report frequent diarrhoea (20.3%) than were women (9.7%).A significant difference in the intake frequency of green leafy vegetables and in smoking status across the BM groups was observed only among women: those who reported BMs daily or every 2–3 days were more likely to consume green leafy vegetables daily and less likely to be smokers. In addition, women who reported BMs every 2–3 days were, on average, younger than those in the other BM groups. Alcohol consumption did not differ between BM groups in women.Among men, the number that reported daily alcohol intake increased linearly with BM frequency. Male subjects who reported BMs every 2–3 days had the lowest rate of frequent diarrhoea, whereas the number of women who reported frequent diarrhoea decreased linearly with BM frequency.During the follow-up period , a total of 649 cases of colorectal cancer were identified (379 in men and 270 in women), which included 429 cases of colon cancer (225 in men and 204 in women).Age-adjusted IRRs were calculated for colorectal and colon cancer according to BM frequency (not shown). Regardless of sex, the ratios were <1.00 for subjects who reported BMs every 2–3 days relative to those who reported daily BMs: the IRRs for colorectal cancer were 0.74 in men (95% CI=0.51–1.09) and 0.71 in women (95% CI=0.52–0.97), whereas the IRRs for colon cancer were lower in men  and the same in women . In contrast, the age-adjusted IRRs for subjects who reported highly infrequent BMs (every 6 days or less) relative to those with daily BMs were >1.00: the IRRs for colorectal cancer were 1.14 in men (95% CI=0.16–8.10) and 2.53 in women (95% CI=1.04–6.15), whereas the IRRs for colon cancer were 1.78 in men (95% CI=0.25–12.7) and 2.59 in women (95% CI=0.96–6.98).Adjustment for potential confounding factors (as discussed above) had no significant effects on the IRRs  in the gastrointestinal tract in many diarrhoeal states (2 might be associated with carcinogenesis in the large intestine (Daily BMs were found to increase the risk of colorectal and colon cancer compared with BMs every 2–3 days, in both men and women. This observation is in line with the results of a previous case–control study carried out in Japan (l states , and incet al suggested that some types of laxative might influence intestinal pH and the metabolism of intestinal flora, thereby modifying colorectal cancer risk. The effects of laxative type were not investigated in the present study because of limitations of the questionnaire. Further prospective studies investigating the types of laxative and duration of use will be necessary to resolve this question.A weak nonsignificant positive association was found between laxative use and the risk of colorectal cancer in both men and women. Previously, the meta-analysis of The risk of rectal cancer was not analysed independently because of the small number of cases in the study group. Larger-scale prospective studies will be necessary to reveal the effects of bowel habits on the development of cancers of the large intestine at specific sites.There were some limitations to the scope of the present study. For example, although the main risk factors for colorectal cancer were adjusted for in the analysis, other factors such as aspirin use and hormone replacement therapy in women might have confounded the results. Also, bowel habits were evaluated only through a self-reported questionnaire that was administered once at the baseline; the reproducibility and validity of the responses of subjects were therefore not confirmed.In conclusion, this study shows that highly infrequent BMs can increase the risk of colorectal cancer in both men and women. Highly frequent BMs may also enhance this risk. Further prospective studies are needed to confirm our findings and to clarify the risk associated with BMs for colorectal cancer by subsite.


P for linear trend=0.03), with women given ⩾2250 mg of clomiphene having a 2.6-fold  increase in risk relative to those who were not treated. These findings do not support strong associations between ovulation-stimulation drugs and cancer risks, but they indicate the need for continued monitoring to establish whether risks are elevated in certain subgroups of users.To assess long-term health effects of ovarian-stimulation drugs we followed-up for over 20 years a British cohort of 7355 women with ovulatory disorders, 43% of whom were prescribed ovarian-stimulation drugs, and identified a total of 274 deaths and 367 incident cancers. Relative to the general population, the cohort experienced lower mortality from most causes, including from all neoplasms combined, and lower incidence of cervical cancer, but higher incidence of cancers of the breast  and corpus uteri . There were, however, no significant differences in the risk of cancers of the breast, corpus uteri, ovary, or of any other site, between women who had been prescribed ovarian-stimulation drugs and those who had not. Further analyses by type of drug and dose revealed a dose–response gradient in the risk of cancer of the corpus uteri ( Several case reports in the 1980s, linking assisted conception and ovarian cancer, raised concerns about the long-term health effects of infertility treatment . These rin vitro fertilisation treatment in the United Kingdom in 2006 corresponding to 44 275 cycles of treatment, a 6.8% increase in the number of patients relative to the previous year  and their outcome. Hospital records (mainly on microfilms) and computer databases were also reviewed. Data on underlying diagnoses and treatments were reviewed by a panel of infertility clinicians and re-classified using more up-to-date and standardised criteria. Underlying ovulatory disorders were classified according to the WHO classification . For then=8), they were no longer NHS patients at the time they joined the cohort (n=79), or they have subsequently undergone a sex change operation (n=2). For a further 183 women information on treatment was lacking and these were excluded from any treatment-related analyses. Women who were known to be still alive and resident in England and Wales, and whose current general practitioner (GP) could be traced through their Health Authorities, were sent (through their GPs) a postal questionnaire to obtain further details on their reproductive and lifestyle characteristics.Study subjects were followed through the National Health Service Central Register (NHSCR) in England and Wales to ascertain their vital status, and to obtain information on site-specific cancer incidence, cause-specific mortality and migrations. A total of 7444 women out of the initial 9152 (81.3%) were traced and flagged through this register. For 95% of the 1708 who could not be traced, there was insufficient detailed information  or the names were foreign suggesting that they might have been non-UK residents. A further 89 subjects were excluded because flagging was considered to be unreliable  to death, emigration, loss to follow-up, or 31 December 2005, whichever occurred first. For cancer incidence analyses, time at risk was from 1 January 1971, when cancer registration reached national coverage, or from date of hospital visit/treatment if these occurred after that date, to the earliest of date of diagnosis of the first primary malignancy, emigration, loss to follow-up, date of death, or 31 December 2005. Period-age-standardised mortality (SMR) and incidence ratios (SIRs) were then calculated as the ratio between the observed and expected number of events  in the cohort, with their 95% percent confidence intervals (CI) estimated using an exact method .Data on mortality and cancer incidence for England and Wales were provided by the Office for National Statistics as tabulations of numbers of female cancers and deaths by single calendar year, single year of age, and four-digit codes of the International Classification of Diseases (ICD) (revision 7 (ICD-7) for 1961–1967; ICD-8 for 1968–1978; ICD-9 for 1979–2000; and ICD-10 for 2001–2005) . ApproprTo account for socioeconomic differences between the cohort and the general population, we also obtained rates for England and Wales by quintiles of socioeconomic deprivation as defined by the Carstairs Index  and, froTwo approaches were used to compare study groups within the cohort. In the first, the risk of dying from a particular cause, or of developing a certain site-specific cancer, among patients ‘exposed’ to a given characteristic  relative to the risk among those ‘unexposed’ was estimated as the ratio between the two corresponding SMRs, or SIRs, to take into account calendar period and age effects. The 95% CI for these relative risks (RRs) were calculated using an exact method . The secn=7355) were similar to those in the original cohort (n=9152)  . The mea(n=9152) . After i(n=9152) .vs 83.8%, respectively, attended the Royal Free Hospital), age at initial clinical evaluation , or type of treatment .Questionnaire data were available for 2545 participants . There was no evidence that respondents differed from the remaining study population in terms of clinic attended  . RelativA total of 367 incident malignant neoplasms occurred from 1971–2005, comprising 177 breast, 31 uterine and 21 ovarian cancers. Relative to the general population, cohort members had increased risks of developing cancers of the breast (SIR=1.13), uterus (SIR=2.02) and nervous system (SIR=1.91), albeit only significant for the latter two, but a significantly lower risk of developing cervical cancer (SIR=0.21) . AnalyseThe lower mortality in the cohort relative to the general population was mainly accounted by socioeconomic differences between the two populations as most SMRs became closer to unity when England and Wales rates for the two most affluent quintiles of the national distribution of area-based deprivation scores were used to derive expected numbers . Having ever been pregnant as recorded in the clinical notes was not a confounder of the association of ovarian stimulation with cancers of the breast ; age and ever-pregnancy-adjusted=RR 1.28 ) or uterus ; age- and ever-pregnancy-adjusted RR=1.73 ). Similarly, adjustment for having ever been pregnant before treatment, or for having become pregnant as a result of it, did not affect the magnitude of these cancer associations. In the subset of women who completed the questionnaire  the age-adjusted RR associated with ovarian stimulation was 1.02  and its magnitude changed little with further adjustment for having ever been pregnant ), age at first pregnancy ), ever-use of oral contraceptives ) or hormone replacement therapy ), or a positive family history of breast cancer ). The small number of cases among respondents precluded similar analyses for cancer of the uterus.vs untreated women among WHO type II ovulatory disorders (53 vs 47%), but lower proportions among thyroid disorders (39 vs 61%) and weight-related problems (48 vs 52%). There were, however, no associations between underlying diagnosis and cancer risks except that women with type II ovulatory disorders had an elevated risk of cancer of the uterus ) relative to women with other diagnoses. Further adjustment for underlying diagnosis did not affect the magnitude of the ovarian stimulation – cancer of the uterus association  and 1.48 , respectively). There was also no evidence that the ovarian-stimulation effects were modified by any of these risk factors although the power of the study to detect interactions was limited. In particular, the magnitude of the associations with cancer risks was not modified by age when the treatment was first prescribed. Only 121 women developed ovarian hyperstimulation syndrome and the small numbers of cases among them (only one cancer of the breast and one of the uterus) precluded examination of whether risks were particularly elevated in this subgroup.Ovarian-stimulation treatment was associated with underlying diagnosis with, for instance, higher proportions of treated P for linear trend=0.034). Thus, women who took ⩾2250 mg were 2.62  times more likely to develop cancer of the uterus than those who were not treated. The risk of cancer of the ovary was not associated with any of the ovarian-stimulation treatments, and there was no evidence of any trends in risk with time since first use, total cumulative dose or number of cycles of clomiphene, but estimates were based on small numbers. Risks for any of these three cancer sites were not associated with time since first treatment with gonadotrophins or number of cycles or ampoules, but again relevant numbers were small (not shown).More detailed analyses by type of ovarian stimulation drug prescribed showed that the risk of developing breast cancer was significantly elevated among women who were prescribed clomiphene only (SIR=1.41), but this risk was not higher than that among women who were not treated (ovarian stimulation or any other) . There wThis cohort study has several strengths. Notably, in the absence of trials, cohort studies are the next best design because information on exposures is obtained prior to onset of disease. Linkage to the NHSCR ensured that information on cause-specific mortality and cancer incidence was also unbiased relative to the exposure status of the cohort members and minimised losses to follow-up. Second, the study had a long follow-up, allowing examination of long-term effects of ovarian stimulation. Third, it benefited from detailed information on causes of infertility and drug exposures from medical records as well as on cancer risk predictors obtained through completed questionnaires . Fourth, about one fifth of women were exposed to high levels of ovarian-stimulation drugs, well above currently recommended maximum levels. Fifthly, the availability of an internal comparison group may have minimised possible confounding by any factors correlated with treatment-seeking behaviour, because women who attended the two reproductive endocrinology practices are likely to differ from the general population in several respects. In particular, our study confirmed that women who seek infertility treatments tend to be healthier and of a higher socioeconomic background as those in the general population. Finally, the availability of information on underlying diagnosis and other risk factors also enabled adjustment for a variety of potential confounding factors.Weaknesses of our study include the fact that follow-up was possible only for 80% of the original cohort; however, there was no evidence that those untraced through the NHSCR differed from those who were traced. Although the number of cancer cases accrued during the follow-up was larger than in most similar cohorts . Such a link has not been reported earlier but it has some biological plausibility as oral contraceptive use is known to be associated with increased risks of benign hepatic adenoma .The significantly lower risk of cervical cancer in this cohort relative to the general population is consistent with a possible surveillance bias and the fact that parity increases the risk of this cancer . There iOverall, the results of this study do not support strong associations between ovulation-stimulation treatments and cancer risks, with the exception of possible increases in the risk of cancers of the uterus and of the liver and biliary tract. These findings support the need for continuing monitoring of the long-term effects of these treatments.


The associations between serum concentrations of oestradiol, testosterone and sex hormone-binding globulin (SHBG) and risk of breast cancer in post-menopausal women were investigated in a prospective study on the island of Guernsey. Sixty-one women who developed breast cancer an average of 7.8 years after blood collection were matched for age, year of blood collection and number of years post-menopausal with 179 control subjects. Women using exogenous hormones at the time of blood collection were excluded from the study. Women who subsequently developed breast cancer had a 29% higher geometric mean oestradiol concentration than control women (P = 0.004). The odds ratio for breast cancer in the top third compared with the lowest third of the oestradiol concentration distribution was 5.03 . Adjusting for testosterone and SHBG concentrations did not substantially alter the odds ratio for oestradiol. Although testosterone and SHBG concentrations were associated with breast cancer risk, the concentrations of these hormones were correlated with those of oestradiol; the associations were not statistically significant after adjusting for oestradiol concentration. These data provide evidence that serum oestradiol concentrations in post-menopausal women may have a substantial effect on breast cancer risk.


Women who experience pre-eclampsia or hypertension during pregnancy may have a reduced risk for breast cancer later in life. The evidence is based on case–control studies, and here we report the results of a cohort study exploring the link between pre-eclampsia and gestational hypertension diagnosed in the first pregnancy and subsequent risk for breast cancer. We combined information from the Medical Birth Registry and the Cancer Registry in Norway, which are both nation-wide. Between 1967, when the birth registry was established, and 1998, 694 657 women were recorded with a first birth, and classified according to whether pre-eclampsia and/or hypertension was diagnosed in the first pregnancy. Linkage to the Norwegian Cancer Registry identified 5474 new cases of breast cancer diagnosed subsequently to their first delivery. Compared to other parous women, women with pre-eclampsia and/or hypertension diagnosed in their first pregnancy had 19% lower risk  for breast cancer, after adjustment for attained age, calendar period of diagnosis, age at first birth, and parity. This result was similar for term and preterm deliveries, across the range of offspring birth weight, and for pre- and postmenopausal women. These results suggest that the pathophysiology surrounding pre-eclampsia and gestational hypertension plays an important role in breast cancer etiology. A better understanding of the underlying processes could provide an insight into the pathogenesis of breast cancer.British Journal of Cancer (2002) 87, 971–973. doi:10.1038/sj.bjc.6600581www.bjcancer.comCancer Research UK© 2002  Several risk factors for breast cancer have been identified , but fewData were derived from the Norwegian Medical Birth Registry that comprises all births since 1967, and the Norwegian Cancer Registry, which has registered incident cancers since 1953. Midwives and doctors have to fill in a standardised form to notify the birth registry about each birth that takes place in the country, and the reporting of cancer by doctors or hospital departments to the cancer registry is also mandatory. The unique identification number of Norwegian citizens enabled linkage between the birth registry and the cancer registry for cancer follow-up.We have identified cases of pre-eclampsia and/or hypertension induced by pregnancy as indicated in the standardised form, and the women were accordingly categorised as having been diagnosed with at least one of these conditions , whichever occurred first.We compared breast cancer risk in women who had experienced pre-eclampsia and/or hypertension induced by their first pregnancy with the risk in other parous women, and adjusted for attained age (nine categories), calendar period of diagnosis (three categories), age at first birth (five categories), and total number of births (five categories). In the multivariate analyses, we applied Poisson regression modelling, using the Epicure software , and we used SPSS, version 10.05 , for the descriptive analyses.During follow-up, 5474 cases of breast cancer were diagnosed among the 694 657 parous women. Of these cases, 280 occurred among women who were diagnosed with pre-eclampsia and/or hypertension in their first pregnancy. These women had a 19% lower risk of subsequent breast cancer than the remaining women , after adjustment for attained age, calendar period of diagnosis, age at first birth, and parity (Table 1We explored whether the association between pre-eclampsia and breast cancer risk could be modified by length of gestation (preterm or term delivery), offspring birth weight, or the woman's age (cut-off at 50 years). The results show that the pre-eclampsia-related reduction of breast cancer risk did not substantially differ across these subgroups (Table 2We found that women who were diagnosed with pre-eclampsia and/or hypertension in their first pregnancy were at reduced risk of breast cancer, compared to other women who did not develop pre-eclampsia or hypertension during their first pregnancy. The inverse association has also been found in the previously reported case–control studies (The prospective nature of this study all but excludes selection or information bias as plausible explanations for the findings, and the large number of women makes it unlikely that chance can play an important role.The clinical manifestations of pre-eclampsia are heterogeneous, and this could indicate that the condition comprises different biological entities . If so, Our analysis focused on the first pregnancy, with adjustment for total ascertainable parity. Although less common, some women will have developed pre-eclampsia or hypertension also during higher order pregnancies, and because of this, the pre-eclampsia-related protection against breast cancer in our study could have been somewhat underestimated.A central characteristic of pre-eclampsia is an abnormal implantation that has been attributed to a shallow connection between the placenta and the endometrium . A combi


In two case–control studies from Italy covering 3533 cases of colorectal cancer and 7062 hospital controls, the odds ratios were 1.04 after cholecystectomy for colorectal, 1.08 for colon and 1.03 for rectal cancers. The results did not differ significantly by gender, colon subsite or time since diagnosis. At least four large record linkage and cohort studies  of 1.21  1.01–1.46) was found in relation to history of gallstones or cholecystectomy , after adjusting for potential confounding factors , residing in the same geographical areas and from the same network of hospitals where cases had been identified, and admitted for a wide spectrum of acute, non-neoplastic conditions, unrelated to known or potential risk factors for colorectal cancer . Less than 4% of cases and controls approached refused to participate. Information was collected in hospital by trained interviewers using a structured food-frequency questionnaire, tested for reproducibility and validity (2) and total energy intake (tertiles), history of diabetes, history of colorectal cancer in parents and siblings, menopausal status , use of oral contraceptives or hormone replacement therapy .Odds ratios (OR) and corresponding 95% CIs were estimated using unconditional multiple logistic regression models, including terms for age , sex, study centre, years of education , cigarette smoking , alcohol drinking and meat consumption (tertiles of consumption), body mass index (BMI, kg/mOur findings indicate that cholelithiasis is not materially associated with colorectal cancer risk after adjustment for major identified confounding factors, including measures of BMI, total energy and meat intake. A modest nonsignificant excess risk was found among men and for less than 10 years after cholelithiasis, but no excess risk could be found after 10 or more years. Such a time-risk relation is inconsistent with a causal relation of cholelithiasis with colorectal cancer risk. The risk estimates were not heterogeneous for men and women. However, the finding that several ORs were apparently higher in men is in broad agreement with the observation, in the same data set, that higher BMI is more consistently related to colorectal cancer risk in men than in women (The apparent association reported from some case–control studies may at least in part be due to a more accurate recall of gall bladder disease by colorectal cancer patients and by the inadequate adjustment for other potential risk factors for colorectal cancer, including diet. In our study, based on a notably large data set, information on medical history was satisfactorily reproducible (


Oral contraceptive use and reproductive factors may initiate long-term changes to the hormonal milieu and thereby, possibly influence colorectal cancer risk.We examined the association of hormonal and reproductive factors with risk of colorectal cancer among 337 802 women in the European Prospective Investigation into Cancer and Nutrition, of whom 1878 developed colorectal cancer.After stratification for center and age, and adjustment for body mass index, smoking, diabetes mellitus, physical activity and alcohol consumption, ever use of oral contraceptives was marginally inversely associated with colorectal cancer risk (hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.83–1.02), although this association was stronger among post-menopausal women . Duration of oral contraceptive use and reproductive factors, including age at menarche, age at menopause, type of menopause, ever having an abortion, parity, age at first full-term pregnancy and breastfeeding, were not associated with colorectal cancer risk.Our findings provide limited support for a potential inverse association between oral contraceptives and colorectal cancer risk. Men tend to have a slightly higher incidence of colorectal cancer than women of similar age . OestrogThe epidemiologic evidence for a causal link between oral contraceptives and colorectal cancer risk is equivocal. Some studies have suggested inverse associations  cohort.Study participants included 1878 female colorectal cancer cases  and 335 924 female non-cases recruited into EPIC, a prospective cohort that was established in the 1990s in 10 European countries with more than half a million participants, mostly aged 35–70 years. Incident cancer cases were identified through linkage to population cancer registries in Denmark, Italy, The Netherlands, Norway, Spain, Sweden and the UK, or with a combination of methods including linkage to health insurance records, cancer and pathology registries, and active follow-up of study participants or their next of kin in France, Germany and Greece. The colorectal cancer diagnosis was confirmed by histology for 80.2% of the cases, by clinical examination for 11.6% and the remaining 8.2% by self-report, autopsy or death certificate. Women were excluded if they had prevalent cancer at recruitment, if they did not return the baseline lifestyle questionnaire, if they never menstruated or if they had missing information on all exposure variables. Details on the cohort population, the data collection procedures and the outcome and covariate assessment methods have been described in detail elsewhere  was also collected. Information on breastfeeding was collected for the first three full-term pregnancies and the last one. Menopausal status was defined according to information on menstruation status and ovariectomy, details of which are provided elsewhere  and induced or spontaneous abortions, age at the first full-term pregnancy, and the reason for menopause , physical activity . Missing values for smoking status (2.2%), diabetes (4.2%), physical activity (13.4%) and alcohol (0.8%) were included as a separate category in the models. An analysis that excluded women with missing values for these covariates provided very similar results, and these are not presented here. Further adjustment for menopausal hormone therapy, waist and hip circumference, waist to hip ratio, dietary variables  or mutual adjustment for oral contraceptive use and reproductive factors in relevant models gave virtually identical results. Analyses were also performed according to EPIC country, cancer subsite (colon vs rectum) and potentially modifying factors , BMI (<25 vs ⩾25 kg m−2), menopausal hormone therapy (ever vs never) and menopausal status ).Hazard ratios (HR) and their 95% confidence intervals (95% CI) for colorectal cancer were estimated using Cox proportional hazards models stratified by EPIC-participating center and age at recruitment  and adjusted for smoking status , self-reported diabetes mellitus (no or yes), body mass index  nor age at start of use  were associated with risk. However, the association of oral contraceptive use on risk varied by menopausal status ; ever use of oral contraceptives was associated with a significantly reduced risk in post-menopausal women , but no significant association was observed among pre- or peri-menopausal women . There was no evidence of an interaction for duration or age at start of oral contraceptive use by menopausal status (data not shown).Overall, there were no statistically significant associations between oral contraceptives, reproductive factors and colorectal cancer risk . Ever usReproductive factors, including age at menarche, age at menopause, type of menopause, ever having an abortion, parity, age at first full-term pregnancy and breastfeeding, were not associated with colorectal cancer risk . The assvs 8.5 years), despite being older at recruitment (58 vs 44 years). However, post-menopausal women were more likely to have started using oral contraceptives during the 1960 s when high-dose formulations were much more common (In this large prospective study, ever use of oral contraceptives was associated with a small reduction in colorectal cancer risk, which was stronger among post-menopausal women compared with pre-/peri-menopausal women. Although our finding of an inverse association with use of oral contraceptives is consistent with the prior literature (e common , which mThe major strength of this study is its size and power to study dose-response associations, and its detailed and standardised assessment of reproductive factors across Europe. In conclusion, oral contraceptive use was associated with a reduced risk of colorectal cancer among post-menopausal women. Duration of oral contraceptive use and reproductive factors were not associated with risk. Our findings provide limited support for a potential inverse association between oral contraceptives and colorectal cancer risk.


The adjusted upper quartile odds ratio compared to the lower quartile was 0.24 (0.1–0.5) for vegetables, 0.36 (0.2–0.7) for fruits, 4.6 (2.2–9.3) for animal fat and 3.4 (2.0–5.8) for preserved  vegetables with significant dose-response relationship. The risk of ovarian cancer also appeared to increase for those women preferring fat, fried, cured and smoked food.This case–control study, conducted in Zhejiang, China during 1999–2000, investigated whether dietary factors have an aetiological association with ovarian cancer. Cases were 254 patients with histologically confirmed epithelial ovary cancer. The 652 controls comprised 340 hospital visitors, 261 non-neoplasm hospital outpatients without long-term diet modifications and 51 women recruited from the community. A validated food frequency questionnaire was used to measure the habitual diet of cases and controls. The risks of ovarian cancer for the dietary factors were assessed by adjusted odds ratios based on multivariate logistic regression analysis, accounting for potential confounding demographic, lifestyle, familial factors and hormonal status, family ovarian cancer history and total energy intake. The ovarian cancer risk declined with increasing consumption of vegetables and fruits but British Journal of Cancer (2002) 86, 712–717. DOI: 10.1038/sj/bjc/6600085www.bjcancer.comCancer Research UK© 2002  Ovarian cancer is the seventh most common cancer in women and the leading cause of death among gynecological cancers . HoweverA case–control study was conducted in Hangzhou, China, between July 1999 and June 2000. Two hundred and fifty-five hospital patients with epithelial carcinoma of the ovary were identified. To ensure complete ascertainment of cases, all medical records and laboratory pathology reports were reviewed during the period of the study. Pathological diagnoses were based on the International Histological Classification of Ovarian Tumours . A totalDuring the same period of recruitment 652 controls were also interviewed. Women recruited for controls were matched with cases by age and geographical area. Exclusion criteria for the controls were neoplasm, long-term dietary modification or who had bilateral oophorectomy. A total of 601 women were recruited from the same hospitals where the cases were identified. The control group consisted of 340 hospital visitors  and 261 outpatients (non-response rate 1.2%).To control for bias in selecting the hospital controls, consulting rooms for outpatients and ward numbers for healthy women were chosen randomly. If no suitable subjects were found in the chosen room/ward, the adjacent room/ward was used instead. All the outpatients recruited had only minor gynecological diseases .An additional sample of 51 community women (non-response rate 7.8%) was recruited from nine different districts of Hangzhou. The project was approved by the appropriate hospital authorities and the human research ethics committee of the researchers' institution.A structured questionnaire, available from the authors upon request, was used to collect the required information on diet, lifestyle and factors relevant to hormonal status. The quantitative Food Frequency Questionnaire (FFQ) component on habitual diet was modified from a dietary questionnaire , the Ausliang .The FFQ contained questions on 120 food items, which included all of the foods in the usual diet of Zhejiang residents. Information was also sought on the quantities of each food consumed per meal as well as cooking methods used and vitamins or mineral supplements taken. Food consumption was based on habitual diet and a ‘reference’ recall period was set at 5 years prior to diagnosis (cases) or interview (controls). The food frequency variables were categorised into never or hardly ever, once a month, 2–3 times a month, once a week, 2–3 times a week, 4–6 times a week, once a day and ⩾2 times a day. The quantitative variables were measured in terms of the most common Chinese measure, the Data were collected by face-to-face interview after obtaining their consent. The interviews usually took between 40 and 50 min. Since Chinese women are typically responsible for buying raw foods and cooking for the household, the participants were able to provide information on the frequency and quantity of each food consumed per meal. Standard sized reference containers were provided to assist respondents to accurately estimate the weight of food items.For the cases, 226 women (89%) were either inpatients or at hospitals for follow-up treatment, 25 women (10%) were interviewed at their homes, while three women (1%) completed their interviews at their work places. The 51 community women were interviewed at their homes, community areas near their homes or their work places.Table of Food Components , marital and menopause status, parity (full-term pregnancy), tubal ligation, oral contraceptive use, physical activity, family history of ovarian cancer and total energy intake.The quantities consumed for the various food groups and the eating habits categorical variables were tested for linear trends in ovarian cancer risk. The quantity variables were also divided into quartiles based on the corresponding distribution in the controls. Odds ratios (OR) and their 95% confidence intervals (CI) were computed, using unconditional multivariate logistic regression models. Food intake and eating habits were assessed separately. Within each setting, all variables were simultaneously considered in a single model to allow for possible reciprocal confounding effects. Both regression equations included terms for age at interview, education, living area, BMI (5 years ago), smoking, alcohol and tea drinking, family income . The mean intakes of food groups by the community controls were also similar but they consumed less salted vegetables and animal fat than the hospital controls. Data from all three control groups were then combined to form a single control group in subsequent analyses. Results from recent patients and all cases were also similar (data not provided for brevity but were available upon request). Therefore, we report the combined results of all cases below.There were no differences in mean age at interview, locality , education, BMI (5 years ago), smoking, alcohol consumption, marital and menopause status, and tubal ligation between cases and controls. Compared to controls, patients with epithelial ovarian cancer tended to have a higher family income, less oral contraceptive use, lower parities, and less physical activity. More of them had apparent family susceptibility. Table 1Table 2Table 3Results from the present study supported the previous findings by Within the vegetables group, the subgroups of allium vegetables and soybean products had appreciable inverse associations with ovarian cancer. The mechanism of protective effects from vegetables and fruits may be partly due to the presence of antioxidants .An elevated risk of ovarian cancer due to an increased consumption of saturated fat had been reported previously (N-nitroso compounds (A new finding was the positive association between salted vegetables and ovarian cancer. Salted foods have been reported to increase the risk of stomach cancer and esophagus cancer in several Chinese case–control studies . Salted In a 13-year follow-up of 142 857 Japanese women, This study also assessed the link between dietary habits and ovarian cancer. Frequent intake of fat and fried foods has led to elevated risks of the cancer. Fried food was related to fat consumption because fat, especially animal fat, was typically used in the process of deep-frying. In a 20-year follow-up of 16 190 females, Several issues should be considered when interpreting the findings. A major feature of this study is that extensive information on food intake and dietary patterns was obtained using a validated and reliable instrument specifically targeted on adult Chinese women. Furthermore, mean energy intake by the controls, as calculated from our FFQ, was 2399 Kcal per day (Case–control studies are subjected to several potential biases. Firstly, in our study, selection bias appeared to be minimal in view of the low refusal rate. The majority of cases were recently diagnosed and the recruitment procedure used was designed to ascertain all cases. Recall bias was minimised by reporting habitual diet and by using a ‘reference’ recall period. Although the small number of community controls consumed less salted vegetables and animal fat than the hospital controls, their exclusion did not influence the findings of this study.In conclusion, our results suggest that a diet rich in fresh vegetables and fruits, but less animal fat, salted vegetables, fried, cured and smoked food, contribute to a lower risk of ovarian cancer.


P for heterogeneity adjusting for other tumour features (Phet)=0.007). On the other hand, multiparity was associated with reduced risk for small tumours (0.76 (0.68–0.86) per additional birth; Phet=0.004). Consideration of all tumour characteristics simultaneously revealed that current or recent use of combined hormone replacement therapy was associated with risk of small (2.29 (1.66–3.15)) and grade 1 (3.36 (2.22–5.08)) tumours (Phet=0.05 for size and 0.0008 for grade 1 vs 3), rather than specific histopathologic types . Finally, elevated body mass index was associated with larger tumour size among both pre- and postmenopausal women . None of these relationships were explained by hormone receptor status of the tumours. In conclusion, these data support distinctive risk factor relationships by tumour characteristics of prognostic relevance. These findings might be useful in developing targeted prevention efforts.Breast cancer is a morphologically and clinically heterogeneous disease; however, it is less clear how risk factors relate to tumour features. We evaluated risk factors by tumour characteristics  in a population-based case–control of 2386 breast cancers and 2502 controls in Poland. Use of a novel extension of the polytomous logistic regression permitted simultaneous modelling of multiple tumour characteristics. Late age at first full-term birth was associated with increased risk of large (>2 cm) tumours  1.19 (1.07–1.33) for a 5-year increase in age), but not smaller tumours ( Breast cancers vary greatly in clinical behaviour, histopathologic appearance, and molecular alterations. In addition, age-specific incidence rates for breast cancer vary by histologic tumour type   and 2502 controls (69% of eligibles) agreed to participate in a personal interview regarding known and suspected risk factors for breast cancer. The main reasons of nonparticipation for cases and controls, respectively, were refusal (19 and 25%) and unable to locate (2 and 6%). Interviews were conducted a median of 6.8 weeks following diagnosis for cases, and 2.4 weeks following identification for controls. A signed informed consent to participate in the study was obtained from all participants in accordance with the National Cancer Institute and local Institutional Review Boards.Women were considered premenopausal if they reported having natural menstrual periods at the time of interview, postmenopausal if periods had stopped, and unclear menopausal status if HRT use had been started before the natural periods stopped. Women who reported having breastfed for 1 month or less were considered as having never breastfed. Women who had used oral contraceptives or oral HRT for 1 month or less were classified as non-users. Users of oral HRT were further classified as current or recent users (<2 years since last use) of combined (estrogen and progesterone) HRT, past users (⩾2 years) of combined HRT, and users of oestrogen or progesterone HRT alone. Body mass index (BMI) was calculated using current weight (kg) divided by standing height (m) squared as measured by a trained nurse. For 114 cases and 156 controls without measures of weight or height, BMI was calculated using self-reported information. Women were classified as non-drinkers if they reported having consumed 12 or fewer alcoholic drinks in their lifetime or they reported consuming less than one drink per month for 6 months without ever having had more than five drinks on any one occasion. Women were considered as having a history of benign breast disease if they reported having had a benign breast biopsy 1 year prior to either the diagnosis date (for cases) or the date of interview (for controls).Information about diagnostic and treatment procedures was obtained from the medical records, and surgical pathology forms that were completed after clinical sign-out of cases. The surgical pathology form documented macroscopic  and microscopic  features. Results for oestrogen receptor (ER) and progesterone receptor (PR) assays performed in Poland were obtained from medical records. In 91% of cases with receptor status information, assays were performed using immunohistochemistry, with biochemical methods used in the remainder.A single US pathologist (MES) reviewed haematoxylin and eosin-stained slides to confirm case status and provide uniform histologic classification. Final diagnoses for 1958 (82%) cases with tumour slides available were based on the pathology review by MES. Tumours were classified as ductal not otherwise specified (NOS) or lobular if they demonstrated a predominant histopathologic appearance; tumours containing mixed patterns were designated as mixed carcinomas. Carcinomas were classified as tubular or cribriform if the characteristic well-differentiated patterns together accounted for 90% of the tumour area. Tubular carcinomas and ductal carcinomas, NOS, grade 1 share morphologic and clinical features. Accordingly, we combined these types in some analyses. Studies have also suggested that low-grade ductal or tubular carcinomas are related to infiltrative lobular carcinomas, with the former being the most highly differentiated and the later the most undifferentiated extreme, a view that is supported by the observation of patterns of low-grade ductal and lobular carcinomas together in tubulo-lobular carcinomas , with thFor the remaining 428 cases without slides available for review, the diagnosis in Poland was considered the final diagnosis. The percent agreement between MES and Poland for invasive diagnosis was 80% for ductal NOS, 68% for lobular, and 18% for mixed carcinomas. The disagreement was mainly explained by reclassification of mixed type tumours as ductals or lobulars.N=1964). Odds ratios (95% CI) and corresponding P-values (Phet) reported from these analyses measure the association between tumour characteristics and risk factors, similar to case-only analyses.Logistic regression was used to estimate adjusted odds ratios (ORs) and associated 95% confidence intervals (CI) from models that included all risk factors simultaneously. Models included continuous terms for age at menarche, number of full-term births, age at first full-term birth, age at menopause and BMI, and dummy variables for education levels, nulliparity, oral HRT use , family history, history of a benign biopsy, ever had a screening mammography and menopausal status , current age in 5-year categories and study site. Because the association between BMI and breast cancer risk is known to differ by menopausal status, our models included separate terms for pre-and postmenopausal women. Estimation of ORs for different categories of variables considered as continuous indicated that the log-linear assumption was reasonable. Standard polytomous logistic regression was used to estimate ORs and 95% CI for different tumour types. Heterogeneity between risk factor ORs for different tumour types was assessed using logistic regression analyses restricted to cases . An extension of the polytomous logistic regression model was used to evaluate heterogeneity in risk factor ORs by multiple tumour characteristics simultaneously . This meAbout two-thirds of women were recruited in Warsaw and one-third in Łódź, with a mean age (±s.d.) of 56 (±10) years. Distribution of characteristics for cases and controls were consistent with most established risk factors . Use of N=2144).Approximately 94% of all cases in the study had a tumour with an invasive component, with ductal carcinomas, NOS, accounting for 58% of invasive cases, lobular carcinoma for 16%, and mixed carcinoma for 12% . LobularOverall, breast cancer risk was directly associated with higher level of education, late age at first full-term birth, late age at menopause, current or recent use of combined HRT, family history of breast cancer and prior benign breast biopsy  online. N=50; ORs (95% CI) of 1.85 (0.67–5.09)), although the precision of the estimate was limited by small numbers. Risk factor associations were similar for mixed and ductal carcinomas, NOS . For these analyses, tubular tumours were included with ductal carcinomas, NOS, grade 1 since they are a grade 1 ductal variant with similar morphological and clinical features.N=628), HRT use was associated with an OR (95% CI) of 2.77 (1.96–3.91).Delayed age at first full-term birth was associated with increased risk for tumours that were large (>2 cm) (OR (95% CI)=1.19 (1.07–1.33)) or with positive nodes (1.12 (1.08–1.35)). In contrast, the reduced breast cancer risk associated with multiparity was strongest for carcinomas that were small (⩽2 cm) (0.76 (0.68–0.86)) or node negative (0.82 (0.73–0.91))  online. Elevated BMI in pre-menopausal women was associated with reduced risks for tumours that were small or node negative. Elevated BMI in postmenopausal women was not associated with overall breast cancer risk; however, data suggested an association with decreased risk of small or node negative tumours, and a small increased risk of larger or node positive tumours  online. P-values , Phet=0.007 for 5-year increase in age at first birth; and 1.30 (1.09–1.55), Phet=0.004 for each additional full-term birth. However, associations between these risk factors and nodal status found in the standard polytomous logistic regression models were no longer significant in models considering multiple tumour characteristics simultaneously (Late age at first full-term birth and multiparity were associated with larger tumour size: OR (95% CI) for size >2 cm aneously .Phet=0.0003, and 0.29 (0.14–0.60), Phet=0.0008 for grades 2 and 3 compared to grade 1, respectively), and smaller tumour size (0.60 (0.36–0.99), Phet=0.05 for tumours >2 cm vs ⩽2 cm), but the association with lobular type suggested in the standard logisitic analyses . This model indicated that HRT use is related to tumour grade, independent of the histological type. Indeed, stratification of lobular tumours by grade 1 (N=60) and grades 2 or 3 (N=250) indicated a stronger increase in breast cancer risk for grade 1 (3.62 (1.52–8.63)) vs grades 2 or 3 (2.18 (1.30–3.65)), Phet=0.12.Recent or current use of combined HRT was significantly related to low tumour grade (0.38 (0.23–0.65), analyses  was no lPhet=0.05; 1.30 (1.14–1.49), Phet=0.0001, respectively); however, the association with nodal status was present for pre-menopausal women (1.28 (1.00–1.62) Phet=0.04) but not for postmenopausal women (1.04 (0.92–1.19), Phet=0.51).Elevated BMI in pre- and postmenopausal women was associated with larger tumour size (1.28 (1.00–1.64), Analysis of data from this large population-based case–control study provides convincing evidence that breast cancer risk factors differ by clinically important tumour features, including histopathological type, grade, size, and nodal status. Thus, exposures that influence the risk of developing breast cancer might also affect the biology and clinical behaviour of the tumours that arise. These findings parallel data suggesting that molecular profiles of breast cancers are generally fixed at inception and represent important determinants of clinical behavior  differ aetiologically . It is uStrengths of our study include large sample size, high participation rates, and standardised histopathologic assessment by an independent pathology review. In addition, we considered different tumour characteristics simultaneously using a novel statistical method  which alIn summary, this population-based study provides evidence that breast cancer risk factors are associated with clinically important tumour characteristics, suggesting that aetiological factors may affect the biological behaviour of breast cancers. In addition, these data suggest that postmenopausal women who are nulliparous have later ages at first birth and are obese might benefit from more frequent screening.


Various aspects of adult diet have been linked to breast cancer development. These include intake of fat (risk factor), and intake of fibre, soy protein and vitamins A, C and E (protective factors). Results of previous studies have been inconsistent. We examined the possible associations between breast cancer and various indices of nutrient and food intake in two Chinese populations who are at relatively low risk for breast cancer (one-fifth the rate in US white women). Two case-control studies of breast cancer were conducted in the cities of Shanghai and Tianjin, China. In Shanghai, 534 women aged 20-69 years with histologically confirmed breast cancer were recruited, whereas in Tianjin 300 women aged 20-55 years with histologically confirmed breast cancer were interviewed. All controls were community controls who were individually matched to the cases by sex and age (case-control ratio = 1:1). All interviews were conducted in person. Findings from the two studies were similar, although the diets in Shanghai and Tianjin were different in many respects. Cases and controls were similar in their consumption of soy protein, measured either in absolute levels or as percentages of total protein. Overall, all components of dietary fat  showed a modest, non-significant association with breast cancer after adjustment for energy intake and other non-dietary risk factors for breast cancer. Intake of crude fibre, carotene and vitamin C, on the other hand, exhibited strong, statistically significant inverse associations with breast cancer risk. The last three indices were highly correlated, rendering it impossible to disentangle their individual effects; they were closely associated with intake of green vegetables in the two study populations. Vitamin E intake was unrelated to breast cancer risk in Shanghai and Tianjin. In the multivariate logistic regression model which included all non-dietary risk factors for breast cancer and energy intake, Shanghai women in the lowest tertile of crude fibre intake and highest tertile of fat intake had a 2.9-fold increased risk for breast cancer relative to those in the highest tertile of crude fibre intake and lowest tertile of fat intake. The comparable relative risk in Tianjin women was 2.4. Our data indicate a strong protective effect against breast cancer development with intake of foods rich in fibre, vitamin C and carotene. Our results are also compatible with dietary fat having a modest, positive effect on breast cancer risk within the range of exposure experienced by women in China.(ABSTRACT TRUNCATED AT 250 WORDS)


Mean, age-standardized breast-cancer mortality rates for women of 41 countries, during 1970-71, were closely correlated with diet for 1964-66. Partial correlation analysis indicated that breast-cancer rates were positively correlated with total fat, animal protein and animal calories, independently of other components of diet. These 3 components were correlated with one another so closely that it was not possible, with available data, to say whether any one was associated with breast cancer independently of the other 2. In addition to, and independently of, these correlations, breast cancer was associated with consumption of refined sugar.Breast-cancer mortality rates at 50-54 years during 1964-67 for 26 countries were closely correlated with childbearing, expressed as mean family size for women aged 45-49 years in 1960-61. However, this correlation was not independent of the correlations with diet, and it was concluded that variation of breast-cancer rates between countries arose predominantly from differences in diet. The variation of breast-cancer risk with childbearing, observed in clinial studies, seemed best regarded as a second gradient of risk, seen more readily as variation of breast-cancer rates within a population, where differences in diet would be relatively small.The physiological basis for the association between breast cancer and diet was not clear. The dietary associations did not correlate in an obvious way with height, obesity and oestrogen levels, factors observed in clinical studies to influence risk of breast cancer. That the observed statistical associations were real was supported by published findings on effects of diet on mammary cancer in experimental animals, as well as the lower rates of breast cancer amongst vegetarians.


Mothers of a population-based series of 86 children with osteosarcoma or chondrosarcoma were traced and their health status or cause of death ascertained. There were 6 cases of breast cancer among these mothers and 6 other cancers. Risk of breast cancer was approximately three times that expected, and appeared to be highest in mothers of boys and in mothers of children under the median age at diagnosis. The mothers who developed breast cancer were relatively young at diagnosis compared with population data. Risk of other malignancies in the mothers was not in excess of expectation. These findings are in line with those reported for breast cancer risk in mothers of children with soft tissue sarcomas, and provide further indications of a genetic component in the aetiology of these cancers.


We have examined the relationship between birthweight and risk of breast cancer, taking into account growth in childhood, using data on a total of 2221 women born in 1946 and followed up to 1997. Thirty-seven breast cancers occurred during follow-up. There was evidence of greater risk of breast cancer with greater birthweight  for birthweight ≥ 3.5 kg vs birthweight < 3.5 kg), which was more marked at pre-menopausal ages . The relation with birthweight was not substantially confounded by any of the measured adult risk factors. A significant interaction was observed between the effects of birthweight and height at age 7 years. Relative to those born lighter than 3.5 kg, women who were heavy at birth (≥ 3.5 kg) and short or average at 7 years (< 1.22 m) had a 21% increase in breast cancer rates , while women who were heavy at birth (≥ 3.5 kg) but tall at 7 years (≥ 1.22 m) had a four-fold increase . These results suggest that the effect of birthweight on breast cancer risk may be modulated by childhood growth. © 2000 Cancer Research Campaign