Only a limited number of studies have performed comprehensive investigations of coding variation in relation to breast cancer risk. Given the established role of estrogens in breast cancer, we hypothesized that coding variation in steroid receptor coactivator and corepressor genes may alter inter-individual response to estrogen and serve as markers of breast cancer risk.EP300, CCND1, NME1, NCOA1, NCOA2, NCOA3, SMARCA4, SMARCA2, CARM1, FOXA1, MPG, NCOR1, NCOR2, CALCOCO1, PRMT1, PPARBP and CREBBP) suggested to influence transcriptional activation by steroid hormone receptors in a multiethnic panel of women with advanced breast cancer (n = 95): African Americans, Latinos, Japanese, Native Hawaiians and European Americans. Association testing of validated coding variants was conducted in a breast cancer case-control study  nested in the Multiethnic Cohort. We used logistic regression to estimate odds ratios for allelic effects in ethnic-pooled analyses as well as in subgroups defined by disease stage and steroid hormone receptor status. We also investigated effect modification by established breast cancer risk factors that are associated with steroid hormone exposure.We sequenced the coding exons of 17 genes . A small number of variants were associated with risk in disease subgroup analyses and we observed no strong evidence of effect modification by breast cancer risk factors. Based on the large number of statistical tests conducted in this study, the nominally significant associations that we observed may be due to chance, and will need to be confirmed in other studies.We identified 45 coding variants with frequencies ≥ 1% in any one ethnic group (43 non-synonymous variants). We observed nominally significant positive associations with two coding variants in ethnic-pooled analyses (Our findings suggest that common coding variation in these candidate genes do not make a substantial contribution to breast cancer risk in the general population. Cataloging and testing of coding variants in coactivator and corepressor genes should continue and may serve as a valuable resource for investigations of other hormone-related phenotypes, such as inter-individual response to hormonal therapies used for cancer treatment and prevention. Breast cancer risk is related to lifetime exposure to steroid hormones.-3 Continhttp://www.nursa.org/.[Cellular response to estrogens is mediated through estrogen receptors (ERα and ERβ), which upon binding to ligand and DNA hormone response elements, recruit coactivator and corepressor proteins that regulate the expression of steroid hormone target genes.,11 More rsa.org/.,13 PolymIn this study, we systematically screened the coding exons of steroid hormone receptor coactivator and corepressor genes in a multiethnic panel of women with breast cancer in an attempt to identify and catalogue potentially functional coding polymorphisms that may serve as genetic markers of breast cancer risk. We targeted 17 genes suggested to influence transcriptional activation by steroid hormone receptors  through direct binding to these receptors or through interactions with other well characterized co-activator/co-repressor protein complexes . To evaluate the relationship between coding variants in these candidate genes and breast cancer risk, we performed association testing in a large nested case-control study within the Multiethnic Cohort Study.The Multiethnic Cohort Study (MEC) is a population-based prospective cohort study that was initiated between 1993 and 1996 and includes subjects from various ethnic groups – African-Americans and Latinos primarily from California (mainly Los Angeles) and Native Hawaiians, Japanese-Americans, and European Americans primarily from Hawaii. State drAll participants  returned a 26-page self-administered baseline questionnaire that obtained general demographic, medical and risk factor information such as ethnicity, prior medical conditions, family history of various cancers, dietary exposures, smoking, physical activity, body mass index (BMI), and for women, reproductive history and exogenous hormone use. All participants were 45 to 75 years of age at baseline. In the cohort, incident cancer cases are identified annually through cohort linkage to population-based cancer Surveillance, Epidemiology, and End Results (SEER) registries in Hawaii and Los Angeles County as well as to the California State cancer registry. Information on stage of disease and estrogen and progesterone receptor status is also obtained through the SEER registries.Blood sample collection in the MEC began in 1994 and targeted incident breast cancer cases and a random sample of study participants to serve as controls for genetic analyses. In this present study, incident cases are defined as those diagnosed with invasive breast cancer after enrollment through December 31, 2002. Cases were over 45 years of age, and consisted primarily of postmenopausal women. Women with a previous diagnosis of breast cancer identified by SEER or self-report at baseline were excluded. Controls were women without a breast cancer diagnosis through December 31, 2002. The controls were frequency matched to cases on ethnicity and the case's age at diagnosis in 5-year intervals. The nested breast cancer case-control study consists of 1,612 invasive breast cancer cases and 1,961 controls , and has been utilized previously for numerous candidate gene association studies in the MEC. -17 This Polymorphism discovery was carried out by sequencing the coding exons and splice-site regions of the 17 candidate genes in a multiethnic panel of 95 women (19 subjects of each ethnic group) with advanced breast cancer  from the MEC. These genes were selected because they are the focus of ongoing structural and functional studies being conducted by the investigators. Advanced cases were targeted for sequencing to increase the likelihood of detecting variants that would be biologically associated with breast cancer. This panel was selected to have ≥ 85% power to detect a potentially functional variant of ~5% frequency (2 of 38 chromosomes) in any one population or an overall frequency of ~1% (2 of 190 chromosomes).DNA was extracted from buffy coat fractions using the Qiagen QiaAMP Blood Kit . All DNA samples were previously whole-genome amplified (WGA) by Molecular Staging Inc. following their standard protocol .-6.[Non-synonymous variants in the coding region or variants in known splice-site regions that were observed in > 1 individual (a minimum of 2 out of the 190 chromosomes) were targeted for association testing. For variants that were observed in only one individual, we sequenced an additional 88–91 subjects of that specific ethnic population. This extra sequencing was performed to determine whether the variant is extremely rare or may have been introduced during the WGA process or through PCR-based sequencing, with each having error rates of ~10http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=probe when available, and PCR conditions are according to the VariantSEQr Resequencing System protocol . In the event that PCR primers were not available (13 exons out of 353 targeted exons), primers were designed in-house (at least 50 bases upstream and downstream from the targeted exon). In the instance that an exon exceeded approximately 550 bases or sequencing did not yield analyzable results, internal primers were designed. Sequencing primers were typically universal primers obtained from ABI or internal primers, as mentioned above. Sequencing purification was performed using DyeDX 96 columns  following their standard protocol. PCR primers, cycling conditions and details of the sequencing protocol can be provided upon request.Bi-directional sequencing was performed on the ABI 3730 × l DNA Analyzer . Gene and exon specific PCR primers were obtained from NCBI Probe Database http://droog.mbt.washington.edu/PolyPhred.html. [PolyPhred was used for analyzing sequence traces and variation discovery ed.html. -22 For ted.html.  The averFOXA1, Gly227Glu; NCOR2, Tyr19Cys, Pro975Ser and Pro2008Ser (rs2230944); SMARCA2, Gly1416Ala (rs3793510)). We could infer genotypes at Pro2008Ser in NCOR2 however as this variant was found to be in near perfect linkage disequilibrium (i.e. r2 = 1) with Ala2007Thr . The association results for the splice-site variant in CCND1  in the MEC is also part of another study . Primers and probes for all assays can be provided upon request. Quality control replicates (~5%) were included to assess the genotyping reliability and reproducibility for the 40 assays. The average concordance for the duplicates was 99.8%, ranging from 98%–100% across all assays. All variants were successfully genotyped in > 94% of cases or controls The genotype of coding variants  in the case-control samples was determined using the allelic discrimination assay. Each assThis study has been approved by the Institutional Review Boards at the University of Southern California and the University of Hawaii.2) among postmenopausal women (≥ 25 vs < 25 kg/m2), use of hormone replacement therapy (current vs past vs never user of estrogen or estrogen + progestin) and age at menarche . Tests for interactions were performed using the Likelihood Ratio Test (LRT). All statistical analyses were done using SAS version 9.0 .Hardy-Weinberg equilibrium was evaluated using an exact test. UnconditCCND1 .[NCOR1 in African Americans . Six of the candidate genes targeted in this study were quite large and included > 30 coding exons . NCOR2 contained both the largest number of coding exons  as well as non-synonymous variants (n = 15). In contrast, NCOR1, an equally large gene was found to harbor no non-synonymous variants . We also identified three known poly-glutamine repeat polymorphisms, one in exon 20 of NCOA3.[NCOR2.[SMARCA2[NCOA3, Met391Val; African Americans, MAF 1.6%) and all variants were in Hardy-Weinberg Equilibrium among controls (p > 0.05) in at least four of the five ethnic groups.In resequencing of the 17 candidate genes (Table o241Pro). as well of NCOA3., one in 3.[NCOR2., and one.[SMARCA2; associaThe median age of the breast cancer cases and controls was 65 and 63 years, respectively. The associations with established breast cancer risk factors for each ethnic group were generally as expected. Briefly, among postmenopausal women, compared to controls, cases were more likely to be heavier and to have used hormone therapy. Cases also reported having an earlier age of menarche and were more likely to report a family history of breast cancer, than controls . His52Arg in NCOR2 was also found to be significantly positively associated regional/metastatic breast cancer  while Arg12His in CALCOCO1 was more closely associated with ER-positive breast cancer  and regional/metastatic disease . Associations were not statistically significantly different between disease subgroups (stage or ER status) however for either variant. Both of these variants were relatively rare among controls in each population, with MAFs of ≤ 2.6% (1 homozygous carrier) and ≤ 0.5% (0 homozygous carriers) for His52Arg and Arg12His, respectively. The associations with each coding variant by race-ethnicity and the genotype counts for each variant are provided , NCOR2 (Lys980Thr) and CREBBP  among ER-negative tumors (Table CCND1 (Pro241Pro) and an inverse association with EP300  for ER-positive cases  by disease stage for variants Ala83Thr and Ser448Asn in FOXA1 and variants Ser2311Gly and Ala2496Thr in NCOR2.Allelic associations were also examined by ER status and stage of disease. We observed significant positive associations with single variants in a priori hypothesis being that conditions related to long-term steroid hormone exposure  may influence the penetrance associated with these candidate coding variants ; and Ala83Thr in FOXA1 and BMI ). Of note we observed a borderline significant positive association with the common Pro241Pro variant in CCND1 among current users of HRT , however no significant interactions were observed by postmenopausal hormone use status . [PALB2 and BRIP1).[Inherited susceptibility to breast cancer is associated with a wide spectrum of allelic variants that convey varying degrees of risk (reviewed in ). Rare mallele). -34 Genomd BRIP1).,36 This d BRIP1). and riskd BRIP1).NCOR2 and Arg12His in CALCOCO1), which is in line with expectation based on the number of tests that were performed (2 of 40 = 5%). The observation that these variants were also significantly associated with stage and ER status will need to be confirmed in other studies.In this study, we examined the role of coding variation in breast cancer in multiple populations, focusing on a set of 17 candidate steroid hormone coactivator and corepressor-related genes selected based on their ability to interact with the estrogen receptor transcription complex and potentially modulate response to estrogen in breast tissue. Sequencing of the coding exons in a multi-ethnic panel of 95 women with advanced breast cancer provided 85% power to identify putative functional coding variants with frequencies as low as 1% in the combined sample. The breast cancer case-control study utilized for association testing was also well-powered to detect nominally significant effects as low as 1.8 for rare alleles  and 1.35 for more common alleles . This study was also well-powered to detect effects as low as 1.36 for more common alleles  after correcting for the number of tests performed . The multiethnic nature of this study was designed to allow for investigating a wide range of risk alleles; however, we found the vast majority of coding variants to be present in more than one population (39 of 40 variants). In this study, we observed nominally significant associations with only 2 variants and breast cancer risk  in a European study , which we were unable to replicate in our much larger study [NCOA3 has also been investigated in multiple populations, with the vast majority of studies reporting no significant correlation between repeat genotype and breast cancer incidence. [Aside from cer risk ,40. The ciation, -43 and ociation, -46. We ociation, , will beer study . The glucidence. -52Although we conducted a comprehensive assessment of coding variants in these candidate genes, there are a number of limitations to our study that should be considered when interpreting our findings. First, our resequencing strategy most likely missed rare coding variants in these genes, including those which may be population- or subject-specific. Second, we did not enrich our sequencing panel with cases with a family history of breast cancer who may be more genetically susceptible and for whom a coding-variant genetic model may be more probable. Nor did we enrich our panel with cases with ER-positive tumors which may increase the likelihood for detecting putative functional coding variants in these genes based on their known modes of action. Most of the variants that we identified were rare, so power was limited. Future studies of these loci and other steroid hormone receptor coactivator and corepressor genes will require even larger samples from these defined population subgroups to ensure complete ascertainment of all rare coding alleles, followed by robust association studies with greater power to assess more modest effects.This study suggests that common coding variation in these 17 candidate steroid hormone receptor coactivator and corepressor genes does not make a substantial contribution to breast cancer risk in the general population. Cataloging and testing of coding variants in coactivator and corepressor genes should continue and may serve as a valuable resource for investigations of other hormone-related phenotypes, such as mammographic density, and of inter-individual response to hormonal therapies used for cancer treatment and prevention.MEC: Multiethnic Cohort; OR: odds ratio; CI: confidence interval; ER: estrogen receptor; BMI: body mass index; WGA: whole-genome amplification; SEER: Surveillance, Epidemiology, and End Results; MAF: minor allele frequency; LRT: likelihood ration test; kb: kilobaseThe authors declare that they have no competing interests.RG, LX and HH carried out the genotyping and sequencing. LX and XS performed the bioinformatic analyses and data cleaning. RG and CH performed the statistical analyses. LM, LK, BH, MS, GG and MP contributed to the conception and design of the study and provided critical revision of the manuscript for important intellectual content. CAH conceived of the study and coordinated all laboratory work and data analysis. The manuscript was drafted by RG and CH. All authors read and approved of the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/9/43/prepubSupplementary Tables. Supplementary tables 1–6.Click here for file


Among 152 600 breast cancer patients diagnosed during 1958–2000, there was a 22% increased risk of developing a second primary non-breast malignancy (standardised incidence ratio (SIR)=1.22; 95% confidence interval (CI): 1.19–1.24). The highest risk was seen for connective tissue cancer . Increased risks were noted among women diagnosed with breast cancer before age 50. Oesophagus cancer and non-Hodgkin's lymphoma showed six- and four-fold higher risks, respectively, in women with a family history of breast cancer compared to those without in the ⩾10-year follow-up period. BRCA1, BRCA2, p53, and PTEN)  or dying (n=3547) within 1 month after the first primary cancer. Additional exclusions included women identified as immigrants as data on previous cancers were unavailable, and women who had emigrated before the diagnosis of breast cancer and left Sweden for ⩾1year (n=7883). Thus, 152 586 women were included in the study. A four-digit diagnostic code according to the seventh revision of the International Classification of Diseases (ICD-7) was used. The following ICD-7 codes were pooled: ‘upper aerodigestive tract’, codes 140–141, 143–148, and 161; ‘colorectum’, codes 153–154; ‘liver’, codes 155–156; ‘non-Hodgkin's lymphoma’, codes 200 and 202; and ‘leukaemia’, codes 204–207.The breast cancer cohort was matched with the Swedish Emigration and Cause of Death Registries. Excluded were women diagnosed with a second cancer  were calculated by dividing the observed number of second primary cancers by the number expected based on population rates. The observed number of cases was assumed to be Poisson distributed, and 95% confidence intervals (CIs) for SIR were calculated . Person The SIRs for second primary malignancies according to family history of breast cancer were calculated similarly, except that the expected numbers of cancers were obtained using age-, sex-, and calendar year-specific rates in the corresponding general population in our database. The ratio of SIR with a family history to SIR without a family history was calculated to easily compare these two groups, and 95% CIs were estimated . Similarn=316 vs SIR=1.92, 95% CI=1.74–2.12, n=401) and non-Hodgkin's lymphoma (NHL) . In contrast, significantly elevated SIRs that were higher for the shorter follow-up period were observed for cancers of the endometrium  and central nervous system .vs 1980–2000) of breast cancer diagnosis was also studied (data not shown). In order to restrict the problem with truncation, the risk was estimated only for follow-up periods 1–9 and 10–14 years after breast cancer diagnosis. There were no apparent differences in risk by calendar period, even after taking time since breast cancer diagnosis into consideration, except for endometrial cancer where the risk in those followed for 10–14 years was higher for the later  compared to the earlier  period.The effect of calendar period , but this difference diminished in the later follow-up period . A similar pattern was seen for connective tissue cancer , particularly of the thorax and upper limbs . For endometrial cancer, a statistically higher risk for older compared to younger women  was observed in the 1- to 9-year follow-up period.Standardised incidence ratios stratified by age (<50 and >50 years) for selected sites with a significantly elevated overall SIR and at least 100 observed cancers are presented in n=5) and NHL  among women with a family history in the ⩾10 year follow-up period. Their respective ratios comparing women with and without a family history were statistically significant (5.89 and 4.33).Risks of second primary cancers for women with and without a family history of breast cancer are presented in Multiple malignancies may reflect increased surveillance, previous therapy, shared aetiological (e.g. lifestyle) factors, and genetic predisposition. By examining the influence of age at first cancer, family history of breast cancer, time since breast cancer, and their interaction, we aimed to explore the aetiology of second primary malignancies.In our study, the SIRs for radiation-related solid tumours  were higher in the 10 or more years follow-up period, whereas leukaemia risk was similar for both time periods. Women diagnosed before the age of 50 years had a substantially higher risk for all cancer sites , possibly due to increased susceptibility as well as more aggressive treatment for breast cancer in younger women. Increased risks analysed as the ratio between women with and without a family history of breast cancer were seen in cancers of the oesophagus, stomach, ovary, NHL, and leukaemia.vs 1.28) suggests an interaction between radiotherapy and inherited factors. In earlier studies, a high familial risk was found  are consistent with the effects of tamoxifen treatment starting in the late 1970s in women over age 50 . An incrBRCA-1 and BRCA-2 genes are known to be involved in inherited susceptibility to breast and ovarian cancer (n cancer  and may CDKN2A and BRCA2 as possible determinants of the higher incidence of melanoma among breast cancer patients (We found an increased risk of melanoma for women with a family history of breast cancer, suggesting genetic influence. A number of studies have suggested mutations of We found a higher overall risk of a connective tissue malignancy with a longer follow-up time. However, when age and time since breast cancer diagnosis were considered jointly, an almost five-fold risk was observed in women <50 years old within the first 10 years following breast cancer diagnosis. The risk was even more pronounced in connective tissue cancers of the thorax or upper limbs, parts often included in the radiation field during breast cancer treatment, as previously reported (In agreement with previous reports, we found that the risk of NHL increased with time . In our A review  as well The strengths of our study are the population-based design, complete follow-up of all patients, and the ability to identify women with a family history of breast cancer. We excluded malignancies diagnosed during the first year of follow-up avoiding detection of indolent tumours by increased surveillance. Among limitations we could not identify potential treatment effects because therapy information is not recorded in the cancer register.In conclusion, we found that women diagnosed with breast cancer had a 22% increased risk of developing a second primary non-breast malignancy. Women with breast cancer before age 50 and women with a family history of breast cancer had elevated risks of developing several cancers, indicating a genetic predisposition to develop multiple tumours and/or susceptibility to the carcinogenic effect of breast cancer therapy.


In a Swedish population-based case–control study, smoking showed no convincing association with risk of postmenopausal breast cancer – regardless of timing or level of smoking exposure – either overall or among subgroups. The role of smoking in breast cancer aetiology has been extensively studied . Smokingvs the ‘anti-oestrogenic mode’, that is recent smoking and risk of breast cancer.We present results from a large population-based study, on the associations between the hypothesised ‘carcinogenetic mode’ of smoking, that is smoking prior to first birth or among nulliparous women, We conducted a case–control study of breast cancer among all Swedish-born women aged 50–74 years, in Sweden between October 1993 and March 1995.Cases were women with an incident invasive breast cancer, identified through the six Regional Cancer Registries. Out of 3979 eligible cases, 3345 (84%) participated. Controls were age-frequency matched according to the age distribution of cases, and randomly selected from the study population, using the Registry of the Total Population. Of the 4188 eligible controls, 3454 (82%) participated in the study.Study participants completed a postal questionnaire on average 4 months after diagnosis. Participants were asked in detail about their life-course smoking history and about other established breast cancer risk factors. Telephone interviews were conducted among controls who declined completion of the postal questionnaires. Out of all participating controls, 14% contributed information in this manner.Women were defined as ever smokers if they had smoked a total of at least 100 cigarettes, or if they had smoked regularly for at least 1 year. Women were attributed a 10-year duration of smoking for each 10-year age period they reported to be smokers, if they smoked during age-periods before and after. If not, they were attributed a duration of 5 years for each 10-year age period they reported to be smokers. Lifetime pack-years was calculated as the average smoking intensity multiplied by the estimated smoking duration.Relative risks were estimated using unconditional logistic regression, adjusted for age in 5-year categories, yielding odds ratios (ORs) and 95% confidence intervals (CIs). Possible confounders were included as covariates in age-adjusted models one at a time and included in the final models if they affected parameter estimates more than 10%. The tested covariates were age at first birth, body mass index, socioeconomic position, alcohol intake 1 year before data collection, age at menarche and menopause, parity, use of menopausal hormone therapy, age at menopause, family history of breast cancer and benign breast disease. The final models were adjusted for age, age at first birth, body mass index and alcohol intake.Linear trends and effect modification were assessed using Wald tests.P-values) quoted are two-sided.Analyses were performed using SAS system, version 9.1 . All statistical significance levels .Neither current nor past smokers were at an altered risk of breast cancer as compared to never smokers, regardless of smoking intensity, total smoking duration or total number of pack-years . NeitherThe relationships between breast cancer and current smoking did not vary significantly with levels of other characteristics, except for alcohol consumption . A similWe did not observe any association between smoking at any time period, duration or intensity, and the risk of breast cancer – either overall or among most subgroups. Yet, we found some evidence of an interaction between alcohol consumption and smoking.Our null finding is consistent with results from a collaborative reanalysis including 53 studies . This anSmoking has been proposed to evoke a dual effect on breast cancer risk . FirstlySmoking has further been proposed to initiate breast carcinogenesis through a genotoxic impact of tobacco-related compounds . The breWe tested the suggested hypothesis (per se and to confound estimates of the relative risks for breast cancer associated with active smoking (A larger proportion of controls than cases were excluded from the analyses since 14% of all eligible controls participated via a telephone interview that did not elicit information on alcohol consumption. Sensitivity analyses evaluating the exclusion of such controls were, however, not indicative of any introduction of selection bias. Subject to debate, passive smoking has been proposed to increase breast cancer risk  smoking . We did In summary, results from this study do not support any association between active smoking and the risk of breast cancer.


The aim of this study was to elicit the level of breast cancer awareness in older women. A cross-sectional study-specific questionnaire survey of 712 British women aged 67–73 years (response rate 83.8%), assessing knowledge of symptoms and risk and confidence to detect a change, was conducted. Over 85% of respondents were aware that a lump was a symptom of breast cancer but knowledge of non-lump symptoms was limited. Knowledge of risk was poor; 50% believed that the lifetime risk of developing breast cancer was less than 1 in 100 women and 75% were not aware that age is a risk factor. Thirty-one percent of women reported low levels of confidence to detect a breast change and 19% rarely or never checked their breasts. Those with fewer educational qualifications had poorer knowledge of symptoms, less awareness of lifetime and age-related risks, but were more likely to check their breasts than more highly educated women. This national survey demonstrates a significant lack of the prerequisite knowledge and confidence to detect a breast change. Raising breast cancer awareness and promoting early presentation among older women is important, as they are more at risk of breast cancer and more likely to delay seeking help with breast cancer symptoms than younger women. Breast cancer is predominantly a disease of older women. Most breast cancers occur in older women . FurtherThe NHS Breast Screening Programme (NHSBSP) has an upper age limit, which leaves older women unprotected by routine mammographic screening. At the same time, among older women there is a high chance that a breast symptom is one of breast cancer. Over 1 in 3 breast symptoms in older women (⩾65) are because of cancer, whereas about 1 in 10 breast symptoms are malignant in women under 65 years  describe the levels of knowledge of breast cancer symptoms and risk in older women, and assess their confidence to detect a breast change; (2) examine levels of knowledge and beliefs in relation to sociodemographic characteristics to determine which older women are most at risk of delayed presentation. The ultimate aim of the survey is to inform interventions that promote early help seeking and increase survival in older women with breast cancer.The survey sample comprised 850 women aged 67–73 years, an age group leaving the routine protection of the NHSBSP. Age Concern Research Services conducted sampling and data collection through their 50plusview panel. This panel consists of 10 000 people aged 50+ years, recruited in two ways: 60% from existing panels recruited by a private sector organisation, GfK information services, and 40% through a recruitment campaign among Age Concern donors. GfK recruit using random digit dialling telephone sampling and aim to fill quotas designed to achieve a representative sample of the UK population, based on age, sex, region and other sociodemographic characteristics. Age Concern recruit their members using an annual donor mailing advertising voluntary membership to the Panel. We invited every woman aged 67–73 years from the panel to participate. We examined the representativeness of the respondents by comparing the sociodemographic characteristics of women recruited to the survey to those of the general female population in the United Kingdom using estimates published by the Office of National Statistics.A letter outlining the survey together with a study-specific questionnaire was sent to each woman in November 2005. The questionnaire was piloted on older women in breast screening clinics and examined the following areas: knowledge of breast cancer symptoms, knowledge of the risk of developing breast cancer and confidence to detect breast changes. In the first question, participants were provided with a description of 11 breast cancer symptoms, taken from public education leaflets  and aske2 test (for comparison of two groups) and the non-parametric test for trend (for comparison of more than two ordered groups). This was followed by a multivariate analysis using logistic regression. For all outcomes, sociodemographic variables with a P-value<0.2 in the bivariate analyses were entered into the multivariate model, then retained in the final model if P<0.05. All analyses were conducted using Stata version 9.1.Summary statistics were reported for all the main questionnaire items. The association between knowledge of symptoms and each sociodemographic variable was firstly examined using the Wilcoxon rank-sum test (for comparison of two groups) and Kruskal–Wallis test (for comparison of more than two groups), followed by a multivariate analysis using ordinal logistic regression. The knowledge of risk items and breast checking were collapsed into binary variables and bivariate analyses were performed using Pearson's χOf the 850 participants surveyed, 712 completed and returned the questionnaire, a response rate of 83.8%. The sociodemographic characteristics of the sample compared with the general population of older women (where possible) are shown in P<0.001).Most women (over 85%) were aware that a lump in the breast or under the armpit was a symptom of breast cancer . HoweverP=0.019).Women were overly optimistic regarding a woman's lifetime risk of developing breast cancer, with half believing that the chances were less than 1 in 100 . Around P<0.001). Interestingly, among those who gave the incorrect answer, the most educated group appeared more likely to believe that old age decreases the likelihood of the disease (24.4% (21/86) vs 14.9% (56/377) in the two lower groups combined).Most of the women were also not aware of the increased risk of breast cancer with age; only a quarter  correctly believed they were more at risk whereas 61.7% perceived no difference . AwareneP=0.024).Around two thirds of the women reported that they checked their breasts on a weekly or monthly basis , but one fifth claimed that they rarely or never checked their breasts for changes . FurtherThe results of the survey indicate that although older women demonstrate some knowledge of the symptoms and risks associated with breast cancer, there was poor awareness about important issues, particularly among those who were less educated. The main insufficiency in knowledge was the lack of recognition of non-lump symptoms as symptoms of breast cancer and a poor understanding about risk. Around half of the women regarded their lifetime risk of developing breast cancer as less than 1 in 100, and the majority (approximately 75%) believed they had the same or lower risk than younger women. There were also a substantial number of older women who rarely or never checked their breasts and had a lack of confidence in being able to detect a breast change.Our findings are in line with other research; large-scale, population-based surveys across a broad range on cancer types in the United Kingdom have consistently shown poor knowledge of the early warning signs of cancer . Of equaExisting research also suggests that cancer awareness is poorer among those who are less well educated and those with a lower socioeconomic status  and the most elderly were not represented. Also, the sample participants in our survey were wealthier and more highly educated than the general population of women in this age group. Responders to surveys are frequently of higher socioeconomic status and education than non-responders , submitted). Such initiatives are supported by the NHS Cancer Reform Strategy (If cancer awareness among the general public is limited then people are ill-equipped to make informed decisions about their health, which may consequently lead to delayed presentation and poorer survival , Touch LStrategy , along w


Effective chemoprevention strategies exist for women at high risk for breast cancer, yet uptake is low. Physician recommendation is an important determinant of uptake, but little is known about clinicians' attitudes to chemoprevention.Focus groups were conducted with clinicians at five Family Cancer Centers in three Australian states. Discussions were recorded, transcribed and analyzed thematically.Twenty three clinicians, including genetic counselors, clinical geneticists, medical oncologists, breast surgeons and gynaecologic oncologists, participated in six focus groups in 2007. The identified barriers to the discussion of the use of tamoxifen and raloxifene for chemoprevention pertained to issues of evidence , practice , and perception .The study demonstrated limited enthusiasm for discussing breast cancer chemoprevention as a management option for women at high familial risk. Several options for increasing the likelihood of clinicians discussing chemoprevention were identified; maintaining up to date national guidelines on management of these women and education of clinicians about the drugs themselves, the legality of "off-label" prescribing, and the actual costs of chemopreventive medications. Effective chemoprevention strategies are now available for women at increased risk for breast cancer . This reFour randomized controlled trials involving over 25,000 women at increased risk have demonstrated that tamoxifen taken daily for 5 years reduces breast cancer risk by 30–50% -9. The pThere are no data on the potential efficacy of Raloxifene for chemoprevention in BRCA1 and BRCA2 mutation carriers and limited data for tamoxifen. Breast cancers arising in BRCA1 mutation carriers are estrogen receptor negative in 80–90% of cases, conversely those arising in BRCA2 mutation carriers are usually estrogen receptor positive  In the NThe type of provider whom patients see for genetic testing has been found to contribute to variations in prophylactic treatment . PhysiciIn Australia, there is a network of Family Cancer Centers (FCCs), funded by State governments, that does the vast majority of assessment and genetic testing of women at high familial risk for breast cancer. A prior Australian study undertaken between 1998 and 2000, demonstrated that FCC clinicians discussed chemoprevention in 58% of pre-genetic testing consultations, although most discussions (41%) were focused on a chemoprevention trial . The purThe study population was clinicians working in any one of five FCCs in one of three Australian capital cities. In the two cities in which there was more than one Center operating, the two largest Centers were selected. Clinicians, including clinical geneticists, genetic counselors, medical oncologists, breast surgeons, breast physicians and gynaecologic oncologists, were eligible for the study if they provided risk management advice to women at high risk for breast cancer. A contact person at each Center, usually the Director, determined the eligibility of the clinicians at that Center. For some Centers, genetic counselors were considered eligible, while for others, only physicians were eligible. The decision depended on clinic protocols for the provision of risk management advice, and was not questioned by the researchers.The time and location of the focus groups was negotiated with the contact person at each Center. A participant information sheet, and invitation to a focus group on the provision of risk management advice was e-mailed to eligible clinicians by the contact person. Focus groups were facilitated by LK, using a list of prompts and two case studies Figure . InitialTranscripts were read to identify the main themes. All relevant data was then coded under one or more of the themes and each theme analyzed by two researchers (KAP & LK) to ensure reliability. The study was approved by the Human Research and Ethics Committees (HREC) at each recruiting institution. Written informed consent from the participating clinicians was only considered necessary by the HREC at one site. For the other sites, attendance at the focus group session was considered to represent implied consent.Twenty three of 36 eligible clinicians participated in six focus groups, (3 to 5 participants per group) between April and August 2007. Participant characteristics are summarized in Table Three main codes were identified from the data; 1) 'Perception of role' (how clinicians described their role in the management of high risk women) 2) 'Case study one' , 3) 'Chemoprevention' . The 'Case study one' and 'Chemoprevention' codes were analyzed for this report. The analysis identified both the similarities and differences in response to case study one, and the barriers and enablers to the discussion of chemoprevention.Participants discussed how they would advise the woman in Case Study 1. Prior to tailoring a risk management strategy, participants said they would outline the options available. The range of options potentially discussed were screening , lifestyle modifications, surgery ) and/or chemoprevention . Mostly, clients leave the FCC with a personalised strategy which is discussed with them, and reiterated in a subsequent letter. Clients are then expected to execute their risk management strategy either through regular attendance at a Risk Management Clinic (only available in selected Centers) , or throAll of these things are on the table at the first instance, for discussion. Then people will make up their mind down which path they want to travel'. In most Centers however, the clinicians would recommend a preferred strategy. In each Center, the preferred strategy for Case Study 1 was BSO : 'explaining where the uncertainty still lies'. Conversely 6D  said 'BRCA mutation carriers, particularly BRCA2, I'm not too sure about high risk women without BRCA mutation ... I would be more comfortable with just the mutation carrier. I mean, if the high risk woman raised that I would discuss that...but it may not be our recommendation to jump in ... and just take it.'.Focus groups who said they did mention chemoprevention were asked who they discussed it with. Groups 1, 2, 5 and 6 identified mutation carriers, but particularly BRCA2 carriers. 1D  was the only participant to suggest that women at high risk without a documented mutation should also be informed about chemoprevention, with the proviso of 'Analysis of the code 'Chemoprevention' revealed several barriers and enablers to the discussion of chemoprevention with women at high risk of breast cancer Tables  and 3. ESome felt the evidence supporting the effectiveness of chemoprevention was not strong enough to justify recommending it to their clients and the evidence was seen as weak in several different ways  acted as barriers among this group of clinicians  than BRCA1 and BRCA2 mutation carriers (60–80%) and thus the balance of risks and benefits is assessed differently.Potential side-effects of chemoprevention are an important issue. The perception that side-effects outweighed the benefits was expressed by clinicians in this study. Vasomotor and gynaecologic symptoms of women on chemoprevention are mostly manageable ,9 or resSimilarly, clinicians cited their clients' lack of knowledge about chemoprevention as a barrier to discussing it with them, but until chemoprevention is discussed as an option, it is unlikely that awareness of chemoprevention will be increased among those eligible to use it.can be prescribed 'off-label' for another. Off-label prescribing is an accepted and common practice in oncology [The fact that Tamoxifen and Raloxifene are not licensed by the Australian Therapeutic Goods Administration (TGA) and not listed on the Australian PBS for the specific indication of breast cancer prevention was perceived as a barrier to discussing and prescribing chemoprevention. The Australian TGA grants marketing approval for specific medicines for specific indications, but once a medicine is approved for one indication (e.g. treatment of breast cancer) it oncology ,30. Our Off-study use of chemoprevention in this setting is supported in international guidelines -33, but In a study of Californian physicians, 40% indicated that they did not have time to adequately discuss breast cancer risk reduction options , but in This study examined the attitudes of clinicians who work in multidisciplinary FCCs around Australia and is likely to be representative of the attitudes of clinicians working in that setting. Although a woman's initial risk assessment would generally occur in such a Center, many women receive their subsequent management from external breast surgeons. It would be of interest to determine the relative importance of the various barriers identified in this and other studies among those clinicians.Of the barriers to the discussion of breast cancer chemoprevention identified, those with the most straightforward potential interventions include the maintenance of up-to-date national guidelines on management of high-risk women and education of clinicians about off-label prescribing and the relatively low costs of chemopreventive medications. More education about chemoprevention options for those specialties that advise these women but that are unfamiliar with prescribing these drugs in other settings may also improve the likelihood that chemoprevention will be discussed in the consultation. Nevertheless women will ultimately need to weigh the potential benefit against side-effects, and further studies on the use of decision aids in this setting may be useful . AddressThe authors declare that they have no competing interests.LK participated in the design of the study, conducted focus groups, analysed data, and drafted the manuscript. JH participated in the design of the study and drafting of the manuscript. DR participated in the design of the study, and edited manuscript. KP participated in the design of the study, analysis of the data and drafting of manuscript. All authors read and approved the final manuscript.


Br J Cancer, for which the relationship between age of women and high-risk human papilloma virus (HPV)-positive breast cancer, has been published. Three of these studies report that the age of women with HPV-positive breast cancer is significantly younger than the women with HPV-negative breast cancer. On an average, Greek women with HPV-positive breast cancer were 15 years, Australian women 8 years, and Canadian and Syrian women were 11 years younger than those with HPV-negative breast cancer (There are now five studies, including the report of Akil and co-workers in this issue of the Based on the younger age of some women with HPV-positive breast cancer, and the higher incidence of HPV-positive cervical cancer among younger women with multiple sexual partners, we have hypothesised that high-risk HPVs may be transmitted to the breast during sexual activities (The underlying assumption to these observations and hypotheses is that high-risk HPVs may have a causal role in some breast cancers. Therefore, a brief overview of the relevant evidence is of value.The presence of high-risk HPV DNA in breast tumours has been shown, mainly by PCR analyses, in 11 out of 13 studies conducted in a various countries (reviewed by Similar high-risk HPVs have been identified in breast tumours and cervical cancer that have occurred in the same women (There is immortalisation and preneoplastic transformation of normal breast epithelial cells by HPVs .High-risk HPVs, in particular HPV types 16, 18, 31, 33 and less commonly additional types, are the accepted cause of cervical and other ano-genital cancers . Less weBecause of the presumably low viral load, PCR analyses for HPV on both formalin-fixed and fresh-frozen breast tumour specimens are difficult and very dependent on the details of the methods used. For example, the negative outcomes by The main means of transmission of HPVs appears to be by surface contact. The human papilloma virions are released when the cornified envelope of cells desquamate . The posWhat meaning might be given to these observations? In our view, the evidence that high-risk HPVs may have an aetiological role in human breast cancer is substantial but far from conclusive. Obviously further work needs to be done.The Editor now considers correspondence on this publication closed.A working hypothesis is that high-risk HPVs may be involved in the initiation of breast cancer among younger women.


Msp1 site and the other located in axon 7 and resulting in the replacement of an isoleucine (Ile) residue by a valine . After simultaneously considering the known or significant risk factors for breast cancer, including the age of study participants, positive family history of breast cancer, early menarche (≤ 13 years), nulliparity and late first full-term pregnancy (≥ 30 years), hormone replacement therapy and smoking, the CYP1A1 Msp1 polymorphism was found to be a significant factor in determining the risk of breast cancer. The homozygous variant was the most susceptible genotype with an adjusted odds ratio of 1.98  = 1.01–3.99) compared with the non-homozygous variants (the homozygous wild-type and the heterozygous variant). In contrast, the CYP1A1 Ile/Val polymorphism was not significantly associated with breast cancer development . Interestingly, the Msp1 polymorphism was especially significant in postmenopausal women, but not in premenopausal women. Further stratification analysis in postmenopausal women who were non-smokers and with no history of hormone replacement therapy showed the cancer risk due to the Msp1 variant to be more significant in women with early menarche. We conclude that CYP1A1 polymorphism is a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Further study with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors. © 1999 Cancer Research CampaignThe incidence of breast cancer has been greatly increasing in Taiwan over the past two decades. Since cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens or oestrogen, we hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for breast cancer. This hypothesis was evaluated in this case control study of 150 breast cancer patients and 150 healthy controls among Chinese women. Two CYP1A1 polymorphisms were studied, one containing a new


In contrast, in the older age group comprising predominantly post-menopausal women, the rate ratios associated with the lowest tertile of A or E were half that of those in the highest tertile . This suggests that there may be different endocrine promotional factors for pre-and post-menopausal breast cancer. Hormonal risk factors may vary during the lifetime of an individual woman and this may have profound consequences for prevention strategies. © 2000 Cancer Research CampaignBetween 1961 and 1967 a cohort of over 5000 women volunteered for a prospective study to determine the relationship between the urinary androgen metabolites, androsterone (A) and aetiocholanolone (E), and risk of breast cancer. During the first 10 years of the study the concentration of urinary A and E was determined in 1887 of the urine specimens. In 1971 we reported that subnormal amounts of urinary A and E were associated with a significantly increased risk of breast cancer. The cohort has been followed regularly during the 37 years since inception of the study and, by May 1998, 248 women had been diagnosed with breast cancer. Urinary androgen metabolites had been measured in 116 of these cases. Analysis of these data confirmed that women diagnosed in the first decade of the study were more likely to have low levels of urinary androgen metabolites. In the following decades, however, those who developed breast cancer were more likely to have manifested an increased A and E excretion. The reversal in the relationship between androgen metabolite excretion and risk suggests that age, or probably more importantly, menopausal status at diagnosis is an important modifying factor. Dichotomizing at age 50 it was found that in the younger age group  the rate ratios in the lowest tertile of A or E excretion were two- to threefold greater than for those in the highest tertile (χ


Women with a family history of breast cancer generally self-refer because they have a feeling that their risk is high. However, they have, in general, only a hazy notion of the population risk of breast cancer and their own risk in relation to this. It is probable that they are helped by genetic counselling and, if at substantial risk, by annual mammography. However, the psychological impact of assigning true risk and the value of mammography need to be evaluated. We have assessed risk perception by questionnaire in 517 new referrals to a family history clinic and 200 women returning to the clinic at least 1 year after counselling. Correct assignment of population lifetime risk of breast cancer was 16% in the uninformed precounsel group and 33% in the post-counsel group, likewise personal risk was correct in 11% and 41% respectively. Post-counsel women were significantly more likely to retain information if they were sent a post-clinic letter or if they assessed their personal risk as too high initially.


P for trend=0.03). There was some suggestion of an inverse association with smoking duration, but this was less clear. The association did not vary with menopausal status, relative body weight, or the use of hormone replacement therapy, but it appeared to be stronger among parous than nulliparous women. The underlying biological mechanisms of this association remain unclear.Case–control studies have shown inverse associations between cigarette smoking and endometrial cancer risk. However, two small prospective cohort studies have not clearly supported an association. Moreover, quantitative measures of smoking have been examined infrequently. Our aim was to study the association between smoking and endometrial cancer risk in a large prospective cohort. We used proportional hazards models to estimate hazard ratios relating cigarette smoking to endometrial cancer risk among 70 591 women aged 40–59 years at recruitment into a randomised controlled trial of mammography screening for breast cancer. During an average of 10.6 years of follow-up (751 833 person–years), a total of 403 women were diagnosed with incident endometrial cancer. We found that a reduced endometrial cancer risk was evident only among women who currently smoked 20 cigarettes per day or more  86, 1430–1435. DOI: 10.1038/sj/bjc/6600278www.bjcancer.comCancer Research UK© 2002  Endometrial cancer is the most commonly diagnosed cancer of the female genital tract in developed countries .Although the number of studies that address this issue is growing, many aspects of the relationship between cigarette smoking and endometrial cancer risk remain under-explored. For example, most previous studies have not directly examined smoking intensity or smoking duration in relation to endometrial cancer risk. The examination of these smoking measures is important, since potentially deleterious effects of the many carcinogens contained in tobacco smoke  may be oProspective cohort studies of smoking and endometrial cancer risk, in which the problems of selection and recall bias are minimised, have been scarce. Indeed, the only two such studies . The NBSS is a multi-centre randomised controlled trial of mammography screening for breast cancer in 89 835 women aged 40–59 years at recruitment , menstrual and reproductive history, use of oral contraceptives and replacement oestrogens. Regarding smoking history, participants were first asked whether or not they had ever smoked. Women who had smoked were then asked how many cigarettes they smoked per day, for how many years they had smoked, and the year they had ceased smoking (former smokers only). Starting in 1982, a questionnaire regarding diet and physical activity was distributed to all new attendees at all screening centres, and to women returning to the screening centres for re-screening  were excluded, as were 86 women for whom no smoking information was available, and follow-up was based on the cohort of 70 591 women with intact uteri and with no history of endometrial cancer. Four hundred and three women with incident endometrial cancer were identified during the follow-up period. Cases of incident endometrial cancer and deaths were ascertained respectively through computerised record linkage to the Canadian Cancer Database and the National Mortality Database, both of which are maintained by Statistics Canada. There is good evidence from the NBSS and from other sources that the use of record linkage to ascertain incident cancer cases and deaths in Canada is both accurate and complete , whichever was the earliest. Cox proportional hazards models were used to estimate hazard ratios (RR) and 95% confidence intervals (CI) for the association between smoking and endometrial cancer risk. Age at smoking commencement was calculated for each smoker by subtracting her total years of smoking (and the time since quitting for ex-smokers) from her age at recruitment. Multivariate models included age in 5-year age groups, Quetelet's index (quartiles), education level , vigorous physical activity , hormone replacement therapy (never + four levels of duration), oral contraceptive use (never + four levels of duration), menopausal status , parity , and alcohol consumption . Alcohol consumption and physical activity were categorised by tertiles or as ‘missing,’ where the latter group was comprised of women who did not complete the questionnaire regarding physical activity and diet. The lowest tertile of alcohol consumption was comprised of non-drinkers. To assess the possibility of residual confounding among women with missing information on alcohol consumption and physical activity, we conducted additional analyses limited to the 44 525 women (including 257 cases) who completed questionnaires regarding diet and physical activity and who did not have a history of hysterectomy. For tests of trend in risk across successive levels of categorical variables, median values of each category were fitted into the risk models as successive integers .−2) and ‘obese’ (BMI ⩾30 kg m−2); those with a BMI <25.0 kg m−2 were classified as ‘non-obese.’Analyses were conducted overall and within strata defined by menopausal status, obesity, and exogenous hormone use. Women who, at recruitment, reported having had regular menstrual periods within the past 12 months were considered to be premenopausal, while those in whom menstrual periods had ceased at least 12 months before baseline assessment (or before recruitment) were considered to be postmenopausal, as were women who had previously undergone oophorectomy (with or without a history of hysterectomy). For the purposes of stratified analyses with respect to obesity, women were categorised according to criteria for obesity established by the World Health Organisation,  namely ‘On average, participants were followed for 10.6 years, yielding a total of 751 833 person-years of follow-up for the cohort. The average age at diagnosis of endometrial cancer was 57.4 years. Current smokers had the lowest median BMI, were the least likely to have completed secondary education, had the greatest percentage of hormone replacement therapy, were most likely to be postmenopausal, and along with former smokers had a higher percentage of oral contraceptive use and alcohol consumption than never smokers (Table 1−2) to the model  and the confidence intervals were wide. On formal testing, an interaction between smoking and parity in relation to endometrial cancer risk was not detected. The association between smoking and endometrial cancer risk did not vary according to levels of physical activity or alcohol consumption (data not shown). Among ex-smokers, there was no clear association with any of the smoking variables in any of the strata of the factors that were examined.Among current smokers, the association between smoking intensity and endometrial cancer risk did not vary appreciably according to menopausal status, relative body weight, history of oral contraceptive use, or hormone replacement therapy ; these women were similar to the remainder of the cohort with respect to the variables included in the multivariate models. The results were also largely unaltered after excluding cases that occurred within the first year of follow-up, thereby reducing the likelihood that changes in smoking habits due to pre-clinical undiagnosed endometrial cancer might have influenced our results.In our large prospective cohort study, we found that current smokers, but not former smokers, had a reduced risk of endometrial cancer. The inverse association among current smokers appeared to be confined to women who smoked one packet of cigarettes per day or more, a group which had also mainly smoked for 20 years or longer. The approximately 40% reduced risk among these women compared with never smokers did not vary appreciably according to strata defined by menopausal status, relative body weight, or exogenous hormone use, but the association appeared to be stronger among parous than nulliparous women. Our results suggest that a reduced relative body weight among current smokers, compared to never smokers and former smokers, explains some, but not all, of the inverse association between smoking and endometrial cancer risk. Although most studies have not specifically examined the contribution of body mass index (BMI) to the association between smoking and endometrial cancer risk, a recent case–control study  found thAmong the strengths of our study was the large sample size of our cohort of women and the relatively long-term follow-up. The completeness of follow-up of the cohort , a greatFactors that influence circulating levels of oestrogen are among the few established risk factors for endometrial cancer . SupportCigarette smoking has been associated inversely with endometrial cancer risk in both population-based  and hospIn the previous examinations of risk in relation to smoking intensity , the higSeveral studies have shown a reduced endometrial cancer risk with current smoking that is stronger among, or limited to, postmenopausal women , women uIn summary, we found that current smoking was associated with a reduced risk of endometrial cancer as in most previous case–control studies; risk was observed primarily among women who had smoked at least one packet of cigarettes per day for a relatively long time, but the association was not observed among former smokers. The mechanisms underlying this association remain unclear.


P for trend 0.01). Ever use of oral contraceptives was associated with a modest reduction in risk. No associations were observed for age at first live birth or use of hormone replacement therapy. The present study provides evidence that high parity may be associated with increased risk of renal cell cancer, and that oral contraceptive use may be associated with reduced risk.We examined the association of reproductive and hormonal factors with renal cell cancer risk in a cohort study of 89 835 Canadian women. Compared with nulliparous women, parous women were at increased risk (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.02–3.09), and there was a significant gradient of risk with increasing levels of parity: relative to nulliparous women, women who had ⩾5 pregnancies lasting 4 months or more had a 2.4-fold risk (HR=2.41, 95% CI=1.27–4.59,  Incidence rates of renal cell cancer have been increasing both in the USA and globally since the 1970s , menstrual and reproductive history, and use of oral contraceptives and hormone replacement therapy (HRT). Specifically, participants were asked questions about their age at menarche, menopausal status, number of pregnancies lasting greater than 4 months (parity), age at first live birth, and ever use and duration of use of oral contraceptives and of HRT. In addition, height and weight were measured at the initial physical examination.Incident cases of renal cell cancer and deaths from all causes were ascertained, respectively, by means of computerised record linkages to the Canadian Cancer Database and to the National Mortality Database, both of which are maintained by Statistics Canada. The linkages to the databases yielded data on cancer incidence and mortality to 31 December 2000 for women in Ontario, 31 December 1998 for women in Quebec, and 31 December 1999 for women in other provinces.n=14), leaving 89 821 women available for analysis, among whom 199 incident cases of renal cancer were observed. We further excluded 27 cases with cancer of the renal pelvis and a morphology code of transitional cell carcinoma, leaving 172 cases with cancer of the renal parenchyma. For these analyses, study participants were considered at risk from their date of enrolment until the date of diagnosis of their renal cell carcinoma, termination of follow-up (the date to which cancer incidence data were available for women in the corresponding province) or death, whichever occurred first. Cox proportional hazards models  were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between reproductive and hormonal factors and renal cell cancer risk. All multivariate models included terms for body mass index (BMI) (kg m−2) (quintiles), pack-years of smoking (never smokers+five levels), menopausal status at baseline , education (three levels), study centre, and randomisation group . Women who reported having regular menstrual periods within the 12 months before baseline or who had had a hysterectomy without bilateral oophorectomy and were less than 45 years of age were classified as premenopausal. Women whose menstrual periods ceased more than 12 months before baseline, those who had had a bilateral oophorectomy, and those who had had a hysterectomy and were over 55 years of age were considered postmenopausal .Of the 89 835 women recruited into the study, we excluded women with prevalent renal cancer at baseline . P for trend=0.01) , and there was a significant gradient with increasing level of parity: relative to nulliparous women, women who had ⩾5 pregnancies lasting 4+ months had a 2.4-fold risk  . A relatP for trend 0.004; compared to the lowest quintile of BMI, women in the highest quintile had a HR of 1.76, 95% CI 1.03–3.03, P for trend 0.02. P for interaction=0.11) and to never smokers (P for interaction <0.005). For women aged 50–59 years at baseline, the HR associated with five or more pregnancies lasting 4+ months was 3.43, 95% CI 1.40–8.43, P for trend 0.009, and a HR of 3.72, 95% CI 1.35–10.24, P for trend 0.0006 was observed among never smokers. The association of parity with renal cell cancer did not differ by the level of BMI. The inverse association of oral contraceptive use with renal cell cancer was more pronounced among never smokers: HR 0.55, 95% CI 0.34–0.88 (P for interaction 0.01). There was also a suggestion that the associations for oral contraceptive use were stronger in younger women (40–49 years old) and overweight women (BMI⩾25.1 kg m−2).Both smoking and BMI showed positive dose–response relationships, in line with previous studies. Compared to never smokers, smokers of 40+ pack-years had a HR of 2.12, 95% CI 1.21–3.71, In the prospective study reported here, we found a statistically significant increased risk of renal cell cancer in women with increasing parity, which was comparable in strength to the associations with smoking and BMI. The association with parity was strongest in women who were older at enrolment and in never smokers. There was a suggestion of reduced risk with a relatively early age at menarche and with ever use of oral contraceptives, but these associations did not achieve statistical significance. Renal cell cancer risk was not associated with age at first live birth or use of HRT. Both smoking and BMI showed positive dose–response relationships with renal cancer risk in this cohort, in line with previous studies.Most previous studies have examined only a limited number of reproductive factors, most commonly parity and age at first live birth. Of nine studies that provided data on parity, four found no association  presenting findings on age at menarche, two (Of four studies of oral contraceptive use (Whereas smoking, obesity, and hypertension are established risk factors for renal cell cancer (The positive association with parity may reflect the association of normal pregnancies with hyperfiltration (et al noted that lipid peroxidation is increased among both obese and hypertensive subjects, and that in animal models lipid peroxidation of the proximal renal tubules has been shown to be a necessary condition for chemically induced renal carcinogenesis. The authors argued that lipid peroxidation may also explain the association of other risk factors, including cigarette smoking, the male preponderance of kidney cancer, parity, diabetes, and a protective effect of antioxidants, as there is evidence indicating that these risk factors are associated with increased lipid peroxidation, and that dietary antioxidants are associated with decreased lipid peroxidation. In keeping with this, pregnant women have been observed to have higher levels of serum lipid peroxide compared to nonpregnant women (Recently, an attempt has been made to provide a unified explanation of the aetiology of renal cell cancer based on the mechanism of lipid peroxidation (Strengths of the present study include its prospective nature, the availability of information on a number of reproductive and hormonal factors as well as other risk factors, and the high level of follow-up over a period of 16 years. A number of limitations should also be noted. First, information was not available on several factors of interest, including history of hypertension, miscarriages and abortions, and the specific regimen of HRT. Second, only information collected at baseline was available, so that we were not able to take into account changes in the exposures of interest over the follow-up period. Nevertheless, we were able to detect monotonic dose–response relationships with smoking and BMI, and our results regarding parity and oral contraceptive use are in agreement with the findings of the larger previous studies. It is unclear, however, whether changes in parity or in oral contraceptive use have contributed to the increasing rates of renal cell carcinoma in women.


Reproductive-related factors play a major role in the aetiology of cancers of the breast, ovary and endometrium. Pregnancy history influences the risk of each of these cancers, and oral contraceptive use modifies the risks of ovarian and endometrial cancers, although its effect on breast cancer risk is less certain. We analysed recent time trends in the incidence and mortality of these cancers in England and Wales and assessed whether they can be explained by changes in fertility and oral contraceptive use. During 1962-87, there were significant increases in the overall incidence of breast cancer (0.95% increase per annum) and ovarian cancer (0.76% per annum) but little increase in endometrial cancer (0.13% per annum). At young ages incidence of each of the cancers has declined in recent years, whereas at older ages there have been substantial increases. Mortality data show similar time trends. In analyses by birth cohort, incidence of each of the cancers increased steeply for successive cohorts born before the turn of the century, and more slowly for cohorts thereafter, reaching a maximum for those born in the 1920s, and decreased for those born subsequently. The increases in incidence for women born before the turn of the century paralleled marked declines in their fertility. The fall in risk for women born after the 1920s was not accompanied by significant increases in their fertility, but coincided with the introduction and increase in use of oral contraceptives. For ovarian and endometrial cancers this accords with strong evidence from person-based studies of the protective effect of oral contraceptives. For breast cancer, the reasons for the recent decline are not clear. It would accord with recent suggestions of a long-term protective effect of oral contraceptives, on which further studies are needed. It is also possible, however, that changes in other risk factors such as dietary fat intake and menarcheal age might have contributed to the recent declines in the risk of these cancers.


Tamoxifen is currently established as the endocrine treatment of choice in breast cancer. In advanced breast cancer, response rates of up to 60% in women with oestrogen receptor (ER)-positive tumours have been reported. In early breast cancer, tamoxifen can produce significant benefits, both statistically and clinically, in terms of reduction in relative risk of relapse or death in all patient subgroups  except premenopausal women with ER-negative tumours. The major benefit, however, is seen in women over 50 years old with ER-positive tumours. The results of randomized trials suggest that the optimum duration of tamoxifen therapy is at least 5 years. Two large pragmatic trials (aTTom and ATLAS) are under way to determine whether additional benefit can be gained from continuing tamoxifen treatment beyond 5 years. Recent data also suggest possible synergism between tamoxifen and chemotherapy in the treatment of early breast cancer in post-menopausal women. Other benefits of tamoxifen treatment include reduction in the risk of developing contralateral breast cancer. Included among the non-breast cancer benefits of tamoxifen are reduced risk of cardiovascular disease and protection against bone loss in post-menopausal women. These benefits must be weighed against the possible increased incidence of endometrial cancer. Notwithstanding its undoubted success, there is a need for agents to improve upon tamoxifen. Newer agents, such as the luteinizing hormone-releasing hormone analogue goserelin and the new-generation aromatase inhibitors, such as anastrozole, will add new life to the search for an improved endocrine therapy for early breast cancer.


An association between insufficient milk supply, the inability of a mother's breast milk to provide sufficiently for her infant, and breast cancer has been suggested by observations in animal models. To determine if an association has been reported in epidemiological studies of human breast cancer, a systematic review of the literature has been conducted. We also sought to identify the methodological limitations of existing studies to guide the design of any future prospective studies in this field.PubMed, EMBASE, Web of Science, BIOSIS, and CAB abstracts were searched. We selected any study that (1) assessed breast cancer in association with breastfeeding history and (2) examined the relationship between insufficient milk supply with breast cancer. Seven relevant studies were identified that met both criteria. There was statistically significant heterogeneity among the results which likely reflects clinically significant differences in definitions of insufficient milk supply and reference groups that were used. Among premenopausal women who had experienced insufficient milk supply, odds ratios (ORs) for breast cancer risk ranged from 0.9 to 16.3. Among postmenopausal women, ORs ranged from 0.6 to 6.7. Based on the range of odds ratios obtained in the studies reported in this review, it remains unclear if there is a true association between insufficient milk supply and breast cancer.Although some studies have shown a strong positive association, there is no consistent evidence for an effect of insufficient milk supply on breast cancer risk. Exposure definitions are in need of improvement in order to focus on primary insufficient milk supply. Reference groups consisting of women who have successfully breastfed may also introduce positive bias (inflation of the odds ratio) into study results because of the protective effect of prolonged breastfeeding in the control group. In North America, breast cancer is the second leading cause of cancer-related death in women Recent evidence from a murine model of breast cancer has suggested there may be a link between breast tumours and insufficient maternal milk supply. Using a well established breast cancer model  to systematically review the literature that addresses the question: among parous women, is insufficient milk supply during lactation associated with an increased risk of breast cancer? and 2) to identify the methodological or study design limitations of existing studies in order to guide the design of any future prospective studies in this field.If insufficient milk supply were caused by elevated PTP1B, or other new biomarkers, then this persistent overexpression would most likely cause cancer in the short-term. It seems unlikely from the current evidence Our goal was to collect relevant studies that examined the risk of breast cancer in relation to breastfeeding history. We first included studies identified in a systematic review by Berrino et al. done for the WCRF/IACR that encompassed a variety of risk factors for breast cancer, including lactation history Our search results underwent a primary screen of titles and abstracts to identify any recent study that addressed breast cancer risk in relation to lactation history or more broadly, ‘reproductive factors.’ Any study identified in the primary screen as potentially eligible for inclusion then was assessed in a full-text screen according to predetermined inclusion and exclusion criteria. The inclusion criteria were intentionally broad so that it would be possible to include all evidence that exists, regardless of the study quality, sample size, or other factors. The articles identified in the breast cancer review by Berrino's team were included in the secondary, full-text screen.The secondary screen of all papers from 1966–2008 that addressed lactation and breast cancer aimed to identify any study that examined an association between insufficient milk supply and breast cancer. For inclusion eligibility, studies must have provided odds ratios (ORs) and 95% confidence intervals (CIs) for estimates of risk of breast cancer associated with insufficient milk supply or data necessary for calculation of unadjusted ORs and 95% CIs. We limited our review to English language studies, and excluded editorials, letters to the editor, conference abstracts, review articles, and meta-analyses were excluded. Studies were also excluded if there was no measure of the relationship between the risk factor and breast cancer reported in the journal article.http://www.strobe-statement.org/Checklist.html). Finally, results from each study were recorded. These included raw data and crude ORs as well as adjusted ORs, when available, and the potential confounders that were adjusted for in each study.Relevant data were independently extracted by two investigators (J.M.C. and J.A.H.) through use of a data extraction form that was tailored for the review and improved via several pilot extractions. Collected data include basic study characteristics such as location and time period, sources of study subjects, age groups included, and other information about study design, including case definitions and participation rates. To elucidate the information that is important for judging study quality, we included a section based on the STROBE statement Extracted data were compared and disagreements were resolved by consensus. Agreement on several predetermined items was assessed to determine inter-rater reliability: Study quality was assessed according to the items identified in the STROBE statement for reporting of observational studies. An item that assessed interviewer blinding was added to the adapted checklist as it is an important quality factor in case-control studies. All items were assessed on a yes/no basis, except for case ascertainment. Quality was assessed subjectively by addressing what were considered by the reviewers to be the most important items related to study quality. These items include participation rate, mean time between diagnosis and interview, reporting of sample size calculation, breast cancer assessment method, interviewer blinding, reporting of missing data, and quality of exposure definition which was addressed based on previous research regarding breastfeeding difficulties.2 test, a measure of variability related to heterogeneity as opposed to chance. Values for the I2 test range from 0–100%; 0–25%, >25–50%, and >50–75% correspond to low, moderate and high heterogeneity Crude ORs and 95% CIs were calculated for the association between insufficient milk supply and breast cancer for each study according to the raw data presented in the report. Heterogeneity between studies was assessed with the IAfter examining the studies to be included, it became apparent that the use of different reference groups slightly altered the research question and therefore, the conclusions that could be drawn from the results. Due to the comparisons with multiple reference groups, studies were stratified based on three broad comparison groups of parous women: 1) successfully breastfed, 2) unsuccessful at breastfeeding for reasons other than insufficient milk supply, and 3) never breastfed. Due to concerns of unadjusted confounding, meta-analysis was not performed on the data comparing women with insufficient milk supply to those women who never breastfed. Meta-analyses of crude and adjusted results were performed separately. Statistical analyses were performed using STATA/SE 10.0 software .The combined searches of Berrino et al. and our group (i.e. 1966–2008) yielded 120 articles for the full-text secondary screen . Seven sFor data extraction, the average number of items that were in agreement was 7.3 out of the 9 pre-specified items (81%). Reviewers discussed disagreements and they were resolved by consensus. Agreement on raw data necessary for calculation of crude ORs and the reported adjusted ORs was 100%.The crude and adjusted ORs for the risk of breast cancer among women with insufficient milk supply are summarized in Exposure to insufficient milk supply was entirely self-reported. While most studies specified the post-partum time period for which insufficient milk supply could be considered the cause of breastfeeding cessation, Byers' did not. Many women may mistakenly report physiologic declines in milk supply several months after delivery as insufficient milk supply if the time period is unspecified. The definition employed in the Newcomb studies may also include some of these women. It would be preferable to restrict the time period for which insufficient milk supply can be reported, for example for the first 1 month after delivery, as a woman who is unable to provide sufficient nutrition to her infant will most likely not continue breastfeeding for much longer. Brinton's definition of the exposure identified in the first two weeks after delivery is probably too limited. Many of these women could have had other explanations for their breastfeeding difficulties and did not explore the root cause as intensively as others who were more persistent in their attempts to successfully breastfeed.Brinton et al. identified premenopausal women who had stopped breastfeeding within 2 weeks of delivery 2 was 78% , indicating that most of the variability is due to heterogeneity rather than chance. It is clear just by looking at the forest plot that the results are not consistent, but suggest a possible association. When adjusted estimates of the association between insufficient milk and premenopausal breast cancer were examined, ORs ranged from 0.9 to 3.1, and only Yang's study (which obtained an adjusted OR of 3.1) reported a 95% CI that excluded the null value 2 was 73% . According to the random effects models, the pooled estimate of the crude OR was 2.0  and the adjusted OR was 1.4 .Studies that compared premenopausal women who had experienced insufficient milk supply to those who had successfully breastfed had crude ORs ranging from 1.0 to 16.3 . Two stu2 was 84% . When adjusted ORs were compared for postmenopausal breast cancer, heterogeneity as measured by I2 was low, and adjusted ORs ranged from 0.6 to 1.6. The I2 was 24% . All of the CIs for the adjusted ORs included OR = 1, suggesting no effect. According to the random effects models, the pooled estimate of the crude OR was 1.2  and the adjusted OR was 0.9 .Studies that compared postmenopausal women who had experienced insufficient milk supply to those who had successfully breastfed found crude ORs ranging from 0.7 to 6.7, and only the 95% CI from Shema's study which reported an OR of 6.7 excluded the null value This systematic review assessed the literature on the risk of breast cancer after experience of insufficient milk supply and has revealed that there has been interest in the question, but studies to date have not brought about any firm conclusions because of heterogeneity in reference groups and exposure definitions. Misclassification seems to be a large problem in these studies due to imprecise or vague definitions of insufficient milk supply. In these studies, the percentage of cases reporting insufficient milk supply ranged from 7–61%. They reported a wide range of results, with estimates of the effect of insufficient milk supply on breast cancer risk ranging from null effects to an odds ratio over 16.harmful effect of insufficient milk supply observed could also be explained as a protective effect of prolonged breastfeeding in the reference group consisting of women with a sufficient milk supply. Women who never breastfed may provide a more appropriate comparison group; however, women who choose not to breastfeed their children may have an overall less healthy lifestyle and this may introduce bias (confounding) into the results of the association between insufficient milk supply and breast cancer.The use of different reference groups was an important source of heterogeneity among studies in this review. Byers, Shema, and Yang's studies all found that insufficient milk supply was a significant risk factor for premenopausal breast cancer Brinton and Yang both chose comparison groups that seemed to be a good compromise between avoiding bias due to the protection afforded by breastfeeding and avoiding unmeasured confounders among women who chose not to breastfeed their infants In addition to the heterogeneity of reference groups, the lack of a clear and consistent definition of insufficient milk supply in these studies was also a cause of concern. Insufficient milk supply may be caused by a variety of factors and has repeatedly been cited in the literature as a common reason that women stop breastfeeding In the studies reviewed, however, the definitions of insufficient milk supply utilized were often non-specific. According to Byers' definition, a woman could report having experienced insufficient milk supply at any time after her first birth. Women have often misinterpreted the physiologic decreases in milk supply that occur over time to be symptoms of insufficient milk supply. The use of this exposure definition will most likely result in many more exposed subjects than would be predicted based on the reported prevalence of this problem. Indeed, 61% of premenopausal cases and 42% of premenopausal controls in Byer's study reported experience of insufficient milk supply The use of non-specific definitions of insufficient milk supply likely lead to important misclassification of the exposure. If both cases and controls equally misclassified themselves as having experienced insufficient milk supply, it is possible that the true association between insufficient milk supply and breast cancer is stronger than that which was found in some of these studies. However, as it is common in case-control studies for cases to over report exposures which they think may be involved in the causal pathway of their disease, it is also possible that differential misclassification could have led to bias towards a positive association.There were some limitations in this review. Only English studies were included for the database search for 2006–2008. It is unlikely that this introduced a meaningful amount of bias. In the Berrino review, which covered the longest time (from 1966–2006) few studies in other languages were identified and were then excluded in our review process. It was unfeasible to include unpublished data and therefore the possibility for publication bias exists. Because this association was often not the main focus of the included papers, the problem may be important as the results may not have been presented if there was an otherwise uninteresting result. However, based on the studies reviewed here, it does not appear that only positive findings are being published. Only one reviewer was involved in the search and selection of studies, which is another potential limitation of this review, but the majority of studies included in the secondary screen were derived from a systematic review in which the studies had been selected in duplicate.Meta-analysis is not conventionally carried out in cases where heterogeneity statistics reveal a great deal of variability in study findings, as was observed among the included studies. However, studies addressing the risk of breast cancer in premenopausal women obtained either null or positive findings. We chose to calculate pooled estimates despite heterogeneity, because it was likely that the tests were significant because of widely different magnitudes of the positive effect estimates as opposed to differences in the direction of the effect estimates. The strength of evidence provided by these meta-analyses is admittedly weak because of small sample sizes and widely varied estimates of the association between insufficient milk supply and breast cancer; however, we felt it was important to provide a summary of the effect according to the evidence presented in this review.In future studies of premenopausal breast cancer, a more specific definition of insufficient milk supply should be used. Interview questions should attempt to identify women with problems breastfeeding whose problems arose at the level of the breast and not from mismanagement of breastfeeding or hormonal imbalance. Follow-up questions should be designed so as to narrow the focus on women who intended to breastfeed but could not do so successfully without supplementing with formula due to poor infant weight gain. It may also be useful to rule out breastfeeding difficulties that were due to the infant's inability to effectively transfer milk from the breast.A major concern for the design of future studies is that both the exposure and the outcome are rare events among premenopausal women. In a case-control study of women with breast cancer, it is unlikely that many of these women would have experienced primary insufficient milk supply due to its low incidence rate, requiring a large sample size. Nevertheless, case-control studies evaluating breast cancer risk may be the most effective approach as multiple risk factors may be examined in one study and cohort studies are less efficient for rare events.No consistent convincing evidence of a link between insufficient milk supply and breast cancer was found. Despite heterogeneous findings of individual studies, a summary of studies comparing women with premenopausal breast cancer with women who successfully breastfed for various lengths of time, however, indicated significantly increased risks of breast cancer among women who experienced insufficient milk supply. More research is needed to determine if a true effect exists, while taking into consideration the importance of the choice of comparison group and the definition of insufficient milk supply. The focus of future research should be on women who do not produce enough breast milk and whose problems cannot be alleviated with current therapies or changes in breastfeeding behavior.