P for trend=0.02), but not in men, in a nested case–control study of 338 cases and 341 matched controls. These findings may be due to chance and more studies are needed to determine whether associations between selenium and bladder cancer risk differ by sex.Prediagnostic selenium concentrations measured in archived toenails were inversely associated with bladder cancer risk in women ( Data from animal studies, observational studies and clinical trials suggest that selenium is anticarcinogenic and can reduce the risk of a number of different cancers . Five stOf the two largest studies to date, only 59 women were available for analysis in one study  and the Nurses' Health Study (NHS) cohorts provided data for our analyses of toenail selenium concentrations and bladder cancer risk. Details on these two cohorts have been previously published  or with an additional letter or phone call. Similar procedures are followed when the National Death Index lists a previously unreported bladder cancer for a deceased participant.Participants with bladder cancer were eligible for this analysis if the cancer diagnosis occurred after the toenail samples were obtained and they had no prior history of cancer (other than nonmelanoma skin cancer). From the time of the toenail collection through 2000, 338 incident cases with toenail samples were available for the selenium analyses . Controls were matched (1 : 1) on gender, age (within 1 year), smoking status  and month of toenail collection. In addition, controls had to be cancer free (other than nonmelanoma skin cancer) at the time of the bladder cancer diagnosis in the matched case.μg g−1  and 1.108±0.031 μg g−1  vs a certified value of 1.1±0.1. The CV% for these quality controls was 6.0 and 2.8 for the first and second batches, respectively. In addition, we obtained a CV% of 5.7 for 24 internal controls (split toenail samples), which were blinded to the laboratory.Selenium concentrations were measured in two batches by Dr Morris at the University of Missouri Research Reactor, Columbia, MO, USA, using neutron activation analysis (NAA)  and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Quartiles of selenium concentrations were created according to the distribution of the controls for each sex, separately. A continuous variable for pack-years of smoking was additionally included in all models. As a secondary analysis, we performed analyses with a 4-year lag to exclude preclinical cases at baseline. All vs 0.787 μg g−1, among controls, respectively), but similar among cases and controls for each sex (Mean selenium toenail concentrations were higher in men than women (0.896 each sex . Even thP for trend=0.02), but not in men : never 0.825, past 0.814, current 0.739; NHS (μg g−1): never 0.777, past 0.785, current 0.716). Among women, the strongest association between selenium and bladder cancer was observed among past smokers ; among men, smoking status did not significantly modify the associations (data not shown).Median selenium concentrations varied by smoking status (HPFS (vs lowest quartile), but resulted in a positive association in men .Removing cases diagnosed with bladder cancer within the first 4 years of follow-up strengthened the inverse association in women  and no associations were noted for never and current smokers. Our findings for women were similar to these as the inverse associations were also strongest among past smokers.In the largest study to date on toenail selenium concentrations and bladder cancer, only 59 cases (out of 431 cases) were women and associations were not presented separately by sex , detailed data on potential confounders, 1 : 1 matching by known confounders and high follow-up rates in the two cohorts used to select cases and controls.In summary, we observed a statistically significant inverse association between prediagnostic selenium toenail concentrations and risk of bladder cancer in women, but not in men. To date, this is the largest study to report findings on selenium concentrations and bladder cancer risk in women. Future studies are needed to confirm our findings.


Low lignan status has been reported to be related to an elevated risk of breast cancer. Since lignan status is reduced by antibacterial medications, it is plausible to hypothesize that repeated use of antibiotics may also be a risk factor for breast cancer. History of treatment for urinary tract infection was studied for its prediction of breast cancer among 9461 Finnish women 19–89 years of age and initially cancer-free. During a follow-up in 1973–1991, a total of 157 breast cancer cases were diagnosed. Women reporting previous or present medication for urinary tract infection at baseline showed an elevated breast cancer risk in comparison with other women. The age-adjusted relative risk was 1.34  = 0.98–1.83). The association was concentrated to women under 50 years of age. The relative risk for these women was 1.74 (95% CI 1.13–2.68), whereas it was 0.97 (95% CI 0.59–1.58) for older women. The relative risk in the younger age-group was 1.47 (95% CI 0.73–2.97) during the first 10 years of follow-up, and 1.93 (95% CI 1.11–3.37) for follow-up times longer than 10 years. These data suggest that premenopausal women using long-term medication for urinary tract infections show a possible elevated risk of future breast cancer. The results are, however, still inconclusive and the hypothesis needs to be tested by other studies. © 2000 Cancer ResearchCampaign


The relationship between oral contraceptives (OCs), menopausal hormone replacement therapy (HRT) and the risk of colorectal cancer was investigated in a case-control study conducted in northern Italy between 1985 and 1992 on 709 women with incident colorectal cancer and 992 controls admitted to hospital for a wide spectrum of acute, non-neoplastic, non-digestive tract, non-hormone-related disorders. A reduced risk of colorectal cancer was observed in women who had ever used OCs . The OR was 0.52 (95% CI 0.27-1.02) for use over 2 years. For women ever using HRT, the multivariate OR was 0.40 (95% CI 0.25-0.66). The risk was inversely related to duration of use, with ORs of 0.46 for 2 years or less and 0.25 for more than 2 years of use. No consistent pattern of trends was observed with time since first or last use. This study provides further evidence that OC and HRT do not increase, and possibly decrease, the risk of colorectal cancer. These results, if confirmed, would have important implications for the ultimate risk-benefit assessment of female hormone preparations.


The relationship between hormone replacement treatment (HRT) and breast cancer risk was analysed using data from a case-control study conducted between June 1991 and February 1994 in six Italian centres on 2569 patients aged below 75 with histologically confirmed breast cancer and 2588 controls admitted to hospital for a wide spectrum of acute, non-neoplastic, non hormone-related diseases. Ever HRT use was reported by 7.5% of cases and 7.5% of controls, corresponding to a multivariate odds ratio (OR) of 1.2 . The risk increased with increasing duration of use: the ORs were 1.0 for use lasting less than 1 year, 1.3 for 1-4 years and 1.5 for 5 years or more. There was no clear pattern of risk with reference to time since starting use, but the OR was significantly elevated  for women who had stopped HRT within the last 10 years. No association was observed in those who had stopped HRT more than 10 years ago (OR = 1.0). The increased OR for women who had stopped HRT within the last 10 years was consistent across strata of identified covariates, and was significantly related to duration of use. This study confirms the absence of a strong association between HRT and breast cancer risk, although the risk estimate was above unity for women who had used HRT for 5 years or longer. However, the risk was significantly elevated in the short to medium term after use, particularly for long-term use. This short-term increased risk is consistent with an effect of HRT on one of the later stages of the process of breast carcinogenesis. The flattening of risk with increasing time since stopping, and hence the absence of a long-term cumulative excess in breast cancer risk after stopping HRT exposure, has relevant implications on individual risk assessment and public health.


We examined the relation between gallstones, cholecystectomy, and the development of pancreatic cancer in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 104 856 women and 48 928 men without cancer at baseline, we documented 349 cases of pancreatic cancer during up to 16 years of follow-up. Participants were classified according to a history of gallstones or cholecystectomy. The age-adjusted relative risk of pancreatic cancer following cholecystectomy or diagnosis of gallstones was 1.31 . However, adjustment for other pancreatic cancer risk factors attenuated the association ; this risk did not increase with increasing time following cholecystectomy or gallstones. Gallstones or cholecystectomy do not appear to be significant risk factors for pancreatic cancer.British Journal of Cancer (2002) 86, 1081–1084. DOI: 10.1038/sj/bjc/6600193www.bjcancer.comCancer Research UK© 2002  Pancreatic cancer is the fifth leading cause of cancer-related mortality in the US . CholecyThe Nurses' Health Study (NHS) enrolled 121 700 female, registered nurses aged 30–55 years in 1976, and information on their health status, medical history, and known and suspected risk factors for cancer and coronary heart disease was gathered through mailed questionnaires. The Health Professionals Follow-up Study (HPFS) began in 1986, when 51 529 American male dentists, optometrists, osteopaths, pharmacists, podiatrists, and veterinarians aged 40–75 years completed a mailed questionnaire on health-related questions similar to those in NHS. Follow-up questionnaires were sent biennially to participants in both cohorts.In 1982, the study participants of the NHS were asked about their history of cholecystectomy and the year of surgery, with information updated biennially. History of gallstones that were not removed was also assessed on the 1982 questionnaire but was updated only through 1986. In the HPFS, participants were asked about their history of cholecystectomy or gallstones at baseline, and both questions were updated with all subsequent questionnaires.We included confirmed pancreatic cancers diagnosed between the return of the 1982 questionnaire and June 1, 1998, for the NHS and between the return of the 1986 questionnaire and January 1, 1998, for the HPFS. With permission from study participants, we confirmed pancreatic cancer through physicians' review of their medical records. If permission was denied, we attempted to confirm the self-reported cancer with an additional letter or phone call. We also searched the National Death Index to identify deaths among the nonrespondents to each 2-year questionnaire. The computerised National Death Index is a highly sensitive method for identifying death in this cohort  and all participants who reported a history of cancer (with the exception of non-melanoma skin cancer). Since the diagnosis of gallstones or the need for cholecystectomy might have been triggered by early symptoms associated with pancreatic cancer, we also excluded the first 2 years of follow-up for all study participants after their first report of either cholelithiasis or cholecystectomy. Therefore, for NHS participants who did not report gallstones or cholecystectomy between 1984 and 1986, we initiated follow-up with the date of return of the baseline 1982 questionnaire, whereas, for women who reported gallstones or cholecystectomy between 1984 and 1986, follow up began in 1988. In the HPFS, however, the baseline 1986 questionnaire assessed history of gallstones and cholecystectomy in timeframes that were larger than a 2-year interval. There, for all HPFS participants, we initiated follow-up with the date of return of the 1988 to ensure that persons reporting a history of either gallstones or a cholecystectomy were excluded from the succeeding 2 years of analysis only. In both cohorts, we computed person years of follow-up to the date of diagnosis of pancreatic cancer, death from any cause, or to the end of the study period  whichever occurred first. After these exclusions, 104 856 women and 48 928 men were eligible for follow-up, and 1 405 681 person years were accrued in the NHS and 441 387 in the HPFS.The primary analysis used incidence rates with person-years of follow-up in the denominator. We used relative risk (RR) as the measure of association; RR was defined as the incidence rate of pancreatic cancer among participants with a history of gallstones or a cholecystectomy divided by the incidence rate among participants without such a history. In the NHS, person time with gallstones history from 1986 on was based on the cumulative history of gallstones up to 1986. For each cohort, we used Cox proportional hazards models to adjust for other potential risk factors for pancreatic cancer. Although rapid weight loss in obese patients constitutes a risk factor for gallstones  to pool A total of 206 women and 143 men were diagnosed with pancreatic cancer during 2 162 077 person-years of follow-up. Of these 349 persons, 333 (96%) died of the disease. At baseline, 9.2% of the women (16.4% by 1996) and 3.7% of the men (7.1% by 1996) reported gallstones or a history of cholecystectomy. Characteristics of the study population are described in Table 1In our primary analysis we excluded participants who reported a history of cholecystectomy or gallstones from the proceeding 2 years of analysis, which left 170 women and 127 men with a diagnosis of pancreatic cancer. Of these, women with a history of gallstones or a cholecystectomy experienced a modest elevation in risk for pancreatic cancer , whereas men with such a history did not experience an obvious increase in risk , men , or women and men combined .We examined the relation between time since cholecystectomy and risk of pancreatic cancer. Among individuals with a cholecystectomy 10 or fewer years in the past, the multivariate RR for pancreatic cancer was 1.12 , whereas for more than 10 years in the past, the RR was 1.13 . For cholecystectomy more than 20 years in the past, the RR was 0.88 . These findings were not materially different when we examined time interval since cholecystectomy or a diagnosis of gallstones; for individuals with a history of either cholecystectomy or gallstones more than 10 years previously, the RR for pancreatic cancer was 1.16 .In two prospective cohorts of women and men, risk for pancreatic cancer following diagnosis of gallstones or cholecystectomy was modestly but not significantly increased. This risk was attenuated substantially after adjustment for potential confounders, including body mass index and physical activity. Furthermore, the risk did not increase in the decades following either cholecystectomy or diagnosis of gallstones.The prospective nature of our studies precluded recall bias and the need of next-of-kin respondents. Moreover, to avoid misclassification of exposure, we updated reports of cholecystectomy and gallstones biennially. Because identification of deaths is highly accurate in these cohorts (P=0.007) but not thereafter (Previous studies have investigated a potential association between gallstones or cholecystectomy and risk of pancreatic cancer. Results from case-control studies have been conflicting . In the ereafter . MoreoveAlthough the age-adjusted findings in our two cohorts are somewhat more consistent with previous positive results, multivariate adjustment suggests considerable confounding in this relation.In summary, our findings do not support a strong relation between gallstones or prior cholecystectomy and pancreatic cancer risk. The effect of gallstones and cholecystectomy on pancreatic cancer risk appears small and residual confounding by risk factors for both cholecystectomy and pancreatic cancer may have explained the results in previous studies.


A high consumption of fruit and vegetables reduces the risk of several types of cancer. There is little information on the association between dietary intake and mesothelioma. A hospital-based case-control study of 94 men and women with malignant mesothelioma and 64 control patients without cancer was conducted to determine the odds associated with consumption of carotenoid-containing fruits and vegetables. After statistical adjustment for occupational asbestos exposure, the odds ratio was 0.2 [95% confidence interval (CI) 0.1-0.8] for carrot consumption and 0.5 (95% CI 0.2-1.4) for tomato consumption. However, the frequency of consuming other foods that have a high vitamin A or carotenoid content was not associated with a decreased risk of cancer. These results provide some justification for the hypothesis that provitamin A or beta-carotene may decrease the risk of mesothelioma. The body mass index was unrelated to the risk of mesothelioma.


There is some evidence that birth weight is associated with breast cancer. Whether this association differs between premenopausal and postmenopausal ages is still unclear. The results from this study suggest that higher birth weight is a risk factor for postmenopausal breast cancer , independent of selected early-life and adult factors. The MDC-study, a collaborative centre of the European Prospective Investigation into Cancer and Nutrition (EPIC) (n=238), due to low statistical power for the analysis in women aged <55 years. Subjects' hospital delivery records were located in the city archive of Malmö using the civil registration number of the mother, which was available through record linkage to the subject. Cases were matched with controls by age (years) at entry of the MDC-study. We aimed at identifying three controls per case. Due to limited resources, and exclusion of twin births, some cases were matched 1 : 1 (n=11) or 1 : 2 (n=7). The breast cancer cases were identified by active follow-up and by record-linkage with regional and national cancer registries using individual civil registration numbers assigned to all residents in Sweden.The present analysis is restricted to breast cancer incidence in the period from study enrolment (1991–1996) until December 2001 among 5313 women born in Malmö between 1924 and 1950. We further restricted the analysis to 89 singleton female cases aged ⩾55 years at breast cancer diagnosis and age-matched controls without history of breast cancer , educational level (low to high). Birth year was included in all analyses to adjust for cohort effects. Birth weight was modelled both as a categorical  and continuous variable.We used conditional logistic regression to examine the effect of birth weight on breast cancer risk, adjusting for other perinatal and later-life factors: gestational age (weeks), maternal hypertension/proteinuria (no/yes), birth year, parental occupation (low to high), BMI , which was itself not a significant risk factor for breast cancer in this study. Other indicators of birth size, such as birth length, ponderal index (g cm−3), and head circumference were positively, but not significantly, associated with postmenopausal breast cancer (data not shown).Birth weight, adjusted for gestational age, was positively correlated with adult BMI , and persisted after adjustment for other perinatal and adult factors.Our finding in postmenopausal women may be contrasted with previous studies on premenopausal women. Case–control (vs reference group) , only one, conducted in Denmark, indicated a significant positive trend in rates of breast cancer with birth weight (9% per 1000 g) (Strengths of our study were the availability of data on recorded birth weight as well as gestational age, an important determinant of foetal growth. Therefore data were not subject to recall bias or residual confounding due to lack of adjustment for gestational duration. Only one other study had information on both recorded birth weight and gestational age (Other perinatal factors that correlate with oestrogen level during pregnancy, particularly twinning, pre-eclampsia, maternal age, and birth order are considered early life risk factors for cancer . MaternaData on birth outcome may be confounded by socioeconomic factors . HoweverDespite lack of statistical significance in some of the modelling, there is a strong suggestion of an increase in breast cancer risk with higher birth weight in this population of Swedish postmenopausal women, independent of adult body size. This finding lends support to the importance of prenatal factors in the aetiology of breast cancer.


P=0.008), with risk increasing in the following order: Bangladeshi Muslims (odds ratio (OR) 0.33, 95% confidence interval (CI): 0.10, 1.06), Punjabi Hindu , Gujarati Hindu (1=reference group), Punjabi Sikh  and Pakistani/Indian Muslims . The statistically significant raised risk in Pakistani/Indian Muslims increased with adjustment for socioeconomic and reproductive risk factors , but was attenuated, and no longer significant, with further adjustment for waist circumference and intake of nonstarch polysaccharides and fat . These findings reveal differences in breast cancer risk between South Asian ethnic subgroups, which were not fully explained by reproductive differences, but were partly accounted for by diet and body size.South Asian women in England have a lower breast cancer risk than their English-native counterparts, but less is known about variations in risk between distinct South Asian ethnic subgroups. We used the data from a population-based case–control study of first-generation South Asian migrants to assess risks by ethnic subgroup. In all, 240 breast cancer cases, identified through cancer registries, were individually matched on age and general practitioner to two controls. Information on the region of origin, religious and linguistic background, and on breast cancer risk factors was obtained from participants. Breast cancer odds varied significantly between the ethnic subgroups ( Breast cancer incidence rates in South Asian women living in England are lower than those in the English native population, but higher than those in the Indian subcontinent , obtaining information about the quantity/portion size and frequency of consumption of 207 food items 2–3 years previously. The average daily nutrient intake was calculated in CompEat  using a n=number of cases and controls):Gujarati Hindu (n=263): Hindu women born in Gujarat, India (38%), or born in East Africa, but whose parents came from Gujarat, India (27%), and Hindu women from other provinces of India (except Punjab) whose mother tongue was Hindi/Gujarati (35%).Punjabi Hindu (n=72): Hindu women born in Punjab, India (58%), or born in East Africa, but whose parents came from Punjab (13%) and Hindu women from other Indian provinces whose mother tongue was Punjabi (29%).Punjabi Sikh (n=163): Sikh women whose mother tongue was Punjabi, regardless of the place of birth. In all, 74% were born in Punjab, 15% in other provinces of India and 11% in East Africa.Pakistani and Indian Muslim (n=177): Muslim and Ismaili Muslim women, who were born/lived in Pakistan (60%), India (19%) or East Africa (20%).Bangladeshi Muslim (n=35): Muslim women born in Bangladesh.Other (n=4): Christian (3) and Buddhist (1) women. Due to small numbers, this group was excluded.We categorised the participants into six relatively homogeneous subgroups according to religion, mother tongue and birth place (both country and province) as follows . The response rate for eligible cases that were successfully traced was 79% (240 out of 303). Of the 480 eligible controls initially selected (matched to the 240 cases), 76% (365 out of 480) agreed to participate. For those who refused, replacement controls were selected.P=0.008). Pakistani/Indian Muslim women had a statistically significant 1.88-fold  higher odds than Gujarati Hindu women (P<0.01). There was also a reduced risk  in Punjabi Hindus and an increased risk  in Punjabi Sikhs relative to Gujarati Hindu women, but neither of these associations were statistically significant. We investigated whether these differences were explained by known and potential breast cancer risk factors by examining (i) whether known breast cancer risk factors had associations in the expected direction; (ii) whether the distribution of these risk factors in the controls varied by ethnic subgroup and (iii) whether adjustment for these factors altered the associations of breast cancer with ethnic subgroup.The odds of breast cancer varied significantly between the ethnic subgroups , were not. Women with diets high in NSP were at a statistically significant reduced risk  comparing the highest to the lowest fourth of energy-adjusted NSP intake).There were large variations in the distributions of potential risk factors by the ethnic subgroup among the controls . This association was not confounded by reproductive risk factors, but was amplified after controlling for years of education and menopausal status. Controlling for all the risk factors in By contrast, Punjabi Hindu women had a nonsignificant 35% reduction in the odds of breast cancer compared to Gujarati Hindu women, although the confidence interval is very wide due to only 18 cases. The magnitude of this reduction decreased slightly with adjustment for the reproductive and socioeconomic factors in The univariable analysis showed that Bangladeshi women were at a much reduced odds compared to all other ethnic subgroups  compared to Gujarati Hindu women). This reduction is possibly driven by their lower mean age at first birth, higher parity and longer lifetime duration of breast-feeding , but as We endeavoured to obtain a representative sample of the South Asian population in England by using population-based controls, the ethnic distribution of which was similar to that expected according to the 1991 Census. The observed/expected percentage of controls by ethnic subgroup was 77%/78%, 18%/14% and 6%/9% for Indians, Pakistanis and Bangladeshis, respectively  is consiWe found great heterogeneity in breast cancer risk between South Asian ethnic subgroups, with risk increasing in the following order: Bangladeshi Muslims (OR=0.33), Punjabi Hindu (0.65), Gujarati Hindu (1=reference group), Punjabi Sikh (1.26) and Pakistani/Indian Muslims (1.88).Pakistani/Indian Muslims were the only group with a statistically significant increased risk compared to Gujarati Hindu women. Their increased risk is consistent with a study of all deaths in 1975–77 in England and Wales, in which proportional mortality ratios were much higher in Muslims compared to Gujarati and Punjabi South Asian female immigrants , more pulse/lentil/dhal dishes (103.2 g day−1) and more fruit (1.8 servings day−1) compared to Pakistani/Indian Muslim women , resulting in their higher NSP intake. These intakes are consistent with a survey in pregnant women  risk relative to Gujarati Hindu women. The distinct characteristics of the Bangladeshi Muslim subgroup, such as a fish-based diet, short stature and favourable reproductive profile, may influence breast cancer risk and will make this an interesting group to study in future years as more of this population reaches the ages when breast cancer risk is highest.In summary, this study reveals that breast cancer rates for South Asian women in England mask great heterogeneity in risk within this diverse ethnic group. Pakistani/Indian Muslim women were at the highest risk compared to all other South Asian ethnic subgroups – an association that appears to be related to differences in diet and body size. These findings may be of use when considering the low uptake of breast screening in South Asian women . They su


Lifetime exercise activity has been linked to breast cancer risk among young women. However, no study has specifically evaluated whether lifetime exercise activity is related to the breast cancer risk of post-menopausal women. We conducted a population-based case-control study of post-menopausal white women  aged 55–64 who lived in Los Angeles County, California, USA to evaluate this relationship. Although neither exercise activity from menarche to age 40 years, nor exercise after age 40 separately predicted breast cancer risk, risk was lower among women who had exercised each week for at least 17.6 MET-hours  since menarche than among inactive women (odds ratio (OR) = 0.55; 95% confidence interval (CI) 0.37–0.83). Exercise activity was not protective for women who gained considerable (> 17%) weight during adulthood. However, among women with more stable weight, breast cancer risk was substantially reduced for those who consistently exercised at high levels throughout their lifetime , those who exercised more than 4 h per week for at least 12 years , and those who exercised vigorously (24.5 MET-hours per week) during the most recent 10 years . Strenuous exercise appears to reduce breast cancer risk among post-menopausal women who do not gain sizable amounts of weight during adulthood. © 1999 Cancer Research Campaign


The more men by whom a woman has children, the more diverse will be the foetal antigens of paternal origin introduced into her bloodstream, and we investigated whether this has an impact on subsequent cancer risks. By using population registries we identified 64 704 women who had children with at least two different partners from 1973 to 1996 in Denmark. We compared their cancer incidence with that of women who during the same time period had at least two births with no indication of partner change, adjusting for age, parity, socioeconomic factors and residence. The overall cancer incidence was more than 50% higher in women with two or more partners. Women having children with multiple partners had a higher incidence of cancer of the cervix and corpus uteri, a lower incidence of melanoma but a similar incidence of breast and ovarian cancer. Uncontrolled differences in lifestyle factors may explain the higher cancer risk associated with having multiple partners. The strong protective effect for melanoma was unexpected and deserves further study. A protective effect of pregnancy on cancer is best documented for breast cancer , although we expect this to have only a limited effect on cancer risk.We examined if having pregnancies with multiple partners influences the risk of some of the commonest cancers.We conducted a historical follow-up study using data from the following population based registries: the Fertility Database, the Prevention Registry , the National Hospital Discharge Registry, the Cause of Death Registry and the Cancer Registry. All the data for this study are located at Statistics Denmark or at the National Board of Health.By means of the above-mentioned registers we identified a cohort comprising all (64 704) women with Danish citizenship who had had at least two births by at least two different men, and whose second birth took place between 1973 and 1996: the exposed cohort. We then selected a random sample of 100 000 women from the population of women with at least two children and who had their index birth (second birth or later) after 1973, as in the exposed cohort. Among these we selected the 86 624 women for whom there was no indication of a change of partner: the unexposed cohort. More details on the study population are provided elsewhere . Linkage was based upon the woman's civil personal registration number (CPR), since 1968 given to all residents in Denmark, and used in all public registers.Incident diagnoses of cancer were extracted from the Cancer Register where they are coded according to the We analysed data using Poisson regression models. Exposure started at the first birth with a father different from the one registered at the previous birth(s). We considered women ‘exposed’ if they had at least one child by a different partner and if at least two different identifiable fathers were registered. Women who had a missing identifier for the father (2%) and no indication of a different father in any of the pregnancies were considered unexposed. Follow-up ended when cancer, death, or emigration occurred, or at the end of 1997 (when follow-up ended), whichever came first.Missing data on social factors were divided into two categories. One consisted of unreported actual missing values (a), while the other consisted of values from years that lacked a classification, or changes to the classification over time (b). The cohorts were stratified by parity for which incidence rates over time are estimated and adjusted for potential confounders: parity ; number of partners ; current maternal age four age groups <25, 25–34, 35–44, >45 years); calendar period ; time since latest pregnancy ; place of residence ; social status ; education ; and 9) occupation .If data were missing for the socioeconomic variables (people out of the workforce had no classification in some time periods), we used information from a previous year down to 1979. In the present analyses, missing data were kept in the analyses as a separate category, but all analyses were also performed after excluding subjects with missing data on social factors in the period 1973–1979. Analyses were performed using Poisson regressions in SAS and STATA software.As expected from their social profile, women with multiple partners had a higher risk of cancer of the cervix, but they also showed a higher incidence of cancer of the corpus uteri , compared women with parity 2, and the rate ratio for parity 4 or higher was 0.65 .The effect of time interval since having a child by a different partner is shown in As breast cancers with an early onset may have a different aetiology than those with a later onset, we estimated the relative risks separately for women prior to 45 years of age and for women aged 46 years or older. When adjusted only for parity, both estimates suggested a protection of partner change (RR=0.80 (95% CI: 0.67–0.95) for women below 46 years and RR=0.68 (95% CI: 0.49–0.95) for older women). When age, age at first delivery, place of residence, education, socioeconomic status and occupation were included in the model, however, there was no significant reduction among younger women (RR=0.94 (95% CI: 0.78–1.14)) and only a nonsignificant decrease remained among older women (RR=0.72 (95% CI: 0.50–1.03)) (raw data not shown).This study did not provide strong support for the hypothesis that having children by different partners reduces the risk of breast or ovarian cancer  and gene–environment interactions may occur at several steps in cancer development . Foetal The study has strengths as well as weaknesses. The strongest features lie in its population-based design with complete follow-up, reliable data on cancer incidence and reproduction, and independently reported paternal identity for live born children. We also had data on sociodemographic conditions of potential importance. All data were recorded independently of the study hypothesis, which might otherwise produce differential misclassification.Without access to the participants we have, on the other hand, no possibility of verifying data on paternity and we have no data on pregnancies that ended with foetal loss. Our data refers to the putative biological father in official statistics but anecdotal evidence suggests that this may be in error in 1–10% of the cases. Misclassification of fathers may bias the effect measure for malignant melanoma, though we consider the magnitude of bias to be small.If the foetal antigen hypothesis is true, the effect on parity level and number of partners is likely to be small. Although we included all women with two or more births by different partners into the study, our power to detect a small effect was limited as indicated by the wide confidence limits. It would be of interest to have data with longer follow-up time.We found a protective effect of parity of having children with different men for malignant melanoma. Whether transmission of foetal cells to the mother's blood stream during pregnancy plays a role for this finding needs further studies.


BRCA1 and BRCA2 genes. The effects of oestradiol (E2), tamoxifen (TAM) and fulvestrant (FUL) on proliferation and steroid receptor expression were assessed in normal breast epithelium taken from women at varying risks of breast cancer and implanted into athymic nude mice, which were treated with E2 in the presence and absence of TAM or FUL. Tissue samples were taken at various time points thereafter for assessment of proliferative activity and expression of oestrogen and progesterone receptors (ERα and PgR) by immunohistochemistry. Oestradiol increased proliferation in the breast epithelium from women carrying mutations in the BRCA1/2 genes, those otherwise at increased risk and those at population risk of breast cancer. This increase was reduced by both TAM and FUL in all risk groups. In the absence of E2, PgR expression was reduced in all risk groups but significantly more so in the BRCA-mutated groups. Subsequent E2 treatment caused a rapid, complete induction of PgR expression in the population-risk group but not in the high-risk or BRCA-mutated groups in which PgR induction was significantly delayed. These data suggest that the mechanisms by which E2 induces breast epithelial PgR expression are impaired in BRCA1/2 mutation carriers, whereas those regulating proliferation remain intact. We conclude that early anti-oestrogen treatment should prevent breast cancer in very high-risk women.There is considerable interest in whether anti-oestrogens can be used to prevent breast cancer in women bearing mutations in the  BRCA1 and BRCA2 genes  arising in these women are oestrogen receptor α (ERα) negative, have a high mitotic rate and are of high histological grade  or raloxifene can prevent breast cancer in women at increased risk of the disease  and fulvestrant, an anti-oestrogen devoid of agonist activity, were able to abrogate the proliferative effects of E2 on normal breast tissue from women carrying BRCA1 and BRCA2 mutations or who were, otherwise, at increased risk of developing breast cancer. To do this, we used a model of normal human breast tissue implanted into athymic nude mice where it was treated with oestradiol (E2) and/or anti-oestrogens. We show that epithelial proliferation in breast tissue from women with BRCA1 and BRCA2 mutations or who are otherwise at high risk is stimulated by oestradiol to the same extent to that in tissue taken from women at population risk of breast cancer. The effects of E2 on proliferation could be reduced by the addition of TAM or fulvestrant in all three risk groups. However, induction of progesterone receptor expression by E2 was impaired in the tissue taken from BRCA1 and BRCA2 carriers compared to that taken from women at population risk of breast cancer.Significant advances have been made towards understanding the mechanisms by which e genome . The preto occur . Howevertability . Conditiry gland . In addin=22) at surgery for removal of a fibroadenoma as described previously (BRCA1 (n=5) or BRCA2 genes (n=3). In the case of BRCA1, one subject was shown to be a mutation carrier through linkage analysis, but was not sequenced, whereas the other four were characterised by direct sequencing which identified the following mutations: 185delAG, 1294del40, 502del5 and 2799delAA. The three subjects with BRCA2 mutations were related and direct sequencing confirmed that they had the same lesion, 6819delTG. ‘Increased-risk’ tissue was taken at either prophylactic mastectomy or biopsy in women judged to be at increased risk of breast cancer either by family history or a previous history of cancer (n=18). Of these, 12 were undergoing bilateral prophylactic mastectomy because their family history indicated a lifetime risk of breast cancer greater than one in four, three were undergoing prophylactic removal of an uninvolved breast contralateral to one containing tumour and in three cases, tissue was obtained at biopsy from women with a more moderate family history calculated to put them at a lifetime risk of one in six or greater. The three groups  of women were well matched for age at operation and for endocrine breast cancer risk factors such as age at menarche, parity and age at first full-term pregnancy , two received the specific anti-oestrogen fulvestrant  and two the appropriate vehicle control (peanut or castor oil). These doses were chosen because they had been shown to inhibit the growth of MCF-7 human breast tumours in athymic nude mice (2 levels were assayed by RIA as described (2 concentration in the mice treated with control silastic pellets was 107 pM with an interquartile (IQ) range of 74–214 pM (n=100), those treated with 0.5 mg E2 pellets had a final median concentration of 386 pM , whereas those treated with 2 mg E2 pellets achieved a final median serum concentration of 1050 pM .All the following procedures were carried out under the Animals (Scientific Procedures) Act of 1986 and complied with UKCCCR Guidelines regarding the ethical use of animals. Implantation of human breast tissue into athymic nude mice was performed as described previously  and a rat monoclonal anti-PR antibody , respectively. Microwave antigen retrieval methods and dilutions were as described previously (Proliferative activity was assessed by immunohistochemistry (IHC) using the mouse monoclonal antibody MIB-1  raised against the Ki67 proliferation-associated antigen. Expression of ERU-test.Throughout, the data are presented as medians together with their respective interquartile ranges (IQRs). Overall changes across treatment or risk groups were analysed using the Kruskal–Wallis nonparametric, one-way analysis of variance. If this proved significant at the 5% level, then pairwise comparisons were made using the nonparametric Mann–Whitney 2 or control treatment. In the absence of E2, epithelial Ki67 expression in the tissue samples from the population- and high-risk tissue groups remained at the levels seen before treatment . The reasons for this decline in proliferative activity in the tissue taken from women carrying BRCA1 mutations compared to that from women at population risk are not clear at present, but it may be due simply to the variability in the data from the latter group. 2. In the population-risk group, there was an increase in the Ki67LI after treatment with the 0.5 mg E2 pellet although this was not statistically significant. In the other three risk groups, the Ki67LI increased significantly after treatment with the low-dose E2 pellet (P<0.001 by Mann–Whitney U-test) compared to the appropriate untreated control. Treatment with the high-dose (2 mg) E2 pellet (P<0.001 by Mann–Whitney U-test) when compared to the corresponding control values.Analysis of the tissue samples, fixed at the time of removal from the patients, revealed no differences in the percentages of breast epithelial cells labelled with the anti-Ki67 antibody between the different risk groups see . At 2 wereatment . The medreatment  decreaseutations  indicate2 pellet  significα and PgR expression between the risk groups at the time tissue was removed from the women (BRCA1 mutations and resulted in the percentage of PgR-positive cells being approximately four-fold lower than that of the population-risk group (P<0.001 by Mann–Whitney U-test). 2-silastic pellets on PgR expression in breast epithelial cells. Levels of PgR expression were not altered in the control-treated samples  and 6.8% (IQR=2.1–20.4), respectively. These increases in PgR expression in the samples from the All mutations and BRCA1 groups almost, but not quite, reached statistical significance when compared to the corresponding control-treated samples . Expression of the PgR in breast epithelium from all the risk groups was also induced by 1 week's treatment with high-dose E2 (P=0.002 by Mann–Whitney U-test). The responses in the All Mutations and BRCA1 groups were diminished considerably in that they reached medians of only 10.3% (IQR=4.6–19.2) and 9.3% (IQR=4.4–20.0), respectively (P=0.062 and 0.012 vs corresponding control-treated samples by Mann–Whitney U-test).There were no significant differences in the levels of breast epithelial cell ERhe women . Howeverhe women . This wa samples , and the-dose E2 . However2 pellet on PgR expression in human breast epithelium at all time points after the start of treatment are shown in 2 pellet and this level was maintained for the remainder of the experimental period. In contrast, the response in the All mutations group was attenuated such that percentages of PgR-positive cells in samples from this group were significantly lower than those of the population-risk group not only before the start of treatment but also for 2 weeks afterwards (P<0.001 by Mann–Whitney U-test at each time point). By the final time point, the median percentage of PgR-positive cells in samples from the All Mutations group had increased such that it approximated to that of the population-risk group. The effects of E2 on PgR expression in tissue samples from the BRCA1 group could not be examined separately due to the small number of tissue samples available for analysis at the later time points. Examination of the effects of E2 on PgR expression in the tissue samples from the high-risk group of women confirmed the results shown above in that the percentage of PgR-positive epithelial cells in this group after 1 week of high-dose E2 treatment was significantly lower than that of the population-risk group but thereafter, there were no significant differences between the two groups.The effects of the high-dose E2 for 1 week followed by a further 2 weeks of treatment in which the E2 was combined with either TAM or fulvestrant. An additional group of mice were treated with 0.5 mg E2 only, whereas the negative control group received vehicle alone. Treatment with 0.5 mg E2 was sufficient to increase Ki67 expression in the population-risk, high- risk and All mutations groups (P<0.01 by Mann–Whitney U-test compared to the appropriate untreated control for each risk group). Addition of TAM at a dose of 1 mg mouse−1 day−1 reduced expression of Ki67 in these three risk groups compared to 0.5 mg E2 alone (P<0.05 by Mann–Whitney U-test in each risk group). The percentage of Ki67-positive cells was also reduced by the addition of fulvestrant (5 mg mouse−1 week−1) in the population risk, increased=risk and All Mutations groups compared to 0.5 mg E2 alone (P<0.05 by Mann–Whitney U-test in each risk group). Both TAM and fulvestrant, when added to 0.5 mg E2, reduced the median percentages of Ki67-positive breast epithelial cells to the levels seen in untreated controls in the population-risk, increased-risk and all mutations groups (no significant difference when compared to controls by Mann–Whitney U-test in each risk group). Separate analysis of the tissue samples from women bearing BRCA1 mutations  although the pattern of changes reflected those seen in the other risk groups.utations  showed t2 treatment on breast epithelial cell Ki67 expression was also investigated (data not shown). Both anti-oestrogens could reduce the effects of E2 on proliferation in all the risk groups but their effects were rather more variable presumably because the serum drug levels achieved with the above dosing schedules were not sufficient to overcome the high plasma E2 levels reached after treatment with the 2 mg E2 pellet.The ability of TAM and fulvestrant to reverse the effects of high-dose (2 mg) EBRCA1 or BRCA2 breast cancer-predisposing genes on the endocrine sensitivity of human breast epithelial cells are unknown. It is important to determine what these effects may be because of the increasing use of endocrine agents such as TAM for breast cancer prevention in BRCA1 and BRCA2 mutation carriers. Although the BRCA1 and BRCA2 proteins play critical roles in DNA damage repair  and an anti-oestrogen (fulvestrant) that is without agonist effects. We have also shown that altered expression of PgR is a phenotype associated with mutations in the BRCA1 and BRCA2 genes. We conclude that early anti-oestrogen treatment should be effective for the prevention of breast cancer in high-risk women.In summary, we have shown that E


P for trend = 0.02), percent free oestradiol , and oestrone . Risk decreased with higher levels of percent SHBG-bound oestradiol  and SHBG . Trends remained in the same directions after adjusting for height and body mass index. A positive association of body mass index with risk was substantially reduced after adjusting for oestrone level. Our results indicate that risk of endometrial cancer increases with increasing postmenopausal oestrogen levels but do not provide strong support for a role of body mass index independent of its effect on oestrogen levels. © 2001 Cancer Research Campaign http://www.bjcancer.comWe assessed the association of postmenopausal serum levels of oestrogens and sex hormone-binding globulin (SHBG) with endometrial cancer risk in a case–control study nested within the NYU Women's Health Study cohort. Among 7054 women postmenopausal at enrolment, 57 cases of endometrial cancer were diagnosed a median of 5.5 years after blood donation. Each case was compared to 4 controls matched on age, menopausal status at enrolment, and serum storage duration. Endometrial cancer risk increased with higher levels of oestradiol (odds ratio = 2.4 in highest vs lowest tertile,


The interpretation of time trends in disease rates can be facilitated using estimable contrasts from age-period-cohort models. Cohort and period trends in breast cancer incidence and mortality rates in Scotland were investigated using contrasts that measure the changes in the linear trends. These contrasts were compared with estimates obtained from mortality rates in the USA and Japan. A significant moderation of both breast cancer incidence and mortality rates was observed in Scotland, associated with cohorts of women born after the Second World War compared with women born between the two world wars. The moderation of breast cancer mortality among cohorts born after 1925 compared with cohorts born before 1925 that was observed in the USA and Japan was also observed in this study. This moderation is not present in the incidence rates. The relative decline in the risk of breast cancer seen in younger cohorts seems to be contradictory to the temporal pattern present among breast cancer risk factors. It may well be that the alteration of eating patterns as a result of rationing in the wartime and immediate post-war period, and the subsequent influence on certain breast cancer risk factors probably produced by such changes, may have had some influence on the development of healthier girls and women. Such speculation could be addressed in a well-designed epidemiological study. There have been no changes in the mortality rate trends with period in Scotland, although the changes in the incidence rate trends with period are consistent with an increase in registration coverage.


Although several dietary compounds are hypothesized to have anticarcinogenic properties, the role ofpecific micronutrients in the development of breast cancer remains unclear. To address this issue, we assessed intake of retinol,β-carotene, vitamin C and vitamin E in relation to breast cancer risk in a case–control study in Greece. Eight hundrednd twenty women with histologically confirmed breast cancer were compared with 1548 control women. Dietary data were collectedhrough a 115-item semiquantitative food frequency questionnaire. Data were modelled by logistic regression, with adjustment forotal energy intake and established breast cancer risk factors, as well as mutual adjustment among the micronutrients. Amongost-menopausal women, there was no association between any of the micronutrients evaluated and risk of breast cancer. Amongremenopausal women, β-carotene, vitamin C and vitamin E were each inversely associated with breast cancer risk, but afterutual adjustment among the three nutrients only β-carotene remained significant; the odds ratio (OR) for a one-quintilencrease in β-carotene intake was 0.84 . The inverse association observed withβ-carotene intake, however, is slightly weaker than the association previously observed with vegetable intake in these data,aising the possibility that the observed β-carotene effect is accounted for by another component of vegetables. ©1999 Cancer Research Campaign


The Northern California county of Marin (MC) has historically had high breast cancer incidence rates. Because of MC's high socioeconomic status (SES) and racial homogeneity (non-Hispanic White), it has been difficult to assess whether these elevated rates result from a combination of established risk factors or other behavioral or environmental factors. This survey was designed to compare potential breast cancer risks and incidence rates for a sample of middle-aged MC women with those of a demographically similar population.A random sample of 1500 middle-aged female members of a large Northern California health plan, half from Marin County (MC) and half from a comparison area in East/Central Contra Costa County (ECCC), were mailed a survey covering family history, reproductive history, use of oral contraceptives (OC) and hormone replacement therapy (HRT), behavioral health risks, recency of breast screening, and demographic characteristics. Weighted data were used to compare prevalence of individual breast cancer risk factors and Gail scores. Age-adjusted cumulative breast cancer incidence rates (2000–2004) were also calculated for female health plan members aged 40–64 residing in the two geographic areas.Survey response was 57.1% (n = 427) and 47.9% (n = 359) for MC and ECCC samples, respectively. Women in the two areas were similar in SES, race, obesity, exercise frequency, current smoking, ever use of OCs and HRT, age at onset of menarche, high mammography rates, family history of breast cancer, and Gail scores. However, MC women were significantly more likely than ECCC women to be former smokers (43.6% vs. 31.2%), have Ashkenazi Jewish heritage (12.8% vs. 7.1%), have no live births before age 30 (52.7% vs. 40.8%), and be nulliparous (29.2% vs. 15.4%), and less likely to never or rarely consume alcohol (34.4% vs. 41.9%). MC and ECCC women had comparable 2000–2004 invasive breast cancer incidence rates.The effects of reproductive risks factors, Ashkenazi Jewish heritage, smoking history, and alcohol consumption with regard to breast cancer risk in Marin County should be further evaluated. When possible, future comparisons of breast cancer incidence rates between regions should adjust for differences in income and education in addition to age and race/ethnicity, preferably by using a sociodemographically similar comparison group. The San Francisco Bay Area (SFBA) has some of the highest breast cancer incidence rates in the United States . Marin CIn response to the Marin community's concerns about the elevated breast cancer rate, Kaiser Permanente Medical Care Program, the largest health care provider in the area, and the Marin County Department of Health Services collaborated on a pilot study designed to compare prevalence of known breast cancer risk factors and breast cancer incidence among Kaiser Permanente health plan members in Marin County with those of health plan members in a defined geographic area of the SFBA that was sociodemographically similar to Marin County.All women in this study were sampled from the KPNC membership based on residential address and age (40–65). The Marin County (MC) group was a random sample of 750 female members who resided within Marin County. The comparison group was a random sample of 750 female members who resided in East/Central Contra Costa County (ECCC), which included the cities of Walnut Creek, Lafayette, Moraga, Orinda, Pleasant Hill, Concord, San Ramon, and Danville. The ECCC catchment area, which is geographically near MC but separated by the San Francisco Bay and the Oakland/Berkeley Hills, was selected because it was found to be demographically comparable to MC with regard to race/ethnicity (>80% non-Hispanic White), education (approximately 50% college graduates), and upper middle class income  based on KPNC's 1999 Member Health Survey , we estiWomen in both areas were sent a confidential "Women's Health Risk Factor Survey" questionnaire, accompanied by a cover letter from KPNC's Division of Research explaining that the study was being conducted to investigate the extent to which breast cancer rates in certain counties could be explained by differences in the percentages of women in those counties who have factors known to increase breast cancer risk. The survey questions were drawn from previous epidemiologic studies of breast cancer in California  or the KThe questionnaire collected information about established breast cancer risk factors, including demographics , breast health (history of breast cancer or breast biopsies), family history of breast cancer, reproductive history , use of birth control pills and hormone replacement therapy (HRT), and behavioral health risks, including cigarette smoking, height and weight to calculate body mass index (BMI), usual frequency of moderate or strenuous exercise per week, and average weekly alcohol consumption . Women were also asked to report the timing of their last mammogram. However, since screening mammography is not recommended to start until age 40, comparisons were restricted to age ≥41 to give the younger women at least 12 months to have had a first mammogram. A copy of the questionnaire can be found in Additional file Based on information about individual risk factors, a Gail risk score  was calcAnalyses were performed using SAS  v.9.1 procedures for analysis of data obtained from complex survey designs . All anaConcurrent with the survey analyses, cumulative breast cancer incidence rates (2000–2004) were calculated for all KPNC female members aged 40 to 64 residing in MC and the ECCC comparison areas, defined by the same cluster of residence zip codes used to pick the survey samples. Cases of newly diagnosed, invasive breast cancer tumors   for each study area were adjusted using the direct method to the age distribution of the 2000 US Census female population residing in that geographic area. Log-linear Poisson regression was used to estimate the relative risk, adjusted for age (ten 5-year age categories) and ethnicity. While KPNC did not have computerized race/ethnicity data on its membership, estimates based on KPNC's 2002 Member Health Survey  suggesteResponse rates for the MC and ECCC samples were 57.1% (427/748) and 47.9% (359/749), respectively, after excluding persons for whom no forwarding address could be found. Interviews with random samples of non-respondents from both areas suggested that non-participation was primarily due to women being too busy with family and work responsibilities.Table Table Further analysis of reproductive responses indicated some additional similarities and differences. The percentage of women who had never been pregnant was similar . Among women who had experienced at least one pregnancy, a significantly higher percentage of MC than ECCC women reported more pregnancies than births . Among those women who had borne at least one child, there was no significant difference between groups in percentage who had given birth by age 30 .The groups did not differ significantly on percentages at above average risk for invasive breast cancer based on Gail risk scores . When we created an adapted Gail variable that combined women with a score ≥1.7 and those with a history of breast cancer into a modified high risk category, there were still no significant differences between the MC and ECCC groups . These results did not change when adjusting for age (results not shown).Table Breast cancer incidence rates for KPNC female members aged 40–64 in the MC and ECCC comparison area for the 5-year period 2000–2004 are shown in Table This study compared the breast cancer risk factor prevalence among a randomly selected group of female KPNC members in Marin County, CA, which has a historically high breast cancer incidence rate, with risk factors among a group of KPNC members in a geographically separate but sociodemographically similar area in nearby Contra Costa County. The study design enabled the comparison of established risks and incidence rates while minimizing potential confounding effects of sociodemographic characteristics associated with breast cancer risk . The results show that matching the KPNC Marin County women with a sociodemographically similar comparison member group outside Marin County substantially diminished differences in breast cancer incidence and prevalence of many, but not all, breast cancer risk factors.The reasons for the documented association between SES and breast cancer incidence is not well understood, but it has been suggested that SES acts as a marker for such factors as screening and reproductive behaviors  and chilThe most salient differences between the women from the high breast cancer incidence county and SES-matched comparison group were in reproductive factors. The Marin County women were less likely to have given birth before age 30 and more likely to be nulliparous. While previous studies have calculated that approximately 30% of breast cancer cases are attributable to late age at first birth/nulliparity , the twoSmoking history and alcohol consumption differed between the Marin County and the comparison group. While both groups had current smoking rates well below the 2004 State of California prevalence of 14.6% , the MarThese differences in smoking history and alcohol consumption could help explain part of any increased incidence of breast cancer in Marin County. While the association between smoking and breast cancer incidence is inconsistent in the literature, a significant association has been found in large studies between one drink per day and breast cancer. For example, based on reanalysis of data from 53 international studies, Hamajima and colleagues estimated that every additional drink per day increases the relative risk of breast cancer by 7.1%, and that 4% of breast cancer cases in developed countries could be attributed to alcohol if alcohol is causally related to breast cancer . While tWomen in Marin County may be more likely to have genetic risks associated with Ashkenazi ethnicity ,29, but Since this study essentially matched KPNC members from Marin and the comparison community on race-ethnicity, income, and education at the outset, the findings of similar breast cancer risk factor profiles and statistically comparable cumulative breast cancer incidence rates among KP members residing in the two areas provide some evidence for what some earlier authors have suggested, i.e., that regional differences in breast cancer rates in the SFBA may be due to regional differences in SES factors . These fThe restriction of the study to female KPNC health plan members for this pilot study had several advantages. Differences between groups with regard to access to care, model of health care delivery, and exposure to breast cancer prevention measures, including screening and risk factor education, were minimized. In addition, breast cancer incidence rates could be calculated using counts of the female membership. However, there are several potential limitations to the study design that could affect interpretation of the results. Our study power was not high enough to detect differences in breast cancer risk factors of less than ten percentage points due to a lower than anticipated response rate. Additionally, if the substantially higher survey response for the Marin County member sample is due to high level of public awareness about elevated breast cancer incidence rates in Marin County created by local media and advocacy groups, this might have introduced response bias. Because KPNC, like most health plans, did not have computerized information about the race/ethnicity of its members, we had to rely on survey estimates to create the ethnicity-adjusted denominators in breast cancer incidence measures. Finally, we do not know how generalizable these results are to the general populations of the two study communities. Data from the 2003 California Health Interview Survey suggest that overall, the KPNC membership has lower percentages of adults at the lower and upper extremes of household income than both the general and privately insured populations in Northern California, and that while the membership is very similar to the privately insured population with regard to educational attainment and health-related behaviors, it is much better educated and has a lower prevalence of behavioral health risks than the general population . If the In these sociodemographically matched health plan member populations, we found statistically comparable breast cancer incidence rates and similar prevalence of many, but not all, established breast cancer risk factors. The effects of reproductive risks factors, Ashkenazi Jewish heritage, smoking history, and alcohol consumption with regard to breast cancer risk in Marin County should be further evaluated in larger and more representative community samples. When possible, future comparisons of breast cancer incidence rates between regions should adjust for differences in income and education in addition to age and race/ethnicity, preferably by using a sociodemographically similar comparison group.SES: socioeconomic status; MC: Marin County; ECCC: East/Central Contra Costa County; CA: California; KPNC: Kaiser Permanente Medical Care Program in Northern California; BMI: body mass index; HRT: hormone replacement therapy.The authors declare that they have no competing interests.SL and NG conceived the study. SL, NG, LP, and RE collaborated on the study design and survey instrument; NG secured funding for the study and her team collected and cleaned all survey data. SL, NG, LP, and RE structured the statistical analyses, and NG and MP analyzed the survey data. CU conducted the analyses comparing breast cancer incidence rates in the two communities. SL, NG, LP, RE, and MP interpreted the results of the analyses and collaborated on writing the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/9/6/prepubSurvey questionnaire used for the study.Click here for file


The relationship between intake of dairy products and risk of breast cancer was studied in 4697 initially cancer-free women, aged 15 years or over. During a 25 year follow-up period after the collection of food consumption data, 88 breast cancers were diagnosed. Intakes of foods were calculated from dietary history interviews covering the habitual diet of examinees over the preceding year. There was a significant inverse gradient between milk intake and incidence of breast cancer, the age-adjusted relative risk of breast cancer being 0.42  between the highest and lowest tertiles of milk consumption. The associations with respect to other dairy products were not significant. Adjustment for potential confounding factors, i.e. smoking, body mass index, number of childbirths, occupation and geographic area, resulted in only a minor change in the milk intake-breast cancer relation. Nor did adjustment for intake of other foodstuffs and nutrients, e.g. energy, carbohydrates, protein, fat, vitamins and trace elements, alter the results. No significant interactions between milk intake and demographic or dietary variables or time of cancer diagnosis were observed. Our data suggest that there is a protective effect, dietary or habitual, associated with consumption of milk that overwhelms the associations between different other factors and risk of breast cancer.


P<0.001) and was increased 9.2-fold among women chewing tobacco 10 times or more a day. The risk increased with the duration of tobacco chewing during the first 20 years of tobacco chewing. Age at starting tobacco chewing was not significantly related to oral cancer risk. This is the first cohort study of oral cancer in relation to tobacco chewing among women.This study examined oral cancer in a cohort of 78 140 women aged 30–84 years in Karunagappally, Kerala, India, on whom baseline information was collected on lifestyle, including tobacco chewing, and sociodemographic factors during the period 1990–1997. By the end of 2005, 92 oral cancer cases were identified by the Karunagappally Cancer Registry. Poisson regression analysis of grouped data, taking into account age and income, showed that oral cancer incidence was strongly related to daily frequency of tobacco chewing ( Globally, oral cancer is the 11th most common cancer and is responsible for about 200 000 deaths each year , two-thiIn this study, we analysed the oral cancer risk among women in relation to tobacco use, and socioeconomic status (SES) in a rural cohort in Kerala. To our knowledge, this is the first cohort study to examine the association of oral cavity cancer risk with tobacco chewing among women. It is relevant that smoking and alcohol drinking were rare in this women population.2 All the households (N=71 674) in Karunagappally taluk were visited by 12–14 trained interviewers, starting from 1 January 1990 and ending on 31 December 1997 ; 166 subjects who had died or been diagnosed as cancer before the base-line interview; and those who died within 3 years of interview, as their lifestyles might have been affected by their health conditions. Thus, there were 79 593 subjects for statistical analysis.In total, this household survey collected personal information on 359 614 subjects in 71 674 households, which correspond to 93% of population and 94% of households in Karunagappally by the 1991 census. There were 81 514 women aged 30–84 years old at the time of interview. We excluded the following from analysis: those younger than 30 years of age, as cancer risk is low in this age range; those aged 85 years or older; workers employed in the local Rare Earth factory, who might have various occupational exposures  diagnosed as cancer other than oral cancer, (ii) died of causes other than oral cancer or (iii) migrated from the study area. Thus, the end of follow-up was the date of diagnosis for cancer cases, of death for those deceased, of the end of follow-up (31 December 2005), of moving out, or reaching the age of 85 years. In person-year calculation, we used the information on migration of cohort members even though this was available only for a part of our observation period; this caused only small changes in relative risk estimates.In this study, we analysed cancer incidence in the period 1990–2005. Cancer cases among the cohort were ascertained by the cancer registry in Karunagappally, which was officially initiated as of 1 January 1990 and has been reported in ‘Cancer Incidence in Five Continents’, vols. VII–IX . As therDeath reports were obtained from the death registers kept in the vital statistics division of each panchayat. House visits of the deceased, to supplement information on cause of death, were started in 1997. The proportion of DCO cases in Karunagappaly cancer registry was 14% during 1990–1994 . The ratThe extent of migration among cohort members was assessed by conducting a door-to-door survey of all the households in the six panchayats  and in the remaining six panchayats in 2001 and 2003, respectively. The survey findings were linked to incident cases through name, address, age, house number and so on; it showed that migration was negligible.Statistical analysis of tobacco chewing in relation to sociodemographic factors were conducted using logistic analysis, adjusting for age at interview. For the association with age, univariate logistic analysis was used.2) and current-chewers (represented by S3): H0  exp (β2S2+β3S3), where H0 represents the baseline, or background oral cancer incidence (among never smokers) for cross-classified strata by attained age and sociodemographic variables. Attained age at the time of the midpoint of 1-year interval during the observational period (1990–2005) was calculated for each cohort members by the DATAB procedure of EPICURE programme. Heterogeneity test was based on a global P-value for a set of indicator variables. Trend test for, for example, duration of tobacco chewing was conducted by assigning the mean duration of tobacco chewing to its each category.Analyses of sociodemographic factors and tobacco chewing were based on the data in cross-classifications by attained age (5-year category), and other covariates. Relative risk (RR) and 95% confidence intervals (95% CI) were obtained from Poisson regression analysis of grouped survival data , using tP<0.001, the lowest income vs other groups).Among the 79 593 eligible women aged 30–84 years, 102 female cases of oral cancer  were identified by the end of 2005. After restricting the examination to women who do not smoke beedis or cigarettes and do not drink alcohol, there were 78 140 women and 92 oral cancer cases. P<0.001), particularly in the first 20 years. Among those who had chewed tobacco for 20 years or longer by the time of baseline study, no further risk increase was observed.P<0.001) and was increased 9.2-fold among women chewing tobacco 10 times or more a day. The effect of age starting tobacco chewing did not evidently modify risk. Oral cavity cancers were grouped into cancers of the tongue (ICD9: 141) and gum and mouth (ICD9: 143–145), there were only four cases in the other location, which were cancer of the lip. As shown in P<0.001) and the tongue (P<0.001).This study showed that daily frequency of tobacco chewing was strongly related to oral cancer incidence among women, and the risk among women chewing tobacco 10 times or more a day was 9.2-fold higher than that of non-tobacco chewers. Moreover, it increased with duration of chewing during the first 20 years.Former tobacco chewers had an RR even larger than current tobacco chewers, as also found by a case–control study in Trivandrum, India .This study, the first cohort study of the question among women, showed that frequent tobacco chewing strongly increases oral cancer incidence (


The possible association between breast cancer and oral contraceptive use before the age of 20 was investigated using Icelandic population-based information from women born after 1944. The design was a nested case-control study within a cohort, using data on duration of oral contraceptive use at young ages. The availability of oral contraceptives before the age of 20 has changed dramatically and is highly dependent on birth years, with 20% and 82% starting before the age of 20 among Icelandic users born in 1945-47 and 1963-67 respectively. The association between total duration of oral contraceptive use and breast cancer was significantly dependent on year of birth. In women born in 1951-67 (based on 81 cases), the relative risk (RR) associated with use for more than 4 years was 2.0 (95% CI 1.1-3.7). The association disappeared when women born in 1945-50 were included , adding 123 cases. A significant trend of increased risk with longer duration was present only in the group born after 1950, with RR 0.9, 1.7 and 3.0 for < or = 4 years, >4-8 years and > 8 years of use respectively. The results of this study indicate an association between breast cancer and oral contraceptive use at a young age. They also stress the importance of distinguishing between groups with different opportunities for exposure at young age.


Cox proportional hazard models were used to estimate risk of each cancer with individual nutrients and to explore possible effect modification by combinations of nutrients on cancer risk. Few significant associations of intake of individual B vitamins with the five cancers were observed. Alcohol consumption showed a modest positive association with breast cancer risk but not with risk of the other cancers. There was no evidence of effect modification among the nutrients. This large study provides little support for an association of dietary intake thiamin, riboflavin, niacin, folate, or methionine with five major cancers in women.Although folic acid has been investigated for its potential to inhibit carcinogenesis, few epidemiologic studies have assessed the effects of intake of thiamin, riboflavin, and niacin, which may reduce cancer risk by acting as cofactors in folate metabolism or by other mechanisms. Using data from a large cohort of Canadian women, we examined the association of dietary intake of these nutrients, as well as intake of folate, methionine, and alcohol, with cancers of the breast, endometrium, ovary, colorectum, and lung ascertained during an average of 16.4 years of follow-up. After exclusions, the following numbers of incident cases were available for analysis: breast,  Interest in the potential of folate to reduce the risk of common cancers stems from the important role of this B vitamin in one-carbon metabolism. Optimal one-carbon metabolism is necessary for the synthesis of the purines, adenine and guanine, and the conversion of uridylate to thymidylate, which blocks the misincorporation of uracil into DNA . DysreguEpidemiological evidence regarding the association of folate and cancer of various sites has been inconsistent . FurtherGiven the conflicting data on folate and the paucity of studies on the other related nutrients, we examined the associations between dietary intake of folate, thiamin, riboflavin, and niacin and risk of cancers of the breast, endometrium, ovary, colorectum, and lung in the National Breast Screening Study (NBSS), a large cohort of Canadian women. In addition, we assessed the effects of intake of methionine, in view of its role as a methyl donor, and of alcohol intake, as alcohol is a known folate antagonist and may increase the requirement for folate and possibly other B vitamins  or death, whichever occurred first. After exclusions, during an average of 16.4 years (786 588 person-years) of follow-up of the dietary cohort, the following numbers of incident cases were available for analysis: breast, −1  or whose body mass index (BMI) was <15 or >50 kg m−2 were excluded.Separate analyses were carried out for each cancer site. For analyses of endometrial cancer, 14 906 women who had had a hysterectomy were excluded (67 cases and 14 839 noncases). For analysis of ovarian cancer, 318 women who reported a bilateral oopherectomy were excluded (three cases and 315 noncases). In addition, for all analyses, women whose calorie intake was <730 or >5389 kcal day−1. Variables were included in the multivariate models if they were established risk factors for a given cancer or if their inclusion in the model changed the parameter estimate for the nutrients of interest by more than 10%. The covariates included in the main models for the five cancers are listed in the footnotes to Table 2. Addition of indicator variables for screening centre and randomisation group in the original clinical trial  did not affect the risk estimates, and therefore these variables were omitted. To test for trends in risk with increasing levels of an exposure of interest, we assigned the median value for each quintile of that exposure variable and then fitted the medians as a continuous variable in the risk models. We then evaluated the statistical significance of the corresponding coefficient using the Wald test  and 95% confidence intervals (CI) for the association between intake of B vitamins, methionine, and alcohol, and cancer risk. All dietary variables were adjusted for total energy intake, using the residuals method . For theald test . As earl−1 (the median intake among drinkers), ⩾6.6 g day−1); folate ; thiamin ; riboflavin ; niacin ; and methionine . We examined the statistical significance of the HRs in the resulting 3 × 3 tables. Tests for interaction were based on the likelihood ratio tests comparing models with and without the product terms representing the variables of interest as continuous variables. The likelihood ratio test that all of the interaction parameters were 0 was performed by referring 2* the absolute difference in the log likelihoods of the models with and without the interaction terms to the χ2 distribution with 1 degree of freedom. All statistical significance tests were two-sided. All analyses were performed using SAS version 9 .We further examined potential effect modification between nutrients by creating combined variables for each combination of two nutrients categorised into tertiles relative to the reference group containing women in the lowest tertile of both nutrients (HR=1.0). For example, women with low folate/moderate thiamine, moderate folate/moderate thiamin, high folate/moderate thiamin, and so on, were compared with women with low folate/low thiamin. Cutpoints for tertiles were: alcohol , followed by folate and thiamin (r=0.49), riboflavin and methionine (r=0.47), and intake of folate and riboflavin (n=0.43). Intakes of B vitamins and methionine were inversely but weakly correlated with alcohol consumption.Correlations between the B vitamins, methionine, and alcohol are shown in None of the B vitamins or methionine was associated with risk of breast cancer, whereas alcohol intake showed a weak, borderline positive association: the HR for those consuming 30+ g of alcohol per day was 1.17, 95% CI 0.98–1.39 . ResultsNone of the B vitamins, methionine, or alcohol was associated with risk of endometrial cancer . The resP=0.05 . There were no significant interactions between nutrients, or between nutrients and alcohol intake, and colorectal cancer risk.The B vitamins, methionine, and alcohol were not associated with colorectal cancer risk  or with P=0.08  but not with total folate intake ; however, a large study of folate intake and colorectal adenoma  with each other . FurtherStrengths of the present study include large numbers of the five cancers, the high level of completeness of follow-up of the cohort, and the availability of baseline information on a wide range of lifestyle exposures. In the case of breast cancer particularly, the large sample size afforded good statistical power to detect associations in subgroups and interactions. Limitations include the fact that we only had exposure information obtained at baseline and that dietary patterns, and hence intake of specific nutrients, may have changed over the long follow-up period, leading to misclassification of exposure and reduced power to detect associations. Another limitation is that the FFQ, with 86 food items, may have omitted foods that make a substantial contribution to the nutrients that we focused on. Furthermore, information on use of these vitamins as supplements was not obtained in this study. Finally, intake of other vitamins and nutrients, such as vitamin B-6, vitamin B-12, choline, and betaine, which play a role in one-carbon metabolism and may influence cancer risk (In conclusion, the present study provides little evidence for associations between dietary intake of folate, thiamin, riboflavin, niacin, or methionine and risk of cancers of the breast, endometrium, ovary, colorectum, or lung. However, given the potential role of these vitamins and nutrients in carcinogenesis and particularly given the paucity of studies to date regarding intake of thiamin, riboflavin, and niacin and the risk of epithelial cancers, further investigations are warranted.