Earlier work describes a modest association between cholecystectomy and the risk of colorectal cancer. We conducted a prospective study of 85 184 women, 36–61 years old, who had no history of cancer to evaluate whether known risk factors for colorectal cancer, including dietary history, that have not been controlled for in previous analyses can help explain the observed association. During 16 years of follow-up, 877 cases of colorectal cancer were documented and 1452 women who underwent endoscopy during the follow-up time were diagnosed with distal adenomas. After adjustment for age and other known or suspected risk factors, we found a significant, positive association between cholecystectomy and the risk of colorectal cancer . The risk was highest for cancers of the proximal colon  and the rectum . However, we did not observe a significant association between cholecystectomy and distal colorectal adenomas. In this large prospective cohort study, a history of cholecystectomy appears to increase modestly the risk of colorectal cancer, even after adjustment for other colorectal cancer risk factors. More than 60 epidemiologic studies have investigated a possible relation between cholecystectomy and colon cancer risk. However, the strength of any association remains uncertain because of the small size and retrospective design with a failure to control for potential confounders of most analyses. A meta-analysis of studies conducted through 1993  and cholecystectomy  in 1982. This information was updated biennially for gallstones until 1986 and for cholecystectomy until 1998. Other questions relevant to the association between cholecystectomy/gallstones and colorectal cancer provided information on the study participants' age, smoking history, height, weight, physical activity, aspirin use, menopausal status, postmenopausal hormone use, family history of colorectal cancer, and previous examination by colonoscopy or sigmoidoscopy and the indications of the procedure. In the 1980 semiquantitative food-frequency questionnaire, participants reported the average frequency of their consumption of specific foods and beverages and supplemental vitamins during the previous 12 months. The reproducibility and validity of these semiquantitative food-frequency questionnaires have been documented previously .We excluded nurses who had not answered the 1982 questionnaire. To control adequately for dietary factors, we further excluded women who left 10 or more items blank on the 1980 food-frequency questionnaire and women with implausibly high or low values for total energy intake. Women who reported previous cancer (except nonmelanoma skin cancer), ulcerative colitis, Crohn's disease, or a familial polyposis syndrome were also excluded. After these exclusions, 85 184 women remained eligible for follow-up from 1982 through 1998.in situ from the analysis. This left 877 cases of invasive colorectal carcinoma.For this analysis, the follow-up data were available for 96% of the total possible person-years through 1998. Most of the deaths in the cohort were reported by family members or the postal system in response to the follow-up questionnaire. In addition, we used the National Death Index, a highly sensitive method of identifying deaths among nonrespondents ; colorectal cancer in parent or sibling (yes or no); screening endoscopy during the study period (yes or no); consumption of beef, pork, or lamb as a main dish ; current alcohol consumption status ; quintiles of total energy intake, use of postmenopausal hormones ; menopausal status (yes or no); height in seven categories ; and diabetes (yes or no). For all factors, indicator variables were created for missing values and included in the analyses. We conducted stratified analyses to determine whether the influence of a history of cholecystectomy was modified by other risk factors for colorectal cancer. Tests for the homogeneity of risk estimates across strata were based on a weighted sum of the squared deviations of the stratum-specific log-odds ratios from their weighted mean  as the measure of association, defining RR as the incidence of colorectal cancer among study women who reported a history of gallstones or cholecystectomy divided by the corresponding rate among the women who had no history of gallstones or cholecystectomy. Mantel Haenszel summary RRs were calculated, adjusting for age in 5-year categories . All stated mean .In 1982, a history of cholecystectomy was reported by 7. 7% of the 85 184 women who were eligible for analysis (14.9% by 1998). Women with a history of cholecystectomy were slightly older and slightly more likely to be postmenopausal than women without such a history (During 16 years of follow-up (1 308 490 person-years), 877 women were diagnosed with colorectal cancer. Among these 877 participants with colorectal cancer, 195 (22.2%) had previously reported a history of cholecystectomy.In age-adjusted and multivariate analyses based on 16 years of follow-up, a history of cholecystectomy was positively associated with the risk of colorectal cancer  1.01–1.46). This risk associated with cholecystectomy was greater for proximal colon and rectal cancers . We analysed the relation between a history of cholecystectomy as assessed in 1982 and the risk of colorectal cancer from 1988 through 1996. Despite the 6-year latency period, a history of cholecystectomy was associated with a similar increase in the risk of colorectal cancer .vs RR 1.19, 95% CI 0.96–1.46, respectively).To evaluate possible distortions of our findings by higher rates of screening endoscopy among women who reported a history of cholecystectomy, we repeated our analysis after stratification according to whether or not women had undergone screening endoscopy during the study period. Among women who had undergone screening endoscopy, the risk of colorectal cancer associated with gallstones or cholecystectomy was not significantly different when compared to women who had not undergone screening .We further investigated the possibility that the excess risk of colorectal cancer associated with cholecystectomy was the result of a detection bias caused by closer surveillance of people with a history of gallstones or cholecystectomy. When we excluded from the analysis women whose cancer may have been detected incidentally or only by screening (Duke's stages A and B) and restricted the outcome to more advanced lesions, the RR for colorectal cancer was not materially altered .We assessed the relation between cholecystectomy and the risk of distal colorectal adenomas among 26 005 women who reported having undergone colonoscopy or sigmoidoscopy between 1982 and 1996. There was no elevation of risk for distal colorectal adenoma with a history of cholecystectomy, even when we restricted our analysis to women who had undergone endoscopy before 1982 and were found at that time to be free of polyps (P=0.02).Finally, we examined the relation between the time since cholecystectomy and the risk of both colorectal cancer and distal colorectal adenomas  and rectum . We did not, however, observe the same association between gallstones or cholecystectomy and distal colorectal adenomas. We did detect a slight nonsignificant increase of risk according to time interval between cholecystectomy and cancer of the rectum in this cohort, as well as a significant trend for rectal adenomas with increasing time following a cholecystectomy.Abnormal bile acid metabolism may facilitate the development of gallstones and may also increase the risk of colon cancer. The composition of bile acid is altered among patients who have undergone a cholecystectomy, with a high portion of secondary bile acids in their pool  for women with 15+ and 24+ years, respectively, since cholecystectomy. No significant trend was seen in the third study (Prior evidence for the hypothesis that a history of gallstones or cholecystectomy is related to the risk of colorectal cancer has been inconclusive. A meta-analysis of five either small (Fewer studies have examined the influence of cholecystectomy or gallstones on the risk of colorectal adenomas. The prospective nature of our study precluded recall bias and the need of next-of-kin respondents. It is therefore unlikely that our results were due to biased assessment of a history of gallstones or cholecystectomy or colorectal cancer and adenomas. Moreover, to avoid misclassification of exposure, we updated reports of cholecystectomy and gallstones biennially. Differential follow-up is unlikely to have had a material influence, since follow-up was nearly complete for both fatal and nonfatal end points. Furthermore, the identification of deaths is highly accurate in this cohort (Residual confounding remains yet another possible explanation for the positive association between gallstones or cholecystectomy and colorectal cancer risk, and may have explained the positive findings in prior studies. However, in the current study, the association with rectal, proximal colon, or total colorectal cancer was not altered after adjustment for known or suspected risk factors for colorectal cancer. We further stratified the analyses by screening endoscopy and did not observe any substantial differences in the relation between gallstones/cholecystectomy and colorectal cancer.In conclusion, our study demonstrates a modest though statistically significant increased risk of colorectal cancer following gallstones or cholecystectomy, even after adjusting for other known or suspected risk factors for colorectal cancer. Consistent with other studies the risk appeared slightly greater for cancers of the proximal colon and rectum. We therefore cannot refute the hypothesis that a history of gallstones or cholecystectomy may promote colorectal carcinogenesis.


Epidemiological evidence suggests that breastfeeding protects against breast cancer. Whether an effect of age at first breastfeeding is independent of an effect of age at first birth is unclear. We hypothesized that nausea and vomiting in pregnancy, which are associated with elevated serum oestradiol levels during pregnancy, may increase risk. Cases were 452 parous, premenopausal women, 40 years or younger, diagnosed with breast cancer in Los Angeles County from July 1983 to December 1988. Control subjects were matched to cases on age, race, parity and neighbourhood. Pregnancy and breastfeeding histories were obtained from in-person interviews. Odds of breast cancer among women who breastfed for at least 16 months relative to those among women who did not breastfeed was 0.66 [95% confidence interval (CI) 0.41-1.05]. Number of children breastfed was not associated with risk. Risk was lower in women who first breastfed at older ages. Having ever been treated for nausea or vomiting during pregnancy was associated with an increased risk, especially in women experiencing recent pregnancies . These results support a protective role of breastfeeding and an adverse role of nausea or vomiting during pregnancy in the development of premenopausal breast cancer, especially in the years immediately following pregnancy.


Assessments by the handful of prospective studies of the association of serum antioxidants and breast cancer risk have yielded inconsistent results. This multiethnic nested case-control study sought to examine the association of plasma carotenoids, retinol, and tocopherols with postmenopausal breast cancer risk.From the biospecimen subcohort of the Multiethnic Cohort Study, 286 incident postmenopausal breast cancer cases were matched to 535 controls on age, sex, ethnicity, study location , smoking status, date/time of collection and hours of fasting. We measured prediagnostic circulating levels of individual carotenoids, retinol, and tocopherols. Conditional logistic regression was used to compute odds ratios and 95% confidence intervals.Women with breast cancer tended to have lower levels of plasma carotenoids and tocopherols than matched controls, but the differences were not large or statistically significant and the trends were not monotonic. No association was seen with retinol. A sensitivity analysis excluding cases diagnosed within 1 year after blood draw did not alter the findings.The lack of significant associations in this multiethnic population is consistent with previously observed results from less racially-diverse cohorts and serves as further evidence against a causal link between plasma micronutrient concentrations and postmenopausal breast cancer risk. An expert panel recently concluded that an inverse association of carotenoids with breast cancer risk is possible because of their antioxidant properties , but metThe study population included participants in the biospecimen subcohort of the Multiethnic Cohort Study ,6. BriefMicronutrient analyses included prediagnostic blood from 334 postmenopausal women with breast cancer identified through linkage with Hawaii and California cancer registries through 2006. Two control individuals for each case were randomly chosen from the women in the biospecimen subcohort who were alive and free of breast cancer at the age of the case's diagnosis, and who matched the case on birth year (± 1 year), race/ethnicity, location , date (± 6 months) and time (± 2 hours) of blood draw, fasting hours (8 to < 10 hours and 10+ hours), and hormone therapy use (current versus not current). Plasma concentrations of carotenoids, retinoids, and tocopherols were determined by high-pressure liquid chromatography with photodiode array detection from our earlier protocol ,8, with The Multiethnic Cohort Study and the nested case-control study from the biospecimen subcohort were approved by the Institutional Review Boards of the University of Hawaii and the University of Southern California. Cohort participants provided informed consent for both studies.Conditional logistic regression, with matched sets as strata, was used to compute odds ratios and 95% confidence intervals. Biomarker variables were categorized into quartiles based on the distribution of cases and controls in order to optimize the distribution of cases and controls in each of the strata of interest so that none of the cells had overly small numbers of subjects. A trend variable for each biomarker was created by assigning the median value of the appropriate category. Aside from matching variables, the full models were adjusted for the following established breast cancer risk factors [Only matched sets that included one case and at least one control with no missing data on plasma micronutrients or any of the adjustment variables were retained in these analyses, resulting in a study population of 286 cases and 535 controls. Cases were similar to controls for most baseline characteristics, except that cases were more likely to be former or current smokers and ever drinkers than controls Table .Pinteraction = 0.17) between smoking and circulating carotenoids on risk; nor was there evidence that other variables modified the micronutrient-breast cancer risk association. A sensitivity analysis excluding cases diagnosed within 1 year after blood draw did not alter the findings.Women with breast cancer tended to have lower levels of plasma carotenoids and tocopherols than matched controls, but the differences were not large or statistically significant and the trends were not monotonic Table . When stThe present case-control study – nested within a large prospective cohort – does not support an association of plasma carotenoids, retinol, or tocopherols with postmenopausal breast cancer risk.The observation of a lack of an association between breast cancer risk and plasma tocopherols and retinol mirrors what has been seen in recent prospective studies ,10-13. APinteraction = 0.10) [The suggested inverse association of carotenoids with breast cancer risk limited to ever smokers, observed in our study, is biologically plausible as cigarette smoke contributes to oxidative stress and a reduction in plasma carotenoids . Accordi = 0.10) ; the oth = 0.10) ,18.Limitations to the current study include the use of only one measure to assess exposure, the possibility that the exposure was not assessed during the relevant time period, a relatively short follow-up time, and the inability to stratify by tumor characteristics. These limitations would most probably bias the risk estimates toward the null. We were also unable to assess whether the associations we observed with carotenoids were due to factors other than a high consumption of fruits and vegetables that are also related to a healthy lifestyle. We did, however, adjust for maximum years of education obtained, and saw no significant changes in the results. The study is strengthened by its multiethnic population, which had similarly high levels of antioxidants, including carotenoids, as those reported in the Nurses' Health Study . These lThe lack of significant associations in the present multiethnic population is consistent with previously observed results from less racially-diverse cohorts and serves as further evidence against a causal link between plasma micronutrient concentrations and postmenopausal breast cancer risk.The authors declare that they have no competing interests.All of the authors made substantial contributions to the study concept and design or analysis and interpretation of the data. Specifically, ME designed the analysis, analyzed the results, and was the primary author of every section of the text. YBS aided in the design of the analysis and performed much of the initial statistical analyses. LRW helped to design the study's analytic strategy and prepare the Materials and methods section of the text. AAF and RVC carried out the micronutrient assays. LLM, BEH, and LNK were instrumental in the design of the study, and commented on and approved the manuscript. MTG originally conceived of the study and helped to draft the manuscript.


P-value for trend=0.01); the multivariate rate ratio (RR) for the comparison of three or more servings of vegetables per day with one or fewer servings per day was 0.61 , 0.38–0.97). For fruit consumption a modest, not statistically significant, positive association was found ; the multivariate RR for the highest compared with the lowest category of consumption being 1.37 . The associations with fruit and vegetable consumption did not vary by subtype of ovarian cancer. These findings suggest that high consumption of vegetables, but not of fruits, may reduce the risk of ovarian cancer.We prospectively examined the incidence of epithelial ovarian cancer and its subtypes in relation to baseline fruit and vegetable consumption in the Swedish Mammography Cohort, a population-based cohort study of 61 084 women aged 38–76 years in 1987–1990. During an average follow-up of 13.5 years, 266 incident cases of invasive epithelial ovarian cancer were diagnosed. After adjustment for potential confounders, we observed a statistically significant inverse association between consumption of vegetables and ovarian cancer risk ( As for many other cancers, high consumption of fruit and vegetables is supposed to reduce the risk of ovarian cancer. In addition to being a major source of dietary vitamin C, folate, and fibre, fruits and vegetables also contain numerous other potentially anticarcinogenic phytochemicals . The majWe have therefore examined overall fruit and vegetable consumption as well as consumption of specific fruits and vegetables in relation to total ovarian cancer incidence and its subtypes in a large prospective population-based cohort of Swedish women.The Swedish Mammography Cohort is an ongoing population-based prospective study of 66 651 women who were 38–76 years of age and living in Uppsala and Västmanland counties in central Sweden when they responded to a mailed questionnaire in 1987–1990. The questionnaire sought information on diet, parity, age at first birth, family history of breast cancer, education level, weight, and height. Data on age at menarche, age at menopause, and use of exogenous hormones were received only from women in Uppsala County at the time of their mammography examination. In 1997, all surviving participants were mailed a follow-up questionnaire that inquired about age at menarche, age at menopause, and history of oral contraceptive and postmenopausal hormone use. This study was approved by the Ethics Committees at the Uppsala University Hospital  and the Karolinska Institutet .In the current analysis, we excluded women with inadequate dietary data , women with a previously diagnosed cancer (other than nonmelanoma skin cancer). Furthermore, by linkage with the Swedish Inpatient Register, we identified and excluded all women who had a bilateral oophorectomy or a hysterectomy with unknown number of ovaries removed before baseline. After these exclusions, a total of 61 084 women remained for this analysis.The self-administered food-frequency questionnaire covered 67 food items over the past 6 months. Participants chose from among eight possible responses, ranging from never/seldom to four or more times per day. We used age-specific  portion sizes that were based on mean values obtained from 213 randomly chosen women from the study area whose food intake for 5922 days was weighed and recorded . Nutrient intakes were computed by multiplying the consumption frequency of each food item by the nutrient content per serving, using composition values obtained from the Swedish National Food Administration Database  and estimates from the questionnaire ranged from 0.4 to 0.6 for individual fruit items and from 0.2 to 0.5 for individual vegetable items.Incident cases of invasive epithelial ovarian cancer were identified by linkage of the study population with the national Swedish Cancer Registry (from March 1987 to 31 December 1997) and the Regional Cancer Registry in the study area (from 1 January 1998 to 30 June 2003). Follow-up of the cohort through these registries is estimated to be 98% complete . Deaths P-values are based on two-sided tests.For each participant, person-years of follow-up accrued from the entry to the cohort (i.e. the date of mammography screening) and ended at the date of diagnosis of ovarian cancer, of a bilateral oophorectomy or a hysterectomy with unknown ovaries removed, of death, of migration out of the study area, or the end of the follow-up period (30 June 2003), whichever came first. Participants were grouped into categories of fruit and vegetable consumption, and age-specific incidence rates of ovarian cancer were calculated by dividing the number of incident cases by the number of person-years in each category. Rate ratios (RRs) of ovarian cancer were computed as the incidence rate in a specific category as compared with that for the reference category (i.e. the lowest consumption category). The data met the assumptions for using Cox's proportional-hazards modelling, and we used this method to estimate RRs ), controlled for age at baseline, body mass index, educational level, parity, use of oral contraceptives, fish consumption, and dietary lactose intake. We also assessed the potential confounding by age at menarche, age at first birth, age at menopause, postmenopausal hormone use, and family history of breast cancer. However, as adjustment for these variables did not appreciably alter the results, we omitted them from the final multivariate model. We performed tests for trend across categories by assigning the median value to each category and modelling this variable as a continuous variable. All reported Among 61 084 women followed for an average of 13.5 years (823 572 person-years), a total of 266 women were diagnosed with invasive epithelial ovarian cancer, including 125 serous cancers, 48 endometrioid cancers, and 21 mucinous cancers; 72 cancers were of other histologic subtypes or could not be classified. Baseline characteristics of the cohort by categories of consumption of total fruit and total vegetables are shown in Table 1−1) compared with the lowest (⩽1 serving day−1) category of consumption was 0.61  (Table 2vs the lowest category)  compared with those who consumed less than two servings per day (data not shown). When we examined total vegetables and total fruits separately, a significant inverse association was observed between consumption of vegetables and risk; the multivariate RR for the highest  and for nonserous  histologic subtypes of ovarian cancer, and were consistent across subgroups defined by age, body mass index, parity, and use of oral contraceptives (data not shown). The results were essentially unaltered after omitting cases diagnosed during the first 2 years of follow-up (data not shown).The association of consumption of fruits and vegetables with risk was similar for serous (In this large population-based prospective cohort study, we found no association between overall fruit and vegetable consumption and ovarian cancer risk. Nonetheless, a high consumption of vegetables was associated with a significantly lower ovarian cancer incidence, even after controlling for potential risk factors. For each daily serving increase in vegetable consumption, the risk decreased by 10%. We found no evidence for a reduction in ovarian cancer risk associated with high fruit consumption and, if any, the evidence was for a positive rather than an inverse association.Only two previous prospective cohort studies – the Iowa Women's Health Study (All four case–control studies on total vegetable consumption and ovarian cancer risk have reported an inverse association  and one The strengths of this study are its population-based design, its large size, and the virtually complete case ascertainment through the Swedish Cancer Register system. In addition, the prospective nature of this study avoided recall and selection biases.A potential limitation of any observational study is that dietary assessment is inevitably subject to measurement error. However, because our data were gathered before the diagnosis of ovarian cancer, misclassification would be expected to be nondifferential between cases and noncases and would tend to attenuate any true relationship. The somewhat limited number of fruit items listed on the food-frequency questionnaire probably resulted in some degree of measurement error, but this should not be related to disease status and only make our RR estimates conservative. Although we adjusted for a wide range of potential confounders, the possibility of unmeasured confounding or residual confounding cannot be entirely excluded.In conclusion, findings from this population-based prospective cohort study suggest that a high consumption of vegetables, but not of fruits, may reduce the incidence of ovarian cancer. Our results along with a recent systematic review on fruit and vegetables by the


Women who have inherited mutations in the BRCA1 or BRCA2 genes have substantially elevated risks of breast and ovarian cancer. Mutation carriers have various options, including extensive and regular surveillance, chemoprevention and risk-reducing surgery. The aim of this review is to provide an up-to-date analysis and to subsequently summarise the available literature in relation to risk-reducing strategies, with a keen focus on prophylactic surgery.The literature review is facilitated by Medline and PubMed databases. The cross-referencing of the obtained articles was used to identify other relevant studies.Prophylactic surgery  has proved to be the most effective risk-reducing strategy. There are no randomised controlled trials able to demonstrate the potential benefits or harms of prophylactic surgery; therefore, the evidence has been derived from retrospective and short follow-up prospective studies, in addition to hypothetical mathematical models.Based on the current knowledge, it is reasonable to recommend prophylactic oophorectomy for BRCA1 or BRCA2 mutation carriers when childbearing is completed in order to reduce the risk of developing breast and ovarian cancer. In addition, women should be offered the options of rigorous breast surveillance, chemoprevention with anti-oestrogens--especially for carriers of BRCA2--or bilateral prophylactic mastectomy.The selection of the most appropriate risk-reducing strategy is not a straightforward task. The impact of risk-reducing strategies on cancer risk, survival, and overall quality of life are the key criteria considered for decision-making. Notably, various other factors should be taken into consideration when evaluating individual mutation carriers' individual circumstances, namely woman's age, morbidity, type of mutation, and individual preferences and expectations.Although prospective randomised controlled trials concerned with examining the various interventions in relation to the woman's age and type of mutation are needed, randomisation is extremely difficult and rather deemed unethical given the current available evidence from retrospective studies. Breast cancer remains the leading cause of death in women aged 40-55 years. SporadiHistologically, BRCA1-related breast cancers are predominantly of the basal subtype, with predominant lymphocytic infiltration, and are often more aggressive and associated with negative prognostic factors, as characterised by numerous mitoses, pleomorphic pattern, poor differentiation and higher proliferation rates -11, as wClinically, breast cancer is believed to begin at an earlier age in BRCA1 and BRCA2 gene mutation carriers compared with sporadic cases. The median age of breast cancer onset ranges from 40-50 years in BRCA1 and BRCA2 carriers compared with 60-70 years in sporadic cases,19. Furtet al., for example, recently conducted a meta-analysis of 11 previously published articles [Several studies have suggested no significant differences between BRCA-associated breast cancer and non-BRCA associated breast cancer in relapse-free, event-free, and overall survival -24. On tarticles . The anaet al. observes that short-term progression-free survival in BRCA1 carriers was worse than in non-BRCA carriers (HR = 1.54). Such observations were not witnessed in long-term progression survival. In addition, BRCA2 mutation was not observed to affect either short- or long-term survival rates, which may be attributed to the different carcinogenic pathways for BRCA1 and BRCA2 [Moreover, Lee nd BRCA2 .et al. suggest that peritoneal papillary serous carcinoma risk amongst BRCA2 carriers is lower than amongst BRCA1 carriers[Most ovarian cancers associated with germ line BRCA mutations are diagnosed at a younger age and are ultimately determined as high-grade and advanced-stage serous carcinomas. They ha carriers. Further carriers. Notably carriers, and adv carriers.The identification of BRCA1 and BRCA2 genes in 1994 and 1995 respectively,35 has hWomen who have an increased risk of breast and ovarian cancer are advised to consider risk-reducing strategies; however, such methods vary in their effectiveness. These strategies include surveillance , trans-vaginal ultrasound scanning and serum CA125), chemoprevention and prophylactic surgery ,39. Risk25, chemoThe aim of this review is to provide an up-to-date analysis and to subsequently summarise the available literature in relation to risk-reducing strategies, with a keen focus on prophylactic surgery.MEDLINE and PubMed were used to search for relative articles. Articles identified using the key words "breast cancer", "BRCA1", "BRCA2", "ovarian cancer", "risk reducing", "prophylactic", "mastectomy", "oophorectomy" and "life expectancy". Cross referencing was performed to identify other articles not identified at the initial search.The efficacy of surveillance in BRCA1/2 mutation carriers is difficult to determine. Importantly, it has been suggested that some BRCA1/2 carriers will not develop cancer during their lifetime, althougImportantly, annual ovarian surveillance--conducted by pelvic examination, trans-vaginal ultrasound scanning and serum CA125 measurement--in women at increased familial risk of ovarian cancer is found to be ineffective in detecting tumours at a sufficiently early stage, which substantially influences survival in BRCA1/2 mutation carriers-52. SeruIt is well recognised that oestrogen plays an essential role in mammary carcinogenesis by exerting a carcinogenic effect (through metabolites) on cellular DNA and thereby promoting the growth of ER positive breast cancer. TherefoProphylaxis with SERMs was estimated to prolong survival by 1.6 to 2.2 years in BRCA gene mutation carriers. The ablTargeting oestrogen synthesis is considered to be an alternative to SERMs as a chemo-preventative risk-reducing strategy in high-risk women. Aromatase inhibitors (AIs) have been shown to be superior to Tamoxifen in the treatment of ER-positive breast cancer and the prevention of contralateral breast cancer in postmenopausal women with fewer side effects. It is likely that AIs will have a prophylactic role to play in BRCA gene carriers who opt to have prophylactic oophorectomy (PO) and breast surveillance. However, this potential role requires further evaluation through prospective controlled trials, with the inclusion of quality of life issues and skeletal complications as secondary endpoints.Based on the knowledge that the risk of ovarian cancer and mortality is reduced by 50% and 80% respectively in long-term users of oral contraceptive pills (OCPs),62, OCPsThe non-specific action of existing DNA damage reagents poses a problem regarding chemoprevention in BRCA women. Such agents have been found to cause a similar extent of damage in both BRCA1 mutant and wild-type cells. The recent discovery that PARP-1 inhibitors kill BRCA1/2 deficient cells with a high level of specificity subsequently opens up a potential therapy which looks very hopeful for BRCA1 cancer patients. A number of studies have illustrated that BRCA1/2 pre-cancerous cells are very sensitive to PARP inhibition, whilst cancer cells exhibit different responses to PARP inhibition under a variety of different conditions. Furthermore, it has been suggested that these differences in PARP sensitivity can be attributed to distinct phases in BRCA associated tumorigenesis. Work conducted by De Soto & Deng demonstrRisk-reducing surgery in BRCA1/2 gene mutation carriers includes prophylactic bilateral salpingo-oophorectomy (PBSO) and/or prophylactic bilateral mastectomy (PBM). The aim of surgery is to reduce the risk of cancer development and to reduce mortality.Notably, extensive counselling should be offered to all women who consider prophylactic surgery, including a detailed explanation of the cancer risk, complications associated with surgery, aesthetic outcome, quality of life issues, and potential life expectancy gain. The decision to proceed with prophylactic surgery is largely patient-driven depending on whether the patient feels comfortable living with the estimated risk and how she values the psychosexual function of the breast and ovaries. It is observed that many women who undergo BRCA testing use these results to make clinical decisions; those who choose risk-reducing surgeries typically do so within months of receiving BRCA-positive results. Predictors of risk-reducing surgery uptake include age below 60 years, prior breast cancer, and utilisation of another risk-reducing surgery.Since the establishment of the link between breast and ovarian cancers and BRCA1/2 genes mutations, in addition to the increasing availability of genetic testing, research groups were faced with many questions concerning the efficacy and usefulness of risk-reducing surgery. Earlier studies have more keenly focused on decisions concerning whether or when to undergo prophylactic surgery. The magnitude of the potential benefit fundamentally depends on the risk of cancer associated with specific mutations, the prognosis of the tumours in carriers of the mutations, and the extent to which relief of anxiety could result from surgical prophylaxis. These benefits were to be weighed against an array of potential costs, including surgical complications and the potential impacts of mastectomy or oophorectomy on a woman's self-image, as well as on their sexual and reproductive function.There are no randomised controlled trials which have previously examined the potential impacts of PBM on survival; therefore, evidence has been derived from retrospective and short follow-up prospective studies in addition to hypothetical mathematical models with variable estimates.et al., it was concluded that a 30-year-old BRCA1/2 positive woman could prolong her survival by 0.9 years  by having bilateral oophorectomy, 3.4 years (2.7-3.7 years) by having bilateral mastectomy, and 4.3 years (3.6-4.6 years) by having both procedures compared with surveillance alone. Chemoprevention with Tamoxifen and raloxifene was estimated to increase survival by 1.6 years (1.0-2.1 years) and 2.2 years (1.3-2.8 years), respectively. These findings suggest that prophylactic surgery is associated with substantial survival benefits[et al. [Earlier studies have utilised the Markov model, which w benefits,68. Othe benefits. Furthers[et al. ; howeverFurthermore, in the case of carriers of BRCA1/2 mutations who subsequently developed breast cancer, it was found that, with the use of the Markov model and depending on the assumed penetrance of the BRCA mutation, probabilities associated with developing contra lateral breast cancer and ovarian cancer, dying from these cancers, dying from primary breast cancer, and the reduction in cancer incidence and mortality due to prophylactic surgeries and compared with surveillance alone, 30-year-old early-stage breast cancer patients with BRCA mutations showed a gain in life expectancy of approximately 0.4 to 1.3 years from Tamoxifen therapy, 0.2 to 1.8 years from PO, and 0.6 to 2.1 years from prophylactic contralateral mastectomy (PCM). The magnitude of these gains is believed to be least for those women with low-penetrance mutations  and greatest for those with high-penetrance mutations . Notably, older age and poorer prognosis from primary breast cancer further attenuate such gains . UndoubtIn recent years, a few cohort and case control studies have considered the effectiveness of prophylactic surgery. However, it is of great importance to mention that they differ in quality, with some having significant methodological flaws--mainly owing to selection bias and retrospective study design.et al., 483 women with BRCA1/2 mutations were studied. After a mean follow-up of 6.4 years, breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy, and in 184 (48.7%) of 378 matched controls who did not have the procedure. The group therefore subsequently concludes that BPM reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%[Prophylactic bilateral mastectomy reduces the risk of breast cancer in BRCA mutation carriers by 85%-100%-74. In aately 90%. Similarately 90%.It is accepted that no surgical technique for prophylactic mastectomy removes all breast epithelium; simple mastectomy removes approximately 95%-99% of breast glandular tissue; however, it causes a significant deformity, changes in body image and sexuality, as well as adverse effects on the psychosocial status of the affected woman, but not quality of life. MoreoveSkin sparing mastectomy and immediate breast reconstruction (SSM & IMR) has been proved to be oncologically safe, and is associated with high satisfaction rate and low morbidity,80. MoreSince breast tumours are largely oestrogen-driven, it has been suggested that the hormonal blockade by oophorectomy inhibits the development of breast tumours. Importaet al. found that, during a 3-year follow-up, BPSO was associated with 85% reduction in BRCA1-associated gynaecologic cancer risk and 72% reduction in BRCA2-associated breast cancer risk. Although protection against BRCA1-associated breast cancer and BRCA2-associated gynaecologic cancer was suggested, neither effect reached statistical significance. The authors postulate that the protection conferred by PBSO against breast and gynaecologic cancers may differ between the carriers of BRCA1 and BRCA2 mutations[In a large, retrospective analysis of 551 BRCA carriers, BSO was found to have reduced the risk of ovarian cancer by 96% and breast cancer by 53% at a mean follow-up of 9 years. Similarmutations.Although several studies demonstrate that PBSO decreased the risk of both breast and ovarian cancers in BRCA1/2 mutation carriers-94, theset al. carried out a meta-analysis of ten studies which investigated breast or gynaecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone PBSO. The authors subsequently concluded that PBSO was associated with a statistically significant reduction in breast cancer risk amongst BRCA1/2 mutation carriers. Similar risk reductions were observed in BRCA1 mutation carriers and in BRCA2 mutation carriers. Furthermore, PBSO was associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer; however, data were deemed insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction. Moreover, PBSO was strongly associated with reductions in the risk of breast, ovarian, and fallopian tube cancers, and should provide guidance to women in planning cancer risk-reduction strategies[Recently, Rebbeck trategies.Furthermore, in a prospective study with a short-term follow-up, PBSO was associated with a 90% reduction in breast cancer-specific mortality, a 95% reduction in gynaecologic cancer-specific mortality, and a 76% reduction in overall mortality . Such daThis review paper provides an up-to-date analysis of our understanding of the advantages of risk-reducing strategies in BRCA carriers. Although the article summarises the evidence which suggests that different strategies are associated with varying degrees of cancer risk-reduction, such evidence is nevertheless derived from retrospective and short follow-up prospective studies in addition to hypothetical mathematical models. It is known that retrospective studies do not provide the highest level of evidence compared with randomised controlled studies; they are often less robust and usually carry a degree of bias. Furthermore, they tend not to be standardised in relation to confounding factors, such as patients' age, socio-economic class, and other factors.Currently, there are no randomised controlled trials concerned with the demonstration of the potential benefits or harms of prophylactic surgery. This is due to different factors, such as the small number of BRCA mutation carriers, which necessitate multiple centres to participate. Conducting a randomised controlled trial in multiple centres poses potential problems, namely a lack of standardisation, which is the main issue as different surgeons have different surgical risk-reducing techniques. Furthermore, in light of the currently available evidence from retrospective studies, randomisation is deemed unethical, and women may therefore opt for risk-reducing surgery rather than observation.Selecting the most appropriate risk-reducing strategy is not a straightforward task. The impact of risk-reducing strategies on cancer risk, survival, and overall quality of life are the key criteria considered for making a good decision. There is no sole risk-reducing strategy which is able to fully meet all expectations and requirements in an individual woman. On the one hand, non-surgical procedures provide a good body image and quality of life, but may be associated with increased risk of advanced-stage cancer and mortality; on the other hand, surgery ensures a very high protection from cancer but is associated with a number of disadvantages of invasiveness, non-reversibility and surgical morbidity.Based on the available literature, it is deemed appropriate to acknowledge that the clinical management of cancer risk in BRCA1 and BRCA2 mutation carriers is a rather complex and stressful task, which should consider individual patients' expectations and preferences. Such preferences can be informed by accurate knowledge of the risks and benefits of the interventions considered. Available studies confirm the essential role of PBSO in reducing the risk of both breast and ovarian cancer. Furthermore, other options for risk reduction should be considered, such as chemoprevention and risk-reducing mastectomy. AlthougIt is recommended that prophylactic surgery should be performed as soon as possible, simply because of the early development of cancer in BRCA mutation carriers. Although ovarian cancer rarely occurs in premenopausal women, it is advised that BRCA mutation carriers should undergo PBSO immediately after childbearing is complete in order to reduce the risk of early breast cancer development.Prospective randomised controlled trials examining the various interventions in relation to the woman's age and type of mutation are needed. However, the randomisation of BRCA carriers to different arms of trials is an extremely difficult and rather impossible process given the current available evidence.DCIS: Ductal carcinoma in-situ; MRI: Magnetic resonance imaging; SERMs: Selective oestrogen receptor modulators; AIs: Aromatase inhibitors; PO: Prophylactic oophorectomy; OCPs: Oral contraceptive pills; PBSO: Prophylactic bilateral salpingo-oophorectomy; PBM: Prophylactic bilateral mastectomy; PCM: Prophylactic contralateral mastectomy; SSM: Skin sparing mastectomy; IBR: Immediate breast reconstructionThe authors declare that they have no competing interests.MS performed literature search/review and manuscript writing. SB: helped in manuscript writing, KM involved in the concept, manuscript revision and writing. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/10/28/prepub


Familial breast cancers are known to be of early onset. This article provides differences in the age of onset of breast cancer and death by breast cancer between women with and without a family history.The Swedish Family-Cancer Database was used to estimate the cumulative risk of breast cancer and death by breast cancer according to family history with a stratified Cox model. Family history was defined separately for affected mother or sister considering their diagnostic ages.The age to reach the same cumulative incidence as women without family history decreased with decreasing diagnostic age of the affected relative. Women with a maternal history reached the risk of women lacking a family history at the age of 50 years between 12.3 (mother affected <40 years) and 3.3 years (mother affected >82 years) earlier. The trend for breast cancer mortality was essentially similar.Women with mother or sister affected by breast cancer are diagnosed and die at earlier ages than do women without family history. The differences depend on the diagnostic age of the affected relative. The present data may provide a rationale to derive recommendations for the starting age of screening in women with affected family members. A family history of female breast cancer is associated with an increase in the risk of breast cancer in first-degree female relatives by about two-fold, but the magnitude of risk depends on a number of factors, such as diagnostic age . AlthougThe aim of this study was to assess (1) the cumulative incidence and risk of death from breast cancer in women with a family history of breast cancer compared with those without a family history of breast cancer and (2) the impact of the relative's age at diagnosis on the diagnostic age. We used the nation-wide Swedish Family-Cancer Database to estimate the cumulative incidence of breast cancer and the cumulative risk of death by breast cancer in women with a family history of breast cancer, compared with those lacking a family history. Family history was defined separately for an affected mother or sister considering their diagnostic ages. The results may encourage appropriate future analysis to derive recommendations for the starting time of screening in women with an affected family member.The Swedish Family-Cancer Database was created in the 1990s by linking information from the Multigeneration Register, national censuses, Swedish Cancer Registry and death notifications . The 200Women with mother or sister affected by breast cancer were defined to be at familial risk. Here, the register-based definition of family history was used, that is, family history was defined independently of the maternal or sororal diagnostic date. Cumulative risks of breast cancer and death due to breast cancer according to family history were estimated using a stratified Cox model based on Tsiatis' method  PROC PH. In thisWomen with an affected mother and sister, and women with more than one affected sister were considered separately (data not shown). The numbers of women affected by breast cancer in these groups were small. For women with a mother and a sister affected, the ages to reach the same risk as the general population at the age of 50 and 40 years were 41.3 years : 39.2–43.1 years) and 32.8 years , respectively. The corresponding ages for women with two affected sisters were 42.3 years  and 25.8 years , respectively. The numbers of deaths in women with a mother and a sister affected (27) or with two affected sisters (12) were too small for a separate analysis.Our results provide initial data on the age of onset of familial cancer estimated with a large population-based data set. For example, if the general starting age of mammography screening is defined to be 50 years, our data show that the same cumulative risk is reached 9–12 years earlier for women with a mother or a sister affected by breast cancer before 40 years. According to previous recommendations, an earlier start of screening is not recommended for women with mother or sister who was affected older than 50 years. However, the present results indicated that these women are at an increased risk. The estimation of the age at which familial cases reached the risk of death in women without a family history permitted essentially identical conclusions, even though the results were based on a smaller numbers of events.The American Cancer Society recommends average-risk women begin mammography screening at the age of 40 years . In mostThe rationale of mammography screening is the reduction of mortality by breast cancer. As evidence of an impact of family history on the survival of breast cancer patients in general is lacking .BRCA1/2, taking cancer status and age of first- and second-degree relatives into account  seemed to have a minor function. Under the discussed limitations, the present data should encourage further analysis in order to derive evidence-based recommendations for the starting age of screening in women with a family history of breast cancer.


We have examined the relation of lactation, by total duration, with breast cancer risk among pre- and post-menopausal women. In a hospital-based case-control study conducted in Athens (1989-91), involving 820 patients with confirmed breast cancer and 795 orthopaedic patient controls and 753 hospital visitor controls, logistic regression was used to analyse the data controlling for demographic, nutritional and reproductive factors, including parity and age at any birth. Among post-menopausal women, there was no association between breastfeeding and breast cancer risk, but among premenopausal women those who has breastfed for > or = 24 months had an odds ratio of 0.50 . A reduction of the odds ration was also evident among premenopausal women who had breastfed between 12 and 23 months . In conjunction with several other recent reports these results support the hypothesis that breastfeeding of prolonged duration may reduce the risk of breast cancer among premenopausal women but not among post-menopausal women. The biology underlying this different effect remains unknown, and the practical implication of the finding is a marginal importance.


Epidemiological findings indicate that hormonal influences may play a role in the etiology of renal cell cancer (RCC). The possible effect of childbearing remains enigmatic; while some investigators have reported a positive association between number of births and renal cell cancer risk, others have not. A case–control study, nested within a nation-wide Fertility Register covering Swedish women born 1925 and later, was undertaken to explore possible associations between parity and age at first birth and the risk of renal cell cancer. Among these women a total of 1465 cases of RCC were identified in the Swedish Cancer Register between 1958 and 1992 and information on the number of live childbirths and age at each birth was obtained by linkage to the Fertility Database. For each case, five age-matched controls were randomly selected from the same register. Compared to nulliparous women, ever-parous women were at a 40% increased risk of RCC . The corresponding OR for women of high parity (five or more live births) was 1.91 (95% CI 1.40–2.62). After controlling for age at first birth among parous women, each additional birth was associated with a 15% increase in risk . The observed positive association between parity and renal cell cancer risk is unlikely to be fully explained by uncontrolled confounding, but warrants further evaluation in large studies, with allowance for body mass index.British Journal of Cancer (2002) 86, 1425–1429. DOI: 10.1038/sj/bjc/6600263www.bjcancer.comCancer Research UK© 2002  Cancer of the renal parenchyma, or renal cell cancer (RCC), represents about 80% of all kidney cancer cases in Sweden and is about twice as common in men than among women. Incidence rates in Sweden have tended to decrease among both men and women , during Experimental findings of oestrogen-induced renal cell carcinogenesis in animals  have proTo further examine this issue, we utilised a large population-based data set to explore possible associations between pregnancy and the risk of renal cell cancer among Swedish women.We merged data from two population-based Swedish registers, the Fertility Register and the Cancer Register, both updated through 1992, through a unique national registration number.The Fertility Register was originally based on women born between 1925 and 1960 who were resident citizens of Sweden in 1960. For these women, reproductive data  during the period 1943–1960 were collected retrospectively at the 1960 Census. Later birth cohorts of all Swedish women have been added continuously, with the women's births being recorded annually via vital statistics records. For the present study, the Fertility Register included almost 3.4 million live births recorded from 1943 to 1992 among approximately 2.4 million women born between 1925 and 1972. Based on a nation-wide reporting system of all births to women residing in Sweden, the quality of data concerning number and dates of birth is generally high . In the The Swedish Cancer Register started in 1958. All newly diagnosed malignant tumours must be reported to the Register separately by both the clinician and the pathologist or cytologist. Nearly 100% of all diagnosed cancers are recorded . Among rA nested case–control study was undertaken to evaluate possible associations between the recorded reproductive variables and RCC. For every case, five comparison women (controls) matched on year and month of birth were randomly selected among those in the Fertility Register. The controls had to be alive at the date of the diagnosis of the case and be residents of Sweden, without themselves having been diagnosed with kidney cancer. Controls were assigned an index date that was the same as the diagnosis date of their matched case. For both cases and controls, only pregnancies before the date of the diagnosis of the case (the index date for the control) were included in the analysis. Controls with more than nine births were excluded, leaving five case–control sets being matched 1:4.The statistical analyses used matched conditional logistic regression . AssociaMore than half of all renal cell cancers (59.9%) in women were diagnosed at age 50 or over , weight cycling, hypertension, and smoking habits. Furthermore, in our assessment, pregnancy histories on complications or outcomes such as spontaneous and induced abortions were not available.Of particular concern was the influence on our risk estimates by uncontrolled confounding by BMI. Childbearing is associated with a considerable increase in weight, usually followed by some degree of permanent weight-retention after delivery and lactation . Results3.3). In the present study, we found an estimated risk increase of 62% for women of parity 5+, relative to uniparous women. Taken together, these data provide evidence of an independent risk-modifying effect of parity on the risk of developing RCC, over and beyond the influence of BMI. This assumption is supported by the findings of the collaborative international study on renal cell cancer, where neither adjustment for smoking nor body mass index altered the estimates for parity (Thus, pregnancy-associated weight gain may have influenced the observed relation to parity. To indirectly assess the relative importance of parity and BMI, we obtained data from the Swedish Medical Birth Register, a population-based database that since 1992 records pre-pregnancy weight among expecting mothers. These data showed that pre-pregnancy BMI increased by an average of 3.3 units between a first and sixth pregnancy (Table 4We can only speculate about the biological mechanisms whereby childbearing could affect renal carcinogenesis. Pregnancy-associated hormonal changes, particularly high oestrogen levels, may act as promotors of malignant change by stimulating renal cell proliferation either directly or via paracrine growth factors . The proThe results of the present study are interesting because of both the highly regular trend between increasing parity and the risk of RCC, and the strength of the associations. Our observations appear unlikely to be fully explained by uncontrolled confounding and warrant further evaluation in large studies where detailed information on other risk factors for RCC and possible confounders also can be considered.


We assessed breast cancer risk in relation to weight at birth and adolescence. In-person interviews were completed with the biological mothers of women aged 45 years and younger who participated in the Shanghai Breast Cancer Study in 1996–98 . After adjustment for confounding, women who were 4000 g or more at birth were not at increased risk of breast cancer  relative to women whose birth weight was 2500–2999 g. Compared with women of average perceived weight at age 15 years, no relation was apparent for heavier than average weight based on maternal report  or self-report . Perceived adolescent weight and height did not modify the association of birth weight with breast cancer risk. These results suggest that weight early in life is not related to premenopausal breast cancer risk in this low-risk population.British Journal of Cancer (2002) 86, 84–88. DOI: 10.1038/sj/bjc/6600009www.bjcancer.comThe Cancer Research Campaign© 2002  Premenopausal breast cancer has been linked to high birth weight  or weighSince self-report of body size in early life is prone to misclassification, maternal report may be less subjective. Maternal report was available for two of the studies investigating breast cancer risk associated with birth weight  based on the number of incident breast cancer cases by age group reported to the Shanghai Cancer Registry from 1990 through 1993. Women who did not reside at the registered address at the time of the study were ineligible. A total of 1556 controls (90.4% of eligible controls) completed a standardized in-person interview. The remaining 166 potentially eligible controls (9.6%) refused to participate. Two women died prior to the interview and were excluded.The study was approved by relevant institutional review boards in Shanghai and the United States. Women were interviewed at hospitals (cases) or at home (cases and controls) by trained interviewers. The subject questionnaire collected information on demographic factors, reproductive and medical histories, family history of cancer, use of oral contraceptives and hormone replacement therapy, diet, physical activity, lifestyle factors, and adolescent and adult body size. Women were asked how their perceived weight and height compared with their peers at the ages of 10, 15 and 20. After completing the interview, women were weighed and had their standing and sitting height, and waist and hip circumferences measured. Information on exposures pertained to the period before an assigned reference date, the diagnosis date for breast cancer cases and a similar date for controls.The biological mothers of women the age of 45 and younger who resided in Shanghai provided detailed information about the subject's adolescent diet and body size, and about her pregnancy with the subject. In-person interviews were completed with the mothers of 296 cases and 359 controls (with respective response rates of 79.6 and 81.8%). Eight cases and nine controls were subsequently excluded because they were postmenopausal, resulting in 288 cases and 350 controls for this analysis.We used unconditional logistic regression to estimate the relative risk of breast cancer associated with weight at birth and adolescence while controlling for confounders . All varTable 1Table 2r=0.46, height r=0.59).The risks for breast cancer associated with maternal and subject perceptions of subjects' weight and height at the age of 15 separately and combined are shown in Table 3Table 4in utero may be a possible risk factor for subsequent breast cancer. In a study conducted in Greece, high birth weight was associated with high pregnancy estrogen levels   and their mothers  minimizes selection bias. We adjusted for known breast cancer risk factors, and evaluated the weight at birth and adolescence and breast cancer associations in conjunction with suspected effect modifiers of these relations. An additional strength of the study was the good agreement between maternal and subject reporting of adolescent body size. There are, however, some measurement errors, which may have attenuated the estimated odds ratios is this study.In summary, our study indicates that weight at birth and adolescence has little influence on breast cancer risk in Chinese women. These results suggest that weight early in life is not related to premenopausal breast cancer risk in this low-risk population. Future studies should assess these relations to clarify the role that weight early in life may play in breast cancer risk.


Neither oestrogen nor progesterone receptor status of the tumours materially influenced the association. These prospective findings suggest that approximately 10 mg of isoflavones per day, obtained in a standard serving of tofu, may have lasting beneficial effects against breast cancer development.We investigated the effects of soy isoflavone intake on breast cancer in a prospective study of 35 303 Singapore Chinese women enrolled during April 1993 to December 1998 in the Singapore Chinese Health Study. At recruitment, each subject was personally administered a validated semiquantitative food frequency questionnaire covering 165 food and beverage items. As of December 31 2005, 629 had developed breast cancer following an accumulation of 338 242 person-years. Using Cox regression and adjusting for age at interview, year of interview, dialect group, education, family history of breast cancer, age when periods became regular, parity, menopausal status, body mass index (BMI), n-3 fatty acid, and other covariates, we found breast cancer risk was reduced significantly in association with high soy intake. Relative to women with lower (below median) soy intake , women with higher (above median) intake showed a significant 18% risk reduction (relative risk (RR)=0.82, 95% confidence interval (CI)=0.70–0.97). This inverse association was apparent mainly in postmenopausal women , and was not observed in premenopausal women . Among postmenopausal women, the soy–breast cancer association was stronger in those above median BMI  than in leaner women . Duration of follow-up modified the soy–breast cancer association, the effect being twice as large among women with 10+  Of at least 28 detailed studies of soy and breast cancer risk published in English since 1990, 14 were in western populations with very low intake of soy (<1 mg of isoflavone per day) and in these, intake was unrelated to breast cancer risk , a cohort study of diet and cancer.The SCHS was a prospective investigation of the role of dietary factors in cancer aetiology  of plain tofu, 1 g of cooked foopei is equivalent to 3.8 g (42/11) plain tofu, and so on. The total soy intake for each subject was estimated as the summation of all soy foods expressed in units of plain tofu equivalent. In a dietary validation study of SCHS subjects, we found correlation coefficients of 0.63, 0.39, and 0.32 between the FFQ and a series of 24-h recalls for tofu, isoflavone, and soy protein, respectively. Furthermore, dietary intake of soy was statistically significantly correlated with urinary isoflavonoid . Histological, staging information, oestrogen receptor (ER), and progesterone receptor (PR) status on all breast cancer diagnoses were confirmed by manual review of the pathology reports and clinical charts.−2), menopausal status, and n-3 fatty acid intake were adjusted in the analysis. As adjusting for green tea intake, tobacco smoking (never and ever), alcohol intake , and history of diabetes left the results unchanged; we show results without these further adjustments. We conducted subgroup analyses of soy isoflavone intake and risk, stratified by menopausal status and examined the potential effect modification by including interaction terms for body size. We also investigated the effect of soy isoflavone intake by ER and PR status , and ER/PR status combined . P-value less than 5% are considered statistically significant and all P-values quoted are two-sided.Data were analysed using standard methods for cohort studies. We calculated person-years from the baseline questionnaire to the date of breast cancer diagnosis, death or December 31, 2005, whichever was sooner. Proportional hazards regression methods were used to examine the association between quartiles of isoflavone intake and breast cancer risk, measured by relative risks (RR) and their corresponding 95 percent confidence intervals (95% CI) in all subjects and among those postmenopausal at baseline. Relevant demographic factors including age (years) at recruitment, year of recruitment (1993–1998), dialect group , education , and established risk factors including age when period became regular , number of live births , body mass index  among women with above median soy intake  compared to those with lower intake . Results were unchanged after adjustment for intake of green tea, tobacco smoking, alcohol intake, and history of diabetes (data not shown). P=0.82), but was significantly inversely associated with risk in postmenopausal women with an adjusted RR for those above the median of 0.74 .The mean age of breast cancer patients at diagnosis was 62.0 years (standard deviation (s.d.) 8.2 years; range: 46–86 years). The mean interval between interview and diagnosis was 5.6 years (range: 1 month–12 years). P for interaction=0.29). The inverse association between soy intake and breast cancer was statistically significant in postmenopausal women with higher  BMI  but not in those below the median BMI value  . The twoThe protective effect of high soy intake was very clear and statistically significant among women with 10 or more years of follow-up  . High so−1), a degree of risk reduction compatible with the results that we found in a combined analysis of eight studies in Asian populations with soy intake . Of these, no association was found in three studies in populations with very low soy intake , one of the few non-Asian populations with moderate soy intake. The mean daily soy isoflavone intake was 2.9 mg among non-vegetarians and 10.2 mg among vegetarians, but only about 30% of the 37 643 cohort participants were vegetarians, limiting the investigation of this question  than women with lower BMI irrespective of menopausal status  was associated with a significant 18% reduction in breast cancer risk. Our results adds to the compelling results obtained from case–control studies on soy and breast cancer and suggest that the soy isoflavones may have lasting beneficial effects against breast cancer development. The level of soy isoflavones implicated to have benefit (∼10 mg isoflavones per day or one standard serving of tofu) is achievable even in populations that do not typically eat soy foods.


P-value for test of trend = 0.016), with diabetics diagnosed at least 10 years prior to diagnosis having a significant 50% increased risk. Those treated with insulin had risks similar to those not treated with insulin (odds ratio (OR) = 1.6 and 1.5 respectively), and no trend in risk was associated with increasing duration of insulin treatment. Cholecystectomy also appeared to be a risk factor, as well as a consequence of the malignancy. Subjects with a cholecystectomy at least 20 years prior to the diagnosis of pancreatic cancer experienced a 70% increased risk, which was marginally significant. In contrast, subjects with a history of duodenal or gastric ulcer had little or no elevated risk . Those treated by gastrectomy had the same risk as those not receiving surgery, providing little support for the hypothesis that gastrectomy is a risk factor for pancreatic cancer. A significant 40% reduced risk was associated with hay fever, a non-significant 50% decreased risk with allergies to animals, and a non-significant 40% reduced risk with allergies to dust/moulds. These associations, however, may be due to chance since no risk reductions were apparent for asthma or several other types of allergies. In addition, we observed significantly increased risks for subjects reporting a first-degree relative with cancers of the pancreas (OR = 3.2), colon (OR = 1.7) or ovary (OR = 5.3) and non-significantly increased risks for cancers of the endometrium (OR = 1.5) or breast (OR = 1.3). The pattern is consistent with the familial predisposition reported for pancreatic cancer and with the array of tumours associated with hereditary non-polyposis colon cancer. © 1999 Cancer Research CampaignIn a population-based case-control study of pancreatic cancer conducted in three areas of the USA, 484 cases and 2099 controls were interviewed to evaluate the aetiologic role of several medical conditions/interventions, including diabetes mellitus, cholecystectomy, ulcer/gastrectomy and allergic states. We also evaluated risk associated with family history of cancer. Our findings support previous studies indicating that diabetes is a risk factor for pancreatic cancer, as well as a possible complication of the tumour. A significant positive trend in risk with increasing years prior to diagnosis of pancreatic cancer was apparent (


Past studies have shown that women with abnormal cytology or epithelial cells in nipple aspirate fluid (NAF) have an increased relative risk (RR) of breast cancer when compared to women from whom NAF was attempted but not obtained (non-yielders). This study analyzed NAF results from a group of women seen in a breast clinic between 1970–1991 (N = 2480). Our analysis presented here is an aggregate of two sub-groups: women with questionnaire data (n = 712) and those with NAF visits beginning in 1988 (n = 238), the year in which cancer case information was uniformly collected in California.Cytological classification was determined for a group of 946 women using the most abnormal epithelial cytology observed in fluid specimens. Breast cancer incidence and mortality status was determined through June 2006 using data from the California Cancer Registry, California Vital Statistics and self-report. We estimated odd ratios (ORs) for breast cancer using logistic regression analysis, adjusting for age. We analyzed breast cancer risk related to abnormality of NAF cytology using non-yielders as the referent group and breast cancer risk related to the presence or absence of epithelial cells in NAF, using non-yielders/fluid without epithelial cells as the referent group.Overall, 10% (93) of the 946 women developed breast cancer during the follow-up period. Age-adjusted ORs and 95% confidence intervals (C.I.) compared to non-yielders were 1.4 (0.3 to 6.4), 1.7 (0.9 to 3.5), and 2.0 (1.1 to 3.6) for women with fluid without epithelial cells, normal epithelial cells and hyperplasia/atypia, respectively. Comparing the presence or absence of epithelial cells in NAF, women with epithelial cells present in NAF were more likely to develop breast cancer than non-yielders or women with fluid without epithelial cells .These results support previous findings that 1) women with abnormal epithelial cells in NAF have an increased risk of breast cancer when compared to non-yielders or women with normal epithelial cells in NAF and 2) women with epithelial cells present in NAF have an increased risk of breast cancer when compared to non-yielders or women who had NAF without epithelial cells present. Breast cancer is the second leading cause of cancer death in women in the United States . Of the Since 95% of breast tumors arise in the lining of the milk ducts, evaluation of these ducts might be a means of identifying abnormal cells that could progress to cancer. Past studies have shown that women with abnormal cytology in nipple aspirate fluid (NAF) have an increased relative risk (RR) of breast cancer when compared to women with normal cytology in NAF and non-yielders (women from whom NAF was attempted but not obtained) ,4. In adThis present study analyzed NAF results from a group of women seen by Dr. Otto Sartorius in his Santa Barbara breast clinic between 1970–1991. The purpose of this paper is to present the results of a historic prospective study determining 1) whether or not the type of epithelial cells present in NAF  influenced subsequent breast cancer development and 2) whether or not there was an increased risk of breast cancer development if epithelial cells were present in NAF, regardless of cytological category.Subjects were a cohort of 3,203 women seen by Dr. Otto Sartorius in his Santa Barbara breast clinic between 1970–1991. The women were self-referred or referred by physicians. Dr. Sartorius performed all NAF collection during this period of time and utilized one pathologist to determine cytological diagnoses for all specimens. NAF collection/classification information and covariate information  used in this analysis was abstracted from the subjects medical records by a team of registered nurses in Santa Barbara, California. Age was the only covariate information that could be consistently abstracted from the medical records. The Committee on Human Research of the University of California, San Francisco, and the Department of Defense (DOD) Human Subjects Research Review Board approved this study of human subjects.All women seen by Dr. Sartorius between 1970–1991 were eligible for inclusion in the study . Women who were diagnosed with breast cancer at initial visit with Dr. Sartorius or within six months of initial visit with Dr. Sartorius were excluded from the study. Women were also excluded who did not have NAF collection attempted by Dr. Sartorius.Beginning in October 2005, all women were mailed structured questionnaires and consent forms requesting information on personal and family history of breast cancer and reproductive factors associated with an increased breast cancer risk. After two mailings and no response we attempted to contact the women by telephone. Several methods were used to update the addresses of the non-responders, including requests to the California Department of Motor Vehicles (DMV), California Vital Statistics, and several internet search engines. A modified proxy questionnaire was sent to next-of-kin for subjects identified as deceased. Another source of information about breast cancer status was the California Cancer Registry (CCR), which did not uniformly begin collecting data on breast cancer cases in California until 1988. Follow-up ended in June, 2006.The final model (N = 946) is composed of women who were seen by Dr. Sartorius between 1970–1991  by completed questionnaire data and on 238 (25%) from linkage with the CCR database. The women with completed follow-up were between ages 16–87 at study entry, with a mean age of 42.6. Mean follow-up time was 20.7 years, the median was 20 years and the range was 0.10 to 35 years. The mean age at breast cancer diagnosis was 60.8 years with a range of 34–86. Seventy-five percent (714) of the cohort were non-yielders versus 24% (232) of women who produced fluid either with or without epithelial cells. As of June 2006, 93 of 946 (10%) women had developed breast cancer since enrollment in the study  and in the 45–54 year old age group, the number with breast cancer was only 6. Despite these small numbers, the trend was nearly identical to the original analysis combining all groups.Our findings are consistent with the findings of other recent studies and appear to confirm that women with cellular NAF have a higher risk of cancer than those with no NAF or NAF without epithelial cells -5. WrensThere were limitations involved in the conducting of this study. First, due to the inability to accurately track breast cancer cases prior to 1988, we were unable to use information from the cohort without questionnaire data prior to 1988. In addition, the women in the study were visiting a breast clinic and the majority presented with breast symptoms for evaluation. Although no formal evaluation of breast cancer risk (i.e. the Gail model) was utilized by Dr. Sartorius, this cohort is likely to represent a high risk group and the results cannot be generalized to the population at large. Finally, the ethnic make-up of this cohort was predominantly white; therefore the relative risks found may not be applicable to other ethnicities with varying physiologic factors influencing breast epithelium.These results support our hypothesis that 1) women with abnormal epithelial cells in NAF have an increased risk of breast cancer when compared to non-yielders and women with normal epithelial cells in NAF and 2) women with epithelial cells present in NAF have an increased risk of breast cancer when compared to non-yielders and women without epithelial cells present in NAF. As early detection of breast cancer is critical for a cure, being able to identify women at high risk for breast cancer would justify closer follow-up and the use of multiple methods to ensure early detection. Examining NAF may enhance current risk prediction models and provide an easy and inexpensive way to help identify individuals at increased risk for breast cancer. Future studies are necessary to explain the association between our findings and increased breast cancer risk. It is necessary to test breast fluids for specific biomarkers in order to further the research on etiologic factors involved in breast carcinogenesis and true breast cancer prevention.CCR = California Cancer Registry; CI = Confidence interval; DMV = Department of Motor Vehicles; LCIS = Lobular carcinoma in situ; NAF = nipple aspirate fluid; OR = odds ratio; PI = principal investigator; RR = relative risk.KB conceived of the study and set up the design and coordination of the research team. She also reviewed and interpreted all statistical analyses and drafted the original manuscript. MM performed all statistical analyses. TR and JDS participated in the design of the study and also performed statistical analyses. MW participated in the study design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


P=0.15), but this association was subjected to marked heterogeneity (I2=44%). Restricting the analysis to post-menopausal women, high levels of plant lignan intake were associated with reduced breast cancer risk  and heterogeneity was markedly reduced (I2=0%). High enterolignan exposure was also associated with breast cancer  but, again, there was marked heterogeneity (I2=63%). No association was found with blood enterolactone levels . In conclusion, plant lignans may be associated with a small reduction in post-menopausal breast cancer risk, but further studies are required to confirm these results.Phyto-oestrogens are plant compounds structurally similar to oestradiol, which have been proposed to have protective effects against breast cancer. The main class of phyto-oestrogens in the Western diet is lignans. Literature reports on the effect of lignans in breast cancer risk have been conflicting. We performed three separate meta-analyses to examine the relationships between (i) plant lignan intake, (ii) enterolignan exposure and (iii) blood enterolactone levels and breast cancer risk. Medline, BIOSIS and EMBASE databases were searched for publications up to 30 September 2008, and 23 studies were included in the random effects meta-analyses. Overall, there was little association between high plant lignan intake and breast cancer risk : 0.93, 95% confidence interval (95% CI): 0.83–1.03,  Relevant studies included at least one keyword or Medical Subject Heading from each of the following; (i) plant lignans , (ii) enterolignans (enterolactone and enterodiol) and (iii) breast cancer. The search strategy excluded reviews, animal and cell culture studies but did not impose any language restrictions.Abstracts and full texts, where required, were independently screened by two investigators to establish the suitability for inclusion. Studies had to be of case–control or cohort design, evaluating the risk of invasive breast cancer in relation to lignan exposure and reporting odds ratios (ORs) or relative risks, as well as 95% confidence intervals (95% CIs). Cited references were also reviewed for any studies that may have been missed in the database searches.Eligible publications were then assessed independently by three reviewers. A structured form was used to extract information about the study, subjects’ characteristics including menopausal status, confounding factors and results. Wherever multiple publications of the same study were available, the paper with the most complete set of data was chosen.in vitro fermentation models; and (iii) examining enterolactone levels in the blood (either plasma or serum). The blood levels of enterodiol were measured in a small number of studies (Studies were then categorised as those: (i) assessing total plant lignan intake or intake of individual plant lignans if the total was not measured; (ii) investigating exposure to enterolignans (enterolactone and enterodiol) by using values produced from food by vs the lowest categories of exposure. If different levels of adjustment had been carried out, the results from the most fully adjusted model were used.Separate meta-analyses were performed for each group of studies described in the Methods section using adjusted ORs or relative risks for the highest I2-statistic was used to test for heterogeneity . Statistical analyses were performed using the STATA version 9.2 software .Following screening of abstracts and full texts and grouping into categories, 27 of the 33 articles identified were selected for data extraction. Multiple publications were identified for a number of studies. Four articles , 5 on enP=0.15) that of the lowest intake group , with little sign of between-study heterogeneity  (see P=0.73). The funnel plot of studies examining plant lignan intake and overall breast cancer risk showed symmetry, suggesting a lack of publication bias.There was no association between plant lignan intake and risk when 11 studies were combined, although there was a slight protective effect. The risk in the highest intake group was 0.93 times  see . The samP=0.009) , but there was no association between exposure and risk by menopausal status .There was a statistically significant inverse association between enterolignan exposure and overall risk  , althougP=0.24) (P=0.61) and post-menopausal women .There was no association between blood enterolactone and breast cancer risk  . ResultsThis is the first systematic review and meta-analysis of exposure to lignans and breast cancer risk based on studies using dietary assessments and serum measurements. Although exposure can be assessed by urine analysis, few studies have used this methodology and therefore, these were not included  or for the whole range of foods consumed by the study population. In addition, there are various analytical methods for determining food values ; hence, databases compiled from published values determined by different methodologies may contain inherent errors. It has also been shown that the amount of lignans in food can differ according to crop variety, location, year of harvest and processing (Consumption of soy food, rich in isoflavones, has been shown to reduce breast cancer risk in Asian women but not in Western women (In summary, the meta-analyses presented in this study, indicate that plant lignans and enterolignans are unlikely to significantly protect all women against breast cancer development. However, our results suggest that high plant lignan intake is associated with a 15% decreased risk in post-menopausal women, which is a small reduction that could be due to residual confounding. If real, the reason for the selective effect is not clear. Additional studies of the effect of lignan exposure on post-menopausal breast cancer risk are needed to confirm these findings before reassessing the current dietary guidelines.


P-trend <0.001). Compared to the reference (BMI 20–24 kg m−2), the adjusted relative risk (RR) was 0.53 : 0.19–1.47) for BMI<20 kg m−2, 4.28 (95% CI: 2.58–7.09) for BMI of 35–39 kg m−2 and 6.36 (95% CI: 3.08–13.16) for BMI⩾40 kg m−2. Women with known diabetes at baseline were at three-fold higher risk  than those without diabetes; women who reported current smoking at baseline were at reduced risk compared to never smokers . The strong linear positive association of BMI with endometrial cancer risk and a strongly increased risk among women with diabetes suggest that any increase in body mass in the female population will increase endometrial cancer incidence.We examined the relationship of body mass index (BMI), diabetes and smoking to endometrial cancer risk in a cohort of 36 761 Norwegian women during 15.7 years of follow-up. In multivariable analyses of 222 incident cases of endometrial cancer, identified by linkage to the Norwegian Cancer Registry, there was a strong increase in risk with increasing BMI ( Endometrial cancer is the most commonly diagnosed cancer of the female genital tract in developed countries (−2) (Previous studies have shown high body mass index (BMI) to be associated with increased risk of endometrial cancer (−2) .Few studies have investigated a possible differential effect of BMI on endometrial cancer risk before and after menopause . These sThe marked effect of obesity on endometrial cancer risk and the increasing body weight in many populations indicate that the incidence of this disease will continue to increase. To investigate this issue further, we have studied endometrial cancer risk in a prospective study of 36 761 women in relation to increments of BMI, diabetes and smoking in all women and separately in women younger than or older than 55 years of age.During 1984–1986, a health survey was conducted among men and women aged ⩾20 years in Nord-Trøndelag county in Norway (the HUNT Study). Among 85 100 eligible persons, 77 310 (90.8%) returned the questionnaire that was mailed with the invitation (questionnaire 1), of whom 74 977 (38 274 women) participated in the subsequent clinical examination. At this clinical examination, standardised measurements of height, weight and blood pressure were performed, and participants received a second questionnaire that included items on physical activity, alcohol use, diabetes and smoking. This second questionnaire was filled in at home and returned in a prestamped envelope, but 6255 women (17%) did not do so. Details of the description of the HUNT Study are provided elsewhere  and 419 were excluded because BMI could not be calculated. Thus, 36 761 women constituted the study population and were followed up for cancer incidence.The unique 11-digit identity number of Norwegian citizens enabled linkage of participants to endometrial cancer recorded at the Cancer Registry of Norway. All women so diagnosed among participants  were identified based on mandatory reporting from all pathological laboratories in Norway to the Cancer Registry.Follow-up time was calculated as person-years from the date of clinical examination until the date of cancer diagnosis , emigration, death or to the end of follow-up at 31 December 2002, whichever occurred first. In separate analyses among women before the age of 55 years, follow-up was the time from the date of clinical examination until endometrial cancer diagnosis or until censoring at the age of 55 years.−2) and categorised as <20, 20–24, 25–29, 30–34, 35–39, and 40 kg m−2 and higher. At the clinical examination, blood pressure ⩾140/90 mmHg was classified as hypertension.Body mass index was calculated as weight divided by height squared  included frequency (five categories), average duration (four categories) and intensity (three categories). Marital status  and level of education  were also recorded.We estimated the age-adjusted relative risks (RRs) of BMI, diabetes and smoking with 95% confidence intervals (CIs) by using the Cox regression analysis. Thereafter, we mutually adjusted for each study factor and also for alcohol use, physical activity and hypertension. We used the SPSS statistical package, version 14.0, for the analysis.This study was approved by the Regional Committee for Ethics in Medical Research and the Norwegian Data Inspectorate.We followed 36 761 women for an average of 15.7 years (range 0–19 years). Mean age at baseline was 49 years (range 20–101 years), and during follow-up, 222 endometrial cancers were diagnosed.−2, only 0.13% (4 out of 3067) developed endometrial cancer compared to 3.66% (9 out of 246) of those with BMI⩾40 kg m−2. Only 0.7% women (246) were in the highest BMI category, but they represented 4.1% of those with endometrial cancer. We found a strong and consistent increase in risk with increasing BMI (P-trend <0.001) , and with BMI⩾40 kg m−2, it was 7.89 (95% CI: 3.90–15.94). Adjusting for diabetes, smoking status, alcohol use, physical activity and hypertension reduced the associations with BMI, but they remained strong. The adjusted RRs were 6.36 (95% CI: 3.08–13.16) for BMI⩾40 kg m−2, 4.28 (95% CI: 2.58–7.09) for BMI 35–39 kg m−2 and 0.53 (95% CI: 0.19–1.47) for BMI<20 kg m−2, respectively (Among women with BMI<20 kg m <0.001) . Compareectively .Among women with diabetes at baseline, 1.88% women (19 out of 1010) were diagnosed with endometrial cancer during follow-up compared to 0.57% (203 out of 35 751) among women without diabetes. After multivariable adjustment, diabetes was associated with a three-fold higher risk  .There was an inverse association of current smoking with risk. After multivariable adjustment, the negative association with smoking was moderately reduced but remained strong ; former smoking was not associated with risk  .−2. The RRs were 6.10 (95% CI: 1.95–19.05) for BMI 35–39 kg m−2 and 9.44 (95% CI: 2.01–44.38) for BMI⩾40 kg m−2 (−2).Because information on age at menopause was not available, we conducted separate analyses before and after the age of 55 years. Among the 22 027 women who could be followed until the age of 55 years, 52 developed endometrial cancer, but multivariate analyses revealed a significantly increased risk only for women with BMI⩾35 kg m0 kg m−2  as compa−2 and 4.20 (95% CI: 2.37–7.47) with BMI 35–39 kg m−2  associated with BMI⩾40 kg m9 kg m−2 .Initially, marital status and educational level were included, but since they were not associated with risk, they were not included in the final analysis.−2) compared to those of normal BMI (20–24 kg m−2), whereas those women with BMI<20 kg m−2 had only half the risk. Women with diabetes had three-fold higher risk compared to non-diabetic women, and we found an inverse association with smoking at baseline.Among the 36 761 women followed for 15.7 years, we found a strong positive and linear association of BMI with endometrial cancer risk in the study population as a whole. We found a six-fold increase in risk among very obese women  and possible changes in BMI during follow-up. Generally, Norwegian women were restrictive in HRT use in the 1980s, with an estimated less than 6% of postmenopausal women using it in the late 1980s .Even though the association between obesity and endometrial cancer is ‘convincing’ , it is sThe association with diabetes is also stronger than that previously reported , both of which are endometrial growth factors (Apart from the effects of unopposed oestrogens, insulin and associated growth factors have been identified as risk factors. We found a positive association of diabetes with risk, also after adjusting for potentially confounding factors. Several mechanisms may operate in linking elevated insulin to endometrial cancer development, including growth-enhancing properties of insulin, increased levels of IGF-I receptors in the cancer tissue (The protective effect of smoking on risk cannot be entirely attributed to lower body weight. Reversible processes are probably involved, since the finding was restricted to current, but not former, smokers. Smoking may slow down the decay of progesterone and androgens (In this prospective study of a large unselected population, the linear and strong positive association of BMI with risk implies that even a slight increase in population body mass will lead to an increase in endometrial cancer incidence. More detailed research is indicated.


The possible association between cigarette smoking, alcohol consumption and the risk of development of breast cancer before the age of 45 was investigated by means of a population-based case-control study in Sweden and Norway. Information was obtained, by personal interview, from 422 (89.2%) of all eligible patients with breast cancer newly diagnosed between May 1984 and May 1985, and from 527 (80.6%) of all age-matched controls. The possible confounding effects of oral contraceptive (OC) use, education, and reproductive and several other factors were taken into account in multivariate analyses. No association was found between ever smoking (versus never smoking) and breast cancer  0.8-1.3). Further, there was no relation between breast cancer and duration of smoking, age at start of regular smoking, length of time since the start of regular smoking, or number of cigarettes smoked per day. There was no significant interaction between smoking, use of OCs, parity, and breast cancer. A moderate or high current consumption of beer, wine, liquor or total alcohol did not increase the risk of breast cancer. An alcohol intake of 5 grams per day or more was associated with a decreased risk of breast cancer , but possible effects of a change in habits after diagnosis, of recall bias and of residual confounding, e.g. by dietary habits, need serious consideration.