Breast radiotherapy as practised in the 1970s and 1980s resulted in significant myocardial exposure, and this was higher when the left breast was treated. It has been proposed that this difference might result in greater cardiovascular mortality following irradiation of the left breast when compared with the right.All cases of female breast cancer diagnosed between 1971 and 1988 and recorded on the Thames Cancer Registry database were followed up to the end of 2003 to identify cases who had died from ischaemic heart disease (IHD) or any cardiovascular disease (CVD). A proportional hazards regression analysis was performed, stratified by time since diagnosis, using as the baseline group those women with right-sided disease who did not receive radiotherapy, and adjusting for age at diagnosis.A total of 20,871 women with breast cancer were included in the analysis, of which 51% had left-sided disease. Mortality at 15+ years after diagnosis was increased in recipients of left-breast radiotherapy compared to non-irradiated women with right-sided breast cancer, both for IHD  and all CVD . When irradiated women with left-sided breast cancer were compared with irradiated women with right-sided breast cancer, cardiovascular mortality at 15+ years after diagnosis was raised by around 25% .We have found an elevation in cardiovascular mortality more than 15 years after breast radiotherapy in women diagnosed with breast cancer between 1971 and 1988. The risk was greater following irradiation of the left breast compared with the right. This confirms that radiotherapy as practised in the 1970s and 1980s has resulted in significant long-term cardiac toxicity. In absolute terms, the increase in cardiovascular mortality induced by radiotherapy may be substantial, as these mortality events are relatively common. Studies of survivors of atomic bomb irradiation reveal a radiation dose-related cardiovascular risk . An overBreast radiotherapy as practised in the 1970s and 1980s resulted in significant myocardial exposure, and this was higher when the left breast was treated . It has All cases of female breast cancer diagnosed between 1971 and 1988 were extracted from the database held at the Thames Cancer Registry, a population-based register covering much of South East England. We excluded 3052 cancers of unknown laterality (4%) and 824 which were bilateral (1%). Deaths from breast cancer , ischaemic heart disease (IHD)  or any cardiovascular disease (CVD)  were identified from death certificates.st January 1997, only patients surviving beyond this date contributed to the analysis. Cases were followed up from 1st January 1997 to 31st December 2003 (or date of death if earlier), and were assumed to be alive at the latter time point if no notification of death had been received. Hence there were assumed to be no losses to follow-up. A proportional hazards regression analysis was performed, stratified by time since diagnosis, using as the baseline group those women with right-sided disease who did not receive radiotherapy, and adjusting for age at diagnosis. Further adjustments for tumour stage and socioeconomic status (based on the income score part of the Indices of Multiple Deprivation (IMD) [Patients were considered at risk from the date of cancer diagnosis, but since death codes were not available prior to 1on (IMD) ) had no inter alia for the purpose of monitoring outcomes, and hence no ethical approval was required.The study was based on routine cancer registration data, which are collected A total of 20,871 women with breast cancer were included in the analysis, of which 51% had left-sided disease. The mean age at diagnosis was 56.3 years (standard deviation 12.4 years). Tumour stage was not known in 23% of cases. Of those with known stage, two thirds were Stage 1  and 2.4% Stage 4 (metastases). 53% received radiotherapy. Although our data are insufficiently detailed to enable us to distinguish between different radiotherapy sites, we believe that the vast majority would have been to the breast or chest wall. Table The median length of follow-up was 18.5 years, and was slightly shorter in the irradiated group .We report a substantial elevation in cardiovascular mortality at greater than 15 years following radiotherapy to the left breast during the 1970s and 1980s. These results are consistent with the hypothesis that radiotherapy as practised during this period results in long-term cardiac toxicity, and confirm for the first time in a sample of UK patients the excess previously demonstrated in an American population .Our findings are in general agreement with those of other long-term toxicity studies. A Swedish study covering the period 1970 to 1985  found thOur study has a number of shortcomings. We do not have detailed information on the radiation techniques involved, and it is possible that these may have changed during the period of the study. However, the lack of death details prior to 1997 make an analysis by period of treatment difficult, as period of treatment becomes aliased with period of follow-up. For the same reasons, we have not shown results for mortality at less than 15 years after diagnosis.The comparison of left vs. right in the irradiated group used in our and other studies ,4 is useHowever, the exact quantification of the excess risk of cardiovascular mortality is not straightforward. A contrast between left and right sided breast cancer will tend to produce conservative estimates of risk because radiotherapy to the right breast, especially methods involving internal mammary lymph node (IMN) fields, also entails some cardiac dose.In absolute terms, the increase in cardiovascular mortality that has been induced by radiotherapy may be substantial because these mortality events are relatively common. A woman who had breast cancer at the age of 50 and who survived to the age of 65 would, in the absence of radiotherapy, have a 22% risk of dying from cardiovascular disease in the next 20 years, up to the age of 85 . If All of the patients in our study were treated for breast cancer in the 1970s and 1980s. During this period, techniques involving large fraction sizes, deep tangential fields or direct internal mammary fields were common. Since then, technical improvements in radiotherapy delivery have resulted in lower cardiac dosage, and recent studies ,11 basedWe have found a significant and important elevation in cardiovascular mortality at 15+ years following radiotherapy to the left breast. This result is consistent with the hypothesis that radiotherapy as administered in the 1970s and 1980s results in long-term cardiac toxicity.The author(s) declare that they have no competing interests.RR, DR and HM planned the study and drafted the manuscript. DR and VP analysed the data. JC and SD were involved in interpreting the results and critically revising the manuscript. All authors read and approved the final version.The pre-publication history for this paper can be accessed here:


PTGS2 gene have been associated with various diseases, including inflammatory bowel disease and cancer of the lung, colorectum, and breast.Prostaglandins are integral components in the cellular response to inflammation, promoting cellular proliferation and angiogenesis. The enzyme responsible for the conversion of arachidonic acid to prostaglandins in response to inflammation is prostaglandin endoperoxide synthase 2/cyclo-oxygenase 2 (PTGS2/COX2). Polymorphisms in the PTGS2 are associated with breast cancer risk, using logistic regression analyses. The Nurses' Health Study 2  and Harvard Women's Health Study  were used to further examine putative associations.We genotyped the five most common polymorphisms  in the Nurses' Health Study  to test the hypothesis that polymorphisms in PTGS2 gene was associated with a decrease in breast cancer risk. We therefore genotyped this single-nucleotide polymorphism in the Nurses' Health Study 2 and Harvard Women's Health Study. Similar results were observed in these subsequent analyses, with no statistically significant heterogeneity in risk estimates between studies. In pooled analyses, women homozygous for the T allele at rs5275 had a 20% lower risk of breast cancer than those homozygous for the C allele .The rs5275 polymorphism in the 3' untranslated region of the Although this polymorphism may be associated with a decrease in breast cancer risk among Caucasian women, we provide strong evidence that it is not associated with an increased risk of breast cancer. CellulaAlthough there is an inflammatory type of breast cancer, this accounts for only 1 to 5% of the overall incidence of breast cancer in the United States . Non-stePTGS2 mRNA has a very short half-life regulated by sequence-specific elements in the 3' untranslated region (UTR) of the gene [PTGS2 is a protein that is expressed as part of the acute response to inflammation  and is tthe gene ,13.PTGS2 gene in the breast cancer cases and controls nested within the Nurses' Health Study (NHS). One of these polymorphisms was statistically associated with decreased breast cancer risk, and we therefore sought to confirm this association in the breast cancer cases and controls nested within the Nurses' Health Study 2 (NHS2) and Harvard Women's Health Study (WHS).We hypothesize that polymorphisms in this gene could influence the risk of breast cancer, through altering the levels of expression or activity of the PTGS2 enzyme. We have therefore genotyped five single-nucleotide polymorphisms (SNPs) in the n = 1,270; controls, n = 1,762) is derived from 32,826 women who were free of diagnosed breast cancer at blood collection in 1989 and 1990, since when they were followed for incident disease until 31 May 2000. Medical records were used to confirm the diagnoses in women who reported a diagnosis of breast cancer on the biennial questionnaires. Control subjects were matched to cases on the basis of age, menopausal status, recent hormone replacement therapy, and blood-draw specific variables (such as date and time of day). The NHS2 breast cancer case-control study  is nested in a study of 29,611 women who were free of diagnosed breast cancer at the time of blood draw (between 1996 and 1999) and were followed for incident disease until 1 June 2003. The nested breast cancer case-control study in the WHS began in 1993, when 28,263 women provided blood samples and were followed for incident disease until 7 March 2000, with 702 cases and 703 controls. Cases and controls were selected for the NHS2 and WHS with the use of the same criteria as in the NHS. All three cohorts use similar questionnaires to collect covariate information, administered biennially. Detailed descriptions of these three cohorts have been published previously [The NHS nested breast cancer case-control study , with only five known common polymorphisms; linkage disequilibrium between them is high  for validation. Concordance for quality-control samples was 100%.s4648298 ; see TabCis-interactions, comparing associations with haplotypes to those observed with independent SNPs, were tested by comparing the model with the SNP genotype alone to the model with each haplotype carrying the risk allele by means of likelihood ratio testing. Interaction p values were calculated by likelihood ratio testing, comparing the model with main effects for each exposure (polymorphism and anti-inflammatory use) to the model including the cross-tabulation of the two exposures. Heterogeneity between cohorts was calculated with Cochran-Mantel-Haenszel statistics in PROC FREQ.Statistical analysis was performed with SAS version 9.1 . Haplotype estimation was performed with PROC HAPLOTYPE, tests for deviation from Hardy–Weinberg equilibrium were performed with PROC ALLELE, and haplotype-specific odds ratios and 95% confidence intervals were calculated with unconditional logistic regression with PROC LOGISTIC, controlling for age (at blood draw as a continuous variable), age at first birth (AFB), parity , menopausal status at diagnosis , history of benign breast disease (yes/no), and family history of breast cancer (yes/no). Variables such as AFB, history of benign breast disease, or family history of breast cancer are updated in each questionnaire cycle, and the variable closest to the diagnosis (cases) or index date (controls) is used in these analyses. PTGS2 gene showed an association with risk of breast cancer (Table D' = 0.95) between the rs20417 polymorphism 5' of PTGS2 and rs5275 3' of PTGS2. Similarly, one PTGS2 haplotype carrying the variant allele of rs5275 was associated with a decrease in breast cancer risk. However, the global test for difference in haplotype frequencies between breast cancer cases and controls was not significant .We did not detect any deviation from Hardy–Weinberg equilibrium among the controls in the NHS at any of the polymorphisms studied (data not shown). Only the rs5275 polymorphism in the 3' UTR of the p = 0.12), and the pooled risk estimate shows a moderately statistically significant trend of decreasing risk with each variant rs5275 allele .Similar genotype distributions were observed among both the NHS2 and WHS with respect to the NHS1 at rs5275. On pooling the three data sets Table , no hete2 induces aromatase, the main enzyme in the production of estrogen [Variant expression or activity of PTGS2 could alter the risk of breast neoplasia, independently of exposure to aspirin. Prostaglandins stimulate cell migration and lead to proliferation and neovascularization -5. Last,estrogen .Recently Langsenlehner and colleagues published an association between the rs5275 SNP and breast cancer risk . They obin vitro or in vivo information regarding any putative change in function associated with this polymorphism is available. Given its location in the 3' UTR, the rs5275 polymorphism is a likely candidate to influence mRNA half-life, which is controlled by sequence-specific elements in this region of the mRNA [PTGS2 gene, differences in the degree and extent of linkage disequilibrium between populations may explain variation in risk estimates from one study to another. Linkage between the rs5275 SNP and a causal variant would also explain why the strongest association with breast cancer risk is seen with this polymorphism and not the others. Examination of how the PTGS2 enzyme works in the breast, and in particular neoplastic breast cells, could shed light on its relation to breast cancer risk.No the mRNA . It is pPTGS2 may be associated with a decrease in breast cancer risk, we provide strong evidence that it is not associated with an increased risk of breast cancer.Although polymorphisms, particularly the rs5275 polymorphism in the 3' UTR, of AFB = age at first birth; COX2 = cyclo-oxygenase 2; NHS = Nurses' Health Study; PTGS2 = prostaglandin endoperoxide synthase 2; SNP = single-nucleotide polymorphism; UTR = untranslated region; WHS = Harvard Women's Health Study.The authors declare that they have no competing interests.DGC performed analyses and prepared the manuscript. JB, SEH, and DJH were responsible for sample collection, editing the manuscript, and securing funding for the study. All authors read and approved the final manuscript.


Increasing interest has been focused on DNA ploidy, hormone receptor status and tumour size as prognostic factors in node-negative breast cancer. We analysed these factors in patients operated on for primary invasive breast cancer between January 1981 and December 1987 in a prospective study of 248 women with no involved axillary nodes and 188 women with positive nodes followed until 15 April 1989. Oestrogen or progesterone receptor negativity, aneuploidy and tumour diameter exceeding 20 mm were studied as negative prognostic signs in life table analyses and Cox proportional hazards models of corrected survival. Corrected survival decreased with increasing number of negative signs. Three to four signs yielded a statistically significant, two- to threefold higher risk than the others. Survival estimates by life table analyses differed by 20% at 5 years. In the whole group, women with three or four negative factors had a relative risk of dying from their disease more than twice that of the others. Women with no involved nodes and with three or four negative factors had a risk of dying from breast cancer similar to that of node-positive women with fewer than three.


We analysed the relation between adult breast cancer risk and adiposity in ages 8–25, and among 90 509 women included in the E3N cohort study, and investigated the potential modification effect of certain factors. Participants completed a questionnaire that included a set of eight silhouettes corresponding to body shape at different ages. During the follow-up (mean=11.4 years), 3491 breast cancer cases were identified. Negative trends in risk of breast cancer with increasing body silhouettes at age 8 and at menarche were observed, irrespective of menopausal status, with relative risks of 0.73 (0.53–0.99) and 0.82 (0.66–1.02) for women who reported a silhouette equal or greater than the fifth silhouette at age 8 and at menarche, respectively. We observed no clear effect modification by age at menarche, delay between age at menarche, regular cycling, regularity of cycles in adult life or body mass index at baseline. Adult adiposity is positively associated with postmenopausal breast cancer risk and may be negatively associated with premenopausal breast cancer risk  and anotWe have examined the relation between breast cancer and body shape at adolescence, using the data from the E3N study, a large prospective cohort of French women, followed up from 1990 until 2002 .www.e3n.net) best described their body shape around the age of 8, at menarche and at age 20–25 . Information on nonrespondents was obtained from the MGEN file on reimbursement of hospital fees. The third follow-up questionnaire sent out contained a dietary questionnaire. Participants of the E3N cohort who responded to the dietary questionnaire (n=74 524) were included in the European Prospective Investigation into Cancer and Nutrition (EPIC)  file, which contains information on vital status. Information on cause of death was obtained from the National Service on Causes of Deaths (n (EPIC) .Menopause, if applicable, was recorded in each follow-up questionnaire. To promote accuracy of the constructed menopause variables, all answers on date and type of menopause , date of last menstruation, date of start of menopausal symptoms and date of hysterectomy, if appropriate, were reviewed. Postmenopause was defined as the cessation of periods for natural reasons or not.n=2601) from the analyses, as those who declared a prevalent cancer other than a basal cell carcinoma and an incident cancer other than a breast cancer (n=5447). Also excluded were women with an incident ductal carninoma in situ (n=405). Finally, 90 509 women were included in the analyses; mean follow-up was 11.4 years (s.d.=2.4 years).Follow-up time was between the return of the baseline questionnaire in 1990 and July 2002, when the seventh questionnaire was sent out. Person-years were accrued up to the date of breast cancer diagnosis, death, last questionnaire returned or July 2002 (for replies to the questionnaire received after July 2002), whichever occurred first. Women with a null follow-up were excluded (n=527). Overall, the present analysis is based on 3491 breast cancer cases, 930 diagnosed before the menopause and 2561 women after their menopause.Owing to the high percentage of pathology reports finally obtained (covering 94.9% of the breast cancers reported up to the sixth questionnaires) and because of the high rate of histologic confirmation (97.8% of these), we decided to consider in the present analysis reported breast cancer cases not yet confirmed , history of breast cancer in first-degree relatives (yes/no), age at menarche , age at first full-term pregnancy (FFTP) , parity , history of benign breast disease (yes/no), alcohol consumption , number of years at school , marital status (if ever married or not), oral contraceptive use (yes/no) and physical activity . Additional adjustments were made for BMI at recruitment, the interval between menarche and the establishing of regular menstrual cycles. The four largest silhouettes were grouped together, according to the distribution.P<0.0001) and at menarche (P<0.0001). Concerning silhouette at age 20–25, no difference was observed between cases and noncases. Body silhouette at age 8 and at menarche were correlated . Among women who reported a silhouette at both ages (n=80 956), 45.6% chose the same silhouette and 83.5% chose one at menarche that was equal or adjacent to that at age 8. Body silhouette at age 20–25 was found less correlated with that at age 8  than with that at menarche .Evidence for the following risk factors of breast cancer in the E3N population were found : early aP<0.001) and at menarche (P<0.0005), with relative risks (RR) equal to 0.86 : 0.75–0.99) and 0.89 (0.80–0.99), for women who chose the fourth silhouette at age 8 and at menarche, respectively, and equal to 0.80 (0.63–1.02) and 0.90 (0.76–1.06) for women who chose a silhouette equal or greater than the fifth silhouette at age 8 and at menarche, respectively, as compared to women who chose the first silhouette (data not shown). Considering silhouette at menarche, we observed a weak increase in risk among women who chose the second silhouette ), as compared with the first. The linear decreases in risk observed with silhouettes at age 8 and at menarche were slightly more accentuated after additional adjustment for adult BMI, adult regularity of menstrual cycles and for interval between menarche and regular cycling, with RRs equal to 0.73 (0.53–0.99) and 0.82 (0.66–1.02) for women who chose a silhouette equal or greater than the fifth silhouette at age 8 and at menarche, respectively, as compared to women choosing the first (data not shown). No significant linear relation was found between silhouette at age 20–25 and breast cancer risk, irrespective of menopausal status. However, we observed an increased risk of premenopausal breast cancer among women who chose the second silhouette at this age, with RRs of 1.35 (1.07–1.70), as compared to those choosing the first silhouette =0.57 (0.52–0.62) for age at menarche ⩾14 vs <12), had a longer interval between menarche and regular cycling  for an interval >2 years vs 0), had more often irregular menstrual cycles in adult life (OR=1.16 (1.07–1.27)) and were more adipose at baseline  for women in the fourth vs women in the first quartile). Having a large silhouette at adolescence was not related to age at regular cycling, except when the latter occurred after age 15 (OR=1.18 (1.10–1.28)). Similar results were observed for silhouette at age 8.Logistic regression models  to deterSubgroup analyses  indicateOur results support the hypothesis of a protective effect of adiposity at young ages on breast cancer risk, irrespective of menopausal status, although the magnitude of the effect was not strong and although the CIs around the RRs for obese girls often included unity. Since adjustment for menstrual and anthropometric characteristics in adulthood did not attenuate our estimates, our results suggest that adiposity during adolescence may have an independent protective effect against breast cancer. No clear association was found between silhouette at age 20–25 and risk.Few studies have focused on the relation between high weight at (or around) menarche and risk , perhaps indicating that body fatness at menarche is more relevant to the decreased risk observed in this study.As body silhouettes at age 8 and at menarche are highly correlated, it is difficult to deduce if the protective effect in our study is due to body fatness at age 8, to body fatness at menarche or to both. To try to disentangle these two efforts, we examined the associations between risk and overweight at age 8 among women with a silhouette lesser or equal to 3 at menarche, and also overweight at menarche among those with a silhouette lesser or equal to 3 at age 8. Both analyses showed similar decreases in risk with increasing body silhouette, although the decrease remained significant only with increasing silhouette at menarche . As a prospective cohort, recall bias is prevented. The frequent updating of our data (a questionnaire sent out every 2 years) allowed us to determine accurately the menopausal status of the women and to take account of this evolution in our analyses. Although we included breast cancer cases that were not histologically confirmed, the great concordance between self-declaration of cancer and pathology reports allowed us to strengthen the statistical power of our study, and any misclassifications would only bias our estimates towards unity.However, the fact that the E3N cohort was not population based may reduce the variability of many characteristics and consequently bias our estimates towards unity. This study is based on long-term memory of adiposity between childhood and young adulthood, which may generate important error measurements because many people cannot precisely evaluate their weight and height in childhood, either because of difficulty of accurate recall measurements or because they were not informed of their weight when young. Nevertheless, several previous studies have shown a reasonably high reliability of recalled body weight data, even after long intervals . MoreoveIn summary, our results support the hypothesis that obesity during childhood or adolescence reduces breast cancer risk, and that this reduction is not fully explained by menstrual characteristics after menarche nor by adult BMI, but these results need confirmation; further research is also required to analyse the hormonal characteristics of overweight adolescents and to assess whether hormonal modifications related to overweight at adolescence persist in adult life.


Breast cancer is one of the major public health problems among women worldwide. A number of epidemiological studies have been carried out to find the role of dietary fat and the risk of breast cancer. The main objective of the present communication is to summarize the evidence from various case-control and cohort studies on the consumption of fat and its subtypes and their effect on the development of breast cancer.A Pubmed search for literature on the consumption of dietary fat and risk of breast cancer published from January 1990 through December 2003 was carried out.Increased consumption of total fat and saturated fat were found to be positively associated with the development of breast cancer. Even though an equivocal association was observed for the consumption of total monounsaturated fatty acids (MUFA) and the risk of breast cancer, there exists an inverse association in the case of oleic acid, the most abundant MUFA. A moderate inverse association between consumption of n-3 fatty acids and breast cancer risk and a moderate positive association between n-6 fatty acids and breast cancer risk were observed.Even though all epidemiological studies do not provide a strong positive association between the consumption of certain types of dietary fat and breast cancer risk, at least a moderate association does seem to exist and this has a number of implications in view of the fact that breast cancer is an increasing public health concern. Breast cancer is the most common malignancy amongst women worldwide, constituting 10% of all cancers. It is estimated that more than 1.1 million new breast cancer cases occur worldwide annually representing over twenty percent of malignancies in women . CertainThe objective of the present communication is to summarize evidence from various case-control and cohort studies on the consumption of dietary fat and its sub-types  and their effect on the development of breast cancer. The major sources of saturated fats are meat, poultry, dairy products, eggs and some plant foods such as coconut, coconut oil and palm oil . High codietary fat" and "risk" and "breast cancer". The information on study design, country, data collection method, study period, sample size, study subjects, confounding variables, partition values used for comparisons, odds ratio/relative risk and trend p-value (if available) were obtained from the articles. Only case-control and cohort studies conducted among women were considered for the present review. Reports from symposia, genetic studies, survival/mortality studies of breast cancer patients and all studies associated with breast cancer other than dietary fat in women were excluded from the present review.A Pubmed search of the literature was carried out covering studies conducted over a period of fourteen years (from 1990 to 2003) using keywords "Of the seventeen case-control studies ,9-24 thaOf the twenty cohort studies, which investigated the relationship between total dietary fat intake and breast cancer risk, ten were based exclusively on post-menopausal women -34. FiveFour studies out of the seventeen reviewed here found significant positive associations with dose-response relationships between saturated fat and breast cancer ,18,19,45Among the seventeen cohort studies, three reported positive associations with significant dose-response relationships between the consumption of saturated fat and the risk of breast cancer ,36,41. TTwo studies of increased consumption of oleic acid (the most abundant MUFA) ,57 and fSome cohort studies found that increased consumption of oleic acid reduced the risk of breast cancer but the associations were non-significant ,33,43. HContrary to the studies on oleic acid consumption, three of the twelve case-control studies reported positive associations with a dose-response relationship between increased consumption of total MUFA and the risk of breast cancer ,18,23. TOf the twelve studies that have been reviewed, three showed significant positive associations with dose-response relationships for increased intake of MUFA and the risk of breast cancer ,37,38. TSix studies out of fourteen reported a significantly reduced breast cancer risk with increased PUFA consumption ,48,57,66Contrary to the results based on case-control studies, three out of eleven cohort studies reported significant positive associations with dose-response relationship between the increased consumption of PUFA and the risk of breast cancer ,34,52. TOne study of n-3 fatty acids  and anotSignificantly reduced risk of breast cancer was observed in one study for increased consumption of n-3 fatty acids (RR = 0.72 in the highest quartile of intake) . ContrarOne study from France of linoleic acid (n-6 fatty acid) consumption reported a highly significant increased breast cancer risk (OR = 2.31 in the highest category of consumption of linoleic acid) . Two stuOne study conducted in Sweden among postmenopausal women reported a significantly increased breast cancer risk with dose-response relationship on the consumption of n-6 fatty acids [OR = 3.02 (95% CI: 1.78–5.13) in the highest quintile] . Non-sigMost of the case-control studies discussed here have shown increased breast cancer risk with increased total fat consumption. However, results of cohort studies did not offer the same degree of consistent support.Case-control and cohort studies share some strengths and limitations. The primary advantages are the ability to measure diet and potential confounding factors relatively accurately and uniformly at the individual level in both the types of study designs. Also, the subjects in most of the studies were generally drawn from a relatively uniform population. Despite these advantages, there remains a number of limitations common to both case-control and cohort studies.As fat intake is estimated by food frequency questionnaire (FFQ) in most of the studies discussed in the present review, there remains a certain amount of measurement error in such procedures. Non-differential random measurement error (i.e. independent of case or non-case status) in estimated fat intake might bias estimated risks toward the null and concurrent measurement error in potential confounding variables  could bias results in either direction. Only a few studies mentioned about validated FFQ ,33,53,66The main contrast between case-control and cohort studies lies in their differing potential for bias and in the resources required. Selection bias would occur if participation in a case-control study was correlated with fat intake and if cases and controls have different participation rates. In many of the case-control studies discussed here, particularly those conducted in highly industrialized populations such as the United States, there is often a substantial refusal to participate, particularly among control subjects, and it is possible that there is preferential participation by health-conscious individuals, who might have a relatively low fat intake. Such a phenomenon might introduce an artificial positive association between fat intake and breast cancer risk. Recall bias might occur since cases are interviewed after diagnosis and might report their past diet differently to control subjects. In particular, they could report their diets more accurately through better motivation, or conversely, they could report an over inflated fat consumption if aware of the postulated association between fat intake and breast cancer risk.Since there are many limitations associated with case-control studies, the results from the cohort studies can be considered more authentic. Cohort studies assessing the relationship between total dietary fat and risk of breast cancer have been used since the late 1980's as an alternative to the inconsistent findings of the case-control studies. These are normally considered free of the most common biases that potentially affect case-control studies such as selection and information bias.Even though most of the cohort studies failed to find an association between total dietary fat intake and breast cancer risk, some studies reported a significant positive association with dose-response relationship ,31,34,35When we consider the components of fat, saturated fat, the unhealthiest out of all the types of fat, when consumed in large amounts increases the risk of breast cancer. In the present review, several case-control studies have shown positive association with breast cancer risk ,18,19,45Monounsaturated fats (MUFA) are considered as 'non-essential' because they can be synthesized within our bodies, from foods and oils such as oleic acid and olive oil. Even though a few studies showed a positive correlation between MUFA and breast cancer ,18,34,37In the present review on polyunsaturated fatty acids, we focused mainly on n-6 and n-3 families. Various studies have analyzed the possible relation of (n-3)/(n-6) PUFA ratio and the possible role that it may play in the risk of breast cancer . Most ofet al, [Boyd and others  carried et al,  have difet al,  have, inPreviously published review papers reported increased risk of breast cancer with the increased consumption of total dietary fat ,69,71-75Considering the totality of epidemiologic evidence, it is reasonable to conclude that a positive association exists between total dietary fat intake and breast cancer risk, even though all epidemiological studies do not provide a strong association between consumption of dietary fat and breast cancer risk. Also, increased consumption of saturated fat is positively associated with the development of breast cancer. There exists an inverse association of breast cancer risk with the consumption of oleic acid. A moderate inverse association between breast cancer risk and the consumption of n-3 fatty acids and a moderate positive association between n-6 fatty acids and breast cancer risk were also observed. These have lot of implications in view of the fact that breast cancer is a growing public health problem.The present review paper will be quite useful for surgeons, clinicians, epidemiologists and other public health professionals particularly working in the filed of cancer.BB – collected the literature, summarized the results in the form of tables and wrote the paperAM: provided technical guidance for writing the paper and edited the paperNilTable showing case control studies and risk of breast cancer.Click here for fileTable showing cohort studies and risk of breast cancer.Click here for file


Some earlier studies based on relatively small data sets have suggested that the month of diagnosis affects survival of breast cancer patients. This phenomenon has been suggested to be attributable to daylight-related hormonal factors. Factors related to the holidays of both the medical personnel and the women themselves might also provide the explanation. In this study we assessed the effect of the month of diagnosis on the survival of 32,807 female breast cancer patients diagnosed in Finland in 1956-1985. Our results indicate that the month of diagnosis is a significant prognostic factor after adjusting for age at diagnosis, period of diagnosis, and stage at diagnosis. The adjusted relative excess risk of death was highest among those diagnosed in July and August, and lowest in March and November, the difference between the lowest and highest risk being 18%. Since colorectal cancer should not have any daylight-related hormone dependent risk determinants, a control cohort of 12,950 women with a diagnosis of colorectal cancer in the same calendar period was studied in a similar way. The survival pattern by month of diagnosis among the colorectal cancer patients was similar to that among breast cancer patients, indicating that general factors associated with the health behaviour of women and the health services (such as holidays) rather than biological factors may cause seasonal variations in survival of cancer patients.


African American women have higher rates of breast cancer mortality than their white counterparts. Studies have suggested that this is partly caused by discovery of cancer at a later stage, highlighting the importance of encouraging early detection of breast cancer in this population. To guide the creation of a breast cancer education intervention and help focus other health educators' and clinicians' health promotion efforts, this study explored whether a cohort of African American women living in San Diego would demonstrate the possession of adequate baseline knowledge about breast cancer screening and adherence to widely recommended screening guidelines.African American women  from San Diego, California participated in a beauty salon-based survey about breast cancer knowledge, attitudes, and screening practices. Women's ages ranged from 20 to 94 years, with average age of 42.20 (SD = 13.53) years. Thirty-four percent reported completing college and/or some graduate school training, and 52% reported having some college or post high school formal training. Seventy-five percent of the sample reported working outside their home. Participating cosmetologists and their salons were recruited to the study through word-of-mouth referral by highly respected African American community leaders.Salon clients reported low rates of adherence to recommended breast cancer screening guidelines. Of the 1,055 participants, 31% reporting performing breast self-exam every month. Of those participants 40 and older, 57% reported having had a clinical breast exam and 43% reported having had a mammogram in the past year. Knowledge of breast cancer was associated with adherence to screening guidelines. While women recognized the serious health threat that breast cancer poses and that early detection of breast cancer is important, only 30% of women reported feeling well informed about the disease. Many participants demonstrated a lack of basic knowledge about breast cancer. The Health Belief Model postulates that access to such information is an essential element in the progression toward engaging in screening behaviors.Data from this study reflect a continuing need for increased breast cancer education for African American women. In light of the considerable mainstream information available related to breast cancer, these data reinforce the need for more breast cancer education programs that are clearly intended to attract the attention of African American women. Breast cancer is the most common malignant neoplasm and the second leading cause of cancer death among women in the United States. Even though breast cancer incidence is lower among African American women  than among Caucasian women , African American women's death rate has consistently remained higher . An estimated 19,620 new diagnoses of invasive breast cancer and 5,670 deaths from breast cancer are expected to occur among African American women in 2006 [The Health Belief Model (HBM) , which hThe Black Cosmetologists Promoting Health Program, provided written consent to participate in the program's randomized controlled education trial [This manuscript reports on baseline data about the breast cancer knowledge and screening practices among the sample of 1,055 African American women. The women, who were clients of the 20 salons of on trial ,12. The Research assistants, in collaboration with the stylists, invited the salons' clients to participate in the study. To allow clients to be recruited at times when the research assistants were not present and thereby increase the diversity of the client sample, the participating cosmetologists were also trained to recruit the salons' clients to the study and conduct the consenting process on their own. This was facilitated by placing a study display in the salon next to a large, eye-catching basket of beauty supplies that were to be raffled off at the conclusion of the study accrual. The display included clear instructions on how to complete the baseline survey and consent forms and informed the client to ask the cosmetologist if they needed more information or assistance with the documents' completion. All elements of the study were approved by the University of California, San Diego's Institutional Review Board. A more detailed description of the methodology employed is provided in previously published papers ,12.Of the 530 women who were approached by a research assistant, 13% (71/530) refused . The 71 women who refused to participate were asked by the research assistant if they would anonymously answer four, simple, IRB-approved questions that would help the research team determine whether women who opted not to participated were comparable to women who agreed to participate in the study. All agreed to do so. When asked for their reason for not participating, 12 women reported that they did not want to spend the time, 29 refused to give a reason, and the remainder of the 71 women gave a variety of miscellaneous reasons. T-tests showed no difference in education level between the women who refused to participate versus those who participated. However there was a significant difference in age  between the women who participated and those who opted not to participate. Women who opted not to participate were somewhat older than those who agreed to participate.While San Diego has 184 different postal ZIP codes, the salons that were referred to the research team by the community leaders were from 13 ZIP codes. According to the 1990 and 2000 Census, each of these ZIP codes is home to a high proportion of African Americans. Slightly more than half (52% (550/1055)) of women who participated in this study reported home addresses that were similarly clustered into these same thirteen ZIP codes, suggesting that these salons would be viewed as an integral part of the community's overall neighborhood.The sample was composed of 1,055 African American women. All the participants lived in San Diego County, and all but 42 reported their ages, which ranged between 20 and 94 years of age. For those women who gave their ages, the mean age was 42.20 (SD = 13.53) years. Those with missing age data were not included in the calculation of the mean age and in any of the subsequent analyses on screening behaviors. Thirty-four percent (356/1055) of the women had completed college and/or had at least some graduate school training, half of them (52% (547/1055)) had some college or post high school formal training, and 11% (122/1055) had completed high school or less. Three percent (30/1055) did not provide information on educational level. Most of the women (75% (790/1055)) reported that they worked outside their home; among the 945 women aged 65 years and younger, 80% (756) reported working outside the home. Thirteen (1%) of the 1055 women reported they had breast cancer.In spite of the fact that most women agreed with the statement "The more I know about a disease, the more control I have," only 30% 317/1055) of the women reported feeling that they were very well informed about breast cancer. This perceived lack of knowledge takes on greater significance because women who reported that they perceived that they were well informed about breast cancer were significantly more likely to be adhering to recommended breast cancer screening guidelines for breast self-exams, clinical breast exams, and mammograms  most frequently, followed by their health care providers (543). Other sources of breast cancer information were: television (204); one-on-one conversations with friends, parents, siblings, cosmetologists, and others (194); work/school (57); seminars/health programs (47); nurses and other health professionals (43); and the Internet (25). Total responses add up to more than 100% because women could provide more than one response to this question. These data were reported in an earlier paper that described the participants' perceptions of their most serious health threats .Participant' knowledge of screening guidelines was evaluated by asking the participants to list the age at which women should start: 1) monthly BSE; 2) CBE every three years; and 3) annual mammogram. Only 31% (324/1055) of the women correctly reported that CBE every three years should be done between the ages of 20 and 39 years. For mammography, only 13% (140/1055) correctly reported that annual yearly mammography should be started at age 40. Only 8% (81/1055) of the women reported that monthly BSE screening should begin at age 20. (The most common answer (14% (146/1055)) for this question was puberty.)Even though women's screening rates were low, they were aware of the value of the screening process. Ninety-four percent (992/1055) disagreed with the statement, "I have a fairly fatalistic view when it comes to illness." Most (91% (957/1055)) agreed with the statement, "The more I know about a disease, the more control I have."Adherence to screening guidelines was defined as having had a breast self-exam (BSE) within the past month, and having had a clinical breast exam (CBE) and mammogram in the past year for women 40 years and older . MonthlyLess than half of the women (49% (514/1055)) reported that their closest family members and friends were very supportive in helping them to adopt ways to improve their health, 22% (237/1055) saying that their family and friends were mildly supportive, and 24% (253/1055) stating that their family and friends were not very supportive. Five percent (51/1055) did not respond.To estimate African American women's perceptions of their susceptibility to breast cancer and the severity of the disease in the African American community, they were asked to list "the four most serious health problems facing Black women." Breast cancer was mentioned as one of four serious health problems by 51% (541/1055) of the women . DiabeteResponses from women in this sample indicated that they perceived benefit to taking action in detecting breast cancer early. Ninety-four percent (989/1055) of the women disagreed with the statement, "Breast cancer early detection does not make a difference."Women were asked whether they or other members of their social circle had breast cancer. Women who reported knowing someone with breast cancer were categorized as having personal exposure to breast cancer. Only 1% (13/1055) reported having breast cancer themselves, 8% (82/1055) reported having family members with breast cancer, 21% (227/1055) reported having friends with breast cancer, and the rest had either no exposure (65% (683/1055)) to the disease or did not answer (5% (50/1055)). Using that information, women were categorized as those with prior personal exposure to breast cancer (30%) or those without prior personal exposure to breast cancer (65%).2 = 12.84, p < .0001; 68% of women under 50 reported no exposure versus 56% of women 50 years and older reported no exposure). There was also a significant relationship between prior personal exposure to breast cancer and practice of BSE and mammogram  has recommended annual clinical breast exams and mammograms for all women age 40 and older, and the ACSs California Annual Facts and Figures 2007 noted that only 39% of the women had reported an annual mammogram in 1987, a number that rose to 57% in 2004 . In thisBreast cancer was listed as one of four serious health problem facing African American women by 51% (541/1055) of the women. Additionally, 29% of the women listed breast cancer first in their list of problems. This high awareness of breast cancer shows a heightened sensitivity to it as compared to heart disease, the most common cause of deaths in the African American community . The heiAlthough the women in this study appeared to perceive they were susceptible to breast cancer, their adherence to breast cancer screening guidelines was low. Women who had no personal, familial, or social exposure to breast cancer were also least likely to report having been screened. This underscores the importance of continued work in educating and engaging African American women in dialogues about the importance of breast cancer screening. Further, the women in this study did not demonstrate widespread knowledge of the details related to the recommended screening guidelines. For example, BSE, the least effective method of screening, was reported as a reliable screening method more often than the more effective methods of CBE and mammography.Previous literature suggests that high motivation for health concerns will lead to an increase in health promoting behaviors . In thisNearly all the women in the study believed that they could influence their health. However, few women perceived that they possessed adequate breast cancer knowledge, thereby providing further support for the importance of the randomized controlled trial of a beauty salon-based breast cancer education program to increase breast cancer knowledge, which was planned to follow this baseline data collection. Among those participants who reported that they possessed adequate breast cancer knowledge, there was a high association with adherence to recommended screening guidelines. Thus both the perceived and demonstrated lack of adequate breast cancer knowledge may help to explain the low screening rates reported by the participants in this study.Recommendation by a health care provider is widely considered the most significant predictor of women's adherence to BC screening guidelines. Review of the literature suggests that African Americans view the medical establishment with mistrust and this may contribute to these sub-optimal screening rates ,18. In tIn this study, women most frequently listed the media as their best source of breast cancer information. Since the public spends considerably more time exposed to the media, then to their health care providers, the media represents an important partner for the dissemination of health information. Thus these data also suggest that African American women will also benefit from partnerships between public health educators and media partners to speed the dissemination of breast cancer information and expand the messages' audience.The study participants' awareness that breast cancer poses a serious health threat to African American women, suggests that the many messages about breast cancer that have been widely broadcast to women as well as the messages that have been specifically focused on African American (narrowcast), appear to have successfully reached African American women and have done so in a way that personalized the message. It is at this junction, in alignment with the Health Belief Model, that there seems to be room for improving women's knowledge about breast cancer so they can make well informed decisions, including those related to screening and treatment, as appropriate. The study which follows this baseline assessment will specifically explore whether giving African American women access to essential information about breast cancer, in a manner that makes it clear the information is intended specifically for African American women, will increase their screening rates.The findings that evolved from this sample should be generalized with caution since they were developed based on a regional convenience sample. In addition, recruitment of these women from beauty salons may have led to a biased sample of women who are able to afford such services. As anticipated, the women who could afford to purchase beauty services at a neighborhood salon and would consent to research participation were also more likely to be better educated than the region's African American population at-large. This is a concern that plagues most research studies and must be taken into account when researchers consider the degree to which their findings may reasonably be generalized . Also, fParticipants in this study reported low rates of adherence to recommended breast cancer screening guidelines. This study suggests that African American women are highly aware of the presence of breast cancer as a health concern and that they also perceive that breast cancer presents a serious health threat for African American women. Data from the African American women in this study suggest that an optimal intervention would address their need for information about when breast cancer screening should be started and which of the available screening methods will be the most effective methods for achieving increased rates of early breast cancer detection. Such an intervention was developed and tested via a randomized controlled trial. Those results will be reported in a subsequent manuscript.The author(s) declare that they have no competing interests.GRS designed and conducted the study and helped draft the manuscript. CK performed the statistical analysis and prepared the manuscript. JC, MC, and RW helped to collect data and prepare the manuscript. PW helped to prepare the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Spain has one of the lowest rates of breast cancer in Europe, though estimated incidence has risen substantially in recent decades. Some years ago, the Spanish Cancer Mortality Atlas showed Spain as having a heterogeneous distribution of breast cancer mortality at a provincial level. This paper describes the municipal distribution of breast cancer mortality in Spain and its relationship with socio-economic indicators.Breast cancer mortality was modelled using the Besag-York-Molliè autoregressive spatial model, including socio-economic level, rurality and percentage of population over 64 years of age as surrogates of reproductive and lifestyle risk factors. Municipal relative risks (RRs) were independently estimated for women aged under 50 years and for those aged 50 years and over. Maps were plotted depicting smoothed RR estimates and the distribution of the posterior probability of RR>1.In women aged 50 years and over, mortality increased with socio-economic level, and was lower in rural areas and municipalities with higher proportion of old persons. Among women aged under 50 years, rurality was the only statistically significant explanatory variable.For women older than 49 years, the highest relative risks were mainly registered for municipalities located in the Canary Islands, Balearic Islands, the Mediterranean coast of Catalonia and Valencia, plus others around the Ebro River. In premenopausal women, the pattern was similar but tended to be more homogeneous. In mainland Spain, a group of municipalities with high RRs were located in Andalusia, near the left bank of the Guadalquivir River.As previously observed in other contexts, mortality rates are positively related with socio-economic status and negatively associated with rurality and the presence of a higher proportion of people over age 64 years. Taken together, these variables represent the influence of lifestyle factors which have determined the increase in breast cancer frequency over recent decades. The results for the younger group of women suggest an attenuation of the socio-economic gradient in breast cancer mortality in Spain. The geographical variation essentially suggests the influence of other environmental variables, yet the descriptive nature of this study does not allow for the main determinants to be established. Breast cancer is the leading malignant tumour in women, accounting for 27% of cancers in European women . Spain hOne of the classic approaches in epidemiology is the study of geographical distribution. In administrative terms, Spain is divided into Autonomous Regions known as Comunidades Autónomas. These are in turn divided into provinces and, at the lowest level, into municipalities. Breast cancer mortality has been previously studied at a provincial level. The highest standardised rates observed in Las Palmas Province (Canary Islands) were double those registered for Orense, the province with the lowest rate.Currently, spatial epidemiology allows for a greater level of disaggregation. One of the advantages of this approach is to highlight local effects that might be linked to specific geographic, social or environmental characteristics. This stAs our case source, we used all Spanish individual death entries for the period 1989–1998 corresponding to breast cancer  code 174) broken down by municipality. A municipality is an administrative unit, made up of a clearly demarcated territory and its population, governed by a municipal council. This is the smallest aggregated division for which mortality and population data could be obtained at a national basis for the study period. Mortality data were furnished by the National Statistics Institute. Municipal populations, broken down by age group (18 groups) and sex, were obtained from the 1991 census and 1996 municipal rolls. These years correspond to the midpoints of the two quinquennia that comprise the study period (1989–1993 and 1994–1998). The person-years for each five-year period were obtained by multiplying these populations by 5.As an indicator of socio-economic level, the index provided by the Spanish Credit Bank (Banco Español de Crédito) for 1991 was used. This inStandardised mortality ratios (SMRs) were computed as the ratio of observed to expected deaths. Expected cases were computed, taking Spanish breast cancer mortality rates, broken down by age and five-year period, as reference. SMRs were also calculated by province and category of explanatory variable, and confidence intervals for these categories were duly computed using Byar's approach.Breast cancer mortality was separately studied among women aged under 50 years and comprised deaths from cancers diagnosed mainly in premenopausal women and among women aged 50 years and over. This latter group was made up of a mixture of pre- and postmenopausal cases but was nevertheless dominated by the second group.Smoothed municipal relative risks (RRs) were calculated using the conditional autoregressive model introduced by Clayton and Kaldor, and furλi is the relative risk in area I; Oi is the number of deaths in area I; Ei are the expected cases; βj is the coefficient representing the effect (log(RR)) of the explanatory variable J, xji refers to the value of the explanatory variable J in the area I, hi is the municipal heterogeneity term; and bi is the spatial term.where: Models were fitted using Bayesian Markov Chain Monte Carlo simulation methods. PosteriFor comparison purposes, standard Poisson regression models were also fitted, with the three explanatory variables being included to quantify their effect on mortality. Confidence intervals were computed using robust estimates of variance, as a waA Geographic Information System was used to plot municipal maps that depicted smoothed RR and the distribution of the posterior probability (pp) that RR>1 . Insofar as this indicator was concerned, we followed Richardson's criterion, which rFrom 1989 to 1998, a total of 56711 breast cancer deaths were registered. Eighty-four percent (47789) corresponded to women aged over 49 years, and the remaining 8922 to younger women. In 3328 municipalities there were no deaths due to this cause. Ninety percent of these villages had less than 1000 inhabitants and the number of expected cases in all of these was lower than 1. Furthermore, 3% of the Spanish population lived in municipalities that registered no breast cancer deaths during the study period. Table To give an overall picture, Figure Breast cancer mortality in women 50 and more years old:Figure Figure Breast cancer mortality in women younger than 50 years:Observed deaths among premenopausal women accounted for only 16% of overall breast cancer mortality, and 6237 municipalities registered zero cases Table . As ruraOur results reflect excess breast cancer mortality in women aged over 49 years in the Canary Islands, Balearic Islands, Catalonia and Valencia. Furthermore, high significant excess risks were observed in municipalities of La Rioja, Navarre, Aragon and Catalonia around the Ebro River. Most provincial capitals in the north and east of Spain displayed increased RR. Lastly, Badajoz, Mérida and Almendralejo in Extremadura, Seville and Alcalá de Guadaira in the Province of Seville, and Puerto Real and Puerto de Santa María in Cadiz registered high, significant RRs. The geographical pattern in younger women appeared to be more uniform and no RR over 1.20 were in evidence. The only exception was Tuineje . On the Spanish mainland, a group of municipalities with high RRs were located in two Andalusian provinces, Cadiz and Seville, near the Guadalquivir River.When seeking possible etiological clues, it could be argued that incidence would be more valuable than mortality, given that in Spain breast cancer survival rates are quite high, i.e., around 78% at five years. NeverthMunicipal RRs were estimated, including three ecological variables in the model, namely: the socio-economic index provided by the Spanish Credit Bank; the number of inhabitants categorised by the National Statistics Institute; and the percentage of subjects aged over 64 years. These variables were used as markers of the heterogeneous distribution of lifestyle and reproductive factors influencing breast cancer frequency. Selection of these variables was limited by the availability of information at a municipal level, so they only partially reflect the distribution of breast cancer risk factors in Spain. However, their inclusion served to smooth relative risks, taking into account both the spatial relation among municipalities and the variability associated with these indices. In the model proposed by Besag, York and Molliè, modelling the clustering variation allows for unmeasured risk factors that vary smoothly with location. Where the pattern of covariate variation is similar to that of disease risk, location may act as a confounder. This phSmall area analysis tends to reduce ecological fallacy, since the populations defined by municipal boundaries are more homogeneous. This might well be true of villages and towns of average size. In large cities, however, the results reported here correspond to an overall mean, and socio-economic and mortality differences inside cities have been disregarded. It could be very interesting to assess whether such differences exist in major Spanish cities, such as Madrid, Barcelona, Valencia, Seville and Zaragoza. This internal variability could not been explored in this paper.Risk factors for breast cancer may differ for premenopausal and postmenopausal cancers . Family Research indicates that use of well-chosen census tract socio-economic measures can provide important insights into socio-economic disparities in the burden of breast cancer. In our Socio-economic level was not associated with breast cancer mortality in younger women. This result is in agreement with the few studies available that looked into changes in social inequalities in breast cancer mortality,34,35. SIn our study, breast cancer mortality in both age groups was higher in more urban areas, which is consistent with the increased incidence observed in urban settings. Lower iA negative correlation was observed between the percentage of old population and breast cancer mortality in women aged 50 years or over. Birth-cohort trends reflect demographic patterns that are related to recognised breast cancer risk factors. Age-cohAlthough the three explanatory variables are interrelated, all were retained in the final model for older women, showing that, to a certain extent, they act as surrogates for different risk factors. Nevertheless, RRs for municipalities with high breast cancer mortality seemed to be higher than the predicted trend that had been estimated according to these variables. This implies the intervention of other conditions not properly captured by these ecological variables. Postmenopausal women with high body mass index have an increased risk. FourteeAt an individual level, well-established breast-cancer risk factors account for less than 50% of overall incidence. Like moHigh breast cancer mortality was also observed along the Ebro river in postmenopausal women and near the left bank of the Guadalquivir River in premenopausal women. Both rivers are included among fluvial areas with chemical pollution in Spain. The EbrEven though breast cancer mortality has begun to decline in Spain, a heterogeneous geographical pattern is in evidence, with higher rates in the Canary Islands, the Balearic Islands, the Mediterranean coast of Catalonia and Valencia, and a series of municipalities around the Ebro River. Among premenopausal women, increased mortality was also observed for municipalities located along the last third of the Guadalquivir River. As has been previously reported in other contexts, mortality rates are positively associated with socio-economic status and negatively associated with rurality and the presence of a higher proportion of persons over the age of 64 years (born before 1931). Taken together, these variables represent the influence of lifestyle factors that have determined the increase in breast cancer frequency over recent decades. On the other hand, the results for the younger group of women would suggest an attenuation of the socio-economic gradient in breast cancer mortality. The geographical variation mainly suggests the influence of other environmental variables, though a heterogeneous distribution of genetic factors cannot be ruled out. The descriptive nature of this study means, however, that the main determinants of this pattern cannot be ascertained.DDE: dichlorodiphenyldichloroethane; DDT: dichlorodiphenyltrichloroethane; ICD-9: international classification of diseases, 9th revision; PCBs: polychlorinated biphenyls; RR: relative risk; SMR: standardised mortality ratio.The author(s) declare that they have no competing interests.MP, GLA, NA, and BPG were all involved in designing the study. GLA, RR & MP performed the statistical analysis. DG draw the maps using GIS software. VL & JGP reviewed the information about possible pollutant sources in the areas with high RR, JMC & MJG reviewed the socio-economic index used in this study and the abundant literature on this issue. MP wrote the draft of the manuscript to which all authors subsequently contributed. All authors made contribution to statistical analyses and interpretation of results, and revised the manuscript for important intellectual content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The associations of body fat and body fat distribution with breast cancer risk were examined in a prospective study in 9,746 post-menopausal women with a natural menopause, aged 49-66 at intake, participating in a breast cancer screening project (the DOM project in Utrecht). During a follow-up period of 15 years (mean follow-up time 12.5 years) 260 women developed breast cancer. Fat distribution, assessed by contrasting groups of subcapsular and triceps skinfold thickness, was found to be unrelated to breast cancer incidence. No significant relationship between body fat, measured either by weight, Quetelet's index, triceps skinfold or subscapular skinfold, and breast cancer risk was found when analysed in quartiles. However, women in the upper decile compared with the lower decile of the distribution of Quetelet's index were found to have a 1.9 times (95% CI 1.1-3.3) higher risk for breast cancer. These results seemed to be in contrast with the significant positive association between fatness, analysed in quartiles, and breast cancer observed in a cross-sectional study, based on mammographic screening, carried out previously in the same population. Although the differences between the present, prospective, study and our cross-sectional study may be due to chance it may be that there are differences between characteristics of breast cancer detected at screening and subsequently, which influence the associations between measures of fatness and risk of breast cancer.


Breast cancer is the most common cancer and the leading cause of cancer related deaths in women worldwide. The incidence of the disease is increasing globally and this increase is occurring at a faster rate in population groups that hirtherto enjoyed low incidence. This study was designed to evaluate the role of a simple tandem repeat polymorphism (STRP) in the aromatase (CYP19) gene in breast cancer susceptibility in Nigerian women, a population of indigenous sub-Saharan African ancestry.A case-control study recruiting 250 women with breast cancer and 250 women without the disease from four University Teaching Hospitals in Southern Nigeria was carried out between September 2002 and April 2004. Participants were recruited from the surgical outpatient clinics and surgical wards of the Nigerian institutions. A polymerase chain reaction (PCR)-based assay was employed for genotyping and product sizes were detected with an ABI 3730 DNA Analyzer.n repeats in Nigerian women compared with other populations.Conditional logistic regression analysis revealed that harboring the putative high risk genotypes conferred a 29% increased risk of breast cancer when all women in the study were considered , although this association was not statistically significant. Subgroup analysis based on menopausal status showed similar results among premenopausal women . The data also demonstrated marked differences in the distribution of (TTTA)n repeats of the CYY19 gene is associated with a modest increased risk of breast cancer in Nigerian women.This study has shown that harboring 10 or more repeats of the microsatellite (TTTA) An aging world population with rising global burden of breast cancer , emerginThe CYP19 gene encodes aromatase, which is responsible for the rate-limiting step in the metabolism of C19 steroids to estrogens and is expressed in most breast carcinomas . Five diA total of 500 study participants comprising 250 women with breast cancer and 250 age-matched control women without the disease were recruited from four University Teaching Hospitals located in Southeastern and Midwestern Nigeria, including University of Benin Teaching Hospital, Benin City; University of Nigeria Teaching Hospital, Enugu; Nnamdi Azikiwe University Teaching Hospital, Nnewi; and University of Port Harcourt Teaching Hospital, Port Harcourt. Recruitment was carried out between September 2002 and April, 2004. The study protocol was approved by the Ethics and Research Committees of the participating Nigerian Institutions and the Institutional Review Board of the University of Pittsburgh.Written informed consent was obtained from participants willing to participate in the study prior to commencement of recruitment. At the end of the questionnaire session, anthropometric measurements including height, weight, waist and hip circumferences were taken.3-EDTA tube were collected at the end of the questionnaire session. Samples were centrifuged within 10 h of collection; buffy coat was separated from plasma and red cells in the K3-EDTA vacutainer tubes and carefully aliquoted into 3 ml tubes while clots separated from serum in the plain vacutainer tubes were turned into two 20 ml plain tubes and stored at -20°C in each of the Nigerian study sites until transferred in ice packs to the Nigerian coordinating center at the University of Benin Teaching Hospital where samples were stored at -20°C until transferred to the University of Pittsburgh in dry ice packs. Samples were then stored at -80°C at the University of Pittsburgh until DNA extraction.Biological samples including 40 milliliters of blood in two 15-milliliter plain vacutainer tubes and one 10 milliliter KDNA was extracted from buffy coats using the QIAamp Mini Kit protocol  or blood clots using the QIAamp Midi Kit protocol  for participants in whom buffy coat was unavailable. The DNA was stored at 4°C until amplified by polymerase chain reaction (PCR) and used for genotyping on the ABI 3730 DNA Analyzer .PCR amplification of the polymorphic fragment was generated using primers, 5'-CAA CTC GAC CCT TCT TTA TG-3' (forward) and 5'-GTT TGA CTC CGT GTG TTT GA-3' (reverse). The forward primer was 5'-labeled with a fluorescent dye  for automated fragment analysis. A 50 μl reaction mixture containing 2 μl of genomic DNA, 8 μl of deoxynuclotide triphosphates, 0.5 μl each of forward and reverse primers, 5 μl of 10× buffer, 1.5 μl of MgCl and 2 μl of Taq polymerase was placed in Thermalcycler (MJ Dyad PCR machine). After denaturing for 5 min at 95°C, the DNA was amplified for 35 cycles at 95°C for 30 s, 55°C for 30 s, 72°C for 45 s, followed by a 5 min extension at 72°C. A positive control containing genomic DNA and a negative control containing everything except DNA were included in the PCR experiment. Five μl of each PCR product, including the controls, were run on a 1% agarose gel to ensure that the expected fragment size was generated.The product sizes were then detected with an ABI 3730 DNA Analyzer  at the Genomics and Proteomics Core Laboratory at the University of Pittsburgh. Allele calling was carried out using Genotyper software .Data analysis was carried out using Statistical Analysis Software (SAS), Version 8.0. Association between demographic, reproductive and anthropometric variables and breast cancer risk was first assessed using conditional logistic regression. Each matched case was paired with the corresponding control to enable differences between the cases and controls to be calculated. First each variable was assessed alone in a univariate model. The strength of significant variables was further assessed by building multivariate models.n repeats and breast cancer risk. Based on information available in the literature, the CYP19 genotypes were categorized into two groups for the purpose of conditional logistic regression. There is evidence suggesting that an increased risk of breast cancer is associated with 10 or more (TTTA)n repeats. Genotypes containing at least one allele with 10 or more repeats were categorized as high risk genotypes while genotypes containing alleles with less than 10 repeats were categorized as low risk genotypes. Because of the small number of individuals carrying these genotypes, we had to collapse all genotypes in the high risk category as one group in the logistic regression model. A multivariate conditional logistic regression model containing the significant predictors of breast cancer risk in the descriptive analysis and the CYP19 genotype data was then developed to assess gene environment interactions.Conditional logistic regression was also used to assess the relationship between the distribution of the genotypes of the CYP19 tetranucleotide (TTTA)Conditional logistic regression analysis was used to examine the association between demographic/reproductive variables of study participants and breast cancer risk. In the final multiple conditional logistic regression model, only family history of breast cancer , waist/hip ratio (WHR) , age at first full term pregnancy , and higher level of education  were found to be significant predictors of breast cancer risk.n repeat polymorphism of the CYP19 gene were identified in 228 cases and 228 control subjects in whom polymerase chain reaction (PCR) amplification and genotyping were successful. The most common alleles were A1  and A2  alleles. The A1 allele was slightly more common in the cases  than in the control subjects  while allele A2 was less common in the cases  compared to the control subjects  as shown in Table Seven different alleles The distribution of the CYP19 (TTTA) genotypes in premenopausal women is similar to the general pattern seen in all women. The most common genotypes include A1A2 , and A2A2  as shown in Table 4.92% in Of 108 postmenopausal breast cancer cases and 108 age-matched control subjects in the study, PCR amplification and genotyping was successful in 102 cases and 99 controls. As shown in Table n genotypes and breast cancer risk. For the purpose of this analysis, the genotypes were categorized into two broad groups; genotypes with at least one allele containing 10 or more (TTTA)n repeats were classified as high-risk genotypes while those containing less than ten alleles were considered as low-risk genotypes. This classification was adopted based on evidence in the literature suggesting that the higher number of repeats (10 and 12 repeats) were associated with increased risk of breast cancer. Conditional logistic regression analysis showed a 29% increased risk of breast cancer for harboring at least one high risk allele [[n repeats] when all women were considered . There was a 35% increased risk of premenopausal breast cancer for women harboring at least one high risk allele . Harboring the high risk genotype was associated with a 27% increased risk of postmenopausal breast cancer .Conditional logistic regression was used to evaluate the association between the distribution of the CYP19 (TTTA)n repeats]. Two control participants were homozygous for any of the high risk alleles. When all women were considered together, there was a 4-fold increased risk of breast cancer for women carrying the homozygous genotypes of any of the high risk alleles although this was not statistically significant . There was a 2-fold increased risk of postmenopausal breast cancer  for carriers of the homozygous genotypes.The risk profile of women homozygous for any of the high risk alleles was further considered. Four breast cancer cases were homozygous for any of the high risk alleles; three of these women carried the homozygous A5A5 genotype while one was homozygous for the A4A4  of CYP19 and risk of breast cancer compared with repeat lengths less than 12 . These authors also observed a higher frequency of the 12 allele among estrogen- and progesterone receptor positive cases compared with receptor negative cases , Probst-Hensch et al  observedDifferences in study size and ethnicity may account for the discrepancy between study results. The studies of Siegelmann-Danieli and Buetow  and ProbBecause of the weak association detected in most association studies involving single nucleotide polymophisms and breast cancer risk, haplotype-based studies have been proposed as a more powerful comprehensive approach to identify causal genetic variation underlying breast cancer and other complex diseases. Employing these techniques using data from the Multiethnic Cohort (MEC) Study recruiting African-American, Hawaiian, Japanese, Latina and white women, Haiman et al  utilizedn repeat alleles of the CYP19 (aromatase) gene is in keeping with this proposition. As mentioned previously, some of the current epidemiological studies lack adequate sample size to detect the low risk profile impacted by low-penetrance alleles such as the STRP being considered in this study and this may have affected our results. We hope to further investigate the association between this polymorphism and other variants in the CYP19 gene by recruiting more study participants. There is emerging consensus that future molecular epidemiological studies should focus more on polygenic models employing haplotytpe-based techniques to properly assess the contributions of various low-penetrance genes acting in specific metabolic pathways such as estrogen biosynthesis and metabolism pathway to disease risk. Such studies will require large sample sizes and the collaborative efforts of multi-center investigators. In addition, the combination of high through-put genotyping techniques with emerging technologies including microarray and proteomic technology will enhance our ability to further understand the genetic factors involved in breast carcinogenesis.Despite the inconsistencies in the epidemiological literature and inconclusiveness of current experimental observations on the role of aromatase in breast carcinogenesis, a combination of experimental -17, labo1. STRP: Simple tandem repeat polymorphism2. CYP19: Cytochrome P45019A1 gene3. DNA: Deoxyribonucleic acid4. PCR: Polymerase chain reaction5. SNP: Single Nucleotide Polymorphism6. ABI: Applied Biosystems Incorporated7. SAS: Statistical Analysis Systems8. WHR: Waist/hip ratioThe author(s) declare that they have no competing interests.MNO, CHB, REF, KLH, participated in conceptualization, design of the study and preparation of manuscript; MNO, ERE, SNCA, JO and EEOU recruited study participants from Nigeria and organized the transfer of biological samples to the University of Pittsburgh; MNO, CHB and JMZ carried out the genetic analysis.


Does a young woman living with a smoker or taking a job working in a smoky bar have a greater chance of developing breast cancer? Some scientists believe that such situations can indeed raise a woman’s risk of developing breast cancer before the age of 50. Because epidemiological and toxicological studies show that women’s breast tissue may be especially sensitive to exposure to carcinogens prior to first pregnancy, these researchers contend that public education should be directed at alerting adolescents and young women to the potential risk. However, not everyone in the international public health community agrees that the evidence to date supports a link between passive smoking and breast cancer, and some say that women are being alarmed unnecessarily. This disagreement has sparked debate that is sometimes heated.The stakes are high because breast cancer is the most common cancer in women in industrialized countries, according to the WHO. It is the leading cancer killer of nonsmoking women, and second only to lung cancer deaths among women who smoke.The Health Consequences of Involuntary Exposure to Tobacco Smoke, put it. That characterization is based largely on the fact that the research considered when the Surgeon General’s report was being amassed did not clearly link even active smoking to breast cancer. Researchers in this camp do, however, stress that ongoing campaigns to prohibit smoking in public will protect the whole of society against the wide variety of ills proven to be caused by SHS. These include lung cancer, cardiovascular disease, and sudden infant death syndrome, among others.Among the researchers interviewed for this article who disagree that there is enough evidence to link secondhand smoke (SHS) with breast cancer, the majority call the evidence to date “suggestive but not sufficient,” as the Surgeon General’s 2006 report, A smaller group contends that the question of whether or not SHS causes breast cancer is a political issue with the potential to compromise the scientific process. “A premature decision about causality could jeopardize the credibility of the entire review process and all of the other, established effects of secondhand smoke,” says Michael Thun, national vice president of epidemiology and surveillance research for the American Cancer Society. Adds Valerie Beral, director of the University of Oxford Cancer Research UK Epidemiology Unit, “To prematurely come to conclusions about the causation when there is a big division in the scientific community . . . is bad science.”Thun debated the subject in a series of public forums held in conjunction with scientific meetings. Taking the opposing view was Kenneth C. Johnson, a research scientist with the Public Health Agency of Canada, who was one of the first scientists to discern a potential link. During the debates, Johnson pointed out there are about the same number of studies linking breast cancer to passive smoking as there were linking lung cancer to SHS in 1986, when the Surgeon General concluded that passive smoking caused lung cancer. Johnson also says that more of the breast cancer studies are statistically significant, and that the estimated risk for breast cancer is higher.a,1]pyrene, which the research literature identifies as an extremely potent carcinogen in mammary tissue.The suspicion that exposure to SHS could cause breast cancer dates back more than two decades. Among the more than 50 carcinogens in tobacco smoke are approximately 20 substances listed as mammary carcinogens by the International Agency for Research on Cancer. These include compounds such as dibenzopyrene, that are present in tobacco smoke and induced tumor formation in breast epithelial cells.” What is less clear, she says, is when and how this exposure causes cancer in women.Numerous studies have shown that toxicants from cigarette smoke reach rodent mammary tissue and can form the DNA adducts believed to represent the first step of carcinogenesis. If not repaired or if repaired incorrectly, these modifications may eventually lead to mutations and ultimately cancer. Irma Russo, a member of the Fox Chase Cancer Center’s Medical Science Division, says, “We know that [tobacco smoke] is carcinogenic to the human breast [because we have] utilized some of the carcinogens, such as benzo have to interview a hundred thousand [people] in order to get a thousand cases. In a case–control study, you may have a thousand cases and a thousand controls, so you have to interview two thousand to find out the demographic and exposure information of interest,” he explains. “Because you have to interview fifty times as many people [in a cohort study], there’s a much higher price [in terms of administering the questionnaire] associated with every question you ask about exposure—the depth and quality of the exposure measures tend to be less unless it is a real focus of the cohort study.”Further, says Russo, a woman might not know whether her grandparents, parents, and other relatives living in the same household smoked, and how much and for how long, nor whether her mother smoked during pregnancy.Another issue that continues to plague efforts to link passive smoking to breast cancer is the fact that many researchers feel that epidemiological studies have not conclusively linked even active smoking to the disease. This, says Jonathan Samet, chairman of the Johns Hopkins Bloomberg School of Public Health and the senior scientific editor for the Surgeon General’s 2006 report, is one reason that report called the breast cancer–passive smoke evidence “suggestive but not sufficient.”Preventive Medicine paper says that six large prospective studies have now found a statistically significant elevated risk for breast cancer among smokers for at least some metrics of exposure.Stanton Glantz, a professor of medicine at the University of California, San Francisco, Medical School, claims this is because many of the most recent reports on active smoking weren’t considered when the Surgeon General’s report was being produced. The Journal of the National Cancer Institute. She and her colleagues have been following 116,544 California teachers since 1995, and reported that the incidence of breast cancer among the cohort’s current smokers was higher than that for members who had never smoked. She said that the risk doubled for smokers with more than 31 pack-years—the equivalent of smoking one pack of cigarettes per day over the course of 31 years—compared with nonsmokers.Peggy Reynolds, a cancer epidemiologist at the Northern California Cancer Center, is the lead author of one of the case–control studies that does support a link between active smoking and breast cancer, published in the 7 January 2004 Although Reynolds did not report finding a link between passive smoking and breast cancer in that paper, she stresses that this could be because the questionnaire used to capture the data included information about whether women were exposed to smoking only in their homes. In a follow-up questionnaire, she and her colleagues asked more detailed questions to include other sources of passive exposure, particularly the workplace, and those data are currently being analyzed. These additional data are important because, although household exposures represented the major exposure source for women in this cohort during earlier decades, “following 1970, the workplace became women’s most important source of exposure to secondhand smoke,” she says.In both their report and review article, Johnson and the Cal/EPA researchers also evaluated the biological plausibility of just how exposure to SHS might cause breast cancer, and concluded that “the chain of evidence indicates that a causal association is highly plausible.” Glantz points out that this isn’t always taken into consideration in epidemiological studies, which he argues gives the team’s conclusion all that much more weight.However, the chain of evidence regarding biological plausibility doesn’t fit neatly with the fact that active smoking does not cause a significantly higher number of breast cancers compared with passive smoking exposure. “One reasonable biological explanation for the similarity in risk would be that the tobacco smoke exposure pathways might become saturated at levels of exposure associated with regular secondhand smoke exposure, so that the higher exposure [from active smoking] would not further elevate the risk,” Johnson says.It also appears that active smoking may partially mitigate effects of carcinogen exposure on the breast in smokers by reducing their estrogen levels. This fits with the M.D. Anderson study, which credited the declining popularity of hormone replacement therapy for the decreasing rates of breast cancer among older women. It might also explain why passive smoking, which is hypothesized to have less impact than active smoking on estrogen levels, could be associated with breast cancer. The problem with this, as Thun points out, is that no toxicological data exist to show there is a nonlinear relationship between the effects of low and high doses of smoke exposure.The Lancet, it showed that women who started smoking within five years of menarche were around 70% more likely to develop breast cancer than nonsmokers.Another potential explanation is that women may be especially susceptible during a key “window of exposure” that researchers have previously identified—namely, between puberty and when a woman bears her first child. Data from Hiroshima and Nagasaki, as well as from the treatment of young women with Hodgkin disease, show that the breast is not protected from potentially harmful environmental agents until it becomes fully differentiated in preparation for producing milk. This does not occur until the first full-term pregnancy. Pierre Band of Health Canada’s Division of Epidemiology and Cancer Prevention led a case–control study that supports the “window of exposure” hypothesis. Published in the 5 October 2002 issue of Many researchers interviewed for this article agreed that drinking alcoholic beverages does promote breast cancer, but not everyone felt that this factor has been adequately separated from tobacco exposure. “The breast cancer–alcohol association . . . is quite widely reported, but it is very hard to quantify and separate from the effects of concurrent active and passive smoking,” Salmon points out. “There’s also a complex multiway interaction between alcohol intake, smoking exposures, hormone levels, obesity, and breast cancer,” he adds.British Journal of Cancer, found no link between active smoking and breast cancer, but Reynolds says her study showed otherwise; the data showed that the link between active smoking and breast cancer held whether or not alcohol consumption was considered. She says, “We did a second analysis . . . limited to nondrinkers, and we found the same elevated risk association.”The evidence for a breast cancer–alcohol link was presented in a large meta-analysis by Beral and colleagues that included over 50 studies and data from more than 150,000 women. That analysis, published in the 18 November 2002 Johnson suggests that because passive smoking was not considered in Beral’s meta-analysis of alcohol risk, it is possible that it could have confounded the alcohol association results. He adds that the study simply compared women who said they currently smoked to women who reported smoking previously and those who said they never smoked, with no consideration of how much the women had smoked over their lifetimes.Salmon says that if there is in fact an increase in breast cancer incidence directly caused by alcohol—as opposed to an association related to co-exposures—then promotional effects on cell growth might be involved. “At least,” he says, “there is a contrast with tobacco smoke, where genotoxic carcinogens are clearly present and involved along with other types of effects, and carcinogen–DNA adducts have been observed in the breast tissue of exposed women.”However, Li notes there are numerous studies that show that women metabolize alcohol much more slowly than men, and that serum concentrations of 17β-estradiol are elevated after alcohol ingestion. “This,” he says, “is likely the reason why alcohol ingestion increases breast cancer risk.”Boston Globe said the study focused on 1.3 million women aged 50 to 64, a different population than what the Cal/EPA scientists say is at greatest risk.Although it had yet to be published when this article was being written, a new analysis by Beral and colleagues that linked alcohol to breast cancer is already having an effect on this debate. Thun said that after being briefed on the new data, he decided to hold off on moving forward with a workshop that the American Cancer Society planned to fund to identify the outstanding questions in the breast cancer–passive smoking debate. Beral would not comment on the data other than to say that the “findings are essentially null.” She said the analysis included 22 studies as well as new data and “several measures of exposure to secondhand smoke.” An article in the 1 January 2007 While some members of the research community are perturbed by the disagreement regarding the strength of the evidence connecting passive smoking and breast cancer, Samet says he thinks it is to be expected. “People should not be surprised if review groups don’t exactly come into complete alignment. Different groups bring expert judgment to bear in somewhat parallel but not definitely overlapping processes. I don’t think that the way we approach evidence review and synthesis is leading us astray,” he says.Samet says that he would like to see the biological understanding advanced on ways that SHS could cause breast cancer. “Of course the simple story is that there are carcinogens in tobacco smoke, and they reach breast tissue, which is true,” he says. “[What makes the issue so complex is that] we would expect that far greater doses of these carcinogens would reach the breast tissue of women who actively smoke. We have not seen a clear signal showing that this is the case. I would like to see the biological framework laid out and better understood, as well as watch the epidemiological evidence grow.” Both the National Cancer Institute (NCI) and the NIEHS are funding research aimed at providing additional evidence on the topic. The Cal/EPA researchers contend it is likely that there are a number of subgroups genetically susceptible to breast cancer who could be especially sensitive to tobacco smoke exposure depending upon the polymorphisms of several genes. This is plausible, says Deborah Winn, acting associate director of the NCI’s Epidemiology and Genetics Research Program. “To actually look at gene–environment interactions and then try to look at breast cancer subgroups—you run out of numbers very quickly,” she says.For that reason, researchers with the NCI Cancer Genetic Markers of Susceptibility initiative are doing genome-wide scans on more than 500,000 single-nucleotide polymorphisms and looking for changes between breast cancer patients and controls in a hypothesis-free approach. “Eventually, you might find things that map up to candidate genes that you already thought—on the basis of function or their role in estrogen metabolism—might be involved,” Winn says. Other research is focused on more detailed looks at promising candidate genes, she says.Says Russo, “The fact that carcinogen-metabolizing enzymes such as CYP1A1 are increased in both lung and breast cancers, but that the death rate from lung cancer in American women has increased six hundred percent from 1930 to 1997, whereas breast cancer has remained stationary during the same period, might suggest that women carriers of susceptibility genes would be more prone to develop both breast and lung cancer. Unfortunately, statistics on the incidence of breast lesions in women diagnosed with lung cancer are almost nonexistent.”Sandler is currently in the process of recruiting women for an NIEHS-funded prospective study of sisters of women who have or had breast cancer; this group is twice as likely as other women to develop breast cancer. She has already enrolled 30,000 such women who don’t have breast cancer, and she aims to sign up 20,000 more. “The purpose is to look at environmental and genetic risk factors for breast cancer—certainly . . . we’ll be looking at their life history of exposure to cigarette smoke, their own and through their parents and their spouses and their roommates and their jobs,” she says. “The questionnaires were designed to do a thorough job of looking at it.”Just what all this research will show is unclear. The only certainty, Samet says, is that “scientific evidence will continue to accumulate on this topic.”