However, these selective estrogen receptor modulators can also be associated with several rare, but serious, adverse events. Recently, the third-generation aromatase inhibitors (ais) have demonstrated excellent efficacy in adjuvant breast cancer trials, and they show particular promise in the breast cancer prevention setting. The National Cancer Institute of Canada Clinical Trials Group (ncic ctg) has developed a randomized phase iii study to determine the efficacy of an ai (exemestane) to reduce the incidence of invasive breast cancer in postmenopausal women at an increased risk for developing breast cancer. The ncic ctg map.3 (ExCel) trial is a double-blind placebo-controlled multicentre, multinational trial. Based on the known preclinical and clinical profile of the ais, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifene.Several large phase  Breast cancer is one of the most frequently diagnosed malignancies in women worldwide. In North America, it represents about 30% of all cancers and about 20% of all cancer-related deaths. In the United States and Canada respectively, more than 200,000 and 20,000 new breast cancer cases are diagnosed annually, and beginning in the 1980s and continuing until very recently, the incidence of breast cancer was rising at a rate of approximately 2% per yearThe epidemiology of breast cancer is strongly influenced by genetic and environmental factors. Compared with other women, women with breast cancer are about twice as likely to have a first-degree relative with breast cancer, suggesting that the genetic factors are important determinants of disease risk9.10. To date, most research has focused on endogenous sex steroid exposure, and higher levels of estrogen and androgens have been shown to be associated with a modest increase in the risk of breast cancer in pre- and postmenopausal womenigf) axisigf-1 plays in stimulating the growth of prostate and breast cancer cells alikeDecades of epidemiologic and laboratory research have also identified that hormonal exposures are important in the complex origins of breast cancer. Hormonal events such as early age at menarche, late age at parity, and late onset of menopause can all increase breast cancer riskMany of the established risk factors currently identified for breast cancer cannot be easily modified. However, improved diet and reduced body weight, alcohol intake, hormone use, and mammographic density are examples of factors that canhrt) in 2002 may be the best explanation for the reduction in breast cancer occurrence. Following the disappointing findings in 2002 from the Women’s Health Initiative Study of combination estrogen and progestin, which demonstrated a statistically significant increase (24%) in the breast cancer risk in the treatment arm, hrt prescribing patterns were significantly alteredDr. Ravdin and his team speculate that the dramatic reduction in use of hormone replacement therapy . An alternative strategy of antagonizing (reducing) the effects of estrogen is to inhibit estrogen synthesis with an aromatase (estrogen synthetase) inhibitor (ai).To date, chemoprevention research has focused on strategies directed at antagonizing the effects of estrogens, because these hormones are known to play a key role both in the development of the normal breast and in the pathogenesis of breast cancerserms. As a result, tamoxifen was approved by the U.S. Food and Drug Administration (fda) for short-term reduction in the incidence of ductal carcinoma in situ (dcis) and invasive breast cancer in women at increased risk. Raloxifene is currently under review by the fda for approval as a second chemopreventive agent for women at high risk of developing invasive breast cancer. In fact, tamoxifen and raloxifene both appear effective in reducing breast cancer risk in “all risk” individuals as well, but approval for tamoxifen was granted by the fda only for use in high-risk women because of its complicated therapeutic index. In particular, tamoxifen can cause rare, but serious, adverse events, including endometrial cancer and thromboembolic disease, especially in older postmenopausal womenTamoxifen and raloxifene have both been shown to reduce the incidence of invasive breast cancer by up to 50% in pre- and postmenopausal women at high riskais on risk of breast cancer in postmenopausal women is currently under study. The National Cancer Institute of Canada Clinical Trials Group (ncic ctg) map.3 trial is one such study designed to examine the efficacy of exemestane versus placebo in postmenopausal women at increased risk of developing breast cancer. The International Breast Cancer Intervention Study 2 (ibis 2), initiated in 2004, is the only other large, phase iii trial designed to evaluate the efficacy of anastrozole as compared with placebo in preventing invasive breast cancer. It is underway in a similarly high-risk population in the United KingdomThe effect of ais were developed.Targeting and reducing estrogen synthesis is a way of preventing estradiol from stimulating the estrogen receptor and of reducing the formation of cancer-causing catechol metabolites of estrogen. To that end, ais letrozole, anastrozole, and exemestane are all approved for use in postmenopausal women with estrogen receptor–positive metastatic breast cancer that has progressed after tamoxifen or failed to respond to tamoxifenfda and Health Canada have approved anastrozole, exemestane, and letrozole for use as adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer following varying periods of treatment with tamoxifen.Aromatase is the enzyme complex responsible for the final step in estrogen biosynthesis: the conversion of androgens to estrogens. The third-generation ais in early-stage postmenopausal receptor-positive breast cancer. Published data from four large phase iii double-blind randomized adjuvant trials comparing third-generation ais with tamoxifen or placebo after 5 or fewer years of tamoxifen are currently available.At least eight adjuvant trials are currently testing atac) trial, 9366 patients were randomly assigned to receive anastrozole and placebo, tamoxifen and placebo, or anastrozole and tamoxifen combined. Disease-free survival was significantly lengthened when the anastrozole group was compared with the tamoxifen group  after a median follow-up of 47 months. Importantly, the incidence of new contralateral primary breast cancer was significantly lower in the anastrozole group than in the tamoxifen group In the Arimidex, Tamoxifen Alone or in Combination (ies) randomly assigned 4742 women who had received 2–3 years of tamoxifen to continue tamoxifen for a total of 5 years or to switch to exemestane to complete a 5-year course of hormonal therapy. After a median follow-up of 56 months, a significant improvement in disease-free survival was observed in the exemestane group , together with a significant reduction in contralateral breast cancer events  The Intergroup Exemestane Study  recommends that, to lower the risk of recurrence, adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer should include ais. The optimal timing and duration of ai therapy has yet to be establishedBased on results from these large trials and other smaller randomized trials, the Technology Assessment of Aromatase Inhibitors Status Report 2004 from the American Society of Clinical Oncology  trial (www.excelstudy.com) is a randomized double-blind placebo-controlled, multicentre, multinational trial sponsored by the ncic ctg and supported by Pfizer Inc. Based on the known pre-clinical and clinical profile of the ais, a greater reduction in breast cancer incidence is hypothesized with this class of agents than with tamoxifen or raloxifene.The cox-2) inhibitor, celecoxib (400 mg); exemestane (25 mg) in combination with a placebo; and a placebo (2 tablets) in a phase iii randomized trial, in 5100 post-menopausal women at increased risk of developing breast cancer. The rationale for incorporating celecoxib into the trial design was based on observations that cox-2 is overexpressed in breast cancer and in pre-invasive breast lesionsci: 0.75 to 0.89) for developing breast cancer in women who had a history of taking cox-2 inhibitorsmap.3 protocol was developed, celecoxib was considered to be well tolerated and safe.The initial intent was to compare exemestane (25 mg) in combination with a cyclooxygenase enzyme 2 map.3 steering committee decided to halt the trial and revise the protocol.Unfortunately, in September 2004, early results from a colorectal adenoma chemoprevention trial , or having a prior diagnosis of dcis that was treated with a mastectomy. Women are stratified on their Gail score (≤ 2 vs. >2) and current low-dose (<100 mg daily) aspirin use (yes vs. no) before being randomly allocated to the treatment or placebo group.The revised Despite the fact that tamoxifen has been approved as a means to reduce breast cancer risk in women who would be eligible for this trial, it was decided that the use of a placebo control arm was justified for several reasons:Although tamoxifen is approved for the indication of reducing the short-term incidence of breast cancer, many women whose level of risk would qualify them for the prescription of tamoxifen refuse the drug because of its toxicity profileasco Technology Assessment of Pharmacologic Interventions for Breast Cancer Risk Reduction Including Tamoxifen, Raloxifene and Aromatase Inhibitionmap.3 trial is not expected to demonstrate an impact on survival, the results may well indicate a more favourable therapeutic ratio for exemestane than for tamoxifen or raloxifene.The The placebo arm will allow for a true determination of efficacy in reducing invasive breast cancer, of adverse effects, and of impact on overall and menopausal-specific quality of life.map.3 research study will have a bone-mineral density test and a mammogram before being randomized. Women can be enrolled at centres in Canada, the United States, or Spain. Participants will be asked to return to their local study centre twice during the first year, at 6 and 12 months, and then annually for follow-up visits for the remaining 4 years of the study. At each visit, participants will be given a new supply of the study medications and will be asked to answer questions about their quality of life and about any illnesses or discomfort they may have experienced since their last visit. At each annual visit, participants will undergo a physical and health exam and a mammogram. At three different times during the study, serum samples will also be taken for hormone testing. If additional consent has been given for dna testing, a blood sample taken at baseline will be stored for future genetic testing.Women enrolled in the map.3 trial is to compare the incidence of breast cancer in the two treatment groups. Information will also be recorded and compared between treatment groups on clinical bone fractures, cardiovascular events, quality of life, tolerability and safety, and incidences of other malignancies. A companion study to evaluate the long-term effects of exemestane on bone density and bone biomarkers is planned for a subset of participating sites.The main objective of the Some of the biggest challenges of conducting a breast cancer prevention trial include recruiting women from the general population and defining the groups at high-risk for the development of breast cancer that are most eligible for chemoprevention. Well established cancer cooperative groups with affiliated clinical research centers in North America, Europe, and Australia are available to help with recruitment of cancer patients into therapeutic trials. However, that model is not so easy to replicate for cancer prevention trials. The clinicians that typically see well women are more likely to be primary care physicians or other internal specialists such as gynecologists. However, primary care physicians in particular do not appear to be comfortable prescribing chemoprevention medicationmap.3 trial to be feasible, the ncic ctg had to assemble a consortium of clinical researchers in Canada and the United States who were committed to cancer prevention research and who had participated in earlier prevention trials with the Women’s Heath Initiative (whi) or the National Surgical Adjuvant Breast and Bowel Project. Nonetheless, recruiting to chemoprevention trials is still very challenging, even for experienced research centres. To be successful, each site must consider numerous recruitment strategies. Some of the most successful strategies to date on map.3 include mass mailings, targeting of high-risk screening clinics, and targeting of “enriched” lists .For the Cancer prevention trials tend to be dauntingly large, particularly if cancer is the primary endpoint. The large sample size is necessary because cancer is a very rare occurrence in the general population, and there is a need to complete the study in a reasonable period of time . Selecting a study sample that has a higher-than-average risk of developing cancer is one strategy to increase the event rate in a fixed period and thereby reduce the required sample size.Risk prediction models can be included in the design of chemoprevention studies to help identify high-risk populations for an assessment of the effects of interventions and construction of risk–benefit indices for preventive interventionsAge is one of the most important risk factors for breast cancer. An average 60-year-old woman has a Gail score of 1.8%; an average 35-year-old woman has a Gail score of 0.3%. By designing a prevention trial with a minimum Gail score requirement of 1.66% for women who are under 60 years of age and have no history of benign breast disease, the expected annual incidence rate (event rate) in the placebo group (0.60%) will be more than 6 times the annual incidence rate in the general population (0.10%)iii trials have consistently demonstrated that tamoxifen—and more recently, raloxifene—can effectively reduce the incidence of invasive breast cancer by 50%. However, these serms can also be associated with several rare, but serious adverse events, which may explain their low uptake for chemopreventive purposes.In the 15 years since the first breast cancer prevention trial was initiatedais. These agents have demonstrated excellent efficacy in adjuvant breast cancer trials and show particular promise in the breast cancer prevention setting, based on the significantly higher reduction rates for contralateral breast cancer in the groups of women on an ai than in those on tamoxifenCurrently, a great deal of interest exists in the third-generation ais are generally well tolerated. Side effects are similar to those of decreased estrogen—hot flashes, increased blood pressure, and thinning of bones, for example. However, the toxicity profile of exemestane may have advantages over the serms and the other ais. To date, no evidence has been uncovered that, as compared with placebo or tamoxifen, exemestane is associated with any significant increase in cardiovascular disease or adverse effect on lipid profileais.The ais in chemoprevention and about their overall safety profile, map.3 participants can be assured that their safety will be closely monitored and regularly reviewed by a Data Safety and Monitoring Committee. One important question that will arise from the current series of adjuvant and chemo-prevention trials of ais is whether distinct pharmacodynamic effects are associated with the nonsteroidal ais (anastrozole and letrozole) and the steroidal aromatase inactivator (exemestane) that would favour one type of ai over another in the prevention setting.Although it is too early to speculate about the overall efficacy of


VEGF gene have been associated with changes in VEGF expression levels: -2578C/A, -1154G/A and -634G/C are all located in the promoter region; and +936C/T is located in the 3'-untranslated region.Vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis and is over-expressed in breast cancer. At least four polymorphisms in the VEGF polymorphisms and risk for breast cancer among postmenopausal women in CPS-II (Cancer Prevention Study II) Nutrition Cohort. This cohort was established in 1992 and participants were invited to provide a blood sample between 1998 and 2001. Included in this analysis were 501 postmenopausal women who provided a blood sample and were diagnosed with breast cancer between 1992 and 2001 (cases). Control individuals were 504 cancer-free postmenopausal women matched to the cases with respect to age, race/ethnicity, and date of blood collection (controls).We examined the association between these four n = 380) and in situ cancer (n = 107). The -2578C and -1154G alleles, which are both hypothesized to increase expression of VEGF, were associated with increased risk for invasive breast cancer  but they were not associated with risk for in situ cancer. The +936C allele, which is also hypothesized to increase VEGF expression, was not clearly associated with invasive breast cancer , but it was associated with reduced risk for in situ cancer . The -634 C/G polymorphism was not associated with either invasive or in situ cancer.We found no association between any of the polymorphisms examined and overall breast cancer risk. However, associations were markedly different in separate analyses of invasive cancer (VEGF alleles are associated with increased risk for invasive but not in situ breast cancer in postmenopausal women.Our findings provide limited support for the hypothesis that the -2578C and -1154G  Angiogenesis, the development of new blood vessels, is required for the growth of microscopic cancers into larger, clinically relevant tumors . VasculaVEGF gene includes at least four polymorphisms that are relatively common and may influence VEGF expression. Three of these polymorphisms are located in the promoter region at -2578C/A (rs699947), -1154G/A (rs1570360) and -634G/C (rs2010963), relative to the translation start site. The -2578C, -1154G and -634C alleles have all been associated with increased VEGF expression [The 78C/A rs69947, -114G/C rs20963, relapression . In addipression ,14.VEGF polymorphisms and breast cancer risk. An Austrian study [To our knowledge, three previous studies -16 have an study , includian study , includiVEGF polymorphisms, we examined the association between the three promoter region polymorphisms  and a 3'-untranslated region polymorphism (+936C/T) and risk for incident breast cancer using postmenopausal cases and controls from the CPS-II (Cancer Prevention Study II) Nutrition Cohort.To explore further the role played by potentially functional Women included in the analysis were participants in the CPS-II Nutrition Cohort ; the CPSn = 328) were diagnosed before they provided a blood sample. Sixty-four per cent of these prevalent cases provided a blood sample within 2 years of their diagnosis date, although the maximum time between diagnosis and blood draw was 7.6 years. For each case, we randomly selected one control from among the postmenopausal women who had provided a blood sample and were cancer free at the time of the case diagnosis. Each control was individually matched to a case with respect to birth date (± 6 months), date of blood collection (± 6 months), and race/ethnicity . Eight of the cases and five of the controls initially selected were later excluded because genotyping failed for all polymorphisms examined, because on more detailed review they were found not to have been truly postmenopausal or not to have had breast cancer (if a case), or if no DNA sample was available. A total of 501 cases and 504 controls remained for analysis.From June 1998 through June 2001, participants in the CPS-II Nutrition Cohort were invited to provide a blood sample. After obtaining informed consent, blood samples were collected from 39,371 participants, including 21,963 women. Among postmenopausal women who had provided a blood sample, we initially identified 509 women who had been diagnosed with breast cancer between 1992 and 2001 and had not been diagnosed with any other cancer . Most of these cases (P > 0.05) for all of the polymorphisms examined.DNA was extracted from buffy coat and genotyping assays were performed using TaqMan . Genotyping was performed by laboratory personnel blinded to case-control status and 10% blind duplicates were randomly interspersed with the case-control samples for quality control. Concordance for these quality control samples was 100%. The genotyping success rate was 95% or greater for each of the polymorphisms examined. The genotype distribution among controls was in Hardy-Weinberg equilibrium , blood collection date (in single year categories), and race/ethnicity .VEGF polymorphism . To simplify interpretation of results, we used the low expression allele of each polymorphism as the referent group when calculating ORs. Because the T allele of the +936C/T polymorphism was uncommon , we combined TT and CT genotypes when calculating ORs. P values for trend were calculated using the number of high VEGF expression alleles . We also examined an additional polymorphism, -1497T/C (rs833061), but found this analysis to be uninformative because alleles for -1497T/C were almost perfectly correlated with those for -2578C/A, for which there is more evidence of functional importance.We examined the association between breast cancer risk and each VEGF polymorphisms might be important, we examined the association between breast cancer risk and a VEGF 'blood prediction score', that we created a priori (before any genotyping results were seen). The +936C allele has been associated with increased VEGF blood levels [Because we hypothesized that combined effects of d levels ,14. In ad levels , althougVEGF gene are in linkage disequilibrium [Because promoter region polymorphisms in the ilibrium , we examilibrium . EstimatVEGF polymorphism and risk for breast cancer. Because we hypothesized that VEGF polymorphisms may play a role in breast cancer progression, results are shown separately for in situ breast cancer and invasive breast cancer, as well as for all breast cancers combined. None of the polymorphisms were statistically significantly associated with all breast cancers combined. However, results differed markedly for in situ and invasive breast cancer. For in situ breast cancer, the high expression alleles of all four polymorphisms were associated with ORs below 1, although only the +936C allele was associated with a statistically significant reduction in risk . In contrast, for invasive breast cancer ORs were above 1 for the high expression alleles of all four polymorphisms, although only the -2578C and -1154G alleles were associated with statistically significant increases in risk . These associations did not appear to differ for regional or distant breast cancers compared with only locally invasive breast cancers (results not shown), although there were few regional or distant cases (n = 71). Results did not appear to differ by tumor size or grade (results not shown), although information on tumor size was available for only 38% of in situ cancer cases. Results did not change meaningfully when we adjusted for breast cancer risk factors in this study population, including use of hormone replacement therapy, history of breast cysts, family history of breast cancer, parity, and adult weight gain.Breast cancer cases and controls in this analysis were predominantly white (approximately 98% of both cases and controls) and middle aged or elderly at time of diagnosis (median age 68 years). Table a priori measure that combined information from two polymorphisms (-2578C/A and +936C/T) that are associated with VEGF blood levels . The blood prediction score was not associated with risk for all breast cancers combined. However, the blood prediction score was associated with both significantly reduced risk for in situ breast cancer  and significantly increased risk for invasive breast cancer .Table in situ cancer, and there were relatively few in situ cases (n = 107). The AAG haplotype, the only haplotype that did not include the 1154G allele, was associated with reduced risk . The global test of association between measured promoter haplotypes and breast cancer risk  yielded a P value of 0.04. There was a moderate degree of correlation between the three promoter region polymorphisms. Among controls in our study, r2 (correlation coefficient squared) was 0.55 for -2578C/A and -1154G/A, 0.49 for -2578C/A and -634G/C, and 0.27 for -1154G/A and -634G/C. Among controls in our study, the linkage disequilibrium coefficient (D') was 0.99 for -2578C/A and -1154G/A, 1.00 for -2578C/A and -634G/C, and 1.00 for -1154G/A and -634G/C.The three promoter region polymorphisms we examined are in linkage disequilibrium . We therVEGF promoter diplotypes and risk for invasive breast cancer (results not shown). No diplotype was statistically significantly associated with risk for invasive breast cancer, although ORs were greater than 1.4 for each of the six diplotypes that included two copies of the -1154G allele compared with the AAG/AAG diplotype (the diplotype hypothesized to have the lowest expression and used as the referent group).In addition to examining haplotypes, we also examined the association between in situ breast cancer. Although these results could be due to chance, it is biologically plausible that increased VEGF expression could accelerate the progression from in situ to invasive breast cancer. Whereas in situ breast cancers are by definition confined to narrow ducts and may not require angiogenesis, the development of tumors beyond 1–2 mm in diameter is believed to require angiogenesis [In this study, alleles of two promoter region polymorphisms hypothesized to increase VEGF expression and a combined measure of high VEGF expression alleles (the blood prediction score) were associated with increased risk for invasive breast cancer. In contrast, the blood prediction score was associated with reduced risk for When interpreting results it should be noted that the -2578C/A and -1154G/C polymorphisms that were associated with increased risk for invasive breast cancer are in linkage disequilibrium. Therefore, the associations of these two polymorphisms with breast cancer risk are not statistically independent. In addition, the AAG promoter haplotype, which was associated with significantly reduced risk for invasive cancer, was the only haplotype that did not include the -1154G allele. Therefore the reduced risk associated with the AAG promoter haplotype and the increased risk associated with -1154G allele are simply different ways to describe the same underlying association.VEGF polymorphisms and breast cancer to date, a recent European study that included both unselected cases of breast cancer from Sweden, and a separate group of familial breast cancer cases, predominantly from Poland [VEGF polymorphisms that we did, but they found no associations with breast cancer risk. The difference in results between our study and the European study could be due to chance. Alternatively, there are several notable differences between the types of breast cancer cases included that might have contributed to the differences in results. First, in the European study only familial breast cancer cases were used to examine the -1154G/A polymorphism, which is the VEGF polymorphism most strongly associated with invasive cancer in our study. Second, the European study probably included a substantial number of premenopausal breast cancer cases (the median age of the unselected Swedish cases at diagnosis was 54 years), whereas our study included only postmenopausal cases. Finally, in populations in which detection of in situ breast cancer is common, women carrying high expression VEGF alleles could be at increased risk for invasive cancer because their breast cancers may be more likely to progress rapidly enough to escape detection as in situ cancer. This mechanism could have played an important role in our study, in which approximately 20% of breast cancer cases were diagnosed as in situ cancers , it is important to consider the potential for survival bias. Women with breast cancer in this cohort who did not survive until the time when blood samples were collected could not be included in the study. Therefore, if pro-angiogenic se study  reportedt cancer ,19 also VEGF promoter region. To our knowledge, this is the first study to examine specifically the association between VEGF polymorphisms and in situ breast cancer, although the number of in situ cancers in our study was relatively small.The main limitation of the present study is that it is only of moderate size. Larger studies will be needed to examine potentially important differences by stage more thoroughly. Strengths of the study include the potential functional importance of the polymorphisms examined and the fact that we were able to examine common haplotypes in the VEGF alleles are associated with increased risk for invasive breast cancer in postmenopausal women. Any future studies of the association between VEGF polymorphisms and breast cancer risk should examine whether results differ for in situ and invasive breast cancers.Our findings provide limited support for the hypothesis that the -2578C and -1154G CI = confidence interval; OR = odds ratio; VEGF = vascular endothelial growth factor.The authors declare that they have no competing interests.EJJ conceived the study, contributed to data analysis, and drafted the manuscript. HSF contributed to the study design and data analysis. EBB and KAB performed the statistical analyses. CR contributed to the study design, data collection, and data analysis. VLS contributed to data collection and data analysis. AVP contributed to data analysis. MJT and EEC contributed to the study design. In addition, all authors contributed to critical revision of the manuscript, and read and approved the final manuscript.


Body mass index (BMI) during adulthood is inversely related to the incidence of premenopausal breast cancer, but the role of body fatness earlier in life is less clear. We examined prospectively the relation between body fatness during childhood and adolescence and the incidence of breast cancer in premenopausal women.Participants were 109,267 premenopausal women in the Nurses' Health Study II who recalled their body fatness at ages 5, 10 and 20 years using a validated 9-level figure drawing. Over 12 years of follow up, 1318 incident cases of breast cancer were identified. Cox proportional hazards regression was used to compute relative risks (RRs) and 95% confidence intervals (CIs) for body fatness at each age and for average childhood (ages 5–10 years) and adolescent (ages 10–20 years) fatness.P for trend < 0.0001). The association for childhood body fatness was only slightly attenuated after adjustment for later BMI, with a multivariate RR of 0.52 (95% CI 0.38–0.71) for the most overweight compared with the most lean (P for trend = 0.001). Adjustment for menstrual cycle characteristics had little impact on the association.Body fatness at each age was inversely associated with premenopausal breast cancer incidence; the multivariate RRs were 0.48 (95% CI 0.35–0.55) and 0.57 (95% CI 0.39–0.83) for the most overweight compared with the most lean in childhood and adolescence, respectively (Greater body fatness during childhood and adolescence is associated with reduced incidence of premenopausal breast cancer, independent of adult BMI and menstrual cycle characteristics. Body mass index (BMI) during adulthood is related to breast cancer incidence, although the direction of the association varies by menopausal status. More overweight women have a lower risk of breast cancer before menopause but a higher risk after menopause ,2. In prDespite the consistency of evidence for adult BMI, few studies have examined the role of body fatness during childhood and early adolescence, and results have been inconclusive. The majority have been case-control studies in which body fatness at young ages was recalled after diagnosis of breast cancer. Some -7 but noA variety of evidence points to the importance of early life factors in the etiology of breast cancer. Studies of mammary gland development in rats have shown that developing breast tissue may be most vulnerable to carcinogens before the first birth, when undifferentiated cells are undergoing rapid proliferation ,18. EpidWe examined prospectively the relation between body fatness during childhood and adolescence and incidence of breast cancer among premenopausal women in the Nurses' Health Study II (NHS II). In addition, we investigated whether this relation is independent of characteristics of the menstrual cycle and BMI during adulthood.The NHS II is a prospective cohort study that began in 1989, when 116,671 female registered nurses between the ages of 25 and 42 years completed a mailed, self-administered questionnaire about their health behaviors, lifestyle factors, and medical histories. Follow-up questionnaires have been sent to participants every 2 years to obtain updated information on risk factors and disease diagnoses, and the response rate for each biennial questionnaire has been greater than 90%. Deaths are reported by family members and the postal service, and regular searches of the computerized National Death Index are also conducted . This anOn each of the biennial questionnaires between 1989 and 2001, participants were asked whether they had been diagnosed with breast cancer during the previous 2 years or since the last questionnaire they returned. Study physicians then confirmed the self-reported diagnoses by reviewing participants' medical records and/or pathology reports.in situ) were reported and subsequently confirmed among eligible participants during 12 years of follow-up, from 1989 to 1 June 2001. Because epidemiologic studies have generally shown similar risk factors for in situ and invasive breast cancer [A total of 1318 cases of breast cancer  provided information on dietary factors during adolescence by completing a supplementary questionnaire on high school diet in 1998.Information on other established and hypothesized breast cancer risk factors was collected at various points during the course of the study. Age, menopausal status, reproductive history, oral contraceptive use, smoking status, and diagnosis of benign breast disease were reported at baseline in 1989 and updated on each of the biennial questionnaires. History of breast cancer in a first-degree relative (mother or sister) was reported in 1989 and updated in 1997. Recent alcohol consumption was assessed on the initial questionnaire in 1989 and again in 1991, 1995, and 1999 from semiquantitative food frequency questionnaires, which also evaluated other dietary factors. Participation in physical activity was evaluated in 1989, 1991, and 1997. Height, alcohol consumption between ages 15 and 17 years and ages 18 and 22 years, and strenuous physical activity during high school and between ages 18 and 22 years were assessed in 1989. Other early life factors such as birthweight and being breastfed as an infant were reported on the 1991 questionnaire. A subset of participants , menopause, death, or the end of follow-up on 1 June 2001. Cases and person-time were assigned to the appropriate level of body fatness at each age and other risk factors. For time-varying covariates such as oral contraceptive use and parity, person-time was re-assigned every 2 years.Breast cancer incidence rates for each level of body fatness at ages 5, 10, and 20 years, and during childhood and adolescence were calculated as the number of breast cancer cases divided by the total number of person-years at each level. Few participants recalled their body fatness as greater than level 5 at ages 5 and 10 years; for example, for body fatness at age 10 years, 9.1% of participants recalled their figure as level 5, 2.6% recalled their figure as level 6, 0.4% recalled their figure as level 7, and only 0.1% recalled their figure as either level 8 or level 9. For this reason, figures 5 through 9 were combined into a single category for most analyses, and similar categories were created for childhood and adolescent body fatness. Relative risks (RRs) were calculated by taking the ratio of the incidence rate for each level compared with the lowest level, which was used as the referent category.Cox proportional hazards regression was used to estimate multivariate RRs and 95% confidence intervals (CIs) for body fatness at young ages while adjusting for age, time period, and other covariates. Body fatness at each age was examined in a separate Cox model, because recalled figures at these ages are highly correlated with one another. Indicator variables were used to obtain RRs for levels of body fatness at each age, and tests for linear trend were conducted by entering body fatness at each age into a Cox model as an ordinal variable with values 1 through 5. Changes in body fatness between ages 5, 10, and 20 years were also examined in Cox models, using the categories decreased, no change, increased 1 level, and increased 2 or more levels, with no change being the referent category.Because BMI during adulthood and menstrual cycle characteristics could be intermediate factors on the pathway from body fatness at young ages to breast cancer, these were considered separately from other covariates. To determine whether the association between body fatness at young ages and breast cancer is independent of later BMI, we adjusted for later BMI using several different variables, included in separate models: BMI at age 18 years, current BMI (updated every 2 years), and the cumulative average of BMI at age 18 years and all subsequent BMI reports up until the current time period. These variables were each divided into five categories (not including those who were missing) and included as continuous terms by assigning the median value of each category. Childhood body fatness and body fatness at age 20 years were also included in the same multivariate model, to examine the estimates mutually adjusted for one another. Height was included as a continuous term in all multivariate models, because it is positively associated with breast cancer incidence .To determine whether body fatness at young ages may have an impact on breast cancer risk by altering characteristics of the menstrual cycle, we first adjusted for age at menarche and years from menarche until the onset of regular menstrual cycles, because greater body fatness at young ages has been associated with earlier menarche but longer time until the establishment of regular cycles . In addin = 89,129; 1223 cases), women who had no reports of infertility , and women who had no history of irregular menstrual cycles . This was done to explore further whether differential screening or anovulation could account for associations between body fatness at young ages and premenopausal breast cancer incidence. The 1044 invasive cases were also examined in separate models and further stratified by tumor size  and hormone receptor status  when this information was available.After conducting these analyses in the full sample, we then restricted them to certain subgroups of participants: women who had had at least one screening mammography during the follow-up period , or current BMI . Separate models were constructed within each level of these factors to obtain stratum-specific estimates, and interaction terms were created by multiplying childhood body fatness as an ordinal variable by the level of each potential modifier. Wald tests were then used to evaluate whether the trends for body fatness were significantly different according to these factors.We also examined whether associations for childhood fatness varied according to family history of breast cancer , age at menarche , parity , oral contraceptive use , birthweight , BMI at age 18 years  for age 5 years, 0.61  for age 10 years, and 0.70  for age 20 years, after adjustment for age and time period, birthweight, height, recent alcohol consumption, parity and age at first birth, recency and duration of oral contraceptive use, history of benign breast disease, and family history of breast cancer. The associations of average childhood and adolescent body fatness with breast cancer incidence were slightly stronger than the associations at individual ages (Table P for trend < 0.0001). Additional adjustment for adolescent intakes of animal fat, vegetable fat, and vitamin E [Body fatness at ages 5, 10, and 20 years were each inversely associated with premenopausal breast cancer risk . The results were similar when childhood body fatness was adjusted for BMI at age 18 years and current BMI separately. Adjustment for menstrual cycle characteristics had virtually no impact on the association for childhood body fatness. Furthermore, when the analyses were restricted to participants who reported having regular menstrual cycles during both adolescence and adulthood, and to participants with no reports of infertility, the multivariate RRs for childhood body fatness were almost identical to those in the full sample (data not shown).We then evaluated whether the inverse association for childhood body fatness was independent of later BMI and menstrual cycle characteristics Table . When avP for trend = 0.03), whereas the multivariate RR for the most overweight compared with the most lean at age 20 years was 0.82 .In separate models in which BMI at age 18 years and current BMI were adjusted for childhood body fatness, each remained inversely related to breast cancer incidence, although the associations were attenuated and less strong than the association for childhood body fatness. The multivariate RRs for the highest versus the lowest categories of BMI at age 18 years and current BMI, adjusted for childhood body fatness, were 0.84 (95% CI 0.66–1.07) and 0.86 (95% CI 0.71–1.04), respectively. When average childhood body fatness and body fatness at age 20 years were included in the same model as indicator variables, the multivariate RR for the most overweight compared with the most lean in childhood was 0.56  and during adolescence was 0.52 . The decreased risk was apparent both for small and large tumors and for hormone receptor positive and negative tumors (data not shown), although some of the estimates were imprecise because of small numbers of cases. The associations were also very similar among the subgroup of women who had had at least one screening mammography during the follow-up period (data not shown).The associations for childhood and adolescent body fatness were slightly stronger in the analyses including only invasive cases. The multivariate RR for the most overweight compared with the most lean during childhood was 0.45 , although the multivariate RRs for the most overweight compared with the most lean in childhood were very similar in both categories of BMI at age 18 years . In contrast, the association for childhood body fatness did not differ according to current BMI (data not shown).The observed associations for childhood body fatness did not differ appreciably by family history of breast cancer, age at menarche, parity, oral contraceptive use, or birthweight (data not shown). The inverse trend across categories of childhood body fatness was somewhat more apparent among those who were heavy than among those who were lean at age 18 years, and the test for interaction was marginally significant  reported having had a recent screening mammogram compared with those in either of the two extreme categories (74.4% compared with 69.6% for those with BMI <21 kg/m2 and 69.0% for those with BMI ≥ 30 kg/m2). We still observed a strong inverse association between early body fatness and breast cancer risk among women who reported having at least one screening mammography. In addition, if easier detection in lean women were the main explanation for our findings, we would have expected the association to become weaker when in situ cases were excluded, which is not what occurred. The results stratified by tumor size showed an inverse association for both large and small tumors, also arguing against a detection bias.Detection bias is another possibility because women who are obese as adults may be less likely to get regular screening mammograms , which cThese data indicate that greater body fatness during childhood and adolescence may reduce the incidence of premenopausal breast cancer, independently of adult BMI and menstrual cycle characteristics, and that this association may be stronger than the association for BMI at later ages. These findings should be interpreted cautiously, given that greater adiposity in adolescence has numerous adverse long-term health consequences  and thatBMI = body mass index; CI = confidence interval; RR = relative risk.The author(s) declare that they have no competing interests.


The main subject of this hospital-based case-control study was the possible relationship between use of combined oral contraceptives (OCs) containing chlormadinone acetate and breast cancer. Analyses were based on data from 490 cases with newly diagnosed breast cancer and 1,223 controls and were separately performed for combined OCs with and without chlormadinone. For either of the combined OCs, risk was not elevated in ever users, did not increase with duration of use and did not change with time since initial exposure or with time since most recent use. However, the relative risk was increased in current users: RR = 1.72  for combined OCs with chlormadinone and RR = 1.42  for combined OCs without chlormadinone, which is, however, explained as a screening effect. These results show that chlormadinone as a constituent of combined OCs does not influence breast cancer risk.


Breast cancer is one of the highest-profile diseases in women in developed countries. Although the risk for women younger than 30 years is minimal, this risk increases with age. One-third of all breast cancer patients in Sweden, for example, are 70 years or older at diagnosis. Despite these statistics, few breast cancer trials take these older women into account. Considering that nowadays a 70-year-old woman can expect to live for at least another 12–16 years, this is a serious gap in clinical knowledge, not least because in older women breast cancer is more likely to be present with other diseases, and doctors need to know whether cancer treatment will affect or increase the risk for these diseases.In 1992, guidelines were issued to the Uppsala/Örebro region in Sweden (with a population of 1.9 million) that all women with breast cancer should be able to receive equal treatment. At the same time, a breast cancer register was set up to record details about patients in the region, to ensure that the guidelines were being followed. Sonja Eaker and colleagues set out to assess data from the register to see whether women of all ages were receiving equal cancer treatment.They compared the 5-year relative survival for 9,059 women with breast cancer aged 50–84 years. They divided them into two age groups: 50–69 years, and 70–84 years. They also categorized the women according to the stage of breast cancer. They looked at differences between the proliferative ability of breast cancer cells, estrogen receptor status, the number of lymph nodes examined, and lymph node involvement. The researchers also compared types of treatment—i.e., surgical, oncological —and the type of clinic the patients were treated in.They found that women aged 70–84 years had up to a 13% lower chance of surviving breast cancer than those aged 50–69 years. Records for older women tended to have less information on their disease, and these women were more likely to have unknown proliferation and estrogen receptor status.Older women were less likely to have their cancer detected by mammography screening and to have the stage of disease identified, and they had larger tumors. They also had fewer lymph nodes examined, and had radiotherapy and chemotherapy less often than younger patients. Current guidelines are vague about the use of chemotherapy in older women, since studies have included only a few older women so far, but this did not explain why these women received radiotherapy less often. Older women were also less likely to be offered breast-conserving surgery, but they were more likely to be given hormone treatment such as tamoxifen even if the tumors did not show sign of hormone sensitivity. The researchers suggest that this could be because since chemotherapy tends to be not recommended for older women, perhaps clinicians believed that tamoxifen could be an alternative.The researchers admit that one drawback of their study is that there was little information on the other diseases that older women had, which might explain why they were offered treatment less often than younger patients.However, the fact remains that in Sweden, women older than 70 years are offered mammography screening much less often than younger women—despite accounting for one-third of all breast cancer cases in the country—and those older than 74 years are not screened at all.Eaker and coworkers' findings indicate that older women are urgently in need of better treatment for breast cancer and guidelines that are more appropriate to their age group. Developed countries, faced with an increasingly aging population, cannot afford to neglect the elderly.


Breast cancer strikes 1 in 7 American women, making it the most commonly diagnosed cancer among women in the United States. Although certain genetic factors can play a part in the etiology of the disease, scientists are studying other important factors including estrogen-related factors, lifestyle choices, and environmental risk. Understanding these factors can help women make informed decisions about their health and avoid being another breast cancer statistic.Researchers at the NIEHS-funded Center for Environmental Health and Susceptibility, housed in the University of North Carolina at Chapel Hill School of Public Health, are leading the way in determining both the genetic and other causes of breast cancer. And the center’s Community Outreach and Education Program (COEP), headed by Frances M. Lynn, a professor of environmental sciences and engineering, has developed a workshop program to spread the word to North Carolina residents that they need not be helpless victims of this disease.To assist in developing the workshop, the COEP partnered with the Breast Cancer Coalition of North Carolina, a nonprofit organization that advocates on behalf of those with breast cancer and their families. A scientific advisory board representing a variety of medical disciplines reviewed the workshop materials and continues to work with COEP staff to answer participants’ questions and keep the workshop as current as possible.http://www.sph.unc.edu/cehs/outreach/elsi.htm. Visitors can download the 15-slide PowerPoint presentation that is used in the workshop, as well as an agenda, facilitator instructions, case studies, fact sheets, and take-home activities.Visitors to the center’s website can download the workshop materials at The presentation introduces the workshop audience to the known possible risk factors for breast cancer, as well as some risk-reduction measures women can take. The presentation divides risk factors into four groups: personal or estrogen-related risk, lifestyle risk, environmental risk, and genetic or inherited risk.BRCA1 or BRCA2). Despite the frightening prospect of breast cancer running in families, only 5–10% of breast cancer cases are thought to be genetic in origin. Slides describe instances where this inherited risk may be implicated in breast cancer. Participants also learn about the ethical, legal, and social implications of genetic testing—how the testing is done, how they should decide if they need it, and what may happen if they test positive.The environmental risk portion of the presentation explains gene–environment interactions that occur as a result of exposure to toxicants and how that differs from risk associated with inheriting one of the so-called breast cancer genes (The interactive portion of the workshop includes fun learning activities, such as Reduce Breast Cancer Bingo, which has been a hit with the senior citizens that have taken part in the program to date. Participants win when they correctly identify four risk-reduction facts in a row, including the importance of exercising, eating vegetables, and limiting exposure to secondhand smoke. A related activity presents participants with fictional case studies for three women, one with a family history of breast cancer, one with lifestyle risk factors, and one with environmental risk factors. Participants are asked to identify both the risk factors and any protective factors each women has, and to recommend how each woman might reduce her risk.The workshop, which has been conducted across North Carolina, has been developed so that women who have completed it know not only how to better care for themselves but also how to advise other women. In conducting the workshops, COEP staff hope to dispel some of the myths women have about breast cancer and instill optimism instead.


Data on birth outcome and offspring health after the appearance of breast cancer are limited. The aim of this study was to assess the risk of adverse birth outcomes in women previously treated for invasive breast cancer compared with the general population of mothers.Of all 2,870,932 singleton births registered in the Swedish Medical Birth Registry during 1973–2002, 331 first births following breast cancer surgery—with a mean time to pregnancy of 37 mo (range 7–163)—were identified using linkage with the Swedish Cancer Registry.Logistic regression analysis was used. The estimates were adjusted for maternal age, parity, and year of delivery. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate infant health and mortality, delivery complications, the risk of preterm birth, and the rates of instrumental delivery and cesarean section.The large majority of births from women previously treated for breast cancer had no adverse events. However, births by women exposed to breast cancer were associated with an increased risk of delivery complications , cesarean section , very preterm birth (<32 wk) , and low birth weight (<1500 g) . A tendency towards an increased risk of malformations among the infants was seen especially in the later time period (1988–2002) .It is reassuring that births overall were without adverse events, but our findings indicate that pregnancies in previously treated breast cancer patients should possibly be regarded as higher risk pregnancies, with consequences for their surveillance and management. The large majority of births from women previously treated for breast cancer had no adverse events, but such pregnancies might benefit from increased surveillance and management. More women of all ages are developing breast cancer than ever before. In the US, one woman in eight will now develop this disease during her lifetime. For most of these women, their breast cancer diagnosis will come late in life, but a fifth of breast cancers are diagnosed before the age of 50. These days, the long-term outlook for women with breast cancer is quite good; 80% of women who receive a diagnosis of breast cancer survive more than five years. These figures, together with a trend towards starting families later in life—since the late 1970s birth rates for women in their late 30s and 40s have more than doubled in the US, and in Sweden the average age for having a first baby is now 29 years—mean that many women who have had breast cancer want to have children. One estimate is that up to 7% of women who are fertile after treatment for breast cancer will later have children.Pregnancy seems to have no adverse affects on women who have had breast cancer—there is no evidence that pregnancy can trigger a relapse. However, little is known about whether the chemotherapy and radiotherapy used to treat breast cancer have any long-lasting effects that might result in a poor birth outcome such as stillbirth, low birth weight, premature delivery, or abnormalities in the baby . In this study, the researchers assessed the risk of adverse birth outcomes in women previously treated for breast cancer in Sweden.Nearly three million singleton births that occurred between 1973 and 2002 are recorded in the Swedish Medical Birth Registry. The researchers linked this information with that in the Swedish Cancer Registry to identify 331 first births after treatment for invasive breast cancer (cancer that has spread from where it started to grow in the breast). The birth registry includes details on maternal age and health, child's birth weight, whether the delivery was preterm, and whether the child had any congenital abnormalities, so the researchers were able to compare birth outcomes in these 331 births with those in the general population. They discovered that most births after breast cancer treatment went smoothly. There was no increase in stillbirths, but there were slightly more delivery complications in the women who had had breast cancer than in the general population, and a slight increase in babies born prematurely or with low birth weight. Finally, a few more babies with congenital abnormalities were born to women after breast cancer treatment than to women in the general population.Overall, these results should reassure women who are thinking about having children after breast cancer about the health of their future offspring. However, they do suggest that these women may need careful monitoring during late pregnancy and delivery. This result was not predicted by the researchers who performed the study. Before starting the study, they thought that there would be no difference in birth outcomes between patients previously treated for breast cancer and the general population. Furthermore, a recently published similar study in Denmark found no increased risk of preterm birth, low birth weight, or congenital abnormalities after breast cancer. Differences between the two countries in the accuracy of their registries or in the use of chemotherapy and radiotherapy treatments may account for this difference in results. Additional studies are now needed in other populations to resolve this discrepancy and to provide more information about how breast cancer treatment might affect birth outcomes. For example, the current study did not provide any information about whether specific chemotherapy regimens or different types of breast cancer might put women at a higher risk of adverse birth outcomes, or whether the time between the cancer diagnosis and treatment and the pregnancy made a difference.http://dx.doi.org/10.1371/journal.pmed.0030336.Please access these Web sites via the online version of this summary at MedlinePlus encyclopedia entry on breast cancerNational Cancer Institute information for patients and physicians on breast cancer, including links to pages on breast cancer and pregnancyCancer Research UK's information on breast cancer for patients, and statistics on breast cancer in the UKWikipedia page on breast cancer (note: Wikipedia is a free online encyclopedia that anyone can edit)• Royal College of Obstetricians and Gynaecologists guidelines for physicians on pregnancy and breast cancer The average age of women giving birth for the first time has gradually increased during the last decades in Sweden. At present, the mean age at first birth is 29 y. The incidence of breast cancer is increasing in women of all ages.Between 20% and 25% of breast cancer diagnoses are in women under 50 y ,2. Some Knowledge about how breast cancer and its treatment affect birth outcome and offspring health is limited. In a recently published Danish cohort study  there waThe aim of the present study was to assess delivery risks and offspring health for births by previously treated breast cancer patients compared with the general population. When the study was initiated we hypothesized, based on the results of two clinical reports ,5 and ouThe study is based on 2,870,932 singleton births, registered in the Swedish Medical Birth Registry during 1973–2002. Linking this register with the Swedish Cancer Registry, 414 births were identified of women with previously treated invasive breast cancer. Invasive breast cancer was defined according to World Health Organization's histological typing of breast tumors. In total, 331 of the 414 births were the first births subsequent to breast cancer diagnosis, with a mean time between breast cancer surgery and pregnancy of 37 mo (range 7–163). Second and third births subsequent to breast cancer diagnosis were excluded from the analysis in order to analyze one birth linked to each woman exposed to breast cancer who subsequently gave birth. In women without breast cancer, all singleton births were included.The Swedish Medical Birth Registry of the National Board of Health Welfare has data from over 99% of all births in Sweden since 1973 . StartinMaternal age was defined as age in completed years at the time of delivery. Parity was defined as number of previous births, including stillbirths. Information about maternal smoking was collected at the first antenatal visit. Women were classified in this study as nonsmokers or daily smokers (one or more cigarettes per day). The woman's country of birth was also recorded, and whether the woman was living with the child's father.During the period of 1973–2002, three different editions of the International Classification of Diseases were used .The variable hypertension was defined as essential hypertension , gestational hypertension, and/or preeclampsia/eclampsia using the following one or more diagnostic codes: ICD-8: 401 and 637; ICD-9: 642; and ICD-10: O10–O16.Diabetes was defined as insulin-dependent diabetes present before pregnancy, non-insulin-dependent diabetes present before pregnancy, or gestational diabetes .Complications during pregnancy and delivery were classified by a physician when the woman was discharged. For an outcome of pregnancy bleeding we used ICD-8: 632; ICD-9: 640–641; and ICD-10: O20 and O46; and for deliveries complicated by placenta previa, ante- or postpartum hemorrhage, retained placenta, abnormal bone pelvis, fetopelvic disproportion, malpresentation of fetus, prolonged labor, rupture of uterus, laceration of perineum, or other complications we used ICD-8: 651–662; ICD-9: 652–669; and ICD10: O45–O75. To register birth injury we used ICD-8: 772; ICD-9: 767; and ICD-10: P10–P15; and to register both major and minor malformations we used ICD-8: 740–759; ICD-9: 740–759; and ICD-10: Q0–Q99. All diagnostic codes were registered as none or one or more.Estimated gestational age was based on the first day of the last menstruation and/or on ultrasound examination performed routinely at no later than 18 completed weeks of gestation. During the two last decades, anomaly screening ultrasound has been uniformly performed in Sweden.The definition of a live birth was a newborn with a gestational age of 22 wk or more that showed any evidence of life, such as beating of the heart, pulsation of the umbilical cord, or definite movement of voluntary muscles. Stillbirth was defined as late fetal death occurring at 28 or more completed weeks of gestation. Preterm delivery was classified as very preterm (≤32 wk) or preterm (33 to 36 wk).Infants defined as small for gestational age were those with birth weights more than two standard deviations below the mean birth weight for gestational age according to a Swedish reference curve.Apgar score at 5 min was categorized as (1) below seven or (2) seven or greater because a previous population-based study in Sweden showed that a 5-min Apgar score under seven in term infants was associated with an increased risk of neonatal morbidity and neurologic impairment .The study was approved by the Ethical Committee for Human Studies of Uppsala University.http://www.sas.com) was used to calculate the OR and its 95% confidence interval (CI). When there was a multinomial response variable, the generalized (glogit) link function was used [The present study uses a cohort design and logistic regression analysis to estimate odds ratios (ORs) for birth outcome. The exposure of interest was breast cancer prior to birth, and the events adverse birth outcomes as defined above. We considered age of mother, time period of delivery, country of mother's birth, history of infertility, family situation, smoking habits, hypertension, and diabetes to be possible confounders. After studying the distribution of these variables among women exposed to breast cancer those not, we kept age of mother, parity, and year of delivery as variables of interest—both as possible confounders and theoretically also as modifiers of the effect. We started the analysis by stratifying on age of mother, parity, and year of delivery, in periods of 5-y intervals. All crude estimates regarding birth outcome and infant characteristics were adjusted for age of mother (continuous), parity, and year of delivery. When there was a binary response variable, the logistic procedure with canonical  link in SAS version 8.2  compared to the general population of infants.The OR for delivering an infant with an Apgar score below seven at 5 min was not increased among women in the BC group.Malformation, major or minor, was registered in 7.5% of the infants of women in the BC group compared to 4.3% among mothers without a previous breast cancer . A tendeIn infants of women in the BC group, nine malformations were registered between 1973 and 1987 and 15 between 1988 and 2002. The diagnoses in these 24 offspring were as follows: ten cardiac defects , three kidney/ureteragenesis defects, two undescended testes in full-term infants, two unspecified limb malformations, two ear malformations, two skin malformations, one chromosome anomaly (trisomy 21), one congenital hydrocephaly, and one orofacial cleft. Only one malformation diagnosis for each infant was found.In the present study, with 331 births subsequent to breast cancer, the large majority of infants were born alive, full term, with Apgar scores at 5 min of seven or more, and with no malformation. Regarding stillbirth and infant death—arguably the most serious adverse outcomes—the result of the current study is reassuring. Only four deaths in 331 births of mothers in the BC group were identified. Still, we found a slightly increased risk of adverse pregnancy outcomes, such as an increased risk for delivery complications, cesarean section, preterm birth, and low birth weight. These associations remained almost unchanged after adjustment for possible maternal confounders such as age and parity.The strengths of the study are that it is population-based, covers a large number of pregnancies over a long time period, and has no losses to follow-up, and that the registries have near complete information on all key variables. The Swedish Cancer Registry has over 95% sensitivity in registration of all breast cancers in the country.A drawback of the study approach is that we have no information for individuals on the type of treatment for breast cancer they received, or on the timing and course of the disease with respect to the pregnancy. Thus, we cannot define subgroups with higher or lower risks within those exposed to breast cancer. We also had no data on and therefore could not control for maternal use of antidepressants, reported to be associated with preterm birth . There iThere have been studies of the accuracy of the data on pregnancy and malformations in the Swedish Medical Birth Registry –12. A quHowever, most likely any pregnancy and birth misclassifications are non-differential with regard to a previous breast cancer diagnosis on the part of the mother, which, if anything, will lead to an underestimation of the ORs rather than spurious positive findings. The increased use of cesarean section in women with breast cancer may, however, very well be a consequence of increased fetal monitoring.As this is a birth registry study, major malformations that led to pregnancy termination would not be counted in either group. However, it is unlikely that the difference in severe malformations reported here is a consequence of surveillance or diagnostic bias in this study, since a serious malformation would be regarded as a major medical event in all women and not easily overlooked.Healthy offspring have been reported delivered from small series of breast cancer patients ,5, and aAs the incidence of breast cancer in women less than 50 y of age is increasing, data about the impact of adjuvant therapy on reproductive potential and offspring outcome are needed. Cytotoxic agents are preferentially toxic to rapidly dividing cells and demonstrate teratogenic effects that can cause malformations when administered in the first trimester of pregnancy . During Little is known about the late effects of chemotherapy on offspring. Mulvihill et al.  reportedHaving a malignancy and subsequent pregnancy raises questions about the mother and her disease, on the one hand, and the management of the fetus, on the other. Breast cancer survivors who want to become pregnant need information about potential risks. Breast cancer patients' prognosis does not seem to be worsened by pregnancy –20. The We hypothesized wrongly that no increased risk of adverse birth outcomes would be detected. While it should be pointed out that the large majority of births had no complications, one may consider that based on our observations, pregnancies in previously treated breast cancer patients should be regarded as higher risk pregnancies, with consequences for their surveillance and management.


Ki-67 expression is a possible risk biomarker and is currently being used as a response biomarker in chemoprevention trials. Mammographic breast density is a risk biomarker and is also being used as a response biomarker. We previously showed that Ki-67 expression is higher in specimens of benign breast cells exhibiting cytologic atypia that are obtained by random periareolar fine needle aspiration (RPFNA). It is not known whether there is a correlation between mammographic density and Ki-67 expression in benign breast ductal cells obtained by RPFNA.2 test, and continuous variables were analyzed by nonparametric test and linear regression.Included in the study were 344 women at high risk for developing breast cancer , seen at The University of Kansas Medical Center high-risk breast clinic, who underwent RPFNA with cytomorphology and Ki-67 assessment plus a mammogram. Mammographic breast density was assessed using the Cumulus program. Categorical variables were analyzed by χP ≤ 0.001) and younger age . Mammographic density was higher in premenopausal women (P ≤ 0.001), those with lower body mass index (P < 0.001), and those with lower 5-year Gail risk (P = 0.001). Mammographic density exhibited no correlation with Ki-67 expression or cytomorphology.Forty-seven per cent of women were premenopausal and 53% were postmenopausal. The median age was 48 years, median 5-year Gail Risk was 2.2%, and median Ki-67 was 1.9%. The median mammographic breast density was 37%. Ki-67 expression increased with cytologic abnormality (atypia versus no atypia; Given the lack of correlation of mammographic breast density with either cytomorphology or Ki-67 expression in RPFNA specimens, mammographic density and Ki-67 expression should be considered as potentially complementary response biomarkers in breast cancer chemoprevention trials. Mammographic density is an important biomarker of risk for the development of breast cancer and, because it is modifiable, it is a potential response biomarker as well. Cytologic atypia is an established risk factor for the development of breast cancer. A prospective study conducted in high-risk women employed random periareolar fine needle aspiration (RPFNA) to sample breast tissue . It reveil model . Both mail model ,3.Increased proliferation is a fundamental process in carcinogenesis. Shabaan and coworkers , in a crBRCA1 or BRCA2; 5-year Gail risk of 1.7% or those whose relative risk for developing breast cancer was at least three times that in the general population; prior breast biopsy that had exhibited atypical hyperplasia or lobular carcinoma in situ; and having undergone treatment for a prior contralateral invasive breast cancer or DCIS. All women had a normal mammogram at the time of aspiration and had undergone no change in hormone replacement therapy (HRT) or ingested any selective estrogen receptor modulator or aromatase inhibitor for a period of 6 months before RPFNA. They were required also to have been at least 1 year from pregnancy, lactation, or any prior chemotherapy. This study was performed after approval by the University of Kansas Medical Center Human Subjects Committee. The participants signed an informed consent form before each breast aspiration.The study cohort consisted of high-risk women undergoing baseline eligibility assessment for one of several prevention or surveillance trials at the University of Kansas Medical Center Breast Cancer Prevention Center. Women eligible for RPFNA were those with one of the following risk factors: one first-degree relative or more with breast cancer diagnosed at less than 60 years of age; multiple second-degree relatives with breast cancer; known carrier of a mutation in RPFNA was performed to obtain breast epithelial cells under local anesthesia from two sites (upper outer and upper inner quadrant) and cells were pooled from both breasts . Women wMaterial from all breast aspiration sites for each woman was pooled in a 15 ml conical tube containing 9 ml CytoLyt  and 1 ml of 10% neutral buffered formalin. Conical tubes were placed on a Verimix Rocker  at low speed. Cells were then washed with CytoLyt, processed to a pellet, placed in PreservCyt (Cytyc) for 48 hours, and then processed to at least three slides using a standard Thin Prep 2000 (Cytyc) nongynecologic protocol. At least two slides were Papanicolaou stained, with one used for morphology and one for Ki-67 staining. Slides for both cytomorphology and Ki-67 were Papanicolaou stained under RNase-free conditions with hematoxylin, OG-6 and EA-65 , and were prepared on the Thin Prep Processor. Cytomorphology was assessed by a single cytopathologist (CMZ), who assigned a categorical assessment of nonproliferative, hyperplasia, borderline hyperplasia with atypia, or hyperplasia with atypia [2). The percentage of the breast in which density was increased was then calculated. One mammogram from every batch was a duplicate. Because there were 12 batches, 12 mammograms were read twice to determine reproducibility. The R2 for reproducibility was 0.88.Mammography was performed within 6 months of the RPFNA procedure. Cranio-caudal views of mammograms were digitized using a Lumisys Lumiscan 85 . Left mammogram was used for assessment except in women with prior cancer, in which the mammogram of the unaffected breast was used. All mammograms were assessed by a single operator (QJK) using the Cumulus computer-assisted program . The par2 analysis. Continuous variables were assessed using the Mann-Whitney or Kruskal-Wallis nonparametric test. Multivariate analyses were conducted using stepwise linear regression.Frequencies of categorical variables were assessed using χIncluded in this analysis were all women at high risk for breast cancer who had undergone RPFNA for risk assessment or eligibility assessment for one of several clinical chemoprevention trials between March 2003 and May 2006. This provided 344 evaluable individuals for whom sufficient ductal cells (>500) were present in the slide designated for Ki-67 and who had a mammogram for density measurement. Median age was 48 years (range 20 to 78 years). Median height was 1.65 m (1.5 to 1.8 m) and median weight was 68 kg (43 to 119 kg). One hundred and sixty-two (47%) women were premenopausal and 182 (53%) were postmenopausal. Among postmenopausal women, 114 (63%) women were on some form of HRT, including 78 on estrogen alone, nine on estrogen plus testosterone, 27 on estrogen plus progestins (eight with testosterone as well).R2 = 0.99). Median Ki-67 was 3.3% among specimens from premenopausal women as compared with 1.2% in specimens from postmenopausal women  and greater cellularity . There was excellent agreement and low interobserver variance between the two readers for the 344 specimens R = 0.99. P < 0.0001; Figure P = 0.076) but it was not significant in multivariate analysis. Mammographic density was higher in younger women , in women with a lower 5-year Gail risk  and women with lower body mass index . On multivariate analysis, mammographic density was significantly higher in women with a lower BMI (P < 0.0001), premenopausal women (P = 0.002) and women with lower Gail risk (P = 0.004).The median mammographic density for the entire cohort was 37% (range 0% to 95%). Mammographic density was higher in premenopausal women than in postmenopausal women Table . Median P = 0.82; Figure P = 0.81; Table P = 0.61). Sixty-five women had a Masood score of 11 and 12 (lowest category) and 109 had scores of 15 and 16 (highest category). There was no difference in mammographic density between the lowest and the highest Masood category. By multivariate analysis, Ki-67 was higher in specimens with atypia (P < 0.001) and younger women (P < 0.001). However, age is highly associated with menopausal status and Gail risk. If age was omitted from the model, then Gail risk (P = 0.009) and menopausal status (P = 0.029) exhibited significant association with Ki-67 in addition to atypia. Table No correlation was seen between percentage mammographic density and Ki-67 by multivariate analysis using stepwise linear regression . The volume of stroma and collagen in most women influences density to a greater extent than the amount of breast epithelium ,12. MammP < 0.0001) and the relative risk for greater than 75% density relative to no density was 4.04 . Breast density is favorably modulated by some but not all drugs/interventions that are effective in the prevention and adjuvant treatment of breast cancer. Tamoxifen was associated with a 14% reduction in absolute breast density over 54 months, as compared with an 8% reduction for placebo-treated women in the IBIS-1  trial [Boyd and coworkers , in a ca1) trial , in a co1) trial , despite1) trial  that suc1) trial . AlthougBecause prospective prevention intervention studies with cancer as an end-point are expensive and lengthy, surrogate response biomarkers are often used in phase II chemoprevention trials, in which favorable modulation of biomarker by an agent is taken as support for that agent's ability to reduce the incidence of cancer. A response biomarker ideally should also be a risk biomarker in addition to being modifiable. Mammographic density is an established risk factor for breast cancer, as noted above, and is modifiable. Ki-67 expression in benign breast cells obtained from RPFNA is also a reversible, a potential risk and a possible surrogate response biomarker. In a cohort of 147 high risk women, we previously showed that cytomorphologic atypia in benign breast cells obtained by RPFNA is associated with increased Ki-67 expression ,22.We found no correlation between mammographic density and Ki-67 or mammographic density and cytomorphologic atypia in benign breast cells in a cohort of high-risk women for whom sufficient cells from RPFNA were available for both cytomorphology and Ki-67 testing. No study has previously been undertaken to identify such a correlation. Many epidemiologic studies have evaluated a relationship between mammographic density and benign breast histology, with some studies showing an association between histology and mammographic density, whereas others have shown no such association. In a cohort of women taking part in the Canadian NBSS  study , prolifeAssociation between proliferation in benign breast and mammographic density is less well studied. In a recently reported study, Ki-67 (MIB-1) expression was assessed in areas of low, medium, and high mammographic density in benign breast tissue obtained from reduction mammoplasties. Contrary to what might be expected, Ki-67 expression in epithelial cells was less in the areas of medium and high density as compared with the areas of low density . In anotOur cohort of 344 women includes 114 women who were on HRT, which could be a potential confounding factor. However, only 16 women were taking a combination of an estrogen and a progestin. Combined estrogen plus progestin HRT, and not estrogen alone, is associated with increases mammographic density in postmenopausal women ,16. We tOur findings indicate that mammographic density, cytomorphology, and Ki-67 expression are independent variables, and may be complementary when used as risk predictors or response biomarkers in breast cancer chemoprevention trials. Furthermore, our results continue to show that Ki-67 expression is associated with the risk biomarker cytomorphology in high-risk women, and thus they provide evidence that Ki-67 may be used as a response biomarker in proof-of-principle phase II trials.in situ; HRT = hormone replacement therapy; RPFNA = random periareolar fine needle aspiration.BMI = body mass index; DCIS = ductal carcinoma The authors declare that they have no competing interests.QJK contributed to the study design, read all the mammograms and drafted the manuscript. BFK performed the statistical analysis and contributed to the study design. AOD organized and collected the data for analysis. CMZ made all the cytology assessments. PS performed RPFNA to obtain cytology specimens. CJF performed RPFNA, contributed to the study design, and served as a mentor for the entire project.


A population-based case-control study of the association of diet and other factors and thyroid cancer was conducted between 1980 and 1987 on Oahu, Hawaii. Study participants included 51 men and 140 women with thyroid cancer, and 113 male and 328 female controls matched on age (+/- 5 years) and sex. A significant, positive monotonic dose-response relation of weight in late adulthood (5 years prior to interview) and the risk for thyroid cancer was found for men and women. A greater than five-fold increase in the risk for thyroid cancer among men, and more than a two-fold increase in risk among women, was found for subjects in the highest compared with the lowest quartile of weight in late adulthood. Height was significantly related to the risk for thyroid cancer among men, but not women. Among men, there was a significant dose-response relation of weight in early adulthood (20-29 years of age) and the odds ratios (ORs) for thyroid cancer, although the trend was not significant after adjustment for height. Among women, there was also a positive relation of adult weight gain and thyroid cancer, with an OR of 2.6 associated with more than a 14% increase in weight. The effects of relative weight and weight gain on thyroid cancer risk were stronger in post-menopausal women than in premenopausal women. There was a significant positive interaction between fertility drug use and early adult weight and the risk for thyroid cancer in women. Odds ratios were also significantly elevated for women above the median weight in early adulthood who experienced a miscarriage or stillbirth at first pregnancy. In summary, these data show an association of weight, particularly in late adulthood, and the risk for thyroid cancer in men and women, and further suggest a positive interaction between weight in young adulthood and fertility drug use on thyroid carcinogenesis in women.


Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissue and may represent a growth factor in cancer. We examined the association between leptin plasma levels and mammographic density, a biomarker for breast cancer risk.We included data from postmenopausal women aged 55 and older, who participated in a cross-sectional mammography study in Tromsø, Norway. Mammograms, plasma leptin measurements as well as information on anthropometric and hormonal/reproductive factors were available from 967 women. We assessed mammographic density using a previously validated computer-assisted method. Multiple linear regression analysis was applied to investigate the association between mammographic density and quartiles of plasma leptin concentration. Because we hypothesized that the effect of leptin on mammographic density could vary depending on the amount of nondense or fat tissue in the breast, we also performed analyses on plasma leptin levels and mammographic density within tertiles of mammographic nondense area.Ptrend = 0.001). When we additionally adjusted for body mass index and mammographic nondense area, no statistically significant association between plasma leptin and mammographic density was found (Ptrend = 0.16). Stratified analyses suggested that the association between plasma leptin and mammographic density could differ with the amount of nondense area of the mammogram, with the strongest association between leptin and mammographic absolute density in the stratum with the medium breast fat content .After adjusting for age, postmenopausal hormone use, number of full-term pregnancies and age of first birth, there was an inverse association between leptin and absolute mammographic density (We found no overall consistent association between the plasma concentration of leptin and absolute mammographic density. Although weak, there was some suggestion that the association between leptin and mammographic density could differ with the amount of fat tissue in the breast. Obesity has been associated with increased risk of postmenopausal breast cancer in epidemiological studies -3. The iWhether the influence of estrogens on the breast tissue is direct or is mediated via other factors, however, has not been established . In addiLeptin, the most thoroughly studied adipocytokine, is a protein hormone produced mainly by the white adipose tissue ,9, but iLeptin may act as a growth factor in cancer , includiin situ tumors tend to arise in the area of the breast corresponding to the dense part of the mammogram [The radiographic appearance of a mammogram is determined by the relative amounts of translucent fat tissue to the denser epithelial and stromal (fibrous) tissues . Mammogrammogram , and it ammogram .In the present cross-sectional study, we wanted to examine the association between plasma leptin concentration and mammographic density. We hypothesized that the growth-promoting properties of leptin, by stimulating proliferation of epithelial tissue and/or stromal tissue of the breast, could potentially increase the density of the mammogram. As absolute mammographic density is under smaller influence by breast fat and body fat measures than percentage mammographic density, we used absolute density as the main mammographic density variable in our analyses.We used data from the Tromsø Mammography and Breast Cancer Study, which aims to identify genetic, hormonal, reproductive and lifestyle characteristics associated with mammographic patterns/densities that may enhance the risk of developing breast cancer . BrieflyA blood sample was drawn and anthropometric measures were obtained from the participants on the day of the mammographic screening. The study subjects were interviewed by a trained nurse about their current and previous postmenopausal hormone therapy use, their reproductive and menstrual factors, their previous history of cancer and their smoking status. The participants were asked to complete either a four-page questionnaire (2001 participants) or an eight-page questionnaire (2002 participants) at home. The questionnaires contained items on demographic, menstrual and reproductive factors, as well as lifestyle and dietary factors. The study was approved by the Regional Committee for Medical Research Ethics and the National Data Inspection Board. All participants gave written informed consent.125I-leptin as a tracer [Nonfasting venous samples were obtained from the participants on the day of mammographic screening. Samples were stored at -20°C or colder until analysis in December 2002. Samples had been thawed once during storage. The plasma leptin concentration was measured by a competitive radioimmunoassay  with recombinant a tracer . The intAbsolute and percentage mammographic densities were determined using the University of Southern California Madena computer-based threshold method of assessing density, a method that has been described and validated elsewhere . BrieflyX and a pixel value of 255. The reader searches for the best threshold where all pixels X within the region of interest are considered to represent mammographic densities. The software estimates the total number of pixels and the number of tinted pixels within the region of interest.A reader first defines the total breast area using a special outlining tool. Next, the region of interest, excluding the pectoralis muscle, prominent veins and fibrous strands, is defined. The reader then uses a tinting tool to apply a yellow tint to dense pixels with grey levels at or above some threshold The absolute density represents the count of the tinted pixels within the region of interest. The percentage density, or the fraction (%) of the breast with densities, is the ratio of absolute density to the total breast area. As a measure of breast adipose tissue, we used the mammographic nondense area, which we estimated as the total breast area minus the absolute density. All measurements were made on the mammogram from the left breast. The density assessments were performed by GU, whereas the breast area measurements were conducted by a research assistant trained by GU. The readers were blinded to all subject characteristics.In our preliminary analyses, we used analysis of variance to study the associations between leptin and selected variables, and the associations between absolute mammographic density and the same selected variables. We also conducted these analyses adjusted for body mass index (BMI).The association between plasma leptin concentration and mammographic density was studied by multiple linear regression analysis with mammographic density as the outcome variable. Consistent with our previously reported findings on percentage mammographic density from this study , we foun10-transformed in the analyses where they represented the outcome variable. Back-transformed means and 95% confidence intervals are presented. Test for trends across categories of variables were performed by treating the categories as continuous variables in the analyses. For the multivariate analyses on leptin concentration and mammographic density, complete information was available for 967 women.To meet the assumptions of normality of residuals from the regression analyses, both the leptin concentration and mammographic density were logrsp = 0.56, P < 0.001), waist circumference  and breast fat tissue . The body fat measures of BMI, breast fat tissue and waist circumference were also correlated . Because we wanted to investigate the effect of leptin as a possible growth factor independent of body fat, we performed several analyses adjusting for BMI, mammographic nondense area (representing breast fat) and waist circumference one at a time or together, and with various categorizations of the variables.Leptin concentration was correlated with the body fat measures of BMI  between our main independent variable, leptin concentration, and BMI, we additionally performed our multivariate analyses with leptin concentration adjusted for BMI by the residual method [Furthermore, because of the correlation . All P values are two-sided. We considered P < 0.05 statistically significant.From the multiple linear regression model of plasma leptin and absolute mammographic density, we report 2  and the median plasma leptin concentration was 14.5 ng/ml .The characteristics of the study subjects are summarized in Table 2, compared with non-hormone users. Absolute mammographic density was inversely and statistically significantly associated with BMI, waist circumference and the nondense area of the mammogram.Table rsp = -0.12, P < 0.001), and a statistically significant inverse association was found in the unadjusted regression analysis  (results not shown).Plasma leptin levels and absolute mammographic density were weakly correlated (is Table . After ais Table . When we2 higher absolute mammographic density compared with the women in the lowest quartile (Ptrend = 0.003). This apparent effect modification was statistically borderline significant (P for interaction = 0.05). Stratified analyses not adjusted for BMI gave essentially the same results (P for interaction = 0.06). For the percentage density, the association between leptin concentration and mammographic density resembled those of the absolute mammographic density, with an inverse association in the lower stratum of nondense mammographic area (Ptrend = 0.05), a positive association in the medium stratum (Ptrend = 0.004) and no association in the upper stratum (Ptrend = 0.76) (results not shown).In analysis stratified by tertiles of mammographic nondense area, no statistically significant association was found between the plasma leptin concentration and the absolute mammographic density in the strata representing the women with the lowest or the highest breast fat content Table . In the 2 higher in the highest quartile of plasma leptin concentration compared with the lowest quartile  (results not shown). When we restricted the analysis to women having a BMI between 18 and 40 (n = 945) or to women in the 5th-95th percentiles of nondense mammographic area (n = 872), or to non-current hormone therapy users (n = 714), the associations between leptin concentration and mammographic density were essentially unchanged.We also performed the analysis on leptin concentration and absolute mammographic density in the strata of the second tertile and the third tertile of nondense mammographic area combined. In this new stratum, the absolute density was on average 3.9 cmR2 value was 22.6% (P < 0.001) and the R2 change value for leptin concentration was 0.6% (P = 0.05).In the adjusted analyses of plasma leptin levels and absolute mammographic density, with a model where both BMI and nondense area were included, the in situ of the breast. A Swedish nested case-control study on postmenopausal women [Epidemiological studies on leptin and breast cancer have been scarce and inconclusive. One small case-control study found no association between the serum leptin concentration and breast cancer among postmenopausal women, but found an inverse association among premenopausal women . Anotheral women  found noal women  evaluateR2 change of 0.6% for leptin concentration suggests a marginal, if any, role for leptin in determining mammographic density. We did find, however, a statistically significant increase in mammographic density across quartiles of leptin concentration among the women with a medium content of nondense tissue or breast fat.The present study found a crude inverse association between leptin concentration and mammographic density. This association disappeared after adjustment for body fat measures. The small Because leptin is produced and secreted mainly from the adipose tissue, it may seem inappropriate from a biologic point of view to separate the association between leptin concentration and mammographic density from that of the association between body fat and mammographic density. Furthermore, it may seem puzzling that fat measures are inversely associated with mammographic density, whereas tentatively a positive association could exist between leptin and mammographic density, as suggested from our stratified analyses adjusted for fat measures.Obesity is associated with increased breast cancer risk in postmenopausal women . ParadoxAlthough percentage mammographic density is a more commonly used estimate, absolute density has also been associated with breast cancer ,27,44,45A role for leptin in breast cancer tumorigenesis has been hypothesized based on the detection of leptin protein in human breast tumors , the detAlthough it is particularly the effect of leptin on epithelial mammary duct cells of the breast that has been studied, leptin might promote growth in other cell populations of the breast, such as fibroblasts , and theP for interaction = 0.05).Because the level of leptin in breast fat might be biologically important, it seems probable that plasma levels as a marker for breast level leptin are only comparable in women with the same amount of breast adipose tissue – or, in other words, that breast adipose tissue may be a modifier of the leptin-mammographic density association. We therefore stratified our analyses on the mammographic nondense area, and a role for breast fat in modifying the association between leptin and mammographic density was suggested . We were unable to adjust for endogenous estrogen levels, but we adjusted for obesity, the major determinant of estrogen levels in postmenopausal women [There is some evidence for an association between estrogen and leptin, but the direction of this association is not clear. Estrogens have been shown by some investigators , but notstrogens ,61, by mstrogens . In the al women . Leptin al women . If estrThe strengths of our study are the large sample size, and that it was a part of a population-based screening project with a high attendance rate. The reader of the mammograms was experienced, and was blinded to the characteristics of the women.Limitations of our study include potential misclassification of plasma leptin levels because the participants were nonfasting  and theiThe BMI as a measure of body fat is not accurate , and theLeptin was the only adipocytokine measured in the present study. However, several other fat-secreted substances have been suggested to provide links between obesity and breast cancer, such as adiponectin , hepatocOur results do not support a growth-stimulating effect of plasma leptin on mammographic density. Although weak and possibly due to chance, we found some evidence that breast fat may modify the association between the leptin concentration and mammographic density.rsp = Spearman's rank correlation.BMI = body mass index; The authors declare that they have no competing interests.GU, JER and CAD discussed the design of the study. AS performed data analyses, and AS and GU drafted the manuscript. Classification of mammograms was performed by GU. JER carried out the immunoassays. ITG is the principal investigator of the Tromsø Mammography and Breast Cancer Study. YB was responsible for cleaning the data. MBV and GU contributed to the analysis and interpretation of the data, and MBV, JER, ITG, YB and CAD contributed to revisions of the manuscript. All authors approved the submitted manuscript.