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Although breast cancer screening has been shown to work in randomised trials, there is a need to evaluate service screening programmes to ensure that they are delivering the benefit indicated by the trials. We carried out a case-control study to investigate the effect of mammography service screening, in the NHS breast screening programme, on breast cancer mortality in the East Anglian region of the UK. Cases were deaths from breast cancer in women diagnosed between the ages of 50 and 70 years, following the instigation of the East Anglia Breast Screening Programme in 1989. The controls were women (two per case) who had not died of breast cancer, from the same area, matched by date of birth to the cases. Each control was known to be alive at the time of death of her matched case. All women were known to the breast screening programme and were invited, at least once, to be screened. There were 284 cases and 568 controls. The odds ratio (OR) for risk of death from breast cancer in women who attended at least one routine screen compared to those who did not attend was 0.35 (CI: 0.24, 0.50). Adjusting for self-selection bias gave an estimate of the breast cancer mortality reduction associated with invitation to screening of 35% (OR=0.65, 95% CI: 0.48, 0.88). The effect of actually being screened was a 48% breast cancer mortality reduction (OR=0.52, 95% CI: 0.32, 0.84). The results suggest that the National Breast Screening Programme in East Anglia is achieving a reduction in breast cancer deaths, which is at least consistent with the results from the randomised controlled trials of mammographic screening.

Mammographic density and serum sex hormone levels are important risk factors for breast cancer, but their associations with one another are unclear. We studied these phenotypes, together with single nucleotide polymorphisms (SNP) in genes related to sex hormone metabolism, in a cross-sectional study of 1,413 postmenopausal women from the European Prospective Investigation into Cancer and Nutrition-Norfolk. All women were >1 year postmenopausal and had not taken hormone replacement therapy for >3 months before sampling. Serum levels of 7 sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG), androstenedione, 17-OH-progesterone, estrone, and estrone sulfate] and 15 SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were studied. Mammograms nearest in time to the blood sampling were identified through the national breast screening program and visually assessed by three radiologists using the Boyd six-category and Wolfe four-category scales. We found a weak positive association between mammographic density and SHBG levels (P = 0.09) but no association with any other hormones. None of the SNPs, including those shown previously to be associated with estradiol or SHBG, showed significant associations with density. We conclude that mammographic density is largely independent of postmenopausal steroid hormone levels, indicating that these risk factors have, to a large extent, an independent etiology and suggesting that they may be independent predictors of breast cancer risk.

Background: Reports suggest a relationship between circulating sex hormone levels and breast cancer risk, but genetic association studies have been inconclusive. We investigated the association between levels of sex hormones and single nucleotide polymorphisms (SNPs) in genes coding for the enzymes that regulate them., Methods: We assayed circulating levels of estradiol, testosterone, estrone, androstenedione, 17alpha-hydroxyprogesterone, and sex hormone-binding globulin (SHBG) in 1975 normal postmenopausal women. Fifteen SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were genotyped in these postmenopausal women and in a breast cancer case-control study. Associations of genotypes with breast cancer risk were evaluated in the case-control study and with hormone levels in the postmenopausal women using multiple linear regression with assay batch, body mass index, parity, peri- or postmenopausal status, and age band as covariates., Results: CYP19 SNPs (rs10046 and [TCT]+/-) were associated with differences in estradiol level (P =.0006 and P =.0003, respectively) and the estradiol : testosterone ratio (P =.000001() and P =.002). SNP rs10046 explained 1.6% of the variance (r2) in the estradiol : testosterone ratio. SHBG SNPs (5' untranslated region [5'UTR] g-a and D356N) were associated with both SHBG levels (P<10(-6) and P =.005) and the estradiol : SHBG ratio (P =().000008() and P =.01). These SNPs explained 2.4% and 0.6% of the variance in SHBG levels, respectively. SNPs in the other genes were not associated with differences in any hormone levels, and none were statistically significantly associated with breast cancer risk., Conclusion: Genetic variation in CYP19 and SHBG contributes to variance in circulating hormone levels between postmenopausal women, but low r2 values may explain why these genes have given inconclusive results in breast cancer case-control studies.

We aimed to quantify the benefits of detecting ductal carcinoma in situ (DCIS) and of downwards stage-shifting within invasive tumours in mammographic screening. Using data from the Swedish Two-County Trial of breast cancer screening, we examined the 20-year death rates from invasive tumours of stage II or worse, invasive tumours of stage I and DCIS. We then used these rates and their respective incidences in invited (active study population, ASP) and control (passive study population, PSP) arms of the trial, to estimate the numbers of deaths avoided by downward stage-shifting the larger stage II or worse tumours to stage I and the stage I cancers to DCIS. We also studied the association between the mortality reduction achieved and the proportion of DCIS cases detected in the randomised trials of breast cancer screening. In the Swedish Two County Trial, 141 breast cancer deaths were avoided in the ASP compared with the PSP at approximately 20 years of follow-up. Of these, 65% (91/141) were avoided as a result of stage-shifting from invasive stage II or worse to invasive stage I, and 5% (7/141) as a result of stage-shifting from invasive stage I to DCIS. If we assumed that 10% of stage II or worse tumours avoided were shifted not to stage I, but to DCIS, the estimated number of deaths prevented by shifting from invasive disease to in situ was 17, which is 12% of all deaths prevented. When the results of all the randomised trials of breast cancer screening were reviewed, there was no clear association between the percentage of DCIS cases diagnosed and the observed mortality reduction. We conclude that compared with downward stage-shifting of invasive tumours, detection of DCIS plays a small part in saving lives from breast cancer. Treatment decisions in DCIS, as in invasive carcinoma, should take full account of histopathological, clinical and radiological attributes of the tumour.

A substantial proportion of the familial risk of breast cancer may be attributable to genetic variants each contributing a small effect. Polymorphisms in DNA repair genes are good candidates for such low penetrance breast cancer susceptibility alleles. Checkpoint kinase 2 (CHEK2) is a kinase in which the yeast counterpart regulates a cell cycle checkpoint and causes cells to arrest proliferation after DNA damage. A rare, protein truncating mutation in the CHEK2 gene has recently been shown to confer a modest risk of breast cancer. The aim of this study was to determine whether common polymorphic variants in CHEK2 are associated with an increase in breast cancer risk. We assessed two variants in CHEK2 using a case control study design (n = 1786 cases and 1828 controls). No differences in genotype frequencies were found between cases and control for either the IVS1 + 38insa or the a1013g polymorphisms (P = 0.3 and 0.2 respectively), and no genotype-specific risk was significantly different from unity. The haplotype frequency distribution in cases and controls were also similar (P = 0.3). We conclude that the CHEK2 polymorphisms IVS + 1a and a1013g do not confer an increased risk of breast cancer. It is also unlikely that other, as yet unidentified, common polymorphisms that affect risk are present in the gene in the British population.

Dense mammographic patterns are a risk factor for breast cancer. In a recent case-control study, dense patterns were observed to be associated with a higher relative risk estimate for the more aggressive grade 3 tumors than for grade 1 or 2 tumors. The present study was designed to ascertain, by reference to odds ratio estimates of relative risk by tumor size and histologic grade, whether this was more likely to be due to increased innate predisposition of dense parenchymal patterns to grade 3 tumors, or to dedifferentiation of cases missed at screening due to dense patterns. If the observation were due entirely to dedifferentiation, then for a given size the relative risk of grade 3 tumors would be the same as for grades 1-2. Size-specific relative risks of grade 3 tumors were higher than those of grade 1-2 tumors. It is concluded that the majority of the enhanced risk of grade 3 tumors is due to enhanced innate predisposition to grade 3 tumors in dense breasts.

In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene 'BRCA3', and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021-0.125%) and of BRCA2 0.068% (95% CI: 0.033-0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families.

Several studies have investigated polymorphisms in CYP1A1 and breast cancer risk with inconsistent results. We have carried out a population based case-control study of the Thr461Asn and Ile462Val polymorphisms in CYP1A1 to clarify their importance in determining breast cancer susceptibility. A total of 1873 cases and 712 controls were genotyped for Thr461Asn and 1948 cases and 1355 controls were genotyped for Ile462Val. We have also investigated a putative interaction between smoking and CYP1A1 genotype and breast cancer risk using a case only study design. The genotype distribution of Thr461Asp in controls was close to that expected under Hardy-Weinberg equilibrium (HWE). We detected no significant differences in genotype frequencies between breast cancer cases and controls (P = 0.68). Compared with the Thr/Thr homozygotes there was no significant risk for either the Thr/Asp heterozygote [OR = 1.1 (95% CI 0.8-1.4)] or the Asp/Asp homozygote [OR = 0.4 (0.02-6.1)]. The genotype distribution of Ile462Val in controls was also close to that expected under HWE with no significant differences between breast cancer cases and the controls (P = 0.44). No significant risk was found for either the Ile/Val heterozygote [OR = 0.8 (0.6-1.1)] or the Val/Val homozygote [OR = 2.7 (0.3-24)] compared with the Ile/Ile homozygotes. Furthermore, subgroup analyses revealed no effect of age or menopausal status on genotypic risks, and we found no evidence for an interaction between genotype and smoking habit or alcohol consumption and susceptibility to breast cancer. We combined our data for the Ile462Val polymorphism with those from four other published studies, but even with >5000 subjects, none of the genotype-associated risks achieved statistical significance, and there was no consistent pattern to the risks associated with increasing Val allele dosage [Ile/Val OR = 0.9 (0.7-1.1), Val/Val OR = 2.3 (0.4-12), and Val carrier OR = 1.0 (0.9-1.1)].

We used data from a population based series of breast cancer patients to investigate the genetic models that can best explain familial breast cancer not due to the BRCA1 and BRCA2 genes. The data set consisted of 1,484 women diagnosed with breast cancer under age 55 registered in the East Anglia Cancer registry between 1991-1996. Blood samples taken from the patients were analysed for mutations in BRCA1 and BRCA2. The genetic models were constructed using information on breast and ovarian cancer history in first-degree relatives and on the mutation status of the index patients. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene BRCA3, and a polygenic effect. The models were assessed by likelihood comparisons and by comparison of the observed numbers of mutations and affected relatives with the predicted numbers. BRCA1 and BRCA2 could not explain all the familial clustering of breast cancer. The best-fitting single gene model for BRCA3 was a recessive model with a disease allele frequency 24% and penetrance 42% by age 70. However, a polygenic model gave a similarly good fit. The estimated population frequencies for BRCA1 and BRCA2 mutations were similar under both recessive and polygenic models, 0.024 and 0.041%, respectively. A dominant model for BRCA3 gave a somewhat worse fit, although the difference was not significant. The mixed recessive model was identical to the recessive model and the mixed dominant very similar to the polygenic model. The BRCA3 genetic models were robust to the BRCA1 and BRCA2 penetrance assumptions. The overall fit of all models was improved when the known effects of parity on breast and ovarian cancer risks were included in the model-in this case a polygenic model fits best. These findings suggest that a number of common, low-penetrance genes with additive effects may account for the residual non-BRCA1/2 familial aggregation of breast cancer, but Mendelian inheritance of an autosomal recessive allele cannot be ruled out., (Copyright 2001 Wiley-Liss, Inc.)

Background: Preliminary retrospective data suggest it is possible to identify impalpable breast cancer in women presenting with a family history of breast cancer under the age of 50, by using regular mammography. In consequence, this service is offered in a number of centres in the UK. The effectiveness of such a service, however, has not been fully evaluated., Methods: We propose to perform such an evaluation in a cohort of 20000 women under the age of 50 with a significant family history of breast cancer, given regular mammographic surveillance over 5 years. Comparison of surgical and pathological data with completed and ongoing population screening trials using analysis techniques of varying complexity will be performed to obtain an accurate prediction of future breast-cancer mortality reduction. The formal aims are: i) to estimate the difference in breast-cancer mortality in women under the age of 50 with a significant family history of breast cancer having regular mammography, compared with those not being screened; ii) to estimate the cost-effectiveness of regular mammography in this group of women, compared with no screening. The increase in health service resource use attributable to such a policy will be compared with no screening, and costed. Incremental cost-effectiveness ratios of implementing the standardised mammography strategy compared with no screening will be presented in terms of the additional cost per cancer detected, per life saved and per life-year saved.

Objective: To perform a pilot study to compare ultrasound and mammographic screening with particular respect to specificity, in a cohort of women at moderate family history risk of breast cancer., Material and Methods: High resolution ultrasound of both breasts was undertaken in 149 women at moderate risk of breast cancer who were referred for mammographic screening. The two tests were read blind to the other. Core biopsy was undertaken for solid lesions found on ultrasound., Results: 149 Patients, mean age 42.15 years, were screened with bilateral ultrasound. 90 Examinations were normal. 46 Women had cysts, two had lesions previously biopsied and found to be benign, and one had a lymph node. 10 Focal solid lesions were biopsied on account of their ultrasound findings, 6.7% (95% confidence intervals (95% CIs) 2.7% to 10.7%). All but one of the 149 mammograms were normal. In this case both mammography and ultrasound showed a focal solid lesion that at core biopsy was found to be a fibroadenoma. Histology showed seven fibroadenomata, two areas of fibrocystic change, and one adenoid cystic carcinoma. Positive predictive value for biopsy was 10%. Mean follow up was 13.7 months. There was one interval cancer., Conclusion: Screening with breast ultrasound, in a cohort of women at moderate risk of breast cancer due to family history, has an acceptable biopsy rate. Screening with ultrasound and mammography in patients with an increased risk of breast cancer may be beneficial and a randomised study to examine issues of acceptability, reproducibility, and cost effectiveness is apt.

The aims of this study were to estimate the familial relative risk of breast cancer according to the age of the at risk individual and the age at which the relative was affected, and to estimate the proportion of the general population in several breast cancer risk categories because of a family history and, thus estimate the potential to reduce the overall breast cancer burden using interventions targeted at women at increased risk because of family history. Familial relative risks were computed by comparing breast cancer incidence in relatives of 2809 breast cancer cases from a population based case series with that expected from general population incidence rates. The proportion of the general population in different categories of risk according to family history was estimated from the relative risk of breast cancer for that category and the proportion of cases in that category. 389 (13.8%) cases had at least 1 first degree relative with breast cancer. The relative risk of breast cancer in sisters of index cases was 1.90 (95% confidence interval (CI) 1.63-2.36) and that in mothers 1.73 (1.52-1. 97). The risk to mothers of cases diagnosed under 50 years of age tended to decrease in older mothers, but no age effect was seen for mothers of cases diagnosed >/=50 years of age. There was no evidence that relative risk to sisters declined with age. For women with 2 affected first degree relatives the relative risk was 2.85 (2.12-3. 76). From these data, we estimate that in the general population 6. 8% of women under the age of 50 years and 9.7% of women aged 50-65 years have at least 1 first degree relative affected with breast cancer. Two per cent of women under 50 years have a family history which confers an increased risk of at least 2.5-fold. An intervention targeted at this group that reduced breast cancer morbidity by 20% would reduce the total burden of breast cancer in this age group by 1.1% at most. A family history of breast cancer is quite common in the general population, but preventive interventions targeted at women at high risk of breast cancer because of family history will have limited impact on breast cancer morbidity as a whole.

Mammographic breast density has been shown to be associated with up to a 4- to 6-fold increase in risk of breast cancer, whereas tamoxifen therapy increases disease-free survival and reduces mortality. We have therefore investigated whether these effects are related. To determine the effects of tamoxifen on mammographic density, mammograms from 94 women who had received tamoxifen for breast cancer and 188 women (without breast cancer) who had not received tamoxifen were visually classified according to the criteria of Wolfe. Two controls were age-matched to each case. All of the women were postmenopausal (ages, 50-64 years), neither group was taking hormone replacement therapy, and none of the cases had received chemotherapy. There were significant differences in breast density between cases and controls at the initial mammogram (P = 0.0001) but no significant differences at the follow-up mammogram (P = 0.51). A significant change to a more lucent pattern had occurred among the case group (P = 0.0001). The odds ratio for cancer that was associated with the more dense (P2 and DY) patterns with respect to the more lucent (N1 and P1) patterns was 3.6 (95% confidence interval, 2.11-6.18) at the initial mammogram. This was significantly reduced to 1.5 (95% confidence interval, 1.32-1.70) after treatment with tamoxifen (P = 0.019; chi2 = 5.52). The substantial reduction in breast density with tamoxifen provides evidence that tamoxifen has the capacity to favorably alter postmenopausal breast density toward a more lucent pattern, which is associated with reduced risk of breast cancer. Mammographic pattern is, thus, a potential biomarker of breast cancer risk.

Many studies have investigated the association between alterations in the p53 gene and clinical outcome of breast cancer, and most investigators have reported poorer overall and disease-free survival (as indicated by a relative hazard (RH) greater than one) in breast cancer cases with somatic mutations in p53. However, different studies have produced widely differing RH estimates, ranging from no risk (RH = 1) to a relative hazard of 23, and not all of these results have been statistically significant. We have therefore reviewed all the published studies that have investigated the association between somatic mutations in the p53 gene and breast cancer prognosis and used standard techniques of meta-analysis to combine the results of these studies to produce a more precise estimate of the prognostic significance of p53 mutations. Eleven studies investigated overall survival in a total of 2319 unselected cases. The RH estimates from these ranged from 1 to 23.4 with a combined RH estimate of 2.0 (confidence interval 1.7-2.5). Three studies investigated the role of p53 in node-negative patients and in these, the combined estimate of RH was 1.7 (1.2-2.3). For three studies of node-positive breast cancer the combined risk estimate was 2.6 (1.7-3.9). The inclusion of p53 mutation screening in large breast cancer clinical trials seems warranted in the light of these results. Analysis of large numbers of cases matched for stage and therapy will allow definitive clarification of the value of p53 mutational status in prognostication, and possibly choice of therapy.

A recent study showed an association between a single base substitution, T-->C, in the promotor region of the CYP17 gene, the risk of breast cancer and age at menarche in Asian, African-American and Latino women from California and Hawaii. The C allele was associated with increased risk of breast cancer, significantly so for patients presenting with advanced disease, whereas the TT genotype was associated with later age at menarche in control subjects. We attempted to confirm these findings in a large case-control study in East Anglia, England (835 cases and 591 control subjects). We found no evidence of an increased risk of breast cancer [odds ratio (OR) 1.10, confidence interval (CI) 0.89-1.37] or advanced breast cancer (OR 0.88, CI 0.38-2.01) in C allele carriers, nor any association between age at menarche and genotype. We conclude that these alleles do not significantly alter breast cancer risk in the English population.

In this paper, a combined analysis was performed to study the interaction between familial risk and reproductive life factors. In particular, the interaction between familial risk and breast cell mitotic activity (BCMA), as assessed by duration of ovarian activity, was investigated because of the potential importance of mitotic activity on genetically susceptible cells. The present analysis included 3152 cases and 4404 controls in seven case-control studies from four countries. The interaction effect was estimated in each study separately, then combined using two different methods: a multivariate weighted average and a Bayesian random-effects model. The main effects of reproductive life factors on the risk of breast cancer were in agreement with the previous findings. In particular, an increased duration of BCMA before the first childbirth and over life was found to increase the risk of breast cancer (P < 0.001). Slightly increasing but non-significant, familial risks were observed with increasing number of children (P = 0.17), increasing age at first childbirth (P > 0.2) and increasing duration of BCMA (P > 0.2). There was no modification in familial risk with age at menarche and no clear pattern with menopause characteristics. A weak influence of reproductive and menstrual factors on the familial risk emerged from the present study.

An increased risk of breast cancer in women with a family history of breast cancer has been demonstrated by many studies using a variety of study designs. However, the extent of this risk varies according to the nature of the family history (type of relative affected, age at which relative developed breast cancer and number of relatives affected) and may also vary according to age of the individual. The aim of our study was to identify all the published studies which have quantified the risk of breast cancer associated with a family history of the disease, and to summarise the evidence from these studies, with particular emphasis on age-specific risks according to subject and relative age. Seventy-four published studies were identified. The pooled estimate of relative risk (RR) associated with various family histories was as follows: any relative, RR = 1.9 (95% CI, 1.7-2.0); a first-degree relative, RR = 2.1 (CI = 2.0, 2.2); mother, RR = 2.0 (CI = 1.8, 2.1); sister, RR = 2.3 (CI = 2.1, 2.4); daughter, RR = 1.8 (CI = 1.6, 2.0); mother and sister, RR = 3.6 (CI = 2.5, 5.0); and a second-degree relative, RR = 1.5 (CI = 1.4, 1.6). Risks were increased in subjects under age 50 and when the relative had been diagnosed before age 50.

Researchers have noted that mammographic screening has a reduced effect on breast cancer mortality in women in their forties compared to older women. Explanations for this include poorer sensitivity in younger women due to denser breast tissue, as well as more rapid tumor progression, giving a shorter mean sojourn time (the average duration of the preclinical screen-detectable period). To test these hypotheses, we developed a series of Markov-chain models to estimate tumor progression rates and sensitivity. Parameters were estimated using tumor data from the Swedish two-county trial of mammographic screening for breast cancer. The mean sojourn time was shorter in women aged 40-49 compared to women aged 50-59 and 60-69 (2.44, 3.70, and 4.17 years, respectively). Sensitivity was lower in the 40-49 age group compared to the two older groups (83%, 100%, and 100%, respectively). Thus, both rapid progression and poorer sensitivity are associated with the 40-49 age group. We also modeled tumor size, node status, and malignancy grade together with subsequent breast cancer mortality and found that, to achieve a reduction in mortality commensurate with that in women over 50, the interscreening interval for women in their forties should be less than two years. We conclude that Markov models and the use of tumor size, node status, and malignancy grade as surrogates for mortality can be useful in design and analysis of future studies of breast cancer screening.

Close monitoring of data from individual programmes is required to evaluate the potential of the breast screening programme to reach the Health of the Nation target of 25% reduction in breast cancer mortality in the invited age group by the year 2000. This paper outlines the use of indirect age standardisation techniques to compare the performance of individual programmes in terms of their invasive cancer detection rates. Expected invasive cancer detection rates are calculated by applying data from the Swedish two county study to estimated England and Wales background incidence rates for different age strata. If the national programme overall meets these targets then the required mortality reduction should be achieved. The same method can be used by other (national) screening programmes by applying the relevant background incidence figures to produce internationally comparable data.

Several experimental and non experimental studies have shown that mammography every 2-3 years can reduce mortality for breast cancer in women over 50 of about the 30%. On this basis, in the last few years several programmes, population-based, have been organised at Regional and National level in Europe. In this paper the main process indicators useful to assess early the impact of a screening programme are discussed. The proposal of a system for the programme evaluation is mainly based on the experience of the Two County Study, in Sweden, the most important randomised clinical trial in this field.

In a previous study in France, we reported that the relative risk of breast cancer associated with a family history of breast cancer was higher in those subjects with a history of abortions. The present study was undertaken to check the existence of this interaction in other studies and to investigate whether the interaction is modified by the time at which abortions occur. Data were obtained from six case-control studies in France, Australia and Russia, with information on family history of breast cancer and abortion for 2693 breast cancer cases and 3493 controls. The interaction effect was estimated in each study separately, then combined using a multivariate weighted average. The relative risk conferred by a family history of breast cancer increased with the number of abortions (1.8 for no abortion, 1.9 for one abortion, 2.8 for two or more). There was a significant interaction between total number of abortions and family history (P = 0.04), but this was no longer significant when adjusted for other risk factors. The familial risk was highest for those who had had an abortion before first childbirth (1.9 for abortion after first childbirth, 2.7 for abortion before first childbirth). The adjusted risk associated with family history was significantly higher in those with an abortion before first childbirth (P = 0.04). Our findings suggest a synergism between familial factors and abortion. The interaction was not substantially modified by the type of abortion (spontaneous or induced) but was modified by the time at which it occurred in relation to first childbirth. This suggests an effect of abortion itself rather than predisposition to abortion. Further studies of breast cancer cases, particularly among BRCA1 gene carriers and their families, could improve our understanding of this effect.

The sojourn time, time spent in the preclinical detectable phase (PCDP) for chronic diseases, for example, breast cancer, plays an important role in the design and assessment of screening programmes. Traditional methods to estimate it usually assume a uniform incidence rate of preclinical disease from a randomized control group or historical data. In this paper, a two-parameter Markov chain model is proposed and developed to explicitly estimate the preclinical incidence rate (lambda 1) and the rate of transition from preclinical to clinical state (lambda 2, equivalent to the inverse of mean sojourn time) without using control data. A new estimate of sensitivity is proposed, based on the estimated parameters of the Markov process. When this method is applied to the data from the Swedish two-county study of breast cancer screening in the age group 70-74, the estimate of MST is 2.3 with 95 per cent CI ranging from 2.1 to 2.5, which is close to the result based on the traditional method but the 95 per cent CI is narrower using the Markov model. The reason for the greater precision of the latter is the fuller use of all temporal data, since the continuous exact times to events are used in our method instead of grouping them as in the traditional method. Ongoing and future researches should extend this model to include, for example, the tumour size, nodal status and malignancy grade, along with methods of simultaneously estimating sensitivity and the transition rates in the Markov process.

Study Objective: The aim was to demonstrate the benefits of breast cancer screening on mortality., Design: The study was an evaluation of a breast cancer screening programme by means of different approaches: (1) a case-control study, breast cancer deaths being the cases; (2) comparing the numbers of breast cancer deaths in screened and unscreened women; (3) comparing breast cancer mortality before and after start of the programme; (4) comparing breast cancer mortality in different large cities; (5) comparing screening activity with mortality reduction., Setting: The setting was a breast cancer screening programme in the city of Utrecht, the DOM project, for women aged 50-64 years old at intake, birth cohort 1911-1925. The programme started in 1974, and there were five screening rounds up to 1984. Participation rate in the first round was 72% (14,697 women)., Main Results: (1) Screening was protective against dying from breast cancer, odds ratio 0.52, with a stronger effect in older women and no evidence of confounding; (2) risk ratio of dying from breast cancer for women in the response group was the same as the odds ratio, 0.52; (3) breast cancer death rate after the start of the project was nearly 20% lower than before the project started; after correcting for women who could not have benefited from screening the reduction was 33%; (4) a rise in breast cancer mortality in birth cohort 1911-1925 seen in other large cities without a screening programme due to aging of the cohort was not seen in the city of Utrecht; (5) mortality reduction followed the screening activity with a time lag of approximately 5 years., Conclusions: Early diagnosis of breast cancer by mammography reduces breast cancer mortality in women 50-64 years old at intake; different approaches to the evaluation of the project give different estimates of the screening effect, making clear that the effect depends on the intensity of the programme.

A case-control study was conducted among Singapore Chinese women, comprised of 200 histologically confirmed cases of breast cancer and 420 hospital controls. Subjects were interviewed on family history of breast cancer, social and demographic characteristics, reproductive history, and diet one year prior to interview. Differences in risk factors were observed according to menopausal status. In the premenopausal group, the most consistently significant nondietary effect was an increased risk with late age at first birth. In postmenopausal women, the most consistent nondietary effects were increased risks with nulliparity, tall stature, high educational status, and a family history of breast cancer. In premenopausal women, the strongest dietary effects were low risks with high intakes of polyunsaturated fatty acids (PUFA), beta-carotene, soya protein as a proportion of all protein, and a high risk with high red-meat intake. No dietary effects were observed in postmenopausal women. Examination of effects by 10-year age groups suggested that the differences in the effects of age at first birth, nulliparity, height, education, beta-carotene intake, and PUFA intake between premenopausal and postmenopausal women were at least partly attributable to age-related differences in the baseline distributions of these variables. The variation in the effects of red meat and soya protein appeared to be attributable mainly to menopausal status itself, which is consistent with the hypothesis that these factors operate on risk by way of hormonal mechanisms.

The results of the Swedish two-county trial of mammographic screening for breast cancer are presented, updated to December 31, 1990, which is an average of 10.8 years follow-up per person. The main result of the trial in terms of breast cancer mortality remained the same: compared with the control group, the group invited to screening had a relative breast cancer mortality of 0.70 (P = 0.0002) with 95% confidence interval (0.58, 0.85). Analysis of survival showed that relative to the control group, the cancers detected at prevalence screen, incidence screens, and in the interval between screens had a good prognosis, whereas cancers detected in those who had refused screening had a very poor prognosis. When adjusted for tumor size, lymph node status, and tumor grade (differentiation), the better survival associated with incidence screen and interval detection was largely accounted for, indicating that the benefit of incidence screening is largely achieved through the effect of screening on the three prognostic variables, notably size of the tumor. Results indicate that to achieve a substantial mortality reduction, 50% of screen-detected invasive cancers should be less than 15 mm in diameter, at least 30% of screen-detected grade 3 tumors should be less than 15 mm, and at least 70% of screen-detected tumors should not have lymph node metastases. The percentage of grade 3 tumors of a given size should be the same in screen-detected cancers as in clinically detected, and breast cancer prevalence at first screen should be at least three times the expected incidence rate in the absence of screening. This should be achieved without the recall rate for further examination exceeding 9%, and procedures including further imaging techniques and fine needle aspiration or core biopsy should be used before resorting to surgical biopsy. These aims can be achieved in specialist screening centers if particular attention is paid to resources for screening and diagnostic evaluation, specialist training of clinical and technologic screening staff, and ongoing monitoring of mammographic quality, recall rates, and the attributes of the tumors detected.

The results of the Swedish two-county study are analysed with respect to tumour size, nodal status and malignancy grade, and the relationship of these prognostic factors to screening and to survival. It is shown that these factors can account for much of the differences in survival between incidence screen detected, interval and control group cancers but to a lesser extent for cancers detected at the prevalence screen where length bias is greatest. Furthermore, examination of the relationships among the prognostic factors and mode of detection indicates that malignancy grade, as a measure of inherent malignant capacity, evolves as a tumour grows. The proportion of cancers with poor malignancy grade is several fold lower for cancers of diameter less than 15 cm than for cancers greater than 30 cm, independent of the length bias of screening. The implications of these findings for screening frequency are briefly discussed.

A case-control study was conducted in Moscow to assess the effect of diet on risk of breast cancer, and also to study the established reproductive risk factors. A notable finding of the study, which covered 139 case-control pairs matched by age and neighbourhood, is that dietary factors are more important for post-menopausal than for pre-menopausal breast cancer. The decreased risk of post-menopausal breast cancer was associated with high intakes of cellulose (OR 0.04; 95% CI 0.01-0.31), mono- and disaccharides (OR 0.02; 95% CI 0.002-0.27), vitamin C (OR 0.20; 95% CI 0.06-0.70), beta-carotene (OR 0.09; 95% CI 0.02-0.49), and also polyunsaturated fatty acids (OR 0.14; 95% CI 0.03-0.69). High intakes of total fat resulted in a statistically non-significant decrease in the odds ratio (OR 0.52; 95% CI 0.04-6.99), while saturated fats slightly increased the risk of breast cancer (OR 1.67; 95% CI 0.24-11.78). Protein intake was also associated with increased risk of breast cancer (OR 4.62; 95% CI 0.69-30.70). Alcohol use significantly increased the risk of breast cancer in postmenopausal women (OR 3.39; 95% CI 1.37-8.38). In general, the results of our study indicate that high risk of breast cancer is associated with high intakes of nutrients derived from animal products, and low risk with high intake of those from vegetables and fruits.

It is suspected that diet influences the risk of getting breast cancer. A study of diet and breast cancer was done among 200 Singapore Chinese women with histologically confirmed disease and 420 matched controls. A quantitative food-frequency questionnaire was used to assess intakes of selected nutrients and foods 1 year before interview. Daily intakes were computed and risk analysed after adjustment for concomitant risk factors. In premenopausal women, high intakes of animal proteins and red meat were associated with increased risk. Decreased risk was associated with high intakes of polyunsaturated fatty acids (PUFA), beta-carotene, soya proteins, total soya products, a high PUFA to saturated fatty acid ratio, and a high proportion of soya to total protein. In multiple analysis, the variables which were significant after adjustment for each other were red meat (p less than 0.001) as a predisposing factor, and PUFA (p = 0.02), beta-carotene (p = 0.003), and soya protein (p = 0.02) as protective factors. The analysis of dietary variables in postmenopausal women gave uniformly non-significant results. Our finding that soya products may protect against breast cancer in younger women is of interest since these foods are rich in phyto-oestrogens.

Randomised trials of screening have clearly demonstrated a substantial reduction of the order of 40% in breast cancer mortality among women aged over 50 years when regularly screened every two to three years by mammography. No other screening modality has been demonstrated to be of benefit, nor has screening of younger women. The major problem of breast screening at present is the need for greater understanding of the heterogenous natural history of the disease. The extent to which earlier diagnosis improves prognosis is poorly understood, but crucial to determining the full potential of screening.

The role of age at first and at second birth on subsequent breast cancer risk was analyzed using pooled data from 2 hospital-based case-control studies conducted in Italy, for a total of 1,200 biparous cases and 987 controls. Compared with women who gave birth for the first time below age 20, the relative risks were above unity for those with later first birth, even after allowance for age at second birth, although the trend was inconsistent across subsequent strata. A similar direct trend in risk was observed in relation to age at second birth: compared with less than 25 years and after allowance for age at first birth, the point estimates were 1.2, 1.4 and 1.4 for 25-29, 30-34 and greater than or equal to 35 (p for linear trend = 0.04). The results for age at first and at second birth were similar in the 2 studies pooled in this analysis. A significant interaction with age was observed in relation to age at first and at second birth. In younger women (below age 50) a strong and direct association with age at first birth was found, while no apparent protection was conveyed by earlier second birth. Among older women (aged 50 or over), there was no apparent relationship with age at first birth after allowance for age at second, but the role of age at second birth was independent and statistically significant. Thus, our study confirms an independent and significant role of age at second birth in biparous women, after allowance for age at first birth, and indicates that, after reciprocal allowance, the role of first and second birth was not apparently different. The relative risks for both variables were quantitatively moderate, and may be influenced by age or other temporal variables.

It is important that the introduction of breast screening is closely monitored. The anticipated effect on breast cancer mortality will take 10 years or more fully to emerge, and will only occur if a succession of more short-term end points are met. Data from the Swedish two-county randomised trial provide targets that should be achieved, following a logical progression of compliance with the initial invitation, prevalence and stage distribution at the prevalence screen, the rate of interval cancers after the initial screen, the pick-up rate and stage distribution at later screening tests, the rate of interval cancers after later tests, the absolute rate of advanced cancer and finally the breast cancer mortality rate. For evaluation purposes, historical data on stage at diagnosis is desirable; it is suggested that tumour size is probably the most relevant variable available in most cases.

Further results are presented from the Swedish two-county breast cancer screening trial. The reduction in the rate of advanced cancers and of breast cancer mortality in the group allocated to screening when compared to the control group has accelerated with a further year of follow-up. Mortality due to other causes and the rate of other cancers remains similar in the two groups. Attention has been focused on the rate at which cancers start re-emerging among women with negative mammograms. Among women over 50 years of age at entry to the study, relatively few interval cancers are seen in the first two years after a screening test; in the third year the rate rises to nearly 50% of the comparable rate in the control group. Among women aged 40-49 years at entry, by contrast, the rate of interval cancers even in the first post screening year is nearly 40% of that in the controls and in the second year nearly 70%. In older women in the group allocated to screening, much of the breast cancer mortality comes from the refusers and little from the interval cancers; in younger women the picture is reversed. The implications for screening policy, including the interscreening interval are discussed.

A biologically based two-stage model for carcinogenesis is presented that relates events occurring at the cellular level to epidemiologic features of breast cancer in females. This model, which accommodates the physiologic responses of breast tissue to menarche, menopause, and pregnancy, predicts age-specific incidence curves that are in close quantitative agreement with those observed in six test populations: Connecticut, Denmark, Finland, Slovenia, Iceland, and Osaka, Japan. According to the model, hormones influence the epidemiology of breast cancer in females by their action on the kinetics of growth of nonneoplastic breast tissue. As a consequence, it is argued that hormones are likely to be unimportant in determining overall risk in populations. The protective effect of an early first birth predicted by the model is in good quantitative agreement with data from a multinational study. Other epidemiologic features of breast cancer are logically explained within the framework of the model. No feature of the epidemiology of breast cancer requires that premenopausal and postmenopausal breast cancer be considered distinct entities from the point of view of pathogenesis.

A previous publication has shown that there has been a great increase in the incidence of breast cancer in Iceland. The present study was undertaken to evaluate the importance of known risk factors connected with the reroductive history of the women. In a prospective investigation of a cohort of 31,453 women we confirmed previous findings of the increased risk following higher age at first pregnancy and for nulliparous women. The age at first pregnancy and the proportion of nulliparous women have decreased with time in the Icelandic population so that these factors should have tended to decrease the risk, making the found increase still more important. The effect of parity is that the risk decreases with larger number of children and this effect is independent of the effect of age at first pregnancy. Lower age at menarche increases the breast cancer risk, but the contribution of that factor to the overall risk is negligible.

Breast cancer is a major health problem of industrialized countries. It is therefore natural that different opinions are presented in sometimes exaggerated debates about the control of this disease, it is reasonable that this problem should be a matter of public concern. We have tried to take a general view on the ways in which and the extent to which mortality might be reduced. Primary prevention has a potential for bringing about large decreases not only in mortality but also in morbidity, but there is no immediate likelihood of practical measures being introduced. Improved treatment, as we have seen, seems unlikely to reduce overall mortality by more than a marginal amount in the next five to ten years. Secondary prevention, or early detection, seems to offer the immediate possibility of substantial decreases in mortality. As the example of cervical cancer has shown, however, the introduction of effective screening into routine health services poses logistic problems of a different nature.