Breast cancer (BC) detection in women with a genetic susceptibility or strong family history is considered mandatory compared with BC screening in the general population. However, screening modalities depend on the level of risk. Here we present an update of our screening programs based on risk classification.We defined different risk categories and surveillance strategies to identify early BC in 1325 healthy women recruited by the Modena Study Group for familial breast and ovarian cancer. Four BC risk categories included BRCA1/2 carriers, increased, intermediate, and slightly increased risk. Women who developed BC from January 1, 1994, through December 31, 2005 (N = 44) were compared with the number of expected cases matched for age and period. BRCA1/2 carriers were identified by mutational analysis. Other risk groups were defined by different levels of family history for breast or ovarian cancer (OC). The standardized incidence ratio (SIR) was used to evaluate the observed and expected ratio among groups. All statistical tests were two-sided.P < 0.001), women at increased  or intermediate risk  was higher than expected, while the difference between observed and expected among women at slightly increased risk was not statistically significant .After a median follow-up of 55 months, there was a statistically significant difference between observed and expected incidence . The incidence observed among BRCA carriers (SIR = 20.3; 95% CI = 3.1 to 83.9; The rate of cancers detected in women at high risk according to BRCA status or strong family history, as defined according to our operational criteria, was significantly higher than expected in an age-matched general population. However, we failed to identify a greater incidence of BC in the slightly increased risk group. These results support the effectiveness of the proposed program to identify and monitor individuals at high risk, whereas prospective trials are needed for women belonging to families with sporadic BC or OC. Following the discovery the mutant BRCA1 and BRCA2 genes which predispose carriers for BC and OC  or heredSeveral guidelines for hereditary breast cancer (HBC) and familial BC have been published. Particularly, for familial breast cancer, three groups of risk have been defined , according to the number of affected relatives, the age at onset and the cancers associated. All women belonging to moderate/high risk should be offered annual mammography, but MRI and ultrasound should not be used in routine surveillance ,27. WithBeginning in 1994, 1628 family histories were collected by the Modena Study Group for Familial Breast and Ovarian Cancer, in accordance with an oncologist-based model of cancer genetic counselling for HBC and hereditary OC (HOC) , Claus tAfter disclosure of the BC risk to the consultants, they were instructed to convey suggestions concerning surveillance to relatives who were at an increased risk with respect to the general population.To date, 1325 asymptomatic women accepted to be enrolled in our surveillance program, of which 1072 were first degree, and 253 were second degree relatives; 48 women belonged to carrier group , 674 belonged to the high risk group, 257 to the intermediate risk group, and 346 to the slightly increased risk group  consultants failed to communicate the information to other relatives due to a poor relationship between family member; b) although they were informed of belonging to an at-risk family, they decided not to undergo surveillance due to low interest or because they lived too far from the clinic.Genetic testing to identify deleterious BRCA1 and BRCA2 mutations included direct automated sequencing on the entire coding sequence. From 1995 to 2005, 385 index cases affected by BC or OC, in the high risk categories, were tested for BRCA1/2 mutations of which, 82 carrier patients (21.3%) were identified. Of these 82 carriers, 79 asymptomatic relatives were found to carry a BRCA mutation.An open prospective nonrandomized study was designed and approved by the Ethical Committee of Modena. Carriers of BRCA1 or BRCA2 mutations discovered through genetic testing or subjects at risk according to our previously described criteria, who were at least 18 years of age were eligible. Women with symptoms that were suggestive of BC or women who had a personal history of BC were excluded.From January 1994 to September 2000, surveillance consisted of mammography , ultrasonography and clinical breast examination (CBE) for BC prevention, and transvaginal ultrasound plus Ca.125 serum levels for early diagnosis of OC were proposed at different intervals based on the assessed risk. In October 2000, surveillance for carriers of BRCA1 or BRCA2 mutations was modified by introducing a dynamic breast MRI with gadolinium-containing contrast medium Table . WheneveP values. All statistical tests were two-sided.All data regarding family and individual characteristics, surveillance program, follow-up, additional investigations, and the final outcome of each examination from the years 1992 to 2005 were collected in a database. A person-year approach was used to evaluate the BC incidence. Person-years of risk were calculated from the baseline visit to the BC diagnosis  or for those without diagnosis, to the end of the study period December 31, 2005). Detection rates were expressed as the number of events per 1,000 person-years of follow-up, and confidence intervals (CI) were calculated using the exact method . Expecte, 2005. DAfter a median follow-up of 55 months (range 1 to 151 months), a total of 44 breast tumors including 28 infiltrating (64%) and 16 ductal carcinomas in situ (DCIS) (36%) were found in women belonging to different risk categories. Five cancers occurred in BRCA carriers (4 infiltrating and 1 DCIS), 23 in the high risk group , 11 in the intermediate risk group (8 infiltrating and 3 DCIS), and 5 in the slightly increased risk group (2 infiltrating and 3 DCIS). Among the 28 invasive tumors, 21 were ductal, 6 lobular, and one was a tubular carcinoma. All patients were surgically treated. Of the 44 patients, 30 (68%) received conservative surgery, 14 (32%) had a mastectomy of which 6 were bilateral. At the time of diagnosis, 17 patients were diagnosed with stage I (63%), 7 with stage II, 2 with stage III, and 2 with stage IV. Eight (29%) tumors were less then 10 mm in diameter, 10 (36%) were between 10 and 15 mm, 9 (32%) were greater than 15 mm (range 16 to 50 mm) and one was an inflammatory BC. Ten (36%) were node-positive. Five patients were treated with hormonal therapy, 8 patients received chemotherapy, 11 patients were treated with chemotherapy and hormonal therapy, and 7 received surgery only. In 8 cases, chemotherapy was anthracycline-based. After a median follow-up of 55 months, 4 recurrences and 3 deaths were observed, 2 for disease progression and one due to heart failure. The actuarial 5 year survival rate was 93%  was 7.3 per 1000 person-years and 4.6 per 1000 person-years excluding DCIS. Of the 44 patients who developed BC, 11 (25%) were palpable and 33 (75%) were nonpalpable tumors. Thirty-six of the 44 tumors were detected at screening (5 during the first round and 31 at a subsequent round) making the rate of screen-detected cancers 5.9 per 1000. Eight cancers, all identified by CBE, were diagnosed in the interval between screening events . The diagnosis was made only by CBE in 4 cases, , by CBE plus ultrasonography in 3 cases, and by CBE plus ultrasound plus mammography in one case. The time interval from the last negative screen until diagnosis ranged from 1 to 14 months. The characteristics of patients with interval cancers are shown in Table Among the 36 screen-detected BC, 3 were palpable and 33 were nonpalpable cancers. Twenty-eight were diagnosed with mammography (78%), 18 with ultrasound 50%), 35 with mammography plus ultrasound (97%), and 4 by MRI (100%)  and a very high rate (93%) in the oldest age group, with an overall sensitivity of 82%.P < 0.001) and amongst subjects classified at high  or intermediate risk . However the incidence of BC was not higher than expected in the group classified at slightly increased risk  (Table P < 0.001) in the group of women aged less than 50 years and 3.3 (95% CI 1.9–5.5 P < 0.001) among women aged 50 years or older.The detection rates of BC were 31.6 per 1000 person-years in BRCA1/2 gene mutation carriers, 6.9 per 1000 in the high risk-group, 9.9 per 1000 person-years in the intermediate risk group, and 3.5 per 1000 in the slightly increased risk-group. The incidence of BC in the entire study population was significantly higher than expected  = 1.6 to 7.6; p < 0.001). The incidence was significantly higher among BRCA1 and BRCA2 carriers  and BRCA carriers  compared to that expected in the general age-matched population. In the high and intermediate risk groups the SIR reached statistical significance  confirming the effectiveness of our current approach in the identification of women at increased risk. On the other hand, a low SIR  was detected in the slightly increased risk group. Interestingly, a much higher proportion of DCIS (36%) was detected in our screening compared with patients from an age-matched population not considered at increased risk (9%). Furthermore, the performance of our screening compares favourably with the recommendations of the European Commission for quality assurance in mammography screening [Our clinical and radiological imaging surveillance program led to the detection of 44 breast cancers, including 28 infiltrating and 16 in situ. The SIR for BC was very high overall for the women in the study , while this ratio decreased in women aged more than 50 years.The significance of detecting DCIS in mass screening programs is unknown. It is estimated that the risk of invasive cancer following untreated DCIS in the general population is 30–50% and this usually occurs within 10 years. In the context of a family history, several investigators believe detection of these non-invasive lesions may become more important. The meaning of lobular carcinoma in situ (LCIS) is debatable. This lesion was recently considered as a high risk premalignant lesion such as atypical ductal hyperplasia, papillomatosis, and so on .In conclusion the detection rate and the observed versus expected ratio found in our surveillance program were in accordance with the risk group, with a statistically significant value for BRCA carriers, and for the high and intermediate risk groups. Also, the screening sensitivity was improved in the above groups, but fell in the slightly increased risk group. In this latter group, no significant differences in detection rates and SIR were found with respect to the expected number of BCs based on age-specific Modena Cancer Registry (MCR) rates from 1998 through 2002. As already reported by other authors , early bFinally, our operational criteria seemed effective in identifying people at increased risk of developing breast cancer, and are currently being evaluated in a larger group of individuals from families followed at Institutions of the Italian Network on Hereditary Breast and Ovarian Cancer.In conclusion, our data show that the proposed screening program was able to select individuals at risk, in agreement with the Italian Network on Hereditary Breast and Ovarian Cancer. This paper provides evidence based proof that an appropriate surveillance program can identify a relevant number of breast cancers at an early stage in a population at risk.The author(s) declare that they have no competing interests.LC participated in the design of the study and drafted the manuscript.DT participated in the design of the study.IM acquired the data of the centerAF acquired the data of the Modena Cancer Center and performed the statistical analysis.BC performed the surveillance screening.RB performed the surveillance screeningSR carried on the genetic counsellingAP participated the MRI study.PT coordinated the radiological screeningMF designed the study and revised the final manuscript.All authors read and approved the final manuscriptThe pre-publication history for this paper can be accessed here:


To evaluate the association between paternal and maternal age at birth with the risk of breast cancer in female offspring, a case-control study was conducted in Korea.Older paternal age may increase the germ cell mutation rate in the offspring. Maternal age may also mediate st or 2nd degree relatives, and lifetime estrogen exposure duration.Histologically confirmed breast cancer cases  and controls  with no present or previous history of cancer, matched on year of birth and menopausal status, were selected from several teaching hospitals and community in Seoul during 1995–2003. Information on paternal and maternal ages and other factors was collected by interviewed questionnaire. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by unconditional logistic regression model adjusting for family history of breast cancer in 1The risk of breast cancer significantly increased as the paternal age increased (p for trend = 0.025). The association was stronger after controlling for maternal age; women whose fathers were aged ≥40 years at their birth had 1.6-fold increased risk of breast cancer compared with fathers aged <30 years. This association was profound in breast cancer cases in premenopausal women  (p for trend = 0.031). Although the risk of breast cancer increased as maternal age increased up to the intermediate, and then reduced; the risks in women whose mother were aged 25–29, 30–34, and ≥35 yrs at birth compared to women whose mothers were aged <25 years, were 1.2, 1.4, and 0.8, respectively, the trend was not significant (p for trend = 0.998).These findings suggest that older paternal age increases the risk of breast cancer in their female offspring. There have been growing evidences that prenatal factors may play an important role in determining breast cancer risk in adult life. These factors are hypothesized to affect breast cancer risk by altering the hormonal environment of the developing fetus , or by aA numbers of epidemiologic research have suggested that older parental ages may influence risk for subsequent development of breast cancer later in their lives. Several studies found a slightly increased risk of breast cancer for women whose mothers were older -11, but These inconsistent results from previous studies might be due to several factors; small numbers of breast cancer cases, subject selection , improper adjustment of covariates and paternal and maternal ages mutually, other study design issue (no information on known risk factors).There is a trend toward higher paternal and maternal ages predominantly in Korea as well as in developed countries . To our The cases consisted of a consecutive series of breast cancer patients admitted to three teaching hospitals located in Seoul, Korea  between 1995 and 2003. The control subjects consisted of non-cancer patients admitted to the same hospitals as the cases in the same period and of healthy women who participated in the community health screening program provided by a teaching hospital located in Seoul (EWUMC) in 2003. The study design was approved by the Institutional Review Board of Seoul National University Hospital, and the subjects provided their informed consents prior to participation in the study.Of 1,999 histologically confirmed incident breast cancer patients and 1,548 cancer-free controls, 1,709 breast cancer cases and 1,412 cancer-free controls were eligible after exclusion of subjects with previous history of cancer or previous history of hysterectomy and/or oophorectomy due to cervical, ovarian cancer or its precursors. The control group consisted of 577 healthy women and of 835 hospital controls with non-cancerous diseases including infection or stone of gall bladder/bile duct (26%), benign breast disease  (17%), acute appendicitis (14%), hemorrhoid (8%), hernia/perforation (7%), lipoma (2%), and the others . The proportion of atypical hyperplasia was estimated less than 0.2% among benign breast disease in Korean .st and 2nd degree relatives, reproductive and menstrual factors, life-style habits including cigarette smoking, alcohol consumption, oral contraceptive use, and hormone replacement therapy was collected by trained interviewers using a structured questionnaire.Information on demographic characteristics, current and previous residence, education, marital status, family history of breast cancer in the 1st or 2nd degree relatives, and lifetime estrogen exposure duration. Risk factors profiles were not different between hospital and healthy community controls [st and 2nd degree relatives) were similar. The means of paternal and maternal ages at birth were not significantly different between hospital and community controls . The means of paternal and maternal age at birth of patients with benign breast disease among controls were also different from neither hospital controls nor overall controls (data not shown). Although eighty-seven percent of hospital controls and 97% of community controls came from the same catchment areas (Seoul and suburbs), other demographical characteristics  were similar between hospital and community controls. Thus, the final statistical analyses were done by adjusting for all significant covariates identified from the initial analysis.After exclusion of subjects with missing value of either maternal or paternal age , cases were frequency matched to controls by 10-year of birth group  and menopausal status. The final study population consisted of 1,011 cases and 1,011 controls. The distribution of matched controls was similar to that of unmatched controls  with regard to age, family history of breast cancer in 1controls ; althougst or 2nd degree relatives (yes/no), and lifetime estrogen exposure duration (yrs) , which were identified as the significant covariates  in the initial analysis. The variables included in the logistic model were selected among age (yrs), education , family history of breast cancer in 1st or 2nd degree relatives (yes/no), lifetime estrogen exposure duration (yrs), age at full-term pregnancy or nulliparous , cigarette smoking , frequency of alcohol consumption  and body mass index (BMI) . Only the adjusted estimates were reported in the results because the change in the β coefficient for any level of the paternal and maternal ages relative to the referent was less than 20% between unadjusted estimates and those adjusted for family history of breast cancer in 1st or 2nd degree relatives (yes/no), and lifetime estrogen exposure duration (yrs). Tests for trend in risk were conducted by treating categorical values as a continuous variable.The associations between factors of interest and breast cancer risk were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) by unconditional logistic regression model adjusting for family history of breast cancer in 1t-test and the estimates of odds ratios (ORs) with adjustment for other covariates were obtained using unconditional logistic regression analysis. We classified subjects into four groups according to paternal age at birth  and maternal age at birth . Separate analysis was conducted with and without the other paternal or maternal age mutually adjusting. To evaluate the independent effect of paternal and maternal ages, the ORs were calculated after stratified by the each paternal and maternal age group. Finally, we assessed the association of paternal and maternal ages at birth with breast cancer after stratified by menopausal status. All statistical analyses were performed using STATA version 8.0 .Paternal and maternal ages of subjects at birth were first compared using st and 2nd degree relatives , lifetime estrogen exposure duration (per 10 years) , ≥30 age at first full-term pregnancy or nulliparity  and BMI ≥30 kg/m2  increased the risk of breast cancer significantly after adjusting for family history of breast cancer in 1st and 2nd degree relatives, and lifetime estrogen exposure duration , however, the mean of maternal age was not  . In contrast with paternal age, there was no significant trend between maternal age at birth and risk of breast cancer in premenopausal women (p for trend = 0.361) . In contrast, Hodgson et al [The results of previous studies of the relationships of the risk of breast cancer with paternal and maternal ages are summarized in Table on et al  showed ton et al  and Le Mon et al  also repMost previous studies showed that maternal age was not associated with breast cancer risk in white women. However, the finding of this study that the breast cancer risk increased with increasing maternal age up to the intermediate (30–34 years old), then reduced for older than 35 years old, is consistent with previous epidemiological studies -13,24,30With regard to menopausal status, most previous results between the risk of breast cancer and maternal age including ours are inconsistent ,7,9,22. in utero could create a fertile soil for cancer initiation with regard to maternal age [Data published so far shows that maternal and paternal ageing may affect offspring by different mechanisms. Higher concentration of estrogen rnal age . There irnal age . Higher rnal age , of whicrnal age . Spermatrnal age ,3. This rnal age , while ornal age .Although maternal and paternal ages were correlated, we were able to ascribe the risk of breast cancer to the paternal age independent on maternal age. There are, however, several issues in the present results to consider whether the observed effects can be due to confounding or bias. First, potential selection bias because offspring with higher socioeconomic status may have detected their breast cancer earlier than those with lower socioeconomic status and because individuals with higher socioeconomic status may tend to have children later. In this study, however, the education levels of study subjects (offspring) were not associated with paternal or maternal ages and education levels did not change the β coefficient of paternal and maternal ages less than 15%, thus education levels were not included in the final model. Moreover, controlling for subjects' education levels in narrower categories  did not significantly alter the breast cancer risk of paternal and maternal age. However, we could not adjust parental education since we had no information about parental education levels. Seventy-nine percent of cases and 91% of controls came from the same catchment areas (Seoul and suburbs). However, it did not indicate that the subjects came from the different study bases since the hospitals participated in the study were university hospitals which covered the patients in the whole country according to the current health delivery system in Korea . Even ifThis is the first and largest report about paternal and maternal ages and breast cancer in Asian women. These findings suggest that paternal age is associated with an increased risk of breast cancer in female offspring. However, further prospective study is needed to verify the present findings.The author(s) declare that they have no competing interests.J-YC conceived of the study, conducted data analysis, and drafted the manuscript. K-ML contributed to the design and management of data. SKP participated in data analysis and interpretation. D-YN, S-HA, and K-YY designed the study. DK conceived of and designed the study, obtaining funding and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


A cohort comprising 11678 women who had undergone cholecystectomy in the period 1964 through 1967 for a benign gallbladder disease was investigated. They represented almost a total ascertainment from a defined geographic area. Follow-up during 11-14 completed years of observation revealed a total of 202 breast cancer cases after the cholecystectomy. This number was close to the expected incidence of 199.1 (relative risk 1.0). Further analysis of the risk in relation to duration of observation and age at operation did not reveal any trend or subgroup with a significantly increased or decreased risk. It was concluded that despite the many epidemiologic observations indicating that in Western Countries dietary habits are particularly important determinants of the high incidence of both gallstone disease and breast cancer, our results contradict the idea that the diseases share common aetiologic factors.


MBD2, the gene encoding methyl-CpG-binding domain (MBD)2, is a major methylation related gene and functions as a transcriptional repressor that can specifically bind to the methylated regions of other genes. MBD2 may also mediate gene activation because of its potential DNA demethylase activity. The present case-control study investigated associations between two single nucleotide polymorphisms (SNPs) in the MBD2 gene and breast cancer risk.MBD2 gene, one SNP in the noncoding exon (rs1259938) and another in the intron 3 (rs609791) were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate cancer risk associated with the variant genotypes and the reconstructed haplotypes.DNA samples from 393 Caucasian patients with breast cancer (cases) and 436 matched control individuals, collected in a recently completed breast cancer case–control study conducted in Connecticut, were included in the study. Because no coding SNPs were found in the The variant genotypes at both SNP loci were significantly associated with reduced risk among premenopausal women . Further haplotype analyses showed that the two rare haplotypes (A-C and A-G) were significantly associated with reduced breast cancer risk  in premenopausal women. No significant associations were detected in the postmenopausal women and the whole population.MBD2 gene in breast carcinogenesis in premenopausal women. These findings suggest that genetic variations in methylation related genes may potentially serve as a biomarker in risk estimates for breast cancer.Our results demonstrate a role for the  It has recently been recognized that cancer is a manifestation of both abnormal genetic and epigenetic events . DysreguMeCP2, MBD1, MBD2, MBD3, and MBD4 [The methyl-CpG-binding domain (MBD) proteins are among these protein families that bind specifically to a methylated gene and mediate transcriptional repression via effects on chromatin structure. Thus far, five MBD genes have been identified in mammalian cells that encode putative MBDs, namely and MBD4 -7. Humanand MBD4 . Given tand MBD4 ,9.MBD2 gene is mapped to the conserved region within human chromosome 18q21 [MBD2 gene contains six exons and one noncoding exon spanning more than 50 kb in the genome. The MBD2 gene encodes two potential forms of protein MBD2 that correspond to the initiation of translation starting at either the first  or second  methionine codons. The signal functions of MBD2 are to bind specifically to methylated gene promoters and recruit histone deacetylases and chromatin remodeling proteins. The altered chromatin structure resulting from the binding of these factors may be resistant to the transcriptional machinery and, as a result, repress gene expression [The me 18q21 . Genomicpression ,12. A repression , implyinpression ,15, and Although our understanding of the exact function of MBD2 in epigenetics is still in its early stages, several studies in human cancer research have demonstrated that the MBD2 protein plays a role in tumorigenesis. For example, a recent study  showed tMBD2 gene may modify an individual's susceptibility to human cancers. In this molecular epidemiologic study, we genotyped two single nucleotide polymorphisms  in the MBD2 gene to investigate whether genetic variations in the MBD2 gene are associated with breast cancer risk and whether the potential associations are modified by menopausal status.Given that there is a potential role for MBD2 in tumorigenesis, we hypothesized that genetic polymorphisms in the This study was built upon a recently completed breast cancer case–control study that was undertaken in Connecticut, USA. Detailed information regarding the study population is provided elsewhere . BrieflyFor New Haven County, eligible cases were identified from the major hospital of the county  through the computer database system at the Department of Surgical Pathology. Controls were also randomly selected from the computer database system from among women who were histologically confirmed to be without breast cancer. The participation rates were 77% for cases and 71% for controls in New Haven County. For Tolland County, because there was no major county hospital in this county, newly diagnosed breast cancer cases were identified from area hospital records by the Rapid Case Ascertainment system at the Yale Comprehensive Cancer Center. Controls from Tolland Country were recruited through random digit dialing methods for those under age 65 years and randomly selected from Health Care Financing Administration files for those aged 65 years and over. The participation rates were 74% for cases and 64% for controls in Tolland County.in situ, invasive ductal, or lobular carcinoma, and were staged according to the American Joint Committee on Cancer staging system [The study pathologist reviewed all of the pathologic diagnoses for breast cancer patients and benign breast disease controls. Breast carcinoma were classified as carcinoma g system .Informed consent was obtained from all study participants before collection of epidemiologic data through personal interview. The 45-min in-person interview, completed by all study participants, was administered by trained interviewers following institutional guidelines for human subjects. Data on smoking habits, alcohol consumption, and hormone replacement therapy of case and control individuals was obtained. Other information, including menstrual and reproductive factors , family breast cancer history, lifetime occupational history, body mass index, hair dye use, and residence history, was also collected. Dietary information was obtained using a scannable semiquantitative food frequency questionnaire developed by the Fred Hutchinson Cancer Research Center, designed to optimize estimation of fat intake. Menopausal status was assessed at the time of diagnosis. Women with hysterectomy or bilateral oophorectomy were considered to be postmenopausal women, whereas very few women with dubious menopausal status were considered to represent missing data. At the completion of the interview, blood was drawn for DNA isolation and subsequent molecular analysis. The status of all samples – case or control – was concealed before they were handed to laboratory personnel.MBD2 gene. Therefore, two noncoding SNPs were chosen for genotyping. One (rs1259938) is located in the noncoding exon and another (rs609791) is located in intron 3 of the MBD2 gene. The noncoding exon is generally found at the 3'-untranslated region of a gene and this is now widely acknowledged. There is increasing evidence indicating that the 3'-untranslated region of a gene plays a vital biologic role in many post-transcriptional regulatory pathways that control mRNA localization, stability, and translation efficiency [A SNP search using the National Center for Biotechnology Information SNP database  showed nficiency .XbaI  at 37°C. The products were separated for 45 min at 220 V on a 4% agarose gel stained with ethidium bromide. Following electrophoresis, the homozygous G/G alleles were represented by a DNA band with size at 319 bp, whereas the homozygous A/A alleles were represented by DNA bands with sizes at 103 bp and 216 bp, and the heterozygotes displayed a combination of both alleles .The restrictional fragment length polymorphism PCR assay was used to determine the genotypes of SNP rs1259938. The genomic DNA used for the assay was extracted from peripheral blood lymphocytes. The PCR primers used for amplifying this polymorphism were as follows: forward 5'-CCTTGCCTGTGACTTGGACT-3' and reverse 5'-TCGCGAGTTTCAACAGAAAA-3'. Standard PCR was performed in a 25 μl volume with annealing temperature at 58°C and followed by an overnight digestion with The TaqMan Assay was used to determine the genotypes of SNP rs609791. Assays-on-Demand primers and probes  were mixed with PCR reagents following the manufacturer's instructions in the TaqMan assay. Plates were sealed and cycled at 95°C for 5 min, followed by 45 cycles at 92°C for 15 seconds, and 60°C for 1 min in a Stratagene Real-Time Mx3000 thermocycler .Each genotyping plate contained positive and negative controls. Approximately 5% of the samples were duplicated to ensure quality control in genotyping and two reviewers separately performed genotype scoring to confirm results.2 test was used to evaluate differences in the distribution of selected characteristics between cases and controls. Genotype frequencies at both SNP loci in the control population were first checked for compliance with Hardy–Weinberg equilibrium using STATA statistical software . Haplotype estimation was calculated using the PHASE program, which reconstructs haplotypes from population genotyping data [Because more than 90% of the study participants were Caucasians, with about 6% being black, 1% Asian, and 2% other races, we restricted our analysis to Caucasians only (393 cases and 436 controls). Pearson's χing data . The bes2, 25–29.99 kg/m2, >29.99 kg/m2), family history of breast cancer in first-degree relatives, family income (tertiles based on distribution of controls), lifetime months of breastfeeding  and study site . Control of other variables  did not change the ORs significantly, and these variables were not included in the final model.For a SNP genotype, study participants with homozygous common allele were used as the reference group in OR calculation. For haplotype analysis, the most common haplotype (G-C) was used as the reference group in risk estimation. Logistic regression was used to control for confounding by age (as a continuous variable), body mass index .The genotype distributions of both SNP loci for cases and controls Table  were in Among all women, we found no overall associations between genotypes at these two loci and breast cancer risk after adjustment for age, menopausal status, family history of breast cancer in first-degree relatives, family income, body mass index, lifetime months of breastfeeding, and study site. Among premenopausal women, a reduced breast cancer risk was significantly associated with variant genotypes  at both SNP loci. Specifically, women with G/A and A/A at rs1259938 had 59% reduced breast cancer risk  and women with C/G and G/G at rs609791 had 46% reduced breast cancer risk . However, no significant associations were detected among postmenopausal women.MBD2 gene may generate four possible haplotypes, and their frequency distributions among cases and controls are shown in Table P = 0.013) for A-C and 0.47  for A-G. Similar associations were not observed in postmenopausal women.These two SNP loci in the GSTP1, a member of the glutathione S-transferases, which are a supergene family involved in the detoxification of carcinogens, is associated with gene inactivation in about 30% of primary breast carcinomas [BRCA1 [It is becoming clear that carcinogenesis is a stepwise process of accumulation of both genetic and epigenetic abnormalities that can lead to cellular dysfunction. A large body of evidence has demonstrated that the epigenetic process is involved in breast carcinogenesis by influencing several broad gene categories, including cell cycle regulation, cell growth, steroid receptors, tumor susceptibility, carcinogen detoxification, cell adhesion, and inhibitors of matrix metalloproteinase genes. For example, methylation of p16 promoter and exon 1 regions are observed in both human breast cancer cell lines and 20–30% of primary breast cancers ,27. Methrcinomas . DNA mets [BRCA1 ,30, a ges [BRCA1 . Moreoves [BRCA1  and reces [BRCA1 -35. GiveMBD2 gene and breast cancer, which have not previously been examined. These results support a potential role for methylation related genes in breast tumorigenesis. Interestingly, MBD2 polymorphisms have different effects in women depending on menopausal status. Our results demonstrate significant associations between MBD2 genotypes and haplotypes and breast cancer risk in premenopausal women but not in postmenopausal women. In fact, menopausal effects on breast cancer risk have also been observed in a previous study investigating genetic polymorphisms in catechol-O-methyltransferase [O-methyltransferase was associated with increased risk among premenopausal women  but was inversely associated with postmenopausal risk . Our findings support arguments from previous studies suggesting that different etiologies may be involved in breast carcinogenesis between premenopausal and postmenopausal women [Findings from the present study show associations between genotypes and haplotypes of the nsferase . That stal women ,37.Although the mechanisms are not elucidated, menopausal effects on the role of MBD2 in breast cancer development may be related to changes in sex hormone levels. One of the phases of breast cancer pathogenesis is exposure of breast tissue to ovarian hormones that drive the kinetics of breast tissue stem cells, resulting in carcinogenesis . DividinThese biologic and physiologic effects of sex hormones are controlled by hormone receptors, the expression of which is regulated by the methylation status of their promoter regions -35.On the other hand, steroid hormones may influence the epigenetic blue print of methylation of certain genes and consequently activate or inactivate gene expression . Even thThere are limitations to the present study. Only Caucasian women were included in the study, and so hypotheses must be further examined in multi-ethnic groups. In addition, the sample sizes of our study limit the analyses to explore other potential risk factors. Traditional risk factors such as parity and family history of cancer did not differ between cases and controls, which could also be due to the sample sizes. Inaccurate recall may affect our assessment of family history of cancer as well.MBD2 polymorphisms and breast cancer in multi-ethnic groups, this study suggests that genetic variations in methylation related genes may serve as a promising biomarker in risk estimate of breast cancer.These findings imply a potential link between DNA methylation processes and hormonal expression. Although large molecular epidemiologic studies are warranted to further examine associations between bp = base pairs; CI = confidence interval; MBD = methyl-CpG-binding domain; OR = odds ratio; PCR = polymerase chain reaction; SNP = single nucleotide polymorphism.The authors declare that they have no competing interests.YZ designed the study and drafted the manuscript. HNB carried out the genotyping analysis. YZ and TRH performed the statistical analysis. TZ is the principal investigator for the parent case–control study and participated in the design of the present project and manuscript preparation. All authors read and approved the final manuscript.


The main risk factors for oesophageal cancer previously identified in western Europe are tobacco smoking and alcohol drinking. However, a study of the time trend from 1951 to 1985 of the mortality from oesophageal cancer in 17 European countries shows that, except among the younger age groups in men, oesophageal cancer had either decreased or increased only slightly in most countries. This trend differed from that of lung cancer, cirrhosis and alcohol consumption which had in general increased substantially during the period. The results strongly suggest that population-wide changes in certain undetermined risk/protective factor(s), one possibility of which is the consumption of fruit, had overridden the effect of tobacco and alcohol and resulted in a reduction of oesophageal cancer risk. Apart from further efforts to reduce smoking and drinking, studies to identify the factor(s) will be of great public health importance to the prevention of oesophageal cancer.


Aromatase activity in peripheral tissues including the breast is the main source of estrogen in postmenopausal women. There is evidence that local estrogen synthesis by breast aromatase contributes to mammary carcinogenesis. Therefore, we have postulated that high breast weight is associated with ER+ tumours.The mastectomy specimen weight, ER and PgR status for 62 consecutive patients who had a total mastectomy for operable breast cancer were retrospectively reviewed. The ER/PgR positivity was assessed using immunohistochemistry (Quickscore system 0–8) by a breast pathologist. ER/PgR status was considered positive if the score was 4 – 8.Overall the breast weight was higher in patients with ER+ disease. The weight was found to be significantly higher in women aged 50 years or older with ER+ tumours . There was no significant difference in breast weight between ER+ and ER- tumours in women aged less than 50 years . We observed a non-significant association between higher breast weight and PgR positivity  and absence of c-erb B2 (p = 0.088).In women aged 50 years or older with breast cancer, high breast weight is significantly associated with ER+ tumours. If this is confirmed in larger prospective studies, our findings may have implications regarding breast cancer prevention with anti-estrogens.Breast cancer remains the most common cancer in females. It has been estimated that one in eight women will develop breast cancer during their lifetime in the USA Approximately two thirds of postmenopausal breast cancer patients have hormone dependent breast cancer that requires estrogen for tumour growth. It is well established that estrogens enhance growth and proliferation of certain target cells such as breast epithelial cells and estrogen dependent mammary carcinoma cells .In postmenopausal women, estradiol does not appear to function as a circulating hormone; it is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase  which isAromatase has been found and measured in the stromal cell component of the normal breast as well as the breast tumour. Also, the enzyme has been detected in the breast epithelial cells in vitro -8. FurthEvidence that postmenopausal obesity and weight gain are positively associated with postmenopausal breast cancer risk has been substantiated especially in women who never used hormone replacement therapy .The aim of this study was to examine the hypothesis questioning the relationship between oestrogen and progesterone receptor status and breast tissue weight in postmenopausal women who had mastectomy for operable breast cancer.The mastectomy specimen weight, estrogen receptor (ER) and progesterone receptor (PgR) status for 62 consecutive patients who had a total mastectomy for operable breast cancer were retrospectively reviewed. Breast specimen weight was obtained from the pathology laboratory reports in grams. ER and PgR status was determined by immunohistochemistry (IHC) using the Quickscore system by a breast pathologist. ER/PgR status was considered positive if the score was 4 – 8. We also examined other parameters including tumour size, grade, nodal status, c-erb B2 expression and patient's age.Correlation between breast weight and receptor status was examined in two groups of patients according to their age, 50 years and older and younger than 50 years.59 patients had invasive breast cancer and 3 patients had ductal carcinoma in situ (DCIS). Estrogen receptors were positive (ER+) in 50 patients (Quickscore: 4–8) and negative (ER-) in 12 patients (Quickscore: 0)In general, breast weight was higher in patients with ER+ disease; median weight was 570 grams in ER+ patients compared to 413 grams in ER- patients (p = 0.04)Patients were divided into two groups according to age. The first group consisted of patient aged 50 years and over (n = 43) with a median age of 60 years (range 51–83) and the second group contained those patients aged less than 50 years (n = 19) with a median age of 42 years (range 29–48).Within the first group, breast weight was found to be significantly higher in women with ER+ tumours . Figure  and patient's age had no significant impact on the receptor status.We observed a non-significant association between higher breast weight and PgR positivity  and absence of c-erb B2 (p = 0.088).Finally, there was no association between breast weight and nodal status or tumour's grade.It has been established that obesity and weight gain are risk factors of breast cancer in postmenopausal women . This reBreast tissue and particularly the breast adipose tissue in postmenopausal women with breast cancer seem to have an increased aromatase expression. Agrawel et al studied 9 women undergoing breast reduction mammoplasty and 18 breast cancer patients undergoing mastectomies. Non-tumour bearing adipose samples from mastectomies expressed significantly more aromatase than adipose tissue taken from mammoplasty patients, a difference that is unlikely to be due the tumour's influence on aromatase expression .The relationship between a higher body mass index (BMI) and the risk of ER+/PgR+ breast cancer has been studied previously -23. In aThe relationship between increased breast weight in postmenopausal women and receptor status has not been previously examined. In our study we hypothesised that in breast cancer patients; ER+ breast cancer was associated with a higher breast weight than ER- disease. This hypothesis was proved to be correct in postmenopausal women. Furthermore, such an association was not observed in women aged less than 50 years.Our study has several limitations; firstly, we did not include other risk factors such as body mass index. Although a higher BMI is a recognised risk factor for ER+ disease, larger breasts are not always associated with a high BMI; higher breast weight could be found in a normal or low BMI postmenopausal women.Secondly the family and HRT histories were not included in the analysis. Thirdly, the weight of the formatin-fixed mastectomy specimen was measured rather than the weight of the fresh specimen. However this applies to all specimens and is therefore unlikely to alter our findings. Finally we used the age of 50 years rather than the date of the last menstrual period to define the menopausal status. These limitations could be tackled in a larger prospective study.In summary, in women aged 50 years or older with breast cancer, a higher breast weight seems to be significantly associated with ER+ disease. If this is confirmed in larger prospective studies, our findings may have implications regarding breast cancer prevention with anti-estrogens.


Cervical cancer is due to infection with specific high-risk types of human papillomavirus (HPV). Although the incidence of genital HPV infection in various population groups is high, most of these regress without intervention. Investigating genetic host factors and cellular immune responses, particularly cytokines, could help to understand the association between genital HPV infection and carcinogenesis. The tumor necrosis factor alpha (TNF-α) cytokine plays an important role in all stages of cervical cancer and has the ability to induce the regression of human tumors. Therefore the aim of the study was to investigate the allelic distribution of -308 TNF-α gene polymorphism in South African women with cervical cancer compared to control women.Included in our study were women with histologically proven cancer of the cervix (n = 244) and hospital-based controls (n = 228). All patients and controls were from mixed race and black population groups in South Africa. The detection of a bi-allelic -308 (A/G) polymorphism in the promoter region of TNF-α was investigated using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups.2 = 2.26). In addition, using the chi-squared test we found no significant association between the known risk factors for cervical cancer and the allele distribution of -308 TNF-α. However, the frequency of the rare high-producing allele -308A of TNF-α was significantly lower in the South African population when compared to Caucasians and Chinese population groups.In this study we observed no association between the distribution of -308 TNF-α polymorphism and the risk of developing cervical cancer even after combining the data from the two ethnic populations (XWe demonstrated no association between -308 TNF-α polymorphism and the risk of cervical cancer among two South African ethnic population groups. However, as the distribution of the -308A TNF-α was notably different between the control groups of South Africa and other population groups this result suggests that ethnic disparity may influence the levels of TNF-α produced. There is strong epidemiological and experimental data that have demonstrated a definite association of high-risk human papillomavirus (HR-HPV) infection and the development of cervical cancer . InteresCytokines play a significant role in the defense against HPV induced infections, modulating viral replication and polarizing the immune response to a Th1 (cellular) or Th2  pattern  Th2 cellTNF-α is a multifunctional cytokine that was originally identified as a macrophage-derived serum protein that mediates necrosis of solid tumors in vitro and in vivo . In addiTherefore, given the importance of TNF-α in potentially contributing to the progression of cervical cancer with variations in the levels of TNF production in different population groups, we investigated the biallelic polymorphism in the -308 promoter region of the TNF-α gene using the ARMS-PCR methodology and examined its relationship to the development of cervical cancer among two South African ethnic groups.Individuals were selected from a case-control study of cancer of the cervix and related risk factors conducted among colored  and black women residing in the Western Cape Province of South Africa, from January 1998 to December 2001 . The ResGenomic DNA was extracted from 200 μl of whole blood using the QiAamp Spin Blood Kit  in accordance with manufacturer's instructions.The A and G alleles at position -308 in the promoter region of the TNF-α gene were identified using the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) methodology as previously described . A totalGeneric primer (antisense): 5'-tctcggtttcttctccatcg-3'Primer G, allele1 (sense): 5'-ataggttttgaggggcatgg-3'Primer A, allele2 (sense): 5'-aataggttttgaggggcatga-3'The amplified ARMS-PCR products (PCR product size = 184 bp) were identified by gel electrophoresis on 2 % agarose gels stained with ethidium bromide.X2 test. Unconditional logistic regression was used to estimate odds ratios (OR's) for developing cancer of the cervix in relation to the -308 TNF-α gene polymorphism. These OR's were adjusted for the following confounding factors; ethnic group, 5 year age group, years of education, age at first sexual intercourse, number of sexual partners, urban/rural living, number of Pap smears, injectable/oral contraceptive use, smoking, and parity.Statistical analyses were performed using STATA version 8. The allele frequency of the -308 TNF-α polymorphism was compared between the patients and control groups using the To evaluate the accuracy of the assigned TNF-α genotypes a total of twenty-five samples were randomly chosen and the results were confirmed by repeating the ARMS-PCR. Notably there were no discrepant results detected when the ARMS-PCR assay was repeated on the samples.The genotype distribution of the polymorphism at position -308 of the TNF-α promoter region in the cases and controls among the two South African ethnic groups are shown in Table As there were no significant differences in the distribution of the -308 TNF-α alleles in the cervical cancer patients among the two South African ethnic populations, the data was combined to compare allele distributions to other population groups Table . InteresAlthough the Pap smear screening has reduced cervical cancer mortality in developed countries, 35000 women die from this disease every year in the United States and Europe . The curX2 = 2.26) even when the data were adjusted for potential confounders (data not shown).Indeed, other co-factors such as viral load, lifestyle factors, high parity, smoking, long-term use of contraceptives and other sexually transmitted diseases have also been established as risk cofactors for cervical cancer among women with persistent HPV infections . In addiet al., [The findings in our study are similar to those reported by Stanczuk et al., , who invet al., . They foet al., ,22,33 anet al., . In theiet al.,  it wouldet al., . Furtheret al., . Thus, iSeveral reports in cervical cancer survival studies have indicated that the higher mortality rate in black populations is explained primarily by the more advanced clinical stage at time of diagnosis ,36. It wIt is important to identify host or viral genetic markers that may facilitate the risk of developing cervical cancer. In addition, these markers would be useful in providing effective treatments and preventative strategies against HPV-induced infections. However, in this study we found no association between -308 TNF-α gene polymorphism and the risk of developing cervical cancer. Furthermore, our data highlight the need for further studies to clarify the association of ethnic variation and cytokine polymorphism as other potential confounding factors may contribute to the risk of developing cancer of the cervix.The author(s) declare that they have no competing interests.VAG designed the study, carried out the study and drafted the manuscript. DC performed the statistical analysis for the study. MH participated in the design and coordination of the case control study. A-LW participated in the coordination of the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


AIB1, located at 20q12, is a member of the steroid hormone coactivator family. It contains a glutamine repeat (CAG/CAA) polymorphism at its carboxyl-terminal region that may alter the transcriptional activation of the receptor and affect susceptibility to breast cancer through altered sensitivity to hormones.We evaluated this repeat polymorphism in the context of early-onset disease by conducting a case-control study of 432 Australian women diagnosed with breast cancer before the age of 40 years and 393 population-based control individuals who were frequency matched for age. Genotyping was performed using a scanning laser fluorescence imager.BRCA1 and BRCA2 germline mutation status. There was no evidence that the presence of one or two alleles of 26 glutamine repeats or fewer was associated with breast cancer , or that women with alleles greater than 29 repeats were at increased risk of breast cancer. Exclusion of women who carried a BRCA1 or BRCA2 mutation (24 cases) and non-Caucasian women (44 cases) did not alter the risk estimates or inferences. We present raw data, including that on mutation carriers, to allow pooling with other studies.There were no differences in genotype frequencies between cases and control individuals, or between cases categorized by family history or by AIB1 CAG/CAA polymorphism status, even if affected women carry a mutation in BRCA1 or BRCA2.There was no evidence that risk of breast cancer depends on  AIB1, located at 20q12, is a member of the steroid hormone coactivator family that interacts with oestrogen receptor-α, resulting in enhancement of oestrogen-dependent transcription [AIB1 is moderately expressed in the normal mammary epithelium and is required for female reproductive function and mammary gland development [Steroid hormones regulate the expression of proteins that are involved in breast cell proliferation and development, and coactivators that interact with steroid hormone receptors to modulate transcriptional activation have recently been described . AIB1, lelopment . It is oelopment .AIB1 contains a glutamine repeat (CAG/CAA) polymorphism at its carboxyl-terminal region. Although its functional significance is currently unknown, it may alter the transcriptional activation of the receptor (as is the case for the androgen receptor CAG repeat polymorphism), and hence it may affect breast cancer susceptibility through altered sensitivity to hormones [hormones . We evalhormones ,7.BRCA1 and 11 in BRCA2 [The Australian Breast Cancer Family Study is a population-based, case-control family study conducted in Melbourne and Sydney ,8. For tin BRCA2 . WrittenAIBI genotyping was successful for all but 17 (4%) cases and 9 (2%) controls.PCR amplifications were performed with a fluorescent labelled forward primer (5'-GACAACAGAGGGTGGCTAT-3') and an unlabelled reverse primer (5'-AGGAGCTTGTGGCATTGTG-3'). All PCRs were performed in 10 μl volumes containing 10–50 ng genomic DNA, 200 nmol/l dNTPs , 25 ng of each primer, 1 × ReddyMix buffer  and 0.2 units of Thermoprime Plus DNA Polymerase (Abgene). PCR amplification cycle conditions involved an initial denaturation step at 94°C for 5 min, 40 cycles of denaturation at 94°C for 15 s, annealing at 55°C for 30 s, and extension at 72°C for 45 s. This was followed by a further extension step at 72°C for 7 min. The alleles were then separated on sequencing gels and analyzed using a scanning laser fluorescence imager . DNA was available for 410 (88%) out of 466 cases and for 441 (74%) out of 600 controls, and 2 test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression, adjusting for reference age, study centre, country of birth, education level, marital status, number of live births, height, current oral contraceptive use status and reported first-degree family history. Routine model diagnostics procedures and goodness-of-fit were performed to check the adequacy of the logistic regression models. All tests were performed using Stata version 8.0 . Power calculations were performed using StatCalc module of Epi Info version 6 . All statistical tests were two-sided.Allele frequencies and genotypes were compared using Pearson's χP = 0.7) or genotype frequencies defined by the number of repeats (P = 0.3). There were no differences in the genotype distribution of cases by family history (P = 0.1).For controls the allele frequencies for 26, 27, 28, 29, 30 and 31 repeats were 0.12, 0.002, 0.36, 0.50, 0.005 and 0.002, respectively. For cases they were 0.13, 0.001, 0.35, 0.51, 0.004 and 0, respectively. Table BRCA1 or BRCA2 mutation (24 cases) and non-Caucasian women (44 cases) did not alter risk estimates or inferences. For example, the OR for the association with one or two alleles of 26 repeats or fewer became 1.09 (95% CI = 0.76–1.56).Table AIB1 glutamine repeat (CAG/CAA) polymorphism were similar to those reported in previous studies [AIB1 genotype. We have presented the raw data, including that on mutation carriers, to allow pooling with other studies.In the present study of Australian women the allele frequencies and genotype distributions for the  studies . We founBRCA1 or BRCA2 mutation was conducted in women aged 43–69 years [AIB1 repeats were at decreased risk, but we did not find any support for this in women under the age of 40 years.The only other study of breast cancer risk and this polymorphism in noncarriers of a BRCA1 and BRCA2 mutation carriers [Evidence for an increased risk in women with longer repeat lengths has been reported in carriers . There wAIB1 CAG/CAA polymorphism status, even if affected women carry a mutation in BRCA1 or BRCA2.We found no evidence that risk of breast cancer depends on CI = confidence interval; OR = odds ratio; PCR = polymerase chain reaction.The author(s) declare that they have no competing interests.KGM and IGC conceived the study; participated in its design, concept and coordination; and drafted the manuscript. J-HC performed the statistical analysis. DMG, JLH, GGG and MRM participated in the concept and coordination, are the chief investigators and developed ABCFS, and helped to draft the manuscript. GSD contributed to the design and management of data. MCS contributed to the design and management of laboratory processes at the GEL to enable and provide the required biospecimens for genetic analysis.


A matched case-control study in a population of urban, non-menopaused women living in Paris was performed between 1983 and 1985 to investigate the risk of breast cancer (BC) in relation to various factors with a particular interest in the effect of the use of oral contraceptive (OC) and the existence of cyclical mastalgia (CM). Two hundred and ten non-menopaused women, less than 45 years old, with newly diagnosed BC were compared to 210 controls from the same geographic area matched on year of birth, age, education level and age at first full term pregnancy (FFTP), when justified. The adjusted Relative Risk of BC (RRa) was significantly increased for a total duration of OC use longer than 72 months , as well as the RRa for OC use above 48 months before FFTP (3.26 95% CI 1.37-7.76) and, to a lesser extent, the RRa for OC use above 48 months after FFTP (2.02 95% CI 1.07-3.84) respectively. Adjustment was performed on familial history of BC, personal history of Benign Breast Disease (BBD), age at menarche. A previous history of cyclical mastalgia was found to be associated with an increased risk of BC. The significant increase remained after adjustment on the previously mentioned confounding factors and OC use: RRa 2.12; 95% CI (1.31-3.43). Under a precise definition related to the hormonal environment, mastalgia appear to be an interesting marker of breast cell susceptibility, the importance of which can only be validated by prospective studies.


In a prospective study of 5,004 women in Guernsey, plasma samples were collected and stored. Retinol, beta-carotene and vitamin E levels were later measured in the samples from 39 women who subsequently developed breast cancer and from 78 controls who did not develop cancer. Plasma retinol levels were not related to the risk of breast cancer, mean levels among cases and controls being 485 micrograms l-1 and 479 micrograms l-1 respectively. Plasma vitamin E levels showed a clear association, low levels being associated with a significantly higher risk of cancer. The mean vitamin E levels among cases and controls were 4.7 mg l-1 and 6.0 mg l-1 respectively (P less than 0.025), and the risk of breast cancer in women with vitamin E levels in the lowest quintile was about 5-times higher than the risk for women with levels in the highest quintile (P less than 0.01). beta-carotene levels showed a tendency to be lower in women who developed cancer than in controls (36 micrograms l-1 among cases compared with 50 micrograms l-1 among controls) but the difference was not statistically significant.


U.S. studies have reported an increased risk of esophageal and some other cancers in dry cleaners exposed to tetrachloroethylene. We investigated whether the U.S. findings could be reproduced in the Nordic countries using a series of case–control studies nested in cohorts of laundry and dry-cleaning workers identified from the 1970 censuses in Denmark, Norway, Sweden, and Finland. Dry-cleaning work in the Nordic countries during the period when tetrachloroethylene was the dominant solvent was not associated with an increased risk of esophageal cancer , but our study was hampered by some unclassifiable cases. The risks of cancer of the gastric cardia, liver, pancreas, and kidney and non-Hodgkin lymphoma were not significantly increased. Assistants in dry-cleaning shops had a borderline significant excess risk of cervical cancer not found in women directly involved in dry cleaning. We found an excess risk of bladder cancer  not associated with length of employment. The finding of no excess risk of esophageal cancer in Nordic dry cleaners differs from U.S. findings. Chance, differences in level of exposure to tetrachloroethylene, and confounding may explain the findings. The overall evidence on bladder cancer in dry cleaners is equivocal. Previous studies of dry cleaners, primarily from the United States, indicated that exposure to tetrachloroethylene may cause an increased risk of cancer of the esophagus and cervix uteri and of non-Hodgkin lymphoma (NHL) . We inveThe study was undertaken as a series of case–control studies nested in the cohorts of laundry and dry-cleaning workers identified from the 1970 censuses in Denmark, Norway, Sweden, and Finland. The cancer incidence of these cohorts has been reported previously , and theThe purpose of this study was to determine whether dry-cleaning work in the Nordic countries around 1970, when tetrachloroethylene was the dominant dry-cleaning solvent, was associated with an increased risk of the selected cancers. We used the nested case–control design to avoid confounding from socioeconomic group and related lifestyle risk factors.The cohorts included all laundry and dry-cleaning workers from the 1970 censuses in Denmark, Finland, Norway, and Sweden. They had either the occupation code “laundry and dry-cleaning worker” or the industry code “laundry and dry cleaning”  Table 1Table 1. Classification of Diseases for Oncology  exposed persons explicitly described as dry cleaners and other workers in dry-cleaning shops with < 10 workers ; b) other workers in dry-cleaning shops; c) unexposed laundry workers and other persons not working in dry cleaning; and d) unclassifiable.On the basis of various data sources and without knowledge of their case–control status, we categorized cases and controls as follows: Exposed cases and controls were categorized by length of employment in the shop where they worked in 1970. For practical reasons, we included only the period 1964–1979. Data on smoking and alcohol drinking were collected in Norway and Sweden .The person’s specific occupational task as dry cleaner or laundry worker at the 1970 census was written in free text on the original census form. These forms were retrieved from the National Archives in Denmark and Norway. The forms had not been stored in Finland and Sweden.A blinded personal telephone interview, eventually with a next-of-kin, was undertaken with cases and controls in Norway and Sweden. The questionnaire asked about occupational tasks in 1970, and if this was dry cleaning, then about length of employment in the shop, size of the work force, solvents used, and smoking and drinking habits. In Norway, interviews were obtained with 57% of cases (72% with next-of-kin) and with 64% of controls (42% next-of-kin). In Sweden, interviews were obtained with 63% of cases (77% next-of-kin) and with 60% of controls (39% next-of-kin). One-fourth of interviewed next-of-kin was 1970 spouses, and one-third of non-interviewed subjects had no next-of-kin.Denmark and Finland have nationwide databases with individual records on all paid pension scheme contributions, and we used these pension scheme data for this study. In Denmark, these data started for employees in 1964; we used these data to assess length of employment and size of the work force where the employees worked in 1970. In Finland, these data started in 1962 for employees and in 1970 for self-employed persons; the data were used to assess length of employment where the persons worked in 1970. Pension scheme data were found for 91% (151 of 166) of Danish records for employees in dry cleaning, with missing data for 5 employees explained by sick leave and so on at the 1970 census. Pension scheme data were found for 75% of Finnish records.In Denmark, we used a biography of dry-cleaning shop owners  and the For Finland, we used the pension scheme data in combination with other sources  to assesWe identified 1,616 cases and 2,398 controls . TogetheUse of tetrachloroethylene peaked in the Nordic countries around 1970, and the compound was used almost exclusively for dry cleaning . In DenmIn 1968, tetrachloroethylene constituted 75% of the solvents used for dry cleaning in Denmark, 85% in Finland, and 72% in Sweden ; in 19713 in Finland, 350 mg/m3 in Denmark and Norway, and 200 mg/m3 in Sweden. In 1980, these limits were 335, 200, and 135 mg/m3, respectively. Only 168 tetrachloroethylene measurements were made in dry-cleaning shops in the Nordic countries between 1964 and 1979. There was a large variation in exposure level across shops; the median annual level of all measurements was, however, fairly stable during 1964–1979  for dry cleaners versus unexposed controls using logistic regression adjusted for matching criteria and, where relevant, for smoking and alcohol use. For a comprehensive reporting of the data, we also calculated the RRs for the other persons in dry cleaning and for the unclassifiable persons, although the underlying hypothesis did not include these groups. RRs were estimated for all countries together and for Denmark and Norway together. We calculated RRs for the exposed group by length of employment. We used the R survival package R  for thesEight esophageal cancer cases belonged to the dry-cleaner group, giving an RR of 0.76  . The estEleven exposed liver cancer cases gave an RR of 0.76 , and 57 exposed pancreatic cancer cases gave an RR of 1.27 . The highest risks were found for those with short or unknown length of employment . Thirty-Twenty-nine kidney cancer cases belonged to the dry-cleaner group, giving an RR of 0.67 . There was an elevated risk of bladder cancer among the dry cleaners based on 93 exposed cases , with 62 exposed cases coming from Denmark and Norway, giving an RR of 1.69 . The risk did not increase with length of employment. Significantly elevated risks were found for 2–4 years and ≥ 10 years of employment. A similar pattern was seen when the analysis was based only on the uncensored employment periods from 1965 through 1978. The combined estimate for interviewed cases and controls from Norway and Sweden was RR = 1.34 , which was only slightly reduced after control for smoking . The excess risk within the exposed group did not come from the owners of dry-cleaning shops and their employed dry cleaners  but from the supporting staff in small shops  and from owners of combined laundry and dry-cleaning shops . There were 42 exposed NHL cases, giving an RR of 0.95 .We studied the cancer risk in Nordic dry cleaners during the period where tetrachloroethylene was by far the dominant solvent, and we used laundry workers as the comparison group. Dry-cleaning work was not associated with an increased risk of esophageal cancer, but we found a borderline increased risk among persons we were unable to classify as dry cleaners or laundry workers. Dry-cleaning work was not associated with significantly increased risks of cancer of the gastric cardia, liver, pancreas, or kidney or with NHL. Female supportive staff in large dry-cleaning shops had a borderline significant excess risk of cervical cancer not found among women directly involved in dry cleaning. We found a 44% excess risk of bladder cancer among Nordic dry cleaners. The excess risk came from Denmark and Norway, the two countries with the best data. There was no clear pattern with length of employment. Adjustment for smoking in Norway and Sweden changed the estimated risk only slightly. The risk was concentrated among supporting staff in small dry-cleaning shops and among owners of combined laundry and dry-cleaning shops.Our study had several advantages. First, we covered a period where tetrachloroethylene was the dominant solvent. Second, the study was nationwide, including all persons working in dry cleaning in 1970. Third, we used a series of case–control studies nested in the national cohorts of laundry and dry-cleaning workers. The cancer risks of dry cleaners were therefore compared with those of laundry workers, two groups with similar jobs apart from the use of solvents. Smoking was equally frequent among exposed (72%) and unexposed (78%) male controls in Norway, and equally so in Sweden (66% and 69%). In Norway, smoking was slightly less frequent in exposed (45%) than in unexposed (54%) women, whereas the opposite was true in Sweden (49% and 37%). Alcohol drinking was very limited, with only 4 of 675 interviewed controls reporting at least 21 drinks/week. Fourth, population, death, and cancer registries and unique personal identifiers ensured complete ascertainment of incident cancers . Fifth, The study did, however, also have disadvantages. First, because of the limited data sources and mixture of processes, a high proportion of cases and controls from Sweden and Finland were unclassifiable as to whether they had dry-cleaning or laundry work in 1970. We therefore reported risk estimates for all countries and for Denmark and Norway only. Second, data on employment were available only from 1964 through 1979, but the 16-year period allowed a clear distinction to be made between short-term and stable workers. Third, the limited number of air measurements did not allow subdivision of study subjects by exposure level. However, because the data indicated a fairly stable exposure level throughout the study period, duration of employment was an acceptable proxy measure for relative cumulated dose.There was a clear excess risk of esophageal cancer in the two U.S. cohort studies of tetrachloroethylene-exposed dry-cleaning workers, with standardized mortality ratios (SMRs) of 2.2  is in contrast with the U.S. findings , althougThe excess risk of esophageal cancer in U.S. dry cleaners  but not 3 and 157 mg/m,3 respectively (3. The currently recommended threshold from the American Conference of Governmental Industrial Hygienists is 170 mg/m3 [3 in Denmark, Finland, and Sweden and 40 mg/m3 in Norway (In 1991, about one-third of U.S. dry-cleaning plants used an open transfer process where solvent-wet clothes were manually moved from washer to dryer . Based oectively . This trectively , and manectively . The mea70 mg/m3 , whereasn Norway . U.S. drData on primary liver cancer were reported in only two U.S. studies  with no One U.S. dry-cleaner cohort had a borderline excess risk of pancreatic cancer (SMR = 1.53; 95% CI, 0.91–2.42; The two U.S. dry-cleaner cohorts had excess risks of cervical cancer  but not Kidney cancer was not increased in the previous cohort studies  or in ouThe risk of bladder cancer was increased in one U.S. dry-cleaner cohort (SMR = 2.22; 95% CI, 1.06–4.08; International Classification for Diseases, version 8 [ICD-8; In a 1995 monograph on dry cleaning , an exce8 ICD-8;  code 200Dry-cleaning work in the Nordic countries, during a period when tetrachloroethylene was the dominant solvent, was not associated with significantly increased risks of cancer of the gastric cardia, pancreas, or kidney or with primary liver cancer or NHL. Dry-cleaning work was not associated with an increased risk of esophageal cancer, but our study was hampered by some unclassifiable cases. The result for esophageal cancer contrasts findings from U.S. tetrachloroethylene-exposed cohorts, which could be due to chance, confounding, or differences in exposure level. In line with findings from previous studies, our study indicated an excess risk of cervical cancer in supporting staff in larger dry-cleaning shops, but not in women directly involved in dry cleaning. We found an elevated risk of bladder cancer among Nordic dry cleaners. The international data together point to an excess risk of bladder cancer in dry cleaners of about 45%, but there is no pattern with exposure indices. The evidence for an association between exposure to tetrachloroethylene and risk of bladder cancer is equivocal.


Eighty percent of all breast cancers and almost 90% of breast cancer deaths occur among post-menopausal women. We used a nested case control design to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and breast cancer occurrence among women over 65 years of age. The cyclooxygenase (COX)-2 enzyme is expressed more in breast cancers than in normal breast tissue. COX-2 inhibition may have a role in breast cancer prevention.In the Canadian province of Quebec, physician services are covered through a governmental insurance plan. Medication costs are covered for those ≥ 65 years of age and a publicly funded screening program for breast cancer targets all women 50 years of age or older. We obtained encrypted data from these insurance databases on all women ≥ 65 years of age who filled a prescription for COX-2 inhibitors, non-selective NSAIDs (ns-NSAIDs), aspirin, or acetaminophen between January 1998 and December 2002. Cases were defined as those women who have undergone mammography between April 2001 and June 2002 and had a diagnosis of breast cancer within six months following mammography. Controls included those who have undergone mammography between April 2001 and June 2002 without a diagnosis of any cancer during the six months following mammography. The exposure of interest, frequent NSAID use, was defined as use of ns-NSAIDs and/or COX-2 inhibitors for ≥ 90 days during the year prior to mammography. Frequent use served as a convenient proxy for long term chronic use.We identified 1,090 cases and 44,990 controls. Cases were older and more likely to have breast cancer risk factors. Logistic regression models adjusting for potential confounders showed that frequent use of ns-NSAIDs and/or COX-2 inhibitors was associated with a lower risk of breast cancer . Results were similar for COX-2 inhibitors  and ns-NSAIDs , when assessed separately. Frequent use of aspirin at doses > 100 mg/day in the year prior to mammography was also associated with a lower risk of breast cancer . However, use of aspirin at doses ≤ 100 mg/day did not have any association with breast cancer .Women who use NSAIDs or doses of aspirin > 100 mg frequently may have a lower risk of breast cancer. Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in Canadian women. Eighty The well known serious gastrointestinal (GI) toxicity of ns-NSAIDs, thought to be due to the inhibition of the constitutive form of COX, the COX-1 enzyme, has prevented their use for chemoprevention. The COX-2 inhibitors have less GI toxicity compared to ns-NSAIDs ,17. ThesContinuous use of ns-NSAIDs or COX-2 inhibitors for cancer chemoprevention in healthy individuals appears problematic. However, patients who suffer from arthritis have few other options to control their pain and inflammation. Acetaminophen alone at regular doses may be inadequate for these patients and high doses are associated with hepatotoxicity.We sought to determine whether frequent use of NSAID or aspirin reduces the risk for breast cancer. Although ns-NSAIDs and aspirin may be associated with GI toxicity and COX-2 inhibitors may increase CV risk, among patients who require NSAIDs for pain control or aspirin for cardioprotection, breast cancer risk reduction may be an incidental benefit.The Québec provincial government health insurance agency, the Régie de l'Assurance Maladie du Québec (RAMQ), covers all in-patient and out-patient medical services for the entire population of the Canadian province of Québec including a screening program for breast cancer offered to all women 50 years of age or over. The RAMQ also covers the costs of outpatient prescription drugs for all individuals aged 65 years and older residing in Quebec. RAMQ has provided unrestricted coverage for ns-NSAIDs, aspirin and acetaminophen for at least the last two decades, celecoxib since October 1999, and rofecoxib since April 2000 until its withdrawal in September 2004. Ibuprofen, aspirin and acetaminophen are also available over-the-counter. The data in the drug claims database have been validated for accuracy of prescription claims and haveInternational Classification of Diseases, 9th review (ICD-9). RAMQ procedural codes are available upon request.From the RAMQ database, we obtained in- and out-patient physician and procedure claims, prescription drug claims, and demographic data on all patients aged 65 years and older who were dispensed COX-2 inhibitors, ns-NSAIDs, aspirin, or acetaminophen between January 1998 and December 2002 in the province. Patients retained from this population were 1) female, 2) ≥ 66 years of age and therefore had been covered by the drug plan for at least one year, and 3) had undergone bilateral mammography between April 2001 and June 2002. The date of the bilateral mammography was defined as the index date. Women who, in the three years prior to the index date, had a diagnosis of any type of cancer, or a mastectomy were excluded. Under the assumption that women undergoing mammography for screening purposes require these tests at no more than yearly intervals, we excluded patients who underwent a mammogram in the year prior to the index date. RAMQ uses the same diagnostic codes as those given by the We conducted a nested case-control study. From the source population defined above, we identified cases and controls. The cases were those women who underwent a diagnostic or therapeutic test or procedure of the breast , and who were given a diagnosis of breast cancer (ICD codes 174.0 to 174.9 and 233.0) during the six months following the index date. The controls were those patients who were not diagnosed with breast cancer or any other type of cancer in the six months following the index date.We considered regular use of pain suppressing medications in the year prior to the index date as an indicator of chronic use of these medications in preceding years. Patients who filled a prescription for any ns-NSAID, COX-2 inhibitor, aspirin or acetaminophen in the year prior to the index date were identified. The number of days supplied for each study drug during that year was recorded.The primary exposure was the filling of one or more prescriptions for celecoxib and/or rofecoxib and/or any ns-NSAID for a total of ≥ 90 days in the year prior to the index date. We also identified patients who were exposed to ≥ 90 days of aspirin and patients exposed to ≥ 90 days of acetaminophen in the year prior to the index date. Subgroups of exposure were defined for those exposed to ≥ 90 days of ns-NSAIDs, both COX-2 inhibitors, and rofecoxib and celecoxib, separately. We also separated exposure to ≥ 90 days of aspirin into two groups according to the mean daily dose prescribed, whether ≤ 100 mg or >100 mg. Non-exposed patients were those who did not receive any prescription for a COX-2 inhibitor, ns-NSAID, aspirin or acetaminophen in the year prior to the index date.The baseline patient characteristics available from the RAMQ database were determined based on demographic data, prescription claims, and in- and out-patient physician and procedure claims. They were: 1) age, defined categorically as 66–74, 75–84 and ≥ 85 years old; 2) a history of diagnostic and therapeutic breast tests and procedures, namely fine needle aspirate, puncture, core or excision biopsy or capsulectomy, in the three years prior to the index date; 3) a diagnosis of benign neoplasm of the breast (ICD code 217) in the three years prior to the index date; 4) mammography in years 2 or 3 prior to the index date; 5) a diagnosis of another breast disease in the three years prior to the index date ; 6) estrogen replacement therapy in the year prior to the index date; 7) combined estrogen and progesterone replacement therapy in the year prior to the index date; and 8) visit to a gynecologist in the year prior to the index date.The baseline patient characteristics of the cases and controls were compared using descriptive statistics.Logistic regression models were used to determine the association between exposure to ≥ 90 days of ns-NSAIDs and/or COX-2 inhibitors, aspirin at doses ≤ 100 mg/day, aspirin at doses >100 mg/day and acetaminophen and breast cancer, using the non-exposed patients as the reference group. The models were adjusted for patient characteristics at the index date, as defined above. We adjusted for whether patients had at least one visit to a gynecologist in the year prior to the index date and whether they had mammography in the years 2–3 prior to the index date to reduce a possible surveillance bias.We conducted an analysis identical to the primary analysis including only patients who also underwent mammography in the years 2–3 prior to the index date. This limited the analysis to those women who were adherent to the screening program. We also examined the effect of exposure to at least 90 days of ns-NSAIDs and/or COX-2 inhibitors excluding the prescriptions filled in the month prior to index date. This analysis would exclude prescriptions that could have been prescribed for symptoms related to the referral of the patient to mammography.We calculated that 558 cases and 5578 controls  were needed for a two-group continuity corrected chi-square test with a 0.05 two-sided significance level to have 80% power to detect an odds ratio of 0.72 between the cases and the controls, assuming that 15% of cases would be exposed. This sample size calculation was based on a ratio of 10 controls to 1 case. However, since matching on all or some of the patient characteristics may introduce biases and, more importantly, since there were no costs associated to the selection of controls, we decided to use all eligible controls for the analysis.All analyses were performed using the statistical software SAS version 8.2 . We performed our sample size calculation using nQuery20.Among 418,458 women in our dataset, 68,641 were at least 66 years of age and had undergone bilateral mammography between April 2001 and June 2002. Of these patients, 46,080 fulfilled eligibility criteria, including 1,090 (2.4%) cases and 44,990 (97.6%) controls. Patient characteristics are presented in Table Frequency of exposure to the medications of interest are indicated in Table Logistic regression models showed that cases were older  and more likely to have received combined estrogen therapy 1.35  in the year prior to the index date. Cases were also more likely to have a history of diagnostic/therapeutic breast procedures in the three years prior to the index date , benign breast neoplasm diagnosed in the year prior to the index date , and/or other breast disease in the three years prior to the index date . Cases were less likely to have used estrogen replacement therapy in the year prior to the index date . Cases were also less likely to have seen a gynecologist in the year prior to the index date  and to have had mammography in the years 2–3 prior to the index date  (data not shown).Table As shown in Table Consistent with the results of the primary analysis, exposure to ≥ 90 days of ns-NSAIDs and/or COX-2 inhibitors was also associated with a lower risk of breast cancer in a subgroup analysis of patients who had mammography in years 2–3 prior to the index date . Again, in this subgroup, exposure to ≥ 90 days of acetaminophen  and exposure to ≥ 90 days of aspirin at an average daily dose ≤ 100 mg  were not associated with breast cancer. In contrast with the findings of the primary analysis, exposure to ≥ 90 days of aspirin at an average daily dose >100 mg  did not seem to be associated with breast cancer in this subgroup. It is difficult to conclude if this difference was due to chance given the multiple modeling conducted in this study or to differences in the characteristics of the women in the two analyses. In particular, in the primary analysis, only 25% (54/211) of the cases who received aspirin for 90 days or more at an average daily dose >100 mg also received hormone replacement therapy compared to 42% (45/93) of women in the secondary analysis. Thus, there may have been better surveillance of the women in the secondary analysis. Of note, the effect of aspirin at an average daily dose >100 mg in the subgroup analysis differed between women who were not receiving hormone replacement therapy  and those who did .The results of the main analysis did not change substantially when we reassessed the effect of exposure to ≥ 90 days of ns-NSAIDs and/or COX-2 inhibitors , aspirin at an average daily dose ≤ 100 mg  aspirin at an average daily dose > 100 mg  and acetaminophen  excluding the prescriptions filled in the month prior to the index date.In this population-based study of women 65 years of age or older, we found that patients taking ns-NSAIDs and/or COX-2 inhibitors and patients taking aspirin at doses >100 mg/day for a period of ≥ 90 days were at a lower risk of breast cancer compared to those not taking these medications. Given the cardiovascular risk associated with use of some COX-2 inhibitors and ns-NSAIDs, regular use of these agents for primary cancer chemoprevention cannot be recommended. However, for women who require these agents for pain control, a concurrent benefit of such treatment may be reduced risk of breast cancer. Aspirin is used most commonly for the prevention of myocardial infarction and stroke. Although aspirin doses of as little as 80 mg per day are effective for the prevention of cardiovascular events, our results suggest that higher doses may additionally protect women from developing breast cancer.Ns-NSAIDs are COX-1 and COX-2 inhibitors. A significant inverse association has been observed in most observational studies between the use of ns-NSAIDs and the risk of breast cancer. In a meta-analysis of six cohort and 8 case-control studies, the authors found a significant 18% reduction in breast cancer risk among patients taking ns-NSAIDs compared to those not taking them. However, the data were insufficient to estimate a dose-response effect for duration and frequency of use of any particular type of ns-NSAID . A subseAspirin is also an irreversible COX enzyme inhibitor. The litWe cannot exclude the possibility, however, that the apparent protective effect of aspirin observed in our study was a result of surveillance bias among aspirin users. Women prescribed aspirin for prevention of cardiovascular disease may be more likely to consistently undergo preventive interventions such as mammography. Aspirin users may have therefore been more likely to have undergone regular mammographic screening prior to the age of 65 years. Those with a previous history of breast cancer so detected would have been excluded from our cohort. Consistent with this possibility, we found that the protective effect of aspirin prescribed at an average dose >100 mg/day did not persist when we restricted the analysis to women who have undergone mammography in years 2–3 prior to the index mammogram.th birthday. Therefore, to have one full year of prescription data available at index date, women had to be 66 years of age or older at that date. To correctly examine exposure to the drugs of interest in the past 3 years, for example, women would have had to be at least 68 years of age at the index date. In designing the study, we thus had to trade-off the number of patients with the duration of exposure studied.In this study, prescription data were available starting in 1998. However, we used only one year of data to assess frequent use of the study drugs because in Quebec, patients are covered by the provincial drug plan starting at their 65Patients may have used over-the-counter aspirin or ibuprofen . A survey conducted by Santé Québec, a provincial public health agency, showed that in 1998, 17.0% and 2.2% of the elderly who consumed ns-NSAIDs or aspirin, respectively, acquired them over-the-counter. Québec A number of variables associated with breast cancer risk are not available in the RAMQ database, including family history of breast or other cancers, carriage of certain genes and gynecologic and obstetric history. However, these variables are not likely to be associated with exposure to ns-NSAIDs or COX-2 inhibitors and thus are unlikely to have confounded the results. Obesity, however, is a risk factor for breast cancer in post-menopausal women as well We are aware that the main exposure of at least 90 days of ns-NSAIDs and/or COX-2 inhibitors may seem to be a relatively short period of time to attribute a protective effect to a drug on a malignancy that may evolve over many years. However, existing literature also suggests that relatively short durations of exposures to cyclooxygenase inhibitors may protect against the progression of tumors. Recent randomized trials in the field of colorectal adenomas have shown that exposure to aspirin significantly reduced the number and histological grade of recurrent adenomas,37. ThisMoreover, we believe that a minimum of 90 days of exposure is a marker for chronic exposure to ns-NSAIDs in the past. In fact, among women for whom 3 years of data were available prior to their index date and who used ns-NSAIDs and/or COX-2 inhibitors for at least 90 days in the year prior to the index date, 91% had also used them in years 2–3 prior.The ideal agents for chemoprevention and chemotherapy are those that are effective but that have few side effects. Although both ns-NSAIDs and COX-2 inhibitors seem to have similar protective effects on breast cancer, a continuous use of ns-NSAIDs or COX-2 inhibitors for cancer chemoprevention in healthy individuals appears problematic. However, in those women who have arthritis and are in need of frequent use of analgesics, ns-NSAID or COX-2 inhibitor use may offer protection against breast cancer compared with acetaminophen. Although we cannot exclude the possibility of surveillance bias among aspirin users, our findings support the possibility that at doses above 100 mg daily, aspirin may offer protection against the development of breast cancer. Many post-menopausal women require aspirin for the prevention of cardiovascular events. Increasing the dose from 80 mg daily to > 100 mg daily in these women may additionally provide protection against the development of breast cancer. This possibility has important public health implications and requires further investigation.Dr Rahme is a research scholar and Dr Hudson is a research fellow funded by The Arthritis Society. Drs Dasgupta and Rajan are physician scientists funded by the Fonds de la recherche en santé du Québec. This study was partially funded by the Arthritis Society.Dr Rahme has served as consultant for Merck & Co. Inc. and Pfizer Inc., the companies that manufacture rofecoxib and celecoxib, in relation to other studies.The author(s) declare that they have no competing interests.All authors declare that they had full access to the data and participated in the design and conduct of the study, in the analysis and the interpretation of the data and in the writing of the report. All authors have seen and approved the final version. All authors had final responsibility for the decision to submit the paper to publication.The pre-publication history for this paper can be accessed here:


Statistics from the Swedish National Cancer Registry based on all 110,658 cases of invasive breast cancer during the 31-year period 1958-1988 were analysed. Age-specific incidence rates increased over successive calendar periods. The average annual increase in the age-standardised incidence rate was 1.3%, with the greatest percentage changes among the youngest age groups. During the latter half of the study period, the rates of increase tended to diminish in the youngest age groups and even reversed significantly among women from 75 years of age. In analyses using age-period-cohort models, the best fit of the cancer incidence data was found for the full model which simultaneously considered the effects of age, period and cohort. Cohort effects were found to be more important than period effects, in terms of model fit. These effects emerged as a seemingly consistent, and in a logarithmic scale, fairly linear increase in the relative risk of breast cancer incidence with a 3-fold elevation in women born in the 1950's relative to those born in the 1880's. It is concluded that the rising breast cancer incidence in Sweden is explained chiefly by birth cohort effects, which indicate persistent secular changes in largely unknown risk factors associated with life style. We could not in the present data see any clear evidence for an adverse effect of contraceptive or replacement sex steroids on breast cancer incidence.