We assessed ovarian cancer screening outcomes in women with a positive family history of ovarian cancer divided into a low-, moderate- or high-risk group for development of ovarian cancer.545 women with a positive family history of ovarian cancer referred to the Ovarian Screening Service at the Royal Marsden Hospital, London from January 2000- December 2008 were included. They were stratified into three risk-groups according to family history  of developing ovarian cancer and offered annual serum CA 125 and transvaginal ultrasound screening. The high-risk group was offered genetic testing.The median age at entry was 44 years. The number of women in the high, moderate and low-risk groups was 397, 112, and 36, respectively. During 2266 women years of follow-up two ovarian cancer cases were found: one advanced stage at her fourth annual screening, and one early stage at prophylactic bilateral salpingo-oophorectomy (BSO). Prophylactic BSO was performed in 138 women (25.3%). Forty-three women had an abnormal CA125, resulting in 59 repeat tests. The re-call rate in the high, moderate and low-risk group was 14%, 3% and 6%. Equivocal transvaginal ultrasound results required 108 recalls in 71 women. The re-call rate in the high, moderate, and low-risk group was 25%, 6% and 17%.No early stage ovarian cancer was picked up at annual screening and a significant number of re-calls for repeat screening tests was identified. BRCA1 and BRCA2 gene mutations and their relationship to ovarian cancer has resulted in an awareness of family history in many women with ovarian cancer [BRCA1 or BRCA2 gene mutation the cumulative life-time risk of developing ovarian cancer can be as high as 60% and 27%, respectively, although it may be between 11-39% if the family history is less strong [Primary ovarian cancer is the fourth most common cause of cancer-related death in the United Kingdom with 4500 deaths each year . The iden cancer -8. The nn cancer . In womes strong ,11. The s strong .For women at high-risk of developing ovarian cancer, management options still include a) ovarian cancer screening by CA125 measurement and or transvaginal ultrasound, with the intention to reduce mortality by detecting ovarian cancer at an early stage, or b) prophylactic bilateral salpingo-oophorectomy (BSO). The optimal management policy in women with moderate or low-risk of developing ovarian cancer remains unclear.In this study, we assessed ovarian cancer screening outcomes in women with a positive family history of ovarian cancer stratified in a low, moderate or high-risk group of developing ovarian cancer. We defined the number of ovarian cancer cases identified, the number of re-calls because of abnormal test results, and present the characteristics of women who underwent prophylactic BSO.We conducted a retrospective audit of 545 women consecutively referred because of a positive family history of ovarian cancer from January 2000 to December 2008 to the Cancer Genetics Clinic at The Royal Marsden NHS Foundation Trust in London, UK, for consideration of annual screening. At the initial clinic visit the family history was documented, assessed and confirmed in a standardised format. Three risk categories were identified. Women fulfilling the family history criteria shown in Table et al, 2003) [The provision of ovarian screening was discontinued at The Royal Marsden NHS Foundation Trust in 2004 as screening was concentrated in other centres, if appropriate; pending the results of studies of screening in high-risk families (the UKFOCSS study). All patients had a full family history taken out to third degree relatives and their risk was reviewed by a cancer geneticist (RE). Those patients who had been assessed as being at high-risk for ovarian cancer were offered participation in the UKFOCSS study . Those who were been assessed as being at moderate-risk were referred to St Georges Hospital, London, one of the very few NHS Gynaecology Departments which still offered ovarian cancer screening outside a research study to moderate-risk women, or to a local hospital if this was more convenient for the woman. All other patients were considered low-risk, indicating that some women formerly considered at increased risk were reclassified as low-risk and advised that there was no indication for further screening and were discharged. From 2004, new patients were still initially assessed in our clinic but referred according to risk group. Inclusion in the study ended in December 2008. The total number of prophylactic BSO was recorded as were the number of repeat CA125 measurements and transvaginal ultrasound visits due to abnormal findings. The expected number of ovarian cancers to be detected in this study was calculated, divided into women years tested by risk category and age group , with the majority of women in the age group of 35 to 49 years old (61.3%) (Table BRCA1 gene mutation carriers and 45 (43%) women had a BRCA2 gene mutation. In 2 (1.9%) an MLH1 gene defect mutation was identified. One (0.9%) woman was diagnosed with both a BRCA1 and BRCA 2 gene mutation. This 69 year old lady underwent a hysteroscopy, dilatation and curettage for an endometrial polyp which revealed a grade 3 endometrioid adenocarcinoma of the endometrium. She underwent a laparoscopic hysterectomy and bilateral salpingo-oophorectomy showing FIGO stage 1B endometrial cancer. Her ovaries and fallopian tubes were histologically normal.At baseline, the majority of women was in the high-risk group n = 397 (73%). The moderate- and low-risk group consisted of 112 (21%) and 36 (6.6%) women, respectively. In the high-risk group 140 women (35.3%) underwent genetic testing and in 106 (76%) a genetic mutation was identified. Among these women, 58 (55%) women were BRCA1 gene mutation carrier, presented at her fourth annual screening visit with an elevated CA125 of 3874 kU/L and bilateral complex ovarian masses with ascites on transvaginal ultrasound. She was asymptomatic. Her previous screening CA125 levels and transvaginal ultrasounds did not show any abnormalities. At her third annual screening visit, 14 months before she was diagnosed with ovarian cancer, her CA125 was 8 kU/L She underwent optimal debulking surgery and the final histopathology revealed Stage 3C poorly differentiated serous papillary adenocarcinoma of the ovary. The second ovarian cancer case was found in a 40 year old BRCA1 gene mutation carrier. She underwent a routine prophylactic BSO. The adnexa were grossly normal but the histology revealed Stage 1A poorly differentiated serous adenocarcinoma of the ovary. Her preoperative CA125 was 30 kU/L and no abnormalities were seen on transvaginal ultrasound. She had been undergoing annual screening for 5 years. Both patients are still alive after 6 and 4 years of follow-up, respectively.In 2 women, epithelial ovarian cancer was diagnosed. The first case, a 50-year-old Prophylactic BSO was performed in 138 women (25%). In most cases peritoneal washings and an endometrial sample were taken at the same time. Table A total of 2266 women years of follow-up were identified. The majority of women years (1623 women years) were in the high-risk group, with 522 and 121 women years in the moderate- and low-risk group, respectively. A total of 3.89 (95% C.I. 0.22-7.22) ovarian cancer cases were expected in the study population with 3.11, 0.68 and 0.11 cases in the high-, moderate-, and low-risk groups, respectively.Table Forty-three women had an abnormal CA125 measurement, resulting in a total of 59 repeat tests. The majority of elevated CA125 was seen in the high-risk group. Only one moderate-risk woman underwent a prophylactic BSO because of 2 consecutive elevated CA125 measurements . Her transvaginal ultrasounds were normal. No abnormalities were found on final histopathology. In all, but three women, CA125 results came back to normal. Among these three women, one was diagnosed with advanced ovarian cancer, one woman was pregnant and the third diagnosed with recurrent breast cancer.In this retrospective study we assessed ovarian cancer screening outcomes in 545 women with a positive history of ovarian cancer stratified into a low, moderate, or high-risk group of developing ovarian cancer.BRCA gene mutation carriers [A total of 2 (0.4%) ovarian cancer cases were identified. None of them were found during screening. Most studies looking at the effectiveness of ovarian cancer screening found a higher incidence of ovarian cases of about 1-3% ,14. Althcarriers .In our high-risk group 35% underwent genetic testing and in 76% a genetic mutation was identified. The reason for this high percentage could be the high proportion of Ashkenazi women (30%) and women with a previous history of breast cancer (47%) in this group.Prophylactic BSO was performed in 25% of women and in one case early stage ovarian cancer was found, but on histology only. She had normal pre-operative screening results. Transvaginal ultrasound and CA125 measurements as screening tests are known to have their limitations. High false-positive rates have been identified, especially in pre-menopausal women, resulting in a high number of re-call visits, anxiety through equivocal test results, and even, unnecessary surgical intervention -16. In oBRCA positive women who underwent ovarian surveillance concluded low sensitivity and positive predictive values of ovarian screening modalities and no additional benefit from screening [The limitation of our study is that it has not been conducted in the form of a robust prospective protocol, but was an analysis of the clinical management guidelines at the time. Screening results were interpreted and acted on by clinicians involved with no defined protocol other than using the RMI only. Our study revealed a significant number of re-calls for repeat screening tests. No early stage ovarian cancer was identified at annual screening by serum CA125 and/or transvaginal ultrasound. Of the two ovarian cases found, one early stage ovarian cancer was found at prophylactic BSO. The other case was found during screening and presented with an advanced ovarian cancer. Both patients had been under surveillance for more than 4 years and had no abnormal results in their previous annual screening rounds. Several studies have already reported that annual screening of high-risk women will not reduce mortality from ovarian cancer ,19. A lacreening .BRCA1 or BRCA2 mutation by 70-96% [More sophisticated screening criteria have been developed since the start of our study and we are awaiting the results of a large UK multi-centre trial, the UKFOCCS trial to clarify the role of different algorithms of ovarian screening in women with an increased genetic risk to assess if this improves upon the annual re-call algorithm. Since no effective screening programme has yet been identified, prophylactic BSO should be advised to all high-risk women after they completed their family which will reduce the risk of ovarian cancer associated with y 70-96% -22.In conclusion, this study assessed the role of annual ovarian screening in women with a family history of ovarian cancer stratified into 3 different risk-groups. No early stage ovarian cancer was picked up at annual screening. This approach to screening led to a significant number of re-calls for repeat screening tests.The authors declare that they have no competing interests.RE and MG conceived the study, participated in the design of the study, collected data, and interpreted the results. EB, EM, FL, IJ, AW, DPJB, TEJI, JHS, JEB, CH, SS, AA-J, ST, collected data and interpreted the results. PP interpreted the results and performed the statistical analysis. MN collected and interpreted the data and performed the statistical analysis. All authors have been involved in drafting and/or revising the manuscript. All authors read and approved the final manuscript.


Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours.1005 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case–control design, exposure effects were estimated using conditional logistic regression.Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk . Specific sectors with elevated risk included: agriculture ; bars-gambling ; automotive plastics manufacturing , food canning , and metalworking . Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics  and food canning .These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work histories in environmental and occupational epidemiology. Breast cancer is the most frequent cancer diagnosis among women in industrialized countries and North American rates are amongst the highest in the world . There iLifetime exposures to endogenous estrogen affect the risk of breast cancer ,8, and eResearch regarding occupational exposures and breast cancer risk has generally been a neglected topic. Work-history based occupational breast cancer studies often lack demographic and reproductive status information -18. StudThis study was conducted in Essex and Kent counties of Southern Ontario, a region with a stable population and diverse modern agriculture and industry. A geographic clustering of excess breast cancer has persisted there over time . In the The prior hypotheses of the current breast cancer study were based on: a) previous work on the environmental causes of breast cancer, b) current theories of carcinogenesis and endocrine effects, and c) findings of a previous breast cancer study that observed: increased risks among women with an occupational history of farming  and among those who subsequently worked in auto-related manufacturing , or in health care  . In the The WRCC, the area’s regional cancer treatment center, referred subjects to this population-based case–control study. Ethics approval for research on human subjects, which includes prior informed consent, was obtained from the research ethics committees at both the Windsor Regional Hospital and the University of Windsor.The survey instrument was derived from previously developed questionnaires -30 with Cases were recruited over a six year period from mid 2002 through mid 2008 with the following criteria: new diagnosis of histologically confirmed breast cancers (ICD-9 Code – 174) , excludiCommunity controls from the same geographic study area were recruited from 2003 through 2007. Randomly selected households were obtained through computer-generated telephone numbers and linkage to mailing addresses. The same study information which was sent to cases, which made no reference to occupational or environmental factors, was mailed to potential controls and followed-up with telephone calls. Eligibility requirements were the same as the cases, with the exception that only one person per household was allowed and could have no prior history of breast or ovarian cancer. Interviewers followed a scripted recruitment and interview plan. Cases and controls were compensated $20 for their time.Each job was coded using the North American Industry Classification System (NAICS)  and NatiEach unique NAICS/NOC combination was further assigned an exposure classification code signifying the likely presence and intensity of carcinogen and/or EDC exposures in the manner of expert panel assignment ,35. InveIn preliminary analyses minor sectors were examined as: a) categorical variables ; and b) continuous variables  . Next, cBecause food canning was a major activity in this region, related exposures were examined. Polymer lining of cans was approved in the 1960’s by the US Food and Drug Administration  and becaPrior research suggested that early employment in agriculture may predispose individuals to higher risk from subsequent occupational exposures . A bioloCumulative exposures for some analyses were partitioned into time (age) windows representing distinct stages of breast development that could affect risk ,40. CumuResults were based on frequency-matched case–control analyses using a loglinear specification in multiple conditional logistic regression . MatchinThe results display both p-values, showing the probabilities of chance associations, and confidence intervals, showing the range of true parameter values that would produce the observed estimates with probability > 2.5 percent (two-tailed).Of 1,553 breast cancer cases referred, 160 were ineligible and 222 were unable to be reached. Of the remainder, 165 declined, leaving 1006 cases for a participation rate of 86%. Of 3,662 households contacted for community control recruitment, 3,223 individuals were able to be apprised of the study and 926 households (29%) were determined to have no eligible residents. From 2,297 households with eligible residents, 1,146 women participated for a recruitment rate of 50%. The same percentages of cases and controls elected to be interviewed by telephone (46%) and in-person (54%).Compared to controls, cases were slightly older, had a longer period of fecundity  and fewer months of breast feeding; they had less education, lower family income, and smoked more but had almost identical duration of employment Table . There iThere were considerably more cases than controls among subjects whose minor sector of longest duration was a) agriculture: 37 vs. 23 cases, b) food manufacturing: 30 vs. 10, c) automotive plastics manufacturing: 26 vs. 9, d) laundry/dry cleaning: 8 vs. 2 and e) bars-gambling (16 vs. 11) (Table When classified on minor sector of longest (lagged) duration of employment, and analyzed with conditional logistic regression, several demographic and reproductive risk factors exhibited strong, statistically significant associations as did several minor sectors of employment Table . The oddWhen durations in the minor sectors (lagged) were analyzed in the model Table , food maUsing the generic cumulative exposure metric  with the 0, 1, 2 exposure weighting scheme produced a statistically significant excess risk of breast cancer; 10 years in a high-exposed job had an associated 29% increase  Table , model 1The analysis revealed excess risk with work in high exposure food canning jobs  Table , model 4There was no evidence of risk modification related to prior work in agriculture for subsequent work in metals or canning Table , model 5Partitioning the generic Cumulative Exposure Metrics I and II into time-windows suggests that the most important exposures affecting breast cancer risk occur in the third time window – from first full term pregnancy to menopause; the elevation was smaller for the first, second and fourth time-windows although there was limited power to distinguish them Table . For Met-4) sectors all exhibited excesses for the ER+/PR+ receptor type, but farming had a stronger excess in the ER- category . The canning excess appeared to be entirely in the ER+ /PR- and ER- groups. Including the interaction terms for prior farm work identified possible effect modification for metals (ER+/PR-), bars-gambling (ER+ /PR+), and plastics (ER-), and a statistically significant interaction for prior farming and canning for the ER+ /PR- receptor status  but not for ER+/PR+ or ER- receptor status.Examination of specific estrogen receptor (ER) or progesterone receptor (PR) types in the major sectors showing excess breast cancer produced distinct associations across receptor types Table . The farModels fit with an additive relative rate specification generally fit less well than with the loglinear form. For example, the automotive plastics estimate with the loglinear model was OR=2.68 (1.47-4.88), p=0.0013 whereas the linear relative rate model produced OR=4.03 (1.43-6.64), p=0.023. With the interaction terms, the same pattern was observed as with the loglinear form, but confidence intervals were wider.Restricting the analysis to premenopausal women resulted in many fewer cases (373 out of 1006) and considerably higher estimates of relative risk Table  as in hiOur objective was to identify occupations associated with elevated rates of breast cancer. This issue has been largely neglected, possibly because of class  and gendBand et al.  conducteVilleneuve et al.  analyzedLabrèche et al.  analyzedObserving associations between breast cancer incidence and generically assigned exposure ratings in broad industrial categories in the present study suggests that the etiologic agents, whether as carcinogens or EDCs, are widely distributed possibly encompassing many compounds. The specific identification of causative agents should be possible in occupational studies with detailed compound-specific retrospective exposure assessments.Many of the women in this study had a background in farming or in the automotive plastics sector and this provided sufficient statistical power to show consistency with our prior studies ,27. SimiThis study found elevated breast cancer risk among women who had farmed. Agriculture in southwestern Ontario is diverse with tomato, corn and peach production being major activities. No additional risk, beyond what was found for farming in general, was observed for corn cultivation when atrazine was used but the labor-intensive activities there (detasseling) may have had low exposures. Several pesticides act as mammary carcinogens in animal bioassays ; many arThe plastics manufacturing jobs held by the women who participated in this study involved primarily injection molding. Injection molding and related processes take molten mixtures of resins, monomer, multiple additives, and sometimes lamination films, and form them into plastic pieces of defined dimensions and configuration. Emissions of vapors or mists from these hot processes can include plasticizers, ultraviolet-protectors, pigments, dyes, flame-retardants, un-reacted resin components and decomposition products. Further exposure comes from skin contact in handling and performing finishing tasks .Many plastics have been found to release estrogenic chemicals . FurtherA near doubling of the risk for female breast cancer was found among plastics and rubber industry workers  . Two othFood canning industry exposures could include pesticide residues and exposures specific to canning processes involving lead  and coating emissions. Canning processing has been found to significantly reduce levels of residual pesticide  through There were also important findings for those employed in bars or such gambling establishments as casinos and racetracks. The strong (OR = 2.28 after 10 years) Table , model 4The findings for metal work, which includes foundries, metal stamping, fabrication and metalworking, have important implications for a broad range of blue collar industrial operations. Although these industries expose workers to metallic fume, metalworking fluids, PAHs, solvents, and other hazards ,65, therDespite the likely presence of diverse carcinogen or EDC exposures within industrial sectors, some distinct specificity of receptor-type associations was observed. Of sectors showing elevated breast cancer, automotive plastics and the metals-related sectors would be expected to have the most diverse mix of carcinogen and EDC exposures; the canning and bars-gambling sectors would be expected to have the least diverse. Our study found statistically significant associations with canning in two receptor types (ER+/PR- and ER-), one exhibiting a statistically significant interaction with prior farm work. If the association is etiologic, this suggests that more than one mechanism may be involved. There was also a statistically significant increase in ER- tumor status among women employed in farming. Although there has been little research in this area, Danish researchers noted an association between ER- tumor status and exposure to dieldrin . WhetherFinding distinct patterns for pre- versus postmenopausal breast cancer, such as increased premenopausal breast cancer among women employed in automotive plastics, adds confidence that exposure associations may be etiologic even though the exposure specificity is limited. Some of the events leading to a cancer diagnosis could occur throughout a woman’s life, i.e., both pre- and postmenopausal exposures could be involved in postmenopausal cases. Nevertheless, observing differences on menopausal status allows examination of some mechanistic hypotheses. Other studies of premenopausal breast cancer identified smoking  and suchSelection bias arising from participation that jointly depends on exposure history and case-status is unlikely to have played a significant role because study candidates did not know the intent of the study, and the participation rate among cases was relatively high. Among controls there would be even less likelihood of an exposure-driven decision. Uncontrolled confounding was undoubtedly present which is one reason why income terms were included in the model. Many lifestyle and health-related risk factors are associated with income. It would be quite unlikely for minor uncontrolled confounding to produce the strong specific associations observed.Shift work was examined but did not produce statistically significant findings. In a study aggregating diverse workplaces, it is likely that exposures themselves depend on shift, making any shift-effect difficult to interpret. For example, not all employers operate a midnight shift and that shift can have maintenance, support and custodial activities that are absent in day-shift work and that could influence types or levels of exposures.Exposure assessment based on survey instrument-derived work histories coded in NAICS and NOC categories has inevitable misclassification that dilutes or occludes observable associations . ChanginModels using the additive relative rate specification fit less well than with the loglinear choice, which assumes an exponential rather than linear dependence on the exposure metric. This suggests that the weighting scheme assuming a 10-fold higher exposure with “high” vs. “moderate” may have understated this ratio.There was an under-representation of potentially highly exposed migrant farm and greenhouse laborers because they were not treated at the regional cancer center. This exclusion may have underestimated the risk estimate. Furthermore the role of carcinogens and EDCs that are ubiquitous in society will be underestimated in this study against the inflated background.While this study was unable to identify exposure to specific chemicals, associations were observed between breast cancer carcinogens and EDCs. EDCs and biological windows of vulnerability are not currently considered in the establishing of occupational exposure limits (OELs). These findings, along with mounting evidence from other recent studies of harm from low level EDC exposure, point to the need to re-evaluate OELs and their relevancy in regulatory protection.A growing body of scientific evidence suggests that mammary carcinogens and/or EDCs contribute to the incidence of breast cancer ,6,14. YeBPA: Bisphenol A; BMI: Body mass index; CI: Confidence interval; EDC: Endocrine disrupting chemical; ER: Estrogen receptor; Ind: Indicator variable; IpAg: Interaction with farming; NAICS: North American Industry Classification System; NOC: National Occupational Classification; OELs: Occupational exposure limits; OR: Odds ratio; pk-yrs: Smoking pack years; PR: Progesterone receptor; SIR: Standard incidence ratio; WRCC: Windsor Regional Cancer Center.The authors are free of financial or other conflicting interests related to the design, conduct, interpretation, or publication of the research. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the US National Institute for Occupational Safety and Health (NIOSH).JB, MK, AW, AR, IL and MG contributed to the concept and design of the study. HA-Z and KS co-ordinated the informed consent and referral process from the Windsor Regional Cancer Center and the accessing of tumor hormone receptor status for each case. EM-T was responsible for the design and implementation of the study database program. JB and MK supervised data collection and, along with RD, assessed exposure values. RP constructed the analysis files, designed the statistical models and performed the analysis. RP, MK, JB, MB, AW and MG interpreted the data and contributed to the writing of the manuscript and all authors participated in revisions of the manuscript and approved it.


Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer.Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression.P=0.5) for ER-positive or PR-positive tumours and 0.48  for ER-negative and PR-negative tumours .During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 =0.70–1.21; test for trend, Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours. Most of the studies on the risk of breast cancer in relation to individual foods and nutrients have had inconsistent results . Factor Breast cancer, similar to most cancers, is heterogeneous in its pathology, natural history and response to treatment. Breast cancer differ, for example, with respect to oestrogen (ER) and progesterone receptor (PR) status; hormone receptor-positive cancers exhibiting better differentiated morphological appearance and stronger clinical response to hormonal treatment (Using data from the Melbourne Collaborative Cohort Study (MCCS), we analyze the effect of dietary patterns on breast cancer risk overall, by attained age during follow-up and by tumour characteristics, including tumour grade and ER and PR status.The MCCS is a prospective cohort study of 41 514 people (24 469 women) aged 27–76 years at baseline (99.3% of whom were aged 40–69), recruited in 1990–1994 in the Melbourne metropolitan area. Subjects were recruited via the Electoral Rolls , advertisements and community announcements in local media . The Cancer Council Victoria's Human Research Ethics Committee approved the study protocol. Subjects gave written consent to participate and for the investigators to obtain access to their medical records.At baseline interview, questions were asked about conventional risk factors, such as reproductive history, hormone replacement therapy and oral contraceptive use, country of birth, alcohol consumption, physical activity, smoking habits and highest level of education. Subjects also completed a dietary questionnaire that included questions relating to dietary habits and a 121-item food frequency questionnaire (FFQ), specifically developed for the MCCS (N=11); reported extreme values of total energy intake (<1st percentile or >99th percentile) (N=488) or a history of angina, diabetes or heart disease before baseline as their diet might have changed in consequence (N=1421); had a confirmed diagnosis of invasive breast cancer before baseline (N=415); or had missing values in any of the potential confounders (N=1167). These exclusions left 20 967 women eligible for these analyses.Women were excluded from the study if they did not complete the dietary questionnaire  during follow-up until 31 December 2007. Cases were ascertained by record linkage to the population-based Victorian Cancer Registry (VCR), which covers the state in which the cohort resides, and to the National Cancer Statistics Clearing House, which holds cancer incidence data from all Australian states. Women with κ=0.71, P<0.001; for PR, κ=0.62, P<0.001). Because of the good agreement between the ER and PR data, when archival tumour tissue was not available, ER and PR status was assigned according to the histopathology reports held at the VCR.The medical records of women with breast cancer were reviewed and their cancers classified according to tumour grade and ER and PR status as recorded in histopathology reports held at the VCR. We repeated the measurement of ER and PR status for a subset of cases with archival tissue available . The original diagnostic tumour slides for these cases were retrieved from pathology laboratories and reviewed by a single pathologist (CM) who assessed ER and PR status using immunohistochemistry techniques. The archival material was sectioned at four micron and placed on superfrost plus slides. A routine dewaxing procedure was followed by heat-induced epitope retrieval with either citrate buffer pH 6 or TRIS EDTA pH 8 using a DAKO  Pascal pressure chamber. The following antibodies were used: ER  at 1/250, PR (DAKO PGR636) at 1/1200. Immunoreaction was performed using a Lab Vision  autostainer using Lab Vision HRP polymer detection system and DAKO DAB+. The agreements between the ER and PR status assessed by immunohistochemistry and the values held by the VCR were 89 and 81%, respectively . For the 121 items, intake was measured as daily equivalent frequency, intake of oils was measured as ml per week, and alcohol as g per day. The principal factor method was used to extract factors, followed by orthogonal (varimax) rotation to assist in interpretation of the factors and to ensure that the factors were uncorrelated. Factors with Eigenvalues of 2 or greater were retained. Variables with factor loadings having absolute values of 0.2 or greater were used in interpreting the factors. For each rotated factor, scores were computed as the sum of products of the standardized observed variables multiplied by weights proportional to the factor loadings. Scores were categorized in quintiles.Multivariate regression methods were used to calculate how much of the variance in factor scores was associated with country of birth, total energy intake and potential confounders.N=815), diagnosis of unknown primary cases (N=49), death (N=1216), date left the area covered by the cancer registries (N=117) or 31 December 2007, whichever came first. Hazard ratios (HRs) were estimated using Cox regression with age as the time metric. Analyses were adjusted for potential confounders, including country of birth, total energy intake, age at menarche, duration of lactation, parity (parous vs nulliparous), oral contraceptive use (ever vs never), hormone replacement therapy , menopausal status at baseline, level of education , level of physical activity , and ER and PR status (ER− vs ER+ PR− vs PR+ and ER+ or PR+ vs ER− and PR−), Cox's proportional regression models were fitted using a data duplication method .The mean age at diagnosis of cases was 63 years (range: 41–85 years), 22% were diagnosed before age 55 years, 12% within the first 2 years of follow-up and 30% after 10 years. The status of ER or PR was known for 95% of the cases, of which 575 (74%) were ER+ and 202 (26%) ER− and 426 (55%) were PR+ and 349 (45%) PR−. There were 605 (78%) cases expressing ER or PR and 173 (22%) cases expressing neither ER nor PR. Information on grade was available for 741 (91%) cases, including 162 (22%) well-differentiated, 333 (45%) moderately differentiated and 246 (33%) poorly differentiated tumors. Tumours not expressing hormone receptors had a higher grade than those expressing ER or PR (76% of the ER− and PR− tumours and 22% of the ER+ or PR+ tumours were poorly differentiated).Four factors with eigenvalues greater than 2 were identified that explained 66% of the variance in all the food and beverage items. Rotated factor loadings for food items with an absolute value of 0.2 or greater for any factor are reported in r=0.87), which indicates that higher intake of the diet pattern characterized by factor 1 is associated with higher intake of vegetables, and is labelled ‘vegetable’. Factor 2 had a strong positive correlation with fruit (r=0.90); because it was also characterized by high consumption of salad green, it is labelled ‘fruit and salad’. Factor 3 was positively correlated with cereals (r=0.36), dairy products (r=0.30), margarine (r=0.43) and potatoes (r=0.37) and negatively correlated with olive oil (r=−0.43) and leafy green vegetables (r=−0.37); because women born in Australia or New Zealand scored higher on this factor (r=0.75) and is labelled ‘meat’.Correlations with energy intake were 0.36, 0.27, 0.35 and 0.44 for factors 1–4, respectively . Factor s factor  it is laOf all the variables listed in vs the lowest quintile of the factor, 0.81; 95% confidence interval (CI): 0.63–1.03; test for trend, P=0.03; Scores for the ‘fruit and salad’ pattern were inversely associated with breast cancer risk  and PR-negative breast cancer , whereas no association was observed for ER-positive or PR-positive cancers  for ER+ or PR+ tumours and 0.48  for ER− and PR− tumours . cancers . When cavs the lowest quintile, 0.58; 95% CI: 0.36–0.92; test for trend, P=0.001), whereas no association was observed for moderate or low-grade tumours . None of the other three patterns showed heterogeneity by tumour grade (results not shown).Scores for the ‘fruit and salad’ pattern were inversely associated with high-grade tumours, .There was no evidence of heterogeneity of the association between dietary pattern and breast cancer risk by level of alcohol consumption (not shown).Using data from a prospective cohort study of 20 967 women with an average follow up of 14 years we identified four dietary patterns that we described as ‘vegetable’, ‘fruit and salad’, ‘traditional Australian’ and ‘meat’. Overall, we observed an inverse association between breast cancer risk and the ‘fruit and salad’ dietary pattern. This inverse association was more pronounced for hormone receptor-negative tumours and for high-grade tumours. No other dietary pattern was associated with risk.The MCCS is a multicultural cohort that includes a high proportion of Southern European migrants in order to extend the range of lifestyle exposure, including diet. It has long and virtually complete follow-up of participants and has extensive data on potential confounding variables. Baseline diet was measured using an FFQ specifically designed to capture the variety of food consumption. To avoid making assumptions about food consumption patterns, we chose not to group the food items for the dietary factor analysis (Excluding the first 2 years of follow-up did not change the results, suggesting that changes in diet due to preclinical lesions are unlikely to have contributed to the observed associations.A limitation of this study is the single measure of diet. Diet was recorded only once at baseline using a FFQ that only showed a fair to moderate agreement for foods when administered on two occasions 12 months apart (The association between fruit and vegetables and breast cancer is biologically plausible because of their high contents of potentially anticarcinogenic compounds , but epiWe did not find significant evidence of an association with the other two dietary patterns that we identified, the meat pattern, correlated with high consumption of meat, and the traditional Australian pattern, correlated with high consumption of dairy products and margarine. Studies of dietary fat intake and risk have been inconsistent (Our analysis supports the hypothesis that a dietary pattern characterized by high intake of fruit and salad is associated with a slightly lower risk of breast cancer and for hormone receptor-negative breast cancer in particular. Breast cancer is a heterogeneous disease and we have provided additional evidence that risk factors might differ in their relationship to cancer subtypes.


Patients diagnosed with breast cancer are often treated with surgery followed by radiation therapy. In this paper, we evaluate the effect that radiotherapy may have had on the subsequent risk of second malignancies, including the possible influences of age at treatment and menopausal status.In order to evaluate the long-term consequences of radiotherapy, a cohort study was conducted based on clinical records for 5,248 women treated for breast cancer in Florence , with continuous follow-up from 1965 to 1994. The Cox proportional hazards model for ungrouped survival data was used to estimate the relative risk for second cancer after radiotherapy.This study indicated an increased relative risk of all second cancers combined following radiotherapy . The increased relative risk appeared five or more years after radiotherapy and appeared to be highest amongst women treated after the menopause . Increased relative risks were observed specifically for leukaemia  and other solid cancers , excluding contralateral breast cancer. For contralateral breast cancer, no raised relative risk was observed during the period more than five years after radiotherapy.The study indicated a raised risk of second malignancies associated with radiotherapy for breast cancer, particularly for women treated after the menopause. Breast cancer is the most common type of cancer and the major cause of cancer-related mortality among women worldwide . Many paThe aim of this cohort study was to evaluate the incidence of second primary cancers in a group of patients treated with ionising radiation therapy for breast cancer in comparison to patients not treated with ionising radiation therapy. The study involved the analysis of clinical records for female breast cancer patients treated at the University of Florence  with radiotherapy and/or chemotherapy and/or hormonal therapy from 1965 to 1994 and who were subsequently followed-up . In thisData were collected on 5,248 patients with breast cancer who were submitted to radiotherapy, chemotherapy, hormonal therapy or no additional therapy at the University of Florence from June 1965 to December 1994. All of the patients had received surgery for breast cancer. A treatment schedule of 2 Gy/day, 5 days/week, for a total dose up to 60 Gy was used. Of these patients, 51.0% received radiotherapy and, for 74.0% of the patients in this group, the exposed volume was the breast only, compared with breast and lymphatic drainage in 26.0% . The radiation source was a tele-cobalt unit (dose rate 0.80 to 1.20 Gy/minute) or linear accelerator. Different irradiation techniques with a 6 MV X-rays linear accelerator were used in later years, namely: (a) two tangential fields; or (b) two tangential fields plus direct irradiation with an electron beam of 12 MeV. Values calculated on 80 treated patients showed that, in case (a), 12% of the total dose was absorbed at a distance of 3 cm from the irradiated volume and that this value decreased progressively to 2.4% at 12 cm. In case (b), the absorbed dose was 3.8% of the total at 3 cm and 1.4% at 12 cm.Follow-up for second malignancies was mainly conducted through direct contact with the patients at regular visits at out-patient clinics. On some visits information on health status was also verified by accompanying relatives. For this study, the cohort was assembled in 1996 and data were collected retrospectively.Information on second malignancies was collected from hospital records and pathology reports. Vital status was assessed through demographic files at the municipality of residence of each patient. Death certificates were obtained from Mortality Registers at municipality of death for those deceased before 1981, and at the Local Health Unit thereafter. In 1984 the Tuscan Cancer Register was established; therefore, all patients' follow-up data were cross-checked with the Tuscan Cancer Registry from 1984 onwards. The end of follow-up for the subjects was chosen to be the earliest of: date of second cancer incidence, date of lost to follow-up, date of death and 31 December 1994. Only six women were lost to follow-up. The follow-up time among surviving patients ranged from a minimum of 1 year to a maximum of 30 years, with a mean of 8 years. Table λ(t) = λ0(t)•exp[βx], where λ0(t) is the baseline hazard function, x represents one or more explanatory variables, and βx is the logarithm of the relative risk. Parameter estimation and significance tests were carried out using the Epicure software [2 approximations to the distribution of the log likelihood ratio. Some patients received chemotherapy and/or hormonal therapy in both radiotherapy and non-radiotherapy groups; therefore, the relative risks of second cancers due to radiotherapy were reported both unadjusted and adjusted for chemotherapy and hormonal therapy to check if there were any confounding effects from these therapies.The Cox proportional hazards model for ungrouped survival data  was usedsoftware . In partThe researchers carrying out the study had no identifiable details of patients forwarded to them and, therefore, ethical approval was not required under Italian laws when the project was initiated in 1996.As shown in Table In light of this pattern, we examined risks of all second cancers combined based on a follow-up of five or more years. The relative risks are calculated according to different age at the time of treatment groups  as shown in Table P = 0.003).Since the 50 to 64 and 65+ year age-at-treatment groups largely or entirely consist of post-menopausal patients, we examined the relative risk of all second cancers combined in relation to menopausal status at the time of treatment. Table Table Since the relative risk of second cancers other than leukaemia and contralateral breast cancer appeared to be raised after a follow-up of five or more years, we examined the relative risk by age-at-treatment. The results are shown in Table For comparison purposes, an analysis was conducted specifically for women who received chemotherapy or hormonal therapy only. The relative risks for a follow-up of five or more years are shown in Tables The relative risk of all second cancers combined among patients given radiotherapy plus chemotherapy or/and hormonal therapy compared with patients given radiotherapy only is shown in Table In this study, we have used a clinical records-based cohort to analyse the effects of radiotherapy for breast cancer on the incidence of subsequent second cancers. All patients in this cohort received surgery for breast cancer. The advantage of this approach is to minimise any possible systematic difference between the irradiated and non-irradiated groups by reducing variability in the analysis. Such an approach has been used in other epidemiological studies of similar nature, as reported .In our analysis, the relative risk for all second cancers appeared to be increased five or more years after radiotherapy compared to those non-irradiated. This is in agreement with the epidemiological evidence for a latency period of several years between exposure to radiation and a raised risk of second cancers ,24-26. TIncreased risk of leukaemia can arise two to five years after exposure to radiation . In our Raised risks of breast cancer have been reported in various studies of women exposed to radiation; for example, Japanese atomic bomb survivors ,10,29, fIn our analysis, no raised relative risk for contralateral breast cancer was observed during the period five or more years after exposure. This is in agreement with previous epidemiological studies ,36,37,42Other solid cancers have also been reported to link with radiotherapy following breast cancer ,43,44. IWith a fairly small total number of second cancers in this cohort, the excess risk associated with radiotherapy was small over the period of follow-up. Since many of the women were still alive at the end of follow-up, the possibility of raised risks continuing several decades over radiotherapy cannot be ruled out and - based on other studies  - would The study of second cancers involves special problems not inherent to most epidemiological investigations. For a second primary cancer to be classified correctly, a metastatic lesion or local recurrence of the original primary cancer must be ruled out. Other treatments may affect subsequent cancer risks for certain organs, for example, the ovary or uterus might be surgically removed. Direct comparison between the irradiated and non-irradiated groups is not without problems. The non-exposed women generally have an earlier stage disease than do women treated with radiation, and the expected number of second cancers among long term survivors is often too small, as in our analysis, to permit meaningful direct comparisons on a site-by-site basis.It can also be argued that some of the second cancers might occur due to factors other than radiotherapy, such as a family history of breast cancer. It was estimated that up to seven percent of breast cancer cases are estimated to be due to breast cancer susceptibility genes  . AlthougIt appears to be that the patients used radiotherapy along with chemotherapy or/and hormonal therapy had less risks of developing second cancers compared with those patients received radiotherapy alone. However, we do not have detailed information about the staging of breast cancer at the time of diagnosis and what criteria were based on for the prescription of different therapies. Therefore, it is difficult to explain the reasons why the use of chemo- and/or hormonal therapy combined with radiotherapy might lead to a lower risk of second cancer compared to the use of radiotherapy alone. However, it is interesting to note that women who only received chemotherapy or hormonal therapy did not have raised risk of second cancer, although numbers of cases may be too small to detect any raised risk in these subset analyses.This study indicated a raised risk of second malignancies associated with radiotherapy for breast cancer. The relative risk for second cancers appeared to be highest for the 50 to 65 years age-at-treatment group during the period five or more years after radiotherapy and this might be related to the patients' menopausal status. Among specific types of cancer, there were raised risks for leukaemia and for all cancers combined except leukaemia and contralateral breast cancer. The risk of contralateral breast cancer was not raised during the period five or more years after radiotherapy.CI: confidence interval; RR: relative risk.The authors declare that they have no competing interests.WZ and CM participated in the data analysis and interpretation, manuscript drafting and revision. AB and AB participated in the study design, data collection, results interpretation and manuscript revision. They read and approved the final manuscript. PP was the radiotherapist involved in the project but deceased after the data collection.


TGFβ1) gene. The proline-encoding (Pro-) allele of this SNP has been associated with an increased breast cancer risk, which has been attributed to the elevated secretion of this TGFβ1 variant observed in vitro and in male subjects. Here we investigated the association of the L10P SNP with serum levels of TGFβ1 in female breast cancer patients and controls. We genotyped the L10P SNP in 276 breast cancer patients and 255 controls. Serum TGFβ1 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in a subset of the study population (n = 211). We found no evidence for an association of the L10P SNP with breast cancer risk . However, patients with the Pro/Pro genotype exhibited a significantly younger age at breast cancer onset (55.2 ± 14.3 years) than Leu/Leu patients , which may reflect the ability of TGFβ to promote tumor progression. Mean TGFβ1 serum levels of Pro-allele carriers were 39.4 ± 7.4 ng/mL, whereas those of Leu/Leu subjects were 37.6 ± 6.0 ng/mL (p = 0.07). Thus, compared to a previous study of male subjects, we observed only a modest increase, if any, in TGFβ1 levels of female Pro-allele carriers.The L10P single nucleotide polymorphism (SNP) is located in the signal sequence of the transforming growth factor β1 ( Transforming growth factor β (TGFβ) is a multifunctional cytokine and a key growth suppressor in many cell types, eliciting potent anti-proliferative and apoptotic responses –3. Accorvs. Leu/Leu: OR, 1.16; 95% confidence interval, 1.08–1.25 [et al. [TGFβ1 SNPs with breast cancer has also been analysed, such as the promoter SNPs C-509T and G-800A and the R25P coding SNP [The gene encoding TGFβ1, one of the three human TGFβ isoforms, contains a single-nucleotide polymorphism (SNP) at position 29 of its coding sequence, the major allele encoding leucine and the minor allele encoding proline as amino acid 10 . A large study of the Breast Cancer Association Consortium (BCAC) has reported an association of the Pro-allele with a moderate, but significantly increased, breast cancer risk . The Pro/Pro genotype was slightly less frequent in breast cancer patients than in controls  negative vs. 12.9% of ER positive; and 19.7% of progesterone receptor (PR) negative vs. 13.0% of PR positive patients exhibited the Pro/Pro genotype  and control subjects (n = 101) with known L10P genotypes (p = 0.048). Patients with the Leu/Leu genotype (n = 36) had mean TGFβ1 serum levels of 36.5 ± 6.0 ng/mL, whereas mean serum levels of Pro-carriers  were 38.6 ± 7.4  were 38.8 ± 5.8 ng/mL, and of Pro-carriers (n = 68) 40.3 ± 7.3 ng/mL (p = 0.30). Thus, Pro carriers had slightly higher mean TGFβ1 serum concentrations than Leu/Leu individuals both in the control group and in the breast cancer patients, although the observed differences were not significant (n = 69) were determined to be 37.6 ± 6.0 ng/mL, and those of Pro carriers (n = 142) were 39.4 ± 7.4 ng/mL (p = 0.07). Furthermore, no significant differences in TGFβ1 serum levels were observed between patients with ER negative vs. ER positive, ductal vs. lobular, pN0 vs. pN+, pT1 vs. pT2-4 tumors, or between patients younger or older than 55 years (data not shown).Next, serum levels of TGFβ1 protein were analyzed in breast cancer patients , whereas TGFβ1 serum levels in female patients or controls were not reported [vs. female subjects [p < 0.05 level  allele of ecretion . Expresseriments . The in reported . Interessubjects . In a gasubjects . To the 05 level . Collectvs. Leu-carriers: HR, 0.36; 95% confidence interval (c.i.), 0.17–0.75 [We hypothesize that, if the Pro-allele is indeed hypermorphic it should be associated with a reduced overall breast cancer incidence, due to the tumor suppressor activity of TGFβ initially effective in all tumors during the early phases of the multi-step progression. This is reflected by odds ratios below unity reported by some studies, and a particularly pronounced reduction in breast cancer risk in a prospective study Pro/Pro .17–0.75 ). On the7–0.75 . .17–0.75 . Indeed,vs. pT1 tumors, grade 2 vs. grade 1 tumors, and negative vs. positive ER status, although these trends were not significant at the 95% confidence level (data not shown). The BCAC study has reported higher odds ratios associated with the Pro-allele in patients with high tumor grade and stage, and negative ER and PR status, although only the latter association was statistically significant [How is the “advanced stage”, in which tumors are responsive to the tumor promoting activity of TGFβ but no longer to its initial tumor suppressive activity, reflected by clinical tumor parameters? TGFβ primarily enhances a tumor’s invasive and metastatic potential, which are the major determinants of disease outcome –4. Accornificant . Similarnificant . We obsenificant .The study population has been described in detail in . BrieflyTGFβ1 L10P; Leu10Pro; T + 29C; formerly termed rs1982073) was performed by TaqMan PCR with allele-specific, fluorescently labeled probes following the manufacturer’s instructions . 40 ng of genomic DNA were used per reaction in a total reaction volume of 10 μL.Genomic DNA was extracted from patients’ blood with the QIAamp DNA Blood Midi kit  per the manufacturer’s instructions. Genotyping of SNP rs1800470 (n = 25) and controls (n = 26) with the Pro/Pro genotype, and roughly equal numbers of randomly selected samples of the Leu/Leu and Leu/Pro genotypes were subjected to ELISA measurements of TGFβ1 concentrations with the Emax ImmunoAssay System . Prior to measurement, diluted serum samples were treated with hydrochloric acid, following the manufacturer’s instructions to release any latent TGFβ1 from complexes with other serum proteins.Serum samples were collected from a subset of the patients and controls of this study between 2003 and 2004 under identical fasting conditions. None of the patients had undergone cancer treatment prior to serum isolation. Following genotyping, all available samples of patients (t-tests. Confidence intervals given are 95% mid-P exact confidence intervals, i.e., considering all possible configurations of the contingency table that are more extreme than the observed configuration, and half the configurations that are equivalent to the observed one. Likewise, p-values shown in p-values. Associations between the three L10P genotypes and clinical or histopathological characteristics were evaluated with Chi-square tests.Statistical analyses were performed with R version 2.15.1, an open-source language and environment for statistical computing . PotentiTGFβ1 is hypermorphic and reduces the overall incidence of breast cancer. However, if a tumor does develop in Pro-allele carriers, it is likely to progress faster to a more advanced stage, with invasive properties and a poor prognosis. Which of these conflicting effects predominates in a particular study likely depends on the specific composition of the study population. Our study had insufficient cases to detect a significant differential risk in subgroup analyses, thus it would be important to perform such analyses in larger studies and/or meta-analyses to better define the clinical subgroups in which the tumor-suppressive vs. tumor-promoting activities of TGFβ1 might be present.The current evidence is consistent with a model in which the Pro-allele of


Demographic, socioeconomic and cultural changes in India have increased longevity, delayed childbearing, decreased parity and resulted in a more westernised lifestyle, contributing to the increasing burden of cancer, especially among women.We evaluated secular changes in the incidence of breast, cervical and ovarian cancer in Mumbai women aged 30–64 between 1976 and 2005. Age-standardised incidence rates were calculated and presented by site and calendar period. An age–period–cohort (APC) analysis quantified recent time trends and the significance of birth cohort and calendar period effects. The estimated annual percent change (EAPC) was obtained from the drift parameter, expressing the linear time trend common to both calendar period and birth cohort.Over the 30-year study period, the age-standardised rates significantly increased for breast cancer : 1.0, 1.3)), significantly decreased for cervical cancer ) and there was no statistically significant change for ovarian cancer ). For breast and cervical cancer, the best-fitting model was the APC model.The rates of breast, cervical and ovarian cancer remain low in comparison with western countries, and the divergent trends of breast (increasing) and cervical cancer (decreasing) in Mumbai were similar to those observed in several other Asian countries. The changing risk profile in successive generations – improved education, higher socioeconomic status, later age at marriage and at first child, and lower parity – may in combination partially explain the diverging generational changes in breast and cervical cancer in Mumbai in the last decades. The increasing incidence of cancer in India has mirrored trends in developed countries, although the rates for major sites, such as female breast cancer have remained comparatively low. Over the last two decades, the urbanisation and increasing modernisation of India has transformed education, lifestyle, health-care access and longevity, and has contributed to an increased risk profile for chronic diseases such as cancer . A higheThis study aims to quantify the recent time trends in the most commonly occurring female cancers in Mumbai women, with a view to better understanding the contribution of changing lifestyle. An age–period–cohort (APC) analysis of breast, ovarian and cervical cancer incidence trends was conducted, using the population-based cancer registry data in Mumbai, India over a 30-year period, 1976–2005.All incident cases of breast, ovarian and cervical cancer  diagnosed in 1976–2005 were extracted from the Mumbai Cancer Registry. Registry personnel conducted routine visits to 140 collaborating hospitals over a 603 square kilometre area of over 12 million residents to review pathology logs on new cancer diagnoses. Medical charts and pathology reports were reviewed for clinical information including date and method of diagnosis, histological grade and subtype, and stage of disease as well as demographic information such as age, gender, ethnicity and marital status. The Mumbai Registry data set has consistently met IARC's quality standards with respect to inclusion in consecutive volumes of their Cancer Incidence of Five Continents series  and the effects of period and cohort curvature, were obtained using the analysis of deviance of nested models, as suggested by A more formal assessment of the contribution of age, period and cohort effects involved the fitting of APC models to the trends , 1987b. a priori hypothesis that the increasing trends in breast and ovarian cancer, for example, are allied to generational influences; a changing prevalence and distribution of known and unknown lifestyle and environmental factors in the female population of Mumbai, should, given a sufficient time lag, result in changing cancer rates observed in successive birth cohorts. Stata  against a changing prevalence and distribution of risk factors, which may show up as changes in rates among successive generations (cohort effects).vs Asian countries  1992–93: Maharastra, India, 1995; National Family Health Survey India (NFHS-2): 1998–99 Maharastra, India, 2000). In a case series of 11780 tumours (The significant decline in cervical cancer, once the most common cancer of Mumbai women, is likely due to changes in marriage and family planning, supported by underlying improvements in education and socioeconomic status. Generational changes in age at marriage and first pregnancy  have resAlthough ovarian cancer rates in Mumbai were half those in the United States in 1976 , it rankThe APC models yielded significant non-linear cohort effects for underlying changes in breast and cervical cancer risk, which is consistent with the adoption of modern reproductive practices. Lifestyle patterns of Mumbai females changed considerably during the study period; women in Mumbai attained higher levels of education, postponed marriage, had their first child at an older age and had fewer pregnancies over time . Furthera priori epidemiological or biological knowledge – was beyond our present understanding of the trends, and instead we assumed a period slope of zero, allowing for the drift to be included in birth cohort. This method still allows non-linear effects for period to be visible (A graphical display of the APC parameters was included in this study, although a meaningful ‘solution’ – one that numerically allocates the drift to period and cohort on the basis of  visible . There mOverall, trends in breast cancer and cervical cancer incidence rates in Mumbai, India mirrored those observed in Western countries over the same 30-year time period. The changing risk profile among younger generations allied to a westernisation of lifestyle – improved education, higher socioeconomic status, later age at marriage and at first child, and lower parity – explain part of the generational changes that yielded significant changes for both cervical and breast cancer rates over time.


Metabolic syndrome is a cluster of metabolic abnormalities and is defined as the presence of three or more of the following factors: increased waist circumference, elevated triglycerides, low high-density lipoprotein cholesterol, high blood pressure, and high fasting glucose. Obesity, which is accompanied by metabolic dysregulation often manifested in the metabolic syndrome, is an established risk factor for many cancers. Adipose tissue, particularly visceral fat, is an important metabolic tissue as it secretes systemic factors that alter the immunologic, metabolic, and endocrine milieu and also promotes insulin resistance. Within the growth-promoting, proinflammatory environment of the obese state, cross-talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, adipocytokines, and other mediators that may enhance cancer risk and progression. This paper synthesizes the evidence on key molecular mechanisms underlying the obesity-cancer link. In 1998, the World Health Organization recommended a unifying definition and chose the term metabolic syndrome [The clustering of atherosclerotic risk factors that identify metabolic syndrome was first recognized in 1983  introducsyndrome .Metabolic syndrome is now recognized as a cluster of metabolic abnormalities and is defined as the presence of three or more of the following factors: abdominal obesity (increased waist circumference), elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, high blood pressure, and high fasting glucose .IR, along with its associated hyperinsulinemia and hyperglycemia, and adipocyte cytokines (adipokines) may lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease (CVD) , 6–8.The metabolic syndrome involves a proinflammatory, prothrombotic state and is associated with elevated levels of C-reactive protein –12, inteIn addition to the mechanical effects of obesity, such as an increase in intra-abdominal pressure caused by excess adipose tissue, adipose tissue secretes various adipokines, such as tumor necrosis factor (TNF), IL-6, leptin, and insulin-like growth factor-1 (IGF-1), which are considered to have pathogenic effects in relation to gastrointestinal cancer.2 and obesity as BMI >30 kg/m2 [The classification of obesity for epidemiological purposes defines overweight as body mass index (BMI) >25 kg/m30 kg/m2 . Fat is 30 kg/m2 , 16.2 had significantly higher mortality compared with subjects with a BMI of 22.6–25 kg/m2 [2. In the Asian Cohort Consortium, the East Asian, Indian, and Bangladeshi populations with a BMI <20.1 kg/m25 kg/m2 . MortaliOmental adipose tissue, also referred to as visceral adipose tissue, can exert systemic effects that are putatively involved in cancer biology . MetabolOverall, 14% of all cancer deaths in men and 20% of all cancer deaths in women are attributable to overweight and obesity . ObesityHere, we review the association between metabolic syndrome and gastrointestinal cancer, focusing on the pathogenic roles of obesity and adipokines.The prevalence of metabolic syndrome, as defined by the 2001 Adult Treatment Panel (ATP) III criteria, was evaluated in 8814 adults in the United States who participated in the third National Health and Nutrition Examination Survey  . The oveThe prevalence of metabolic syndrome is steadily increasing. Indeed, in NHANES from 1999 to 2002, 34.5% of participants met the ATP III criteria for metabolic syndrome, an increase from 22% in NHANES III (from 1988 to 1994) , 31. In 39% prevalence in moderately obese and 50% prevalence in severely obese children and adolescents, based on study of 439 obese children and adolescents; metabolic syndrome defined as 3 or more criteria for age and sex.Epidemiological and animal studies have demonstrated a close link between maternal nutrition and chronic metabolic disease in children and adults . For exaThe current evidence for the fetal influences on later health is mainly attributed to the mother's diet, as maternal obesity, excessive weight gain during pregnancy, and gestational diabetes are known to increase the risk of various diseases in the offspring. Nutritional imbalance (over- or undernutrition) and exposure to environmental chemicals during development can also increase the risk of these diseases, possibly through common pathways .These pathways include DNA methylation, histone modifications, and noncoding RNA expression. Such epigenetic modifications can be passed from one cell generation to the next and, in some cases, if germ cells are targeted, can be transmitted across generations .Disruption of epigenetic mechanisms can result in oxidative stress, obesity, insulin resistance, diabetes, and vascular dysfunction in animals and humans. Hormones, cytokines, and nutritional components can directly activate receptors that stimulate gene expression and can also activate or inhibit the enzymes and pathways that are responsible for DNA methylation, chromatin remodeling, and noncoding RNAs, which ultimately control gene expression. Thus, epigenetic regulatory pathways are the likely targets that mediate the effects of nutrients and environmental toxicants during development and potentially across the entire lifespan.Adipose tissue, particularly visceral fat , is an iWithin the growth-promoting, proinflammatory environment of the obese state, cross-talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, cytokines, and other mediators that may increase the risk of cancer and its progression .in vitro [Obesity is strongly associated with insulin resistance, in which the levels of insulin and IGF-1 are elevated. Insulin can act as a mitogen and is associated with several cancers . Insulinin vitro –43, whilin vitro , 45.Most research to date has focused on the systemic mechanisms underpinning the association between obesity and cancer. Potentially relevant pathways include the insulin-IGF axis, sex steroid pathways, and adipocytokine pathways.Insulin is an anti-inflammatory agent, and anti-inflammatory agents have been shown to reduce the risk of colorectal neoplasms , 47. TheObesity is also associated with tissue inflammation, which is at least partly mediated by adipose tissue. It was speculated that subclinical inflammation is associated with the development of colorectal cancer  because Therefore, one possible explanation for the link between diabetes and colorectal cancer is hyperinsulinemia. This link was proposed because insulin is an important growth factor for colonic mucosal cells and stimulates the proliferation of colonic tumor cells , 42, 50.The plasma concentrations of IGF-1 and IGF binding protein-3 (IGFBP-3) were reported to influence the risk of colorectal cancer in a prospective cohort of 14,916 men . SubjectGenetic polymorphisms of IGF-1 may also increase the risk of cancer . Polymorin vitro and in vivo [An earlier study  revealed in vivo .Adipocyte-conditioned media can promote tumorigenesis in cancer cells by increasing cell proliferation, invasive potential, angiogenesis, and cross-talk between cancer cells and the surrounding extracellular matrix . These aAdiponectin is the most abundant adipocytokine and is predominantly secreted from visceral fat adipocytes. Adiponectin levels are inversely correlated with BMI  and are Mice with disruptions in the adiponectin gene are more likely to develop intestinal tumors, with decreased activation  of AMP-activated protein kinase and increased PAI-1 levels compared with wild-type mice.In vitro, adiponectin suppressed colon cancer cell proliferation via AdipoR1- and AdipoR2-mediated AMPK activation [Several different molecular weight isoforms  can be detected in the vascular system. The biological effects of these isoforms are mainly mediated through two classical adiponectin receptor subtypes: AdipoR1 and AdipoR2 . Severaltivation . In humativation  in areastivation  to that In vitro studies have confirmed that leptin promotes cell proliferation, angiogenesis, and metalloproteinase expression in esophageal and colon cancer cell lines [Leptin is an adipocyte-specific hormone that acts centrally to regulate appetite and bodyweight  and therll lines .β, IL-6, IL-8, IL-12, TNF, and Toll-like-receptor-2 through the nuclear factor-κB pathway [Resistin, a 12.5-kDa protein encoded by a region on chromosome 19 in humans, is a 108 amino acid prepeptide . In huma pathway . Resisti pathway . In huma pathway , 76 or c pathway  compared pathway . In moleExcess adipose tissue is associated with chronic, systemic, low-grade inflammation . The amoThe immune system plays a fundamental role in antitumor immunity, and, under certain circumstances, it can promote tumor development and progression. In most studies, the density of tumor-associated macrophages was correlated with increased angiogenesis, tumor invasion, and poor prognosis .Gastroesophageal reflux disease (GERD) is a common cause of morbidity and healthcare use in many countries. A positive association between increased BMI and the presence of GERD was reported in the United States, but this relationship became apparent only after stratification by country and the level of BMI .2 or >30 kg/m2 were 1.52 and 2.78, respectively [Overweight and high BMI are associated with an increased risk of esophageal adenocarcinoma and adenocarcinoma of the gastric cardia, even in subjects with a normal BMI –86. In aectively .Adipose tissues, particularly metabolically active visceral adipose tissues, produce large amounts of adipocytokines, including IL-6 and TNF , which mObesity is also associated with upregulated leptin receptor and adiponectin receptor expression in esophageal adenocarcinoma cells. The association between leptin receptor and adiponectin receptor expression with tumor stage suggests that adipocytokines may influence tumor biology. Over 90% of esophageal adenocarcinomas were reported to express the leptin receptor, with most (67%) showing markedly upregulated expression [The systemic inflammatory state that develops as a consequence of disturbed metabolism in obese patients and the associated impact of adipocytokines and procoagulants released by adipocytes in visceral fat may underlie the relationship between obesity and esophageal adenocarcinoma .Interestingly, subjects with serum insulin and IGF-1 levels in the highest tertiles had the highest risk of Barrett's esophagus. Serum IGF-1 levels in the highest tertile were associated with an increased risk of Barrett's esophagus  compared with a control group who underwent screening colonoscopy, but were not significantly different from a control group of subjects with GERD .2) and obesity (BMI > 25 kg/m2) were associated with an increased risk of cancer of the gastric cardia among Asians and non-Asians, and with gastric cancer among non-Asians. The strength of these associations increased with increasing BMI. However, overweight was not an independent prognostic factor for long-term survival in Western patients with gastric cancer [Excess body weight and obesity are associated with an increased risk of gastric cancer . For exac cancer .2) [2 increase in BMI was associated with a 24% increased incidence of colon and rectal cancer in men, and a 9% higher incidence of colon cancer in women [ Obesity is an important risk factor for colorectal cancer. Two large prospective cohort studies have shown that obesity increases the risk of colorectal cancer by approximately 1.5-fold compared with normal weight individuals (BMI 18.5–24.9 kg/m2) , 96. Simin women . Many studies have demonstrated that the association between obesity and colorectal cancer is stronger in men than in women. This was hypothesized to be due to differences in adipose tissue distribution, as the more pronounced visceral adiposity in men than in women mirrors the apparent difference in risk .Colorectal cancer and adenoma disease are associated with dietary factors, such as red meat, high fat content, and inadequate fiber intake. Of note, high intake of red meat and processed meat was associated with increased risk of colorectal, colon, and rectal cancers , 100.Two studies also found an increased risk of colorectal cancer in subjects with metabolic syndrome , 101. InIt is also becoming apparent that adiposity is the factor that is most strongly associated with the risk of colorectal cancer . CentralSeveral epidemiologic studies have revealed a possible link between diabetes mellitus and HCC , 105. HoAn association between diabetes mellitus and cancer of the biliary tract was reported in several case-control and cohort studies. In a meta-analysis of 15 studies, patients with diabetes had a significantly higher risk of cholangiocarcinoma relative to individuals without diabetes . A study2 was associated with a significantly increased risk of pancreatic cancer compared with a BMI of <23 kg/m2. Height was also associated with an increased risk of pancreatic cancer. On the other hand, an inverse association was observed for moderate physical activity when comparing the highest and lowest categories, particularly among individuals with a BMI of ≥25 kg/m2. It was also reported that high BMI is associated with decreased survival in patients with pancreatic cancer, although the mechanism for this association was not determined [Several studies have revealed a link between high body mass, lack of physical activity, and pancreatic cancer risk –117. A Btermined .Other researchers have suggested that overweight and obese individuals develop pancreatic cancer at a younger age than do patients with a normal weight, and the rate and duration of survival are lower, once pancreatic cancer is diagnosed .Metabolic syndrome represents a cluster of metabolic abnormalities and is defined as the presence of three or more of the following factors: abdominal obesity , elevated triglycerides, low HDL cholesterol, high blood pressure, and high fasting glucose. Multiple hormones, growth factors, cytokines, and other mediators associated with the obese state and metabolic syndrome enable cross-talk between macrophages, adipocytes, endothelial cells, and epithelial cells and therefore contribute to cancer-related processes. Efforts to increase our knowledge of the underlying mechanisms are crucial to help us design effective therapeutic strategies to prevent and treat metabolic abnormalities.The association of gastrointestinal diseases with metabolic syndrome is summarized in Recent studies have shown that the risk of disease may be induced very early in the life course and it may be modifiable by nutrients. Consequently, it seems rational to improve nutrition and reduce exposure to environmental chemicals before and during pregnancy, and during the first few years of life. Such changes are likely to have a significant impact on reducing the disease burden and the associated healthcare costs.


The aim of the study was determination of serum Se concentration and identification of genetic variations in genes related to metabolism of selenium as markers of cancer risks for carriers of BRCA1 gene mutation and individuals with susceptibility to other common unselected cancers .Eight genotypes of 4 most common SNPs localised in GPX1, GPX4, TXNRD2 and SEP15 were selected. Genotyping was performed in 93 affected and 186 unaffected matched BRCA1 carriers as well as on pairs matched 1:1 consisting of 108 breast, 50 ovarian and 105 prostate consecutive cancer patients and healthy controls.The following techniques for laboratory analyses have been applied: a) sequencing on ABI310, b) SimpleProbe or TaqMan analysis (a melting-curve genotyping with fluorescence-labeled probes based on the LightCycler 480 System (Roche Applied Science), c) determination of selenium concentration in plasma using atomic absorption spectrometer AAnalyst600 (Perkin Elmer).In none of studied groups statistically significant differences on cancer risk could be found when serum selenium concentration was assessed as a single factor. However, when selenium level data were combined with some selenoprotein genotypes some strong associations with cancer risk have been identified.The strongest association was found for carriers of SEP15 nGG genotype  and GPX1 nCC/TXNRD2 nGG/SEP15 GG .Results were not statistically significant however tendencies similar to those found in BRCA1 carriers and unselected breast cancer were observed.For four genotypes: GPX1 CC, GPX4 nCC, TXNRD2 GG and SEP15 nGG lower risk (~3 times) was found for selenium level ~90µg/l.


Breast cancer is a complex disease which is provoked by a multitude of exogenous and endogenous factors including genetic variations. Recent genome-wide association studies identified a set of more than 18 novel low penetrant susceptibility loci, however, a limitation of this powerful approach is the hampered analysis of polymorphisms in DNA sequences with a high degree of similarity to other genes or pseudo genes. Since this common feature affects the majority of the highly polymorphic genes encoding phase I and II enzymes the retrieval of specific genotype data requires adapted amplification methods. With regard to breast cancer these genes are of certain interest due to their involvement in the metabolism of carcinogens like exogenous genotoxic compounds or steroid hormones. The present review summarizes the observed effects of functional genetic variants of phase I and II enzymes in well designed case control studies to shed light on their contribution to breast cancer risk. FGFR2, CCND1, TOX3, MAP3K1, LSP1, CDKN2A, and 2B , and Methyltransferases. The combined phase I and II metabolism is mainly a detoxification and elimination process, however, both phases bear the risk of formation of toxic and highly reactive compounds which can induce or promote serious health problems such as cancer  polymorphism. The human SULT1A subfamily comprises three genes SULT1A1, SULT1A2, and SULT1A3 which are located in close proximity on the short arm of chromosome 16 and share sequence similarities of more than 90%  which lead to a decreased activity of the CYP2C19 has been associated with increased risk in Asians  causing an ultra rapid metabolizer phenotype leads to a decreased HRT-related breast cancer risk in Europeans  and poorly differentiated breast tumors which may be explained by a potential contribution of the variant allele to increased sex hormone levels  affects lymph node status of breast cancer patients (Jernstrom et al., CYP2C9*2 allele which is in linkage disequilibrium with CYP2C8*4 cannot be excluded (Jernstrom et al., Only a few well designed studies investigated the association between phase I and II enzymes and histo-pathological characteristics of breast tumors Table . One stuGenetic variations of phase I and II enzymes alter their activity or protein biosynthesis leading to defective detoxification and elimination of carcinogenic compounds. Due to a high degree of DNA sequence similarity among genes of subfamilies accurate genotyping requires elaborated methods and exhaustive quality control. Until now a few well designed studies give insights into the effect of polymorphisms in metabolic enzymes on breast cancer risk and point to their crucial action in steroid hormone catabolism. These finding underline the pivotal role of sex hormones in the regulation of proliferation, differentiation, and apoptosis as critical pathways for onset and progression of breast cancer (Schindler et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.