Therapeutic policy switch from tamoxifen to raloxifene among postmenopausal women are implied cost-effective. Findings suggest that introduction of chemoprevention targeting extremely high-risk women in Japan can be justifiable as an efficient use of finite health-care resources, possibly contributing to cost containment.Raloxifene was approved for chemoprevention against breast cancer among high-risk women in addition to tamoxifen by the US Food and Drug Administration. This study aims to evaluate cost-effectiveness of these agents under Japan's health system. A cost-effectiveness analysis with Markov model consisting of eight health states such as healthy, invasive breast cancer, and endometrial cancer is carried out. The model incorporated the findings of National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 trial, and key costs obtained from health insurance claim reviews. Favourable results, that is cost saving or cost-effective, are found by both tamoxifen and raloxifene for the introduction of chemoprevention among extremely high-risk women such as having a history of atypical hyperplasia, a history of lobular carcinoma  Several clinical trials have demonstrated the effectiveness of prophylactic administration of selective oestrogen receptor modulators (SERMs) such as tamoxifen  P-1 trial (in situ (LCIS), and with a history of atypical hyperplasia (AH). A 5-year predicted breast cancer risk of an individual woman used in the trials is based on Gail et al model 2  of a 5-year predicted breast cancer risk, with a history of lobular carcinoma  model 2 , which iWe also model the ages of starting prophylaxis: 35, 50, 60 years old for tamoxifen, and 50, 60 years old for raloxifene taking the menopause into account.We construct a Markov model of courses followed by high-risk women, which is shown in The time span of each stage is set at 1 year, since trials report annual incidence rates. Markov process is repeated until death or age 100, whichever comes first, since all events are expected to occur within this time horizon. Women who survive after the age of 100 years are assumed to die regardless of breast cancer development.Prophylaxis with SERMs is continued for 5 years, or discontinued in case of adverse events, which is similar to the regimen employed in clinical trials.status quo in Japan, without prophylaxis, and hypothetical practise, with prophylaxis, by the agent , the risk classification, and the age of starting prophylaxis. We compare outcomes and costs in terms of incremental cost-effectiveness ratios (ICERs) between Outcomes in terms of life years gained (LYGs) and quality adjusted life years (QALYs) are estimated by assigning transitional probabilities and utility weights to Markov model from the literature.Transitional probabilities from healthy state to disease states in Markov model are shown in It is more preferable to adopt utility weights from a consistent study that assesses our six disease states in Japan, but there is no Japanese utility weight in the literature to date, which may be applied to any health states in our model. To illustrate the typical patient states, we adopt the weights assessed in developed countries considering them as the best available knowledge, and choosing them under the consensus of staff doctors at Tokyo Metropolitan Cancer and Infectious Disease Centre Komagome Hospital  is estimated among women with a history of AH starting at age 50.Between prophylaxis with raloxifene When considering the therapeutic policy switch , the useThere is a suggested criterion for cost-effectiveness in Japan  to be ¥6vs no prophylaxis, favourable results, that is ‘cost less and gain more’ or cost-effective, are obtained in higher risk classifications starting at younger age. Those are: women with a history of AH regardless of starting age, women with a history of LCIS starting at age 35 and 50, and women with a 5-year predicted breast cancer risk of ⩾5.01% starting at age 35 and 50.In the comparison between prophylaxis with tamoxifen vs no prophylaxis. Favourable results are: women with a history of AH regardless of starting age, women with a history of LCIS starting at age 50, and women with a 5-year predicted breast cancer risk of ⩾5.01% starting at age 50.Similar results are found between prophylaxis with raloxifene As shown in vs no prophylaxis among three risk classifications as an example: women with a 5-year predicted breast cancer risk of ⩾5.01%, women with a history of LCIS, and women with a history of AH.One-way sensitivity analyses produce similar results across the agents, the risk classifications and the ages of starting prophylaxis. Therefore, we draw a cost-effectiveness plane to show the comparison between prophylaxis with raloxifene Our model is most sensitive to the utility weight for healthy state under chemoprevention, of which plots are drawn in area B. Its change to 0.79 turns incremental effectiveness into negative. Critical values to change the judgement are 0.98, which makes the ICERs of women with a 5-year predicted breast cancer risk of ⩾5.01% and woman with a history of LCIS cost-ineffective, and the value of 0.96 makes women with a history of AH ‘gain less’. The model is also sensitive to the discount rate, of which plot is drawn in area C. Its raise of 5.9 and 4.3% makes the ICERs of women with a 5-year predicted breast cancer risk of ⩾5.01% and women with a history of LCIS cost-ineffective, respectively. The cost of chemoprevention is also influential to the results, of which results are shown in areas C and D. A price increase of more than 30% for raloxifene makes the ICER of women with a history of LCIS cost-ineffective, whereas a price decrease of more than 16 or 29% make the results for women with a 5-year predicted breast cancer risk of ⩾5.01% and women with a history of LCIS cost saving, respectively. Changes of the probabilities of transition to invasive breast cancer, endometrial cancer, and hip fracture are also plotted in areas C and D. Raising the probability of invasive breast cancer beyond 0.00710 and 0.00683 makes the ICERs of women with a 5-year predicted breast cancer risk of ⩾5.01% and women with a history of LCIS cost-ineffective, whereas lowering to less than 0.00456 or 0.00436 make the results for women with a 5-year predicted breast cancer risk of ⩾5.01% and women a history of LCIS cost saving, respectively. Raising the probability of endometrial cancer beyond 0.00369 and 0.00271 makes the ICERs of women with a 5-year predicted breast cancer risk of ⩾5.01% and women with a history of LCIS cost-ineffective, respectively. Raising probability of hip fracture beyond 0.00098 makes the results for women with a history of LCIS cost saving. The other plots in area C reflect a raise of utility weight for invasive breast cancer after the second year.Prolonging risk reduction effect of tamoxifen from 5 to 10 and 15 years without any risk increase of adverse events after the completion of prophylaxis brings more favourable results. For example, the effect of 10 years results in ‘cost less and gain more’ for every risk classification starting at age 35, whereas the effect of 15 years makes no change in the results of ‘cost more and gain less’ among women with a 5-year predicted breast cancer risk of ⩾1.66% starting at age 50 and 60.status quo in Japan, without prophylaxis, and hypothetical practise, with prophylaxis, by the agent , the risk classification, and the age of starting prophylaxis.We conduct a cost-effectiveness analysis of SERMs as prophylactic agents against breast cancer among high-risk women by making comparisons between We find that prophylaxis with tamoxifen results in ‘cost less and gain more’ among extremely high-risk women such as those with a 5-year predicted breast cancer risk of ⩾5.01%, those with a history of LCIS, and those with a history of AH starting at age 35 and 50. Prophylaxis with raloxifene is also found ‘cost less and gain more’ for women with a history of AH starting at age 50. The younger the age of starting prophylaxis, the more the cost saving and outcome gain. We also find that prophylaxis with tamoxifen for women with a history of AH starting at age 60 results in favourable ICER compared to the suggested criterion of ¥6000 000 (£30 000) for one QALY gain. Prophylaxis with raloxifene is also found cost-effective for women with a 5-year predicted breast cancer risk of ⩾5.01% starting at age 50, those with a history of LCIS starting at age 50 and those with a history of AH starting at age 60. The younger the age of starting prophylaxis, the more favourable the ICER. Within the same risk classification and starting age, raloxifene tends to gain more and cost more compared to tamoxifen. On the contrary, we also find that prophylaxes with tamoxifen or raloxifene for women with a 5-year predicted breast cancer risk of ⩽5.00% tend to result in ‘cost more and gain less’.These findings are similar to the previous economic evaluations of chemoprevention of breast cancer with tamoxifen including analyses of risk level differences such as Our findings suggest that introduction of chemoprevention with SERMs targeting extremely high-risk women in Japan can be justifiable as an efficient use of finite health-care resources, possibly contributing to cost containment. The cost saving results suggest chemoprevention not only cost-effective but also affordable. Taking the superiority of raloxifene in outcome gain and the difference in indication into account, it is recommendable to administer tamoxifen for premenopausal women and raloxifene for postmenopausal women.Our economic model is found sensitive to the utility weight for healthy state under chemoprevention, the discount rate and the cost of chemoprevention, in addition to the probabilities of transition to invasive breast cancer, endometrial cancer, or hip fracture. This is anticipated because these variables are supposed to influence the cost-effectiveness of preventive services. We think that our economic model succeeds in explaining the context under consideration.We also analysed the cost-effectiveness of therapeutic policy switch of agent, tamoxifen to raloxifene among postmenopausal women, although this does not depict any marginal change in Japan. All simulated ICERs by risk classifications starting at age 50 and 60 fall in a favourable level. Due caution is needed in transferring these findings from our Japanese model to other health system , but it et al model 2 (et al model 2 are identified in a model of individualised probability of developing breast cancer for Japanese women (There are a couple of points to consider when interpreting our results. Our model depends on clinical evidence established in the United States by P-1 and P-2 trial. Composition of ethnicity and life styles of participating women are different from those of Japanese women. This also relates to another point, that is the validity of the 5-year risk prediction model defining high-risk women. As already mentioned in Methods section, it is based on Gail  model 2 , which hIn summary, this study suggests that chemoprevention of breast cancer with SERMs targeting high-risk women such as a 5-year predicted breast cancer risk of ⩾5.01%, women with a history of LCIS, and women with a history of AH, clears the hurdles of introducing new intervention by means of cost-effectiveness and affordability, with best available evidence. Although further studies and policy formulations are necessary about breast cancer chemoprevention in Japan, this study also implies that the administration of raloxifene instead of tamoxifen may be cost-effective under the context of developed countries where chemoprevention with tamoxifen has already been adopted.


P-value for trend <0.001 for both). Women who reached puberty later were at a greater odds of a higher Wolfe grade than women who had an earlier puberty . A higher BMI at any age during childhood or adult life was associated with a reduction in the odds of a higher Wolfe grade, after controlling for breast size and BMI at mammography, for example, standardised odds ratio for height at age 7 was 0.72 . These findings reveal the importance of taking life-course changes in body size, and not just contemporaneous measures, into account when using mammographic density as an intermediate marker for risk of breast cancer.Dense mammographic parenchymal patterns are associated with an increased risk of breast cancer. Certain features of body size have been found to be associated with breast cancer risk, but less is known about their relation to breast density. We investigated the association of birth size, childhood growth and life-course changes in body size with Wolfe grade in 1298 perimenopausal women from a British cohort of women born in 1946. The cohort benefits from repeated measures of body size in childhood and adulthood. We obtained mammograms for 90% of women who at age 53 years reported having previously had a mammogram. We found no associations with birth weight or maximum attained height. Body mass index (BMI) at age 53 years and breast size were independently and inversely associated with Wolfe grade ( Ninety percent of women had complete height data on at least four of the six occasions analysed , with a similar percentage (89.7%) of completeness for BMI on at least six of the nine occasions . Birth weight data, recorded to the nearest quarter of a pound, were obtained from hospital records within a few weeks of delivery and converted into grams. Data on the use of hormone replacement therapy (HRT) and menopausal status at the time of mammography, and, where appropriate, age at menopause were derived from information on menstrual and HRT histories obtained from annual questionnaires sent to the women from ages 47–54 years . Women were considered retrospectively to be postmenopausal after 12 months of amenorrhea, perimenopausal if periods had stopped for between 3 and 12 months or had become more irregular in the preceding 12 months and premenopausal if still menstruating. Menopausal status could not be determined for women who had a hysterectomy or bilateral oophorectomy or who were taking HRT preparations that cause bleeding prior to inception of the menopause.In the UK, all women aged 50–64 years are invited for 3-yearly mammographic screening as part of the NHS Breast Screening Programme. At a home visit in 1999 (when the women were aged 53 years), women were asked permission for us to obtain copies of their mammograms and details of the date(s) and clinic(s)/hospital(s) where they were undertaken. Copies of the mammograms (two views for each breast) taken when the women were closest to age 50 years were then requested from the relevant centres for all women who gave consent, providing a cross-sectional sample. The mammograms were jointly classified by two radiologists (NP and SV) using the Wolfe grade. This classification consists of four categories in order of increasing breast density: N1–predominantly fat, no ducts, only small amounts of dysplasia; P1–mainly fat, with ducts up to 25% of the breast; P2–ductal pattern in 25–75% of the breast; DY–dysplasia/fibrocystic change, sheet-like areas of higher density . Breast n=1471) consented access to their mammograms.Of the original 2547 women in the cohort, no attempt was made at age 53 years to contact women who had previously refused to participate (12%), emigrated with no further contact (8%), or had died (8%). Of the 1848 eligible women, 1600 (87%) participated and of these, 1494 (93%) reported having had a mammogram, of whom almost all (vs (N1);  vs ; or (DY) vs . This assumption was tested via an approximate log likelihood ratio test that compares the cumulative logit model with a polytomous logistic model ) at ages 2, 4, 7, 11, 15, 26, 36, 43 and 53 years. Age-specific attained height and BMI were analysed as continuous variables. Average height and BMI velocities between consecutive ages, calculated as the change in height and BMI respectively divided by the time interval  between the two visits, were also analysed as continuous variables. These velocities capture growth during particular age intervals, whereas attained heights or BMIs reflect cumulative exposure up to a particular age. We calculated standardised heights and BMIs for each age and standardised velocities for each interval so that a standardised measure of effect could be compared across different ages/intervals.The main exposures of interest were birth weight, age at menarche and body size in infancy, childhood and adulthood, as measured by height and, as a measure of adiposity, body mass index (BMI)  × heightTo overcome the loss of subjects from multivariable analyses that included several height/BMI measurements simultaneously, we imputed missing growth data. Firstly, we modelled the height and BMI trajectories (separately) using random effects growth models. Height was modelled as a linear function of age between ages 2–4 and 4–7 years and a quadratic function from age 7 to adulthood. Body mass index was modelled as a quadratic function of age during ages 2–7 and 7–15 years and a linear function between ages 15–26, 26–36, 36–43 and 43–53 years. In both growth models, all effects were random, except for the quadratic terms, and the random effects parameters depended on the final Wolfe grade. Imputed values for missing heights/BMIs were generated by firstly taking a random draw of the error terms, then taking a random draw of the growth parameters and using these to predict imputed values for the missing growth data. This procedure was repeated five times to create five datasets with complete data (observed data plus those imputed if missing). Complete case analyses were then carried out on each dataset. Summary odds ratios (geometric means of the five odds ratios) and their 95% confidence intervals were calculated as in Age at first birth, parity, years since last birth, HRT use, menopausal status and years postmenopausal were considered as potential confounders. We adjusted for breast size and BMI at age 53 years in all analyses in order to investigate associations with changes in body size independent of body size at mammography, as obesity at mammography is known to be a strong confounder of the mammographic parenchymal pattern (We successfully obtained copies of mammograms for 1319 of the 1471 women who gave consent (90% tracing rate), the large majority (1249 (95%)) from NHS breast screening centres. Films were not obtained for the remaining women due to insufficient information to contact hospitals/clinics , logistic difficulties in certain centres (57) and other problems (45). We obtained both cranio-caudal and oblique views of each breast for 89% of received sets. In all, 21 women with a diagnosis of breast cancer prior to mammography were excluded from analyses, as treatment for breast cancer may influence the outcome. Thus, the present analyses are based on 1298 women.κ statistic (to account for the ordered nature of the categories) was 0.79 (P<0.001) and using the binary classification (combining DY with P2 and P1 with N1) was 0.83 (P<0.001). Eighty-two percent (90 out of 110) of mammograms that were read twice had the same Wolfe grade on both occasions and the remaining pairs differed by only one grade. The weighted The mean BMI at each age was lower for higher Wolfe grades and the differences between Wolfe-specific means increased from age 11 years onwards . However, in the same group of women, measured adult height at age 53 years had a statistically significant association with Wolfe grade . This apparent discrepancy was explained by greater height reduction, on average, in women who subsequently had lower Wolfe grades, for example, mean (95% CI) height loss between these ages was 1.29 cm  and 0.79 cm  in women with N1 and P2 Wolfe grades, respectively.We found strong and highly statistically significant crude inverse associations with BMI at every age  and a high tracing rate of mammograms (91%). However, we were less likely to include mammograms taken privately or overseas or those taken for diagnostic (symptomatic) rather than screening reasons. Diagnostic mammograms are more likely to be of higher densities, hence there may be a small underestimate of P2 or DY proportions. We avoided the loss of subjects in multivariable analyses by modelling the growth curve and imputing missing values. We used BMI as a measure of weight relative to height at all ages for reasons of consistency and familiarity; however, this index is not independent of height at younger ages (Advantages of this study include the representativeness of the participants (Wadsworth ger ages . Furthervs N1/P1), commonly used to analyse such data, as the latter has reduced statistical power and disregards valuable information by combining categories  were at a reduced odds of a higher Wolfe grade compared to later maturers. In view of the association of early maturation with high adult BMI  and connective (stroma) tissue. Radiodense tissue possibly reflects the number of cells at risk of carcinogenesis as it is in the ducts and lobules of the epithelium where the vast majority of breast cancers originate. In support of this mechanism, The strong associations of adiposity and body size with breast density are more likely to be driven by associations with the area of radiolucent rather than the area of dense breast tissue, as other studies have found positive associations between weight/BMI and the area of nondense tissue and less strong, but inverse, associations with the area of dense tissue . Findinget al, 2002; Similar to body size, the observed associations of age at menarche and breast size with Wolfe grade are more likely to predominantly reflect associations with nondense breast tissue. Earlier menarche was associated with a decreased odds of a higher Wolfe grade. In contrast, and similarly to other studies (The complex and long-term associations of the timing of maturation and life-course changes in body size with Wolfe grade have implications for studies that use breast density as an intermediate marker of breast cancer risk. Our findings suggest that life-course changes in body size, and not just adiposity at mammography, need to be taken into account to avoid spurious findings for exposures that are associated with these factors. The findings also imply that the association of Wolfe patterns and breast cancer risk previously reported may have been underestimated as they only took into account adiposity at the time of the mammography. These findings further emphasise the need to identify measures of mammographic features that are not so strongly influenced by adiposity (In summary, we have found that mammographic parenchymal patterns as measured by the Wolfe grade are not only strongly associated with contemporaneous adiposity and breast size, but also have strong complex associations with the trajectory of growth and body size throughout the life-course. It remains to investigate whether these associations differ for the areas of dense and nondense tissue as these associations may have implications for using these measures of breast density as intermediate markers of breast cancer risk.


To evaluate current guidelines criteria for inclusion of women in special ‘breast cancer family history’ surveillance programmes, records were reviewed of women referred to Scottish breast cancer family clinics between January 1994 and December 2003 but discharged as at ‘less than ‘moderate’ familial risk’. The Scottish Cancer Registry was then interrogated to determine subsequent age-specific incidence of breast cancer in this cohort and corresponding Scottish population figures. Among 2074 women, with an average follow-up of 4.0 years, 28 invasive breast cancers were recorded up to December 2003, where 14.4 were expected, a relative risk (RR) of 1.94. Eleven further breast cancers were recorded between January 2004 and February 2006 (ascertainment incomplete for this period). The overall RR for women in the study cohort exceeded the accepted ‘cutoff’ level (RR=1.7) for provision of special counselling and surveillance. The highest RR was found for the age group 45–59 years and this group also generated the majority of breast cancers. The National Institute for Clinical Excellence (‘NICE’) guidelines appear to be more accurate than those of the Scottish Intercollegiate Guidelines Network (‘SIGN’) in defining ‘moderate’ familial risk, and longer follow-up of this cohort could generate an evidence base for further modification of familial breast cancer services. A family history of breast cancer is recognised as a risk factor for the disease. Most efforts to quantify that risk rely upon two retrospective studies , both ofSince 1994, clinical services for familial breast cancer have been provided for the whole of Scotland by a network comprising four major centres in Aberdeen, Dundee, Edinburgh and Glasgow, involving close collaboration between medical genetics, diagnostic radiology and breast surgery units, with support from the Information Services Division (ISD) of the NHS Scotland Common Services Agency and the Scottish Cancer Registry. Two of the centres operate ‘one-stop’ clinics staffed by geneticists, breast surgeons and radiologists. The others provide comparable, but sequential, services in separate genetics and breast surgery clinics. In all four centres practice is based on guidelines formulated by the With local approval for audit purposes, the records of the four Scottish breast cancer family services were scrutinised to identify all referred women whose risk had been assessed, as below the ‘moderate’ threshold over the 10-year period from January 1994 to December 2003. Then, with consent from the Privacy Committee, Scottish Cancer Registry records were checked to detect any cancers recorded in this cohort of individuals. For breast and ovarian cancers, confirmation and further pathological details were sought from case notes.For each woman referred to a cancer family clinic, but not offered continuing surveillance, the period elapsing between discharge from the service and December 2003 was calculated and, from that and the date of birth, the number of woman years of observation within one or more 5-year age spans  was derived. The data were aggregated to give the total number of woman years of observation per 5-year age group and the corresponding ‘expected’ numbers of breast cancers were obtained from Scottish Cancer Registry figures, which report annual incidence for the same age groups. Where a breast or ovarian cancer had been recorded, the precise details of family history were re-checked in every case from cancer family clinic records. Cancers registered after December 2003 were noted and checked as above. Because registration is still incomplete for that period, these cases cannot be included in calculations of absolute or relative age-specific incidence but can be added to the earlier cases to record age distribution of cancers, their clinical and pathological characteristics and the proportions that would have met NICE criteria for inclusion in special surveillance programmes.The principal findings are summarised in Two women had suffered synchronous bilateral breast cancers, in each case both tumours being detected at first NBSP mammogram at the age of 50 years. One had a family history that would have placed her in the ‘NICE moderate’ risk category . The other had only one affected relative, her mother, diagnosed at the age of 70 years. She would therefore have been considered below threshold risk level for surveillance under any extant guidelines.in situ (DCIS) and one patient in whom an unsuspected second focus of invasive ductal cancer was identified by the pathologist in the mastectomy specimen following surgery for a symptomatic cancer. Although this was considered a second primary, that could not be proved and it has not been treated as such in the present report. One additional case of DCIS was recorded in 2005 and has been excluded from calculations. More than half of all breast cancers were diagnosed at clinical or mammographic screening – mainly through the NBSP, but three at one of the multi-disciplinary breast cancer family clinics, where policy (until the year 2004) had been to see all women referred, even where their risk had been evaluated and the decision already taken to discharge them following that single visit. Since 2004, women whose risk has been assessed as below the ‘moderate’ threshold are no longer seen at the multi-disciplinary clinic and are not offered clinical examination or a mammogram before discharge.In addition to the breast cancers recorded in Twelve of the 39 tumours (31%) occurred in women whose family histories would have placed them in the ‘moderate’ risk category had NICE, rather than SIGN guidelines been applied – that is, they had two affected close relatives (one first degree) at least one of whom had been over 60 at diagnosis. A re-examination of the family histories of our total cohort shows that only 10% would have been reclassified as ‘moderate risk’ under NICE criteria (‘NICE moderate’ subgroup).There were three epithelial ovarian cancers  and one borderline ovarian tumour. Only two ovarian cancers would have been expected but numbers are too small to draw any inference as yet.The overall RR found in this study approached 2.0, appreciably higher than the level of 1.7, which NICE and most other guidelines accept as the threshold above which women should be offered enrolment in a surveillance programme. Given that Cancer Registry data can never be 100% complete since, for example, any cancers occurring in members of our study cohort who had left Scotland would not be recorded, the RR we have calculated is a conservative figure. Furthermore, it is consistent with the findings of the very large reanalysis of epidemiological studies on familial breast cancer , which cWhen NICE criteria are applied, 9 of the 28 cancers recorded before the end of the year 2003 were in women at ‘moderate’ risk. This applies to 12 cancers (in 11 women) from the total series of 39 (30.8%). These potentially ‘moderate risk’ women thus appear to be over-represented among those who subsequently developed breast cancer, relative to their numbers in the study cohort. If they are excluded, the overall RR falls to 1.32 (95% CI=0.8–2.1). However, 6 of the 11 NICE ‘moderate risk’ group were 60 or over at discharge from the cancer family service, whereas women of that age represented less than 10% of our total study population. Elderly people will, of course, have more elderly close relatives and, as breast cancer is an age-related disease, they may have more affected relatives without necessarily implying an increased familial risk.Different issues arise in relation to the other end of the age spectrum. Where the family history is not strong, the chances of a major gene mutation (BRCA1 or BRCA2) being present are small and so too is the risk of very early-onset breast cancer. The RR in our cohort for women up to the age of 44 years is only 1.05, even if the single ‘NICE moderate’ patient is included. This age group comprised 45% of our total cohort and, while little weight can be attached to just three cancers, the findings suggest that NICE referral criteria are satisfactory for women under the age of 45 years, that is, the incidence of breast cancer among those who do not ‘qualify’ for special surveillance through a cancer family clinic is no higher than expected for the general population.P<0.02), suggesting that women who had been discharged from a breast cancer family clinic were particularly motivated to attend for breast screening from the age of 50 years and/or that their tumours were slow growing and hence more amenable to screen detection. NICE criteria include a stipulation that ‘moderate’ risk means at least a 3% absolute risk of breast cancer between the ages of 40 and 50 years. Restricting analysis to the 1994–2003 cohort, we find that, even excluding the ‘NICE moderate’ cases, and assuming that half of the cancers detected at the age of 50 or 51 years would have been diagnosed by the age of 50 years in an appropriate screening programme, the cumulative risk over the 5 years from the age of 45 years was 2.3%, whereas the corresponding figure for the 10-year age span 45–55  is 4.8%. Overall, these findings suggest that, for women aged 45–55 years, family history criteria for inclusion in breast cancer surveillance programmes should be kept under review.Our findings are most relevant to women aged 45–59 years. They accounted for 46% of our total woman years of follow-up but generated 71% of the breast cancers (84% if the NICE ‘moderate risk’ cases are excluded), and had a RR of 2.2 (95% CI=1.4–3.4) or 1.79 (95% CI=1.00–2.85) with the exclusion. Given that all but 3 of these 27 cancers had actually been diagnosed by the age of 56 years, there is a reasonable expectation that most would have been screen detected in a surveillance programme that provided regular mammography upto the age of 55 years. In fact, 10 of the 13 invasive breast cancers (77%) diagnosed in women from this cohort between the ages of 50 and 52 years were screen-detected, which contrasts with the corresponding figure from ISD of only 41% for the same age group in the unselected Scottish population  will now be added to the surveillance programme. Although that is not a trivial consideration, the added workload (and cost) could be offset if it can be confirmed that many women currently enrolled at the age of 35 or 40 years may safely delay entry until 45 years. For at least some of those at ‘moderate’, rather than ‘high’ risk, screening from age 45 to 55 years, perhaps at intervals of 18 rather than 12 months, may prove to be cost-effective and it should be borne in mind that this risk group comprises the bulk of cancer family referrals. Hence, a reduction of some 5% in total workload should be achievable by this approach.For the present, our findings support the NICE modification of threshold for ‘moderate risk’ – that is, removing any ‘age at diagnosis’ restriction where there are two affected close relatives. To extend our findings and to generate evidence that might justify further adjustments to family history criteria for enrolment in special surveillance programmes, we propose to continue follow-up of the cohort of women described in this report, since each additional year provides a further 2000 women years of observation and the incomplete data from 2004 onwards show that accrual of breast cancers is continuing at an undiminished rate.Longer follow-up may also allow us to address the crucial question of whether special surveillance programmes for women with a family history of breast cancer confer any advantage in terms of outcome. It is impractical to assign such women to a randomised trial, deliberately excluding some from clinical/mammographic screening, but our cohort may generate comparable, albeit more limited, data.Recent findings in relation to the identification of ‘low penetrance’ breast cancer susceptibility alleles (


This is the first prospective study of urinary measures of the two major competing pathways of oestrogen metabolism, 16alpha-hydroxyoestrone  and 2-hydroxyoestrone (2-OHE1), in relation to incident breast cancer risk. Experimental and case-control study results suggest that metabolism favouring the more oestrogenic 16alpha-OHE1 pathway may be linked to higher breast cancer risk. Women aged 35 and older from Guernsey (n = 5104) were surveyed in 1977-85 and have been continuously monitored for breast cancer and mortality up to the present . Incident cases of breast cancer were matched to three control subjects for comparison of urinary oestrogen metabolite levels measured by enzyme immunoassay (EIA) in spot urine samples collected at baseline and stored frozen for up to 19 years. Consistent with case-control study results, post-menopausal  women at baseline who went on to develop breast cancer showed about a 15% lower 2:16alpha-OHE1 ratio than matched control subjects. Further, subjects with metabolite ratios in the highest tertile of 2:16alpha-OHE1 had about a 30% lower risk than women with ratios in the lowest two-thirds, although results were not statistically significant . It is of potential importance that, in contrast to most risk factors for breast cancer, such as late age at first birth, oestrogen metabolism appears to be modifiable via diet and exercise, offering women the possibility of lowering breast cancer risk through non-pharmacological measures, although this remains to be tested.


P = 0.01 at age 7 years) and fell across the range of body mass index (P = 0.009 at age 7 years). In a simultaneous analysis the hazard ratio for breast cancer was 1.27  for every kilogram increase in birth weight and 1.21  for every kg/m2 decrease in body mass index at 7. Our findings indicate that tallness in childhood is associated with increased risk of developing breast cancer. One possible explanation is persisting high plasma concentrations of insulin-like growth factors in talll women. In contrast, we found that being overweight in childhood reduces breast cancer risk. The increased adipose tissue-derived oestrogen levels in overweight children could induce early breast differentiation and eliminate some targets for malignant transformation. © 2001 Cancer Research Campaign http://www.bjcancer.comUsing birth and school health records we studied how weight and height during childhood affect breast cancer risk among 3447 women born during 1924–33 at the University Hospital of Helsinki, Finland. Through linkages with the National Hospital Discharge Registry and the Cause of Death Registry we identified177 women who during 1971–1995 had been admitted to hospital with breast cancer, of whom 49 had died from the disease. Of these, 135 (76%) were aged 50 years or more at the time of diagnosis, and therefore likely to have been post-menopausal. Hazard ratios for breast cancer rose with increasing weight and length at birth, though neither trend was statistically significant. At each age, from 7 to 15 years, the girls who later developed breast cancer were on average taller and had lower body mass than the other girls. Unadjusted hazard ratios rose across the range of height (


The results of two case-control studies of breast cancer which included questions on exposure to tobacco and alcohol are reported. One study included 998 hospital cases and a like number of matched hospital controls while the other included 118 cases identified during mammographic screening and a like number of matched normal screenees. Both studies used the same questionnaires and the same methods to obtain information. The results with regard to cigarette smoking differed between the two studies. The hospital-based study showed a decreased risk of breast cancer with increasing amounts smoked  while the screening study showed an increased risk . Evidence is presented that both results may be attributable to bias in the selection of cases and controls. It is concluded that reliable results on the relationship between smoking and breast cancer are only likely to come from population-based studies. These studies, in general, have found no relationship. Neither study produced any hint of an association between alcohol consumption and breast cancer. From this, it appears that bias in subject selection may not be such a significant factor in interpretation of studies of alcohol and breast cancer as it is in studies of smoking and the disease. A number of other difficulties in the interpretation of studies of alcohol and breast cancer are considered, including the great variation in the amount of alcohol consumed. It is concluded that the assertion that alcohol is a risk factor for breast cancer remains unproven.


A case–control study was conducted in Italy and Switzerland between 1992 and 2000 on 527 cases of laryngeal cancer and 1297 hospital controls. The risk of laryngeal cancer steadily decreased from 3 years after stopping smoking. Some decline in risk was observed only 20 years or more after stopping drinking.British Journal of Cancer (2002) 87, 1227–1229. doi:10.1038/sj.bjc.6600638www.bjcancer.com© 2002 Cancer Research UK Cancer of the larynx is extremely rare in individuals who neither smoke nor drink alcohol . The risAn independent role of alcohol has been reported by several studies , and in the Swiss Canton of Vaud , daily number of cigarettes/cigars smoked in different life periods, age at starting, duration of the habit and, for ex-smokers, age at smoking cessation. Information on alcohol consumption included the average number of days per week for each type of alcoholic beverage consumed , the average number of drinks per day and, for ex-drinkers, age at drinking cessation. Ex-drinkers and ex-smokers were subjects who had abstained from any type of drinking or smoking for at least 12 months.Cases and controls were interviewed by Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated using unconditional multiple logistic regression models , includiP<0.001).Table 1In relation to time since stopping alcohol drinking, no consistent pattern of risk was observed up to 20 years, and some risk reduction was evident only 20 years since stopping the habit. The ORs for ex-drinkers, as compared to current drinkers, were 1.24 for 1–5 years since drinking cessation, 1.29 for 6–19 years. The OR was 0.53 among the few subjects who had stopped drinking for 20 or more years, i.e., similar to that of never drinkers (OR=0.56). None of these estimates, nor the trend in risk, was significant.Table 2Our study, based on a large dataset on laryngeal cancer, is one of the few to examine the effect on risk of stopping both smoking and drinking. It confirms that the favourable impact of stopping smoking is already evident in the few years after cessation, and that laryngeal cancer risk is reduced by over 70% ten or more years after stopping smoking. Such a risk reduction has been observed also for oesophageal cancer . Most former drinkers had, in fact, higher alcohol consumption than current drinkers (median number of drinks per week was 42 in ex- and 28 in current drinkers), and it is possible that health related conditions had affected the decision to stop alcohol consumption, though this aspect was not investigated. In any case, it is unlikely that early symptoms of cancer of the larynx had accounted for drinking cessation, since the excess risk persisted up to 20 years prior to cancer diagnosis.In this study information on smoking and alcohol was satisfactorily reproducible and valid (In the present study, 90% of laryngeal cancer was attributable to tobacco, while alcohol explained 58% of cases. Together, these two factors were responsible for 96% of laryngeal cancers (


The risk was reduced with increasing intake of dark green/dark yellow vegetables , fresh legumes , and allium vegetables . Fruit consumption was unrelated to risk. These results suggest that high consumption of certain vegetables may reduce the risk of endometrial cancer.In a population-based case–control study of 832 incident endometrial cancer cases and 846 frequency-matched controls among Chinese women in Shanghai, using a validated food-frequency questionnaire, dietary habits were estimated by in-person interviews. Total vegetable consumption was inversely associated with endometrial cancer risk (highest quartile  The major reasons for nonparticipation were refusals , death before interview , inability to locate the subject , absence during the study period , and other miscellaneous reasons .n=36). Interviews were completed for 846 (72.6%) of the 1165 eligible controls. Reasons for nonparticipation of controls included refusal  and absence during the study period .The Shanghai Resident Registry, which registers all permanent residents of urban Shanghai, was used to randomly select female controls who were frequency-matched to cases by age . The number of controls in each age-specific stratum was determined in advance according to the age distribution of incident endometrial cancer cases in 1996. Women who had had a hysterectomy were not eligible (−2) and waist–hip ratio (WHR).All study participants were interviewed in person by trained interviewers and were measured for weight, circumferences of the waist and hips, and sitting and standing heights. The standardised, structured questionnaire used for the study covered demographic factors, menstrual and reproductive history, hormone use, usual dietary habits, prior disease history, physical activity, tobacco and alcohol use, weight history, and family history of cancer. Usual dietary habits over the past 5 years were assessed through in-person interviews using a validated, quantitative, food-frequency questionnaire (FFQ), which was designed to capture more than 85% of foods consumed in Shanghai. The FFQ listed 71 food items, including 30 fresh vegetable items and eight fruit items. Two measurements were taken with a tolerance of <1 cm for height and circumferences, and a tolerance of 1 kg for current weight. A third measurement was taken if the difference between the first two was larger than the tolerances stated above. The average of the two closest measurements were used to calculate body mass index (BMI) , followed by a question on how many liangs (=50 g) were eaten per unit of time  during the previous 5 years, ignoring any recent changes. For seasonal foods, each participant was asked to describe their consumption during the month(s) when the food was available. Average daily intakes were estimated by calculating the percentage of months that a food was on the market over a 1-year period.Menopausal status was defined as no menstruation during the past 12 months, excluding those lapses caused by pregnancy or breastfeeding. For premenopausal women, years of menstruation were calculated by taking age at diagnosis (cases) or interview (controls) and subtracting age at menarche. For postmenopausal women, years of menstruation were calculated by taking age at menopause and subtracting age at menarche. For both groups, years with oral contraceptive use and years of pregnancy were subtracted from the total years of menstruation.P⩽0.05.Statistical analyses were conducted using SAS Version 9.1 . Quartile distributions among controls were used to categorise dietary intake variables. Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were used to estimate the association of endometrial cancer risk with intake of selected food groups. Unconditional logistic regression was used to obtain maximum likelihood estimates of ORs and their 95% CI, after adjusting for potential confounding variables. Age was included as a continuous variable throughout the data analyses, and categorical variables were treated as dummy variables in the model. Trend tests were conducted by treating categorical variables as the ordinal values in the models. Analyses stratified by menopausal status and BMI were conducted to examine whether the vegetable and endometrial cancer association was modified by the latter two factors. All statistical tests were based on two-sided probability and a significance level of vs the lowest quartile intake of these vegetables were 0.69 (0.50–0.96), 0.70 (0.52–0.95), 0.70 (0.52–0.96), and 0.76 (0.56–1.03), respectively. A significant dose–response relationship was observed for intake of total vegetables, dark green/dark yellow vegetables, fresh legumes, and allium vegetables.The multivariable-adjusted associations of fruit and vegetable consumption with risk of endometrial cancer among all subjects are presented in Consumption of watermelon contributed 55% and 54% of fruit intake for cases and controls, respectively. As watermelon consumption is heavily influenced by seasonal supply and an accurate measurement of consumption level is difficult to obtain, we excluded watermelon from fruit intake levels in subsequent analyses. Total fruit intake was not associated with risk of endometrial cancer. There was no association between risk of endometrial cancer and intake of individual fruits, including citrus fruits, apples, watermelon, grapes, bananas, peaches, pears, and all other fruits (data not shown).The association of consumption of certain fruits and vegetables and endometrial cancer was further evaluated stratifying by menopausal status . Total vP for trend⩽0.05). The ORs and 95% CI for the highest vs lowest quartiles of intake of these vegetables were 0.61 (0.40–0.93), and 0.66 (0.44–0.97), respectively. Allium vegetable intake was found to be associated with a marginally significant reduction in endometrial cancer risk among thinner women . Among overweight women (BMI>25), the inverse association between total vegetable and dark green/dark yellow vegetable intakes and endometrial cancer risk was less evident and not statistically significant. No significant interaction between vegetable intake and BMI or menopausal status was observed. Additional adjustment for soyfood consumption did not appreciably change the risk estimates presented in  0.40–0.9, and 0.6This large, population-based, case–control study revealed an inverse relationship of endometrial cancer risk with increased consumption of total vegetables, dark green/dark yellow vegetables, fresh legumes, and allium vegetables. This association was independent of other major risk factors, including total energy intake, meat and fish intake. We found no association between fruit consumption and risk of endometrial cancer.High consumption of fruits and vegetables has been associated with a reduced risk for many cancers such as cancer of the oral cavity, oesophagus, lung, stomach, and colorectum . HoweverAllium vegetables have previously been associated with a decreased risk of cancer of the stomach, intestine, bladder, and prostate . To our Strengths of our study include the population-based study design, large sample size, and detailed information on a wide range of potential confounders. Additionally, the FFQ used in the study has been validated and covers most usual foods in Shanghai. However, several limitations, common to other observational studies on diet and cancer, should be mentioned. Due to the nature of self-reported dietary information, misclassification of fruit and vegetable consumption is unavoidable, which may bias the diet and endometrial cancer association. While nondifferential misclassification is likely to bias the result towards the null, differential misclassification can be biased in either direction and should be taken into consideration. In order to minimise the potential recall bias attributed to dietary change related to cancer diagnosis, all cases were asked about their diet during the 5 years prior to cancer diagnosis. The median (25–75th percentile) interval between diagnosis and interview for cases was 5 (3–8) months, which minimised the influence of disease related to dietary change on recall of usual dietary habits prior to disease diagnosis. As part of the study, we also collected information on whether study participants had changed their diet in the week before the interview. Approximately, 10% of cases and 1% of controls reported significant dietary changes. Further analyses restricted to subjects reporting no dietary change showed no substantial change in the observed vegetable intake and endometrial cancer association. With 15.3% of cases and 27.4% of controls refusing to participate in the study, selection bias could be a concern. However, the median intake of fruits and vegetables in this study was similar to those found in a previous study of breast cancer that we conducted in Shanghai using the same FFQ, which had a much higher (92%) response rate.In summary, this population-based, case–control study of the risk of endometrial cancer found an inverse association between vegetables, particularly dark green/dark yellow vegetables, legumes, and allium vegetables, with endometrial cancer risk. Further studies are needed to investigate the biochemicals responsible for the inverse association and to clarify the biological mechanisms involved.


Although lung cancer is the leading cause of cancer deaths for Canadian women, breast cancer is the most frequently diagnosed. About 5400 women are expected to die from this disease in 2003. In 1998, a woman's lifetime risk of breast cancer was about one in nine.A number of risk factors for breast cancer have been identified. These include advancing age, hormonal factors , familial risk, BRCA-1 and BRCA-2 gene mutations, diet and postmenopausal obesity.Several interventions have been introduced to assist women at high risk for breast cancer, including genetic counseling and testing for women who have strong family histories of breast cancer; selective estrogen receptor modifiers, such as tamoxifen, that has been shown to reduce breast cancer rates; prophylactic mastectomy and screening.Guidelines are unclear in several areas, particularly in screening. Where clinical guidelines are available, health services research or ongoing monitoring  is needed to assess compliance with the guidelines and to ensure equity of access within the provinces/territories.Key components of organized screening programs need to be established, in part to ensure that screening is carried out in high-quality, co-ordinated programs. There is also a need to develop ways to involve women fully in informed decision-making and to address several policy issues to prevent disparities in access to high-quality services. Patenting issues associated with genetic tests also need to be clarified. The last decade has seen breast cancer come to the foreground as one of the chief health concerns of Canadian women, partly because of the importance of breast cancer as a cause of illness and premature mortality, and also as a result of the work of advocacy groups in bringing this issue to public attention. In 1992, a House of Commons Standing Committee report, Breast Cancer: Unanswered Questions, identified a number of issues in breast cancer research, prevention and care. This resulted in a National Forum on Breast Cancer, a major strategic event sponsored by the Canadian Cancer Society, the National Cancer Institute of Canada, the Medical Research Council and Health Canada, held in Montréal in 1993. [This chapter will provide data on the impact of breast cancer in epidemiologic terms, the progress that has been made in preventing the disease, and the questions – either research- or policy-based – that continue to present themselves to us.This is in large part a review of available literature at the time of publication. Specific data are cited in the Figures, and the methods for their production are listed in the source documents. The work of Health Canada, the National Cancer Institute of Canada and the Alberta Cancer Board is acknowledged in the production of these Figures.Breast cancer is the most common invasive cancer among Canadian women.  Age-stanThere is also speculation that some of the increase in the late 1980s and early 1990s could have been due to additional detections arising as a result of screening mammography.  However,Most women are aware of the lifetime risk of breast cancer as being close to 1 in 10; in 1998, the risk was about 11.4% or 1 in 9.  This is The news about mortality is somewhat better – the age-standardized mortality rate has fallen by about 15% since 1973, with most of the improvement since 1990.  However,The reduction in mortality rates has not resulted from a decrease in the number of cases of breast cancer and must therefore reflect better survival in those affected. There is evidence that this is the case. Data from Alberta indicate temporal trends towards improved 10-year survival  Figure . HoweverWithin Canada, the estimated 2002 mortality rates vary from a low of 22 deaths per 100,000 women inSaskatchewan (age-standardized to the 1991 Canadian population) to 29 in Nova Scotia and Newfoundland and Labrador. [Little is known in Canada about differences in cancer incidence or mortality across different ethnic or racial groups, as Canadian cancer registries do not collect this information. There is a suggestion that rates are lower in Inuit populations, although there was a trend to an increase in the 1969–1973 and the 1984–1988 periods.  Further Worldwide, there seems to be some movement towards convergence of breast cancer mortality rates. Rates are higher in North America and northern Europe than in less industrialized and Asian nations.  However,The strongest risk factors for female breast cancer – those that raise the individual's risk at least fourfold – include age and country of birth, both described earlier.  FamilialReproductive and hormonal factors have long been linked to breast cancer risk. The well-known factors include early age at menarche and late age at menopause, or a late age at the first full-term pregnancy. Nulliparity, or never completing a full-term pregnancy, increases the risk of breast cancer after age 40 (the vast majority of breast cancers occur after this age), although pregnancy may confer an increased risk of cancer before the age of 40.  These riHormone therapy (HT) has been a controversial area in the breast cancer literature. Before publication of the randomized controlled trial known as the Women's Health Initiative (WHI) study in 2002, large pooled analyses of observational studies showed an increase in breast cancer risk among women undergoing HT, which appeared to increase with duration of use.  It was tBecause of the worldwide variations in breast cancer incidence, there have been many studies attempting to link risk to variations in diet. Despite many years of study, there is little conclusive evidence on dietary fat or other putative dietary risk factors.Post-menopausal obesity increases risk to some degree. If population trends in obesity continue,  this mayExposure to high levels of ionizing radiation, especially at a young age, is an acknowledged, if somewhat rare, risk factor.  The leveA family history of breast cancer is perhaps the best-known risk factor. Recent pooling of data from 52 epidemiologic studies indicates that women with no affected first-degree relatives  have a 7.8% probability of developing breast cancer by age 80, whereas those with a historyof breast cancer in one first-degree relative have a risk of 13.3%;  the riskDespite this, there is a small group of women whose familial histories and/or genetic profiles put them at a considerably increased risk. The best-known susceptibility genes, BCRA1 and BCRA2, are believed to have a combined population frequency of about 1.2 per 1,000 women.  About 35Women who have strong family histories with more than one first-degree relative affected, especially with early-age onset, may be considered for genetic counselling and potentially for familial genetic testing. Women with family histories often overestimate their degree of risk,  and counFurther, the steps to be taken if a genetic defect is found are not entirely clear. Although some would recommend increased mammographic screening, others suggest that women with breast cancer susceptibility genes may actually be more sensitive to radiation, and thus they question the wisdom of this strategy. At the time of writing, a controversy exists that may limit the availability of genetic testing for Canadian women.  Some govSome studies are now addressing potential interventional strategies to lower breast cancer risk among women whose current risk is quite high. Tamoxifen is one of a class of drugs known as SERMs, or selective estrogen receptor modifiers. This drug has been shown to reduce breast cancer rates  among women whose family history and other risk factors place them at elevated risk.  However,Unfortunately, tamoxifen has also been associated with increased risk of endometrial cancer and thrombotic (blood clotting) events. This has led to new trials with another SERM, raloxifene. The results of a study designed to look at the effect of raloxifene on osteoporosis prevention showed promising results in breast cancer reduction  with litThe other interventional strategy that could be considered to lower breast cancer incidence in cases of very high risk is prophylactic mastectomy. This has been found to reduce breast cancer risk by about 90%,  althoughFor well over a decade, Canadian women have been advised that breast screening includes three components: breast self-examination (BSE), clinical breast examination (CBE) and, for some age groups, mammography.A report of an international workshop held by the National Cancer Institute (NCI) in 1993 was one of the most influential statements over much of the last decade . This reBecause women in their 40s must come to some kind of a decision in the face of conflicting recommendations, it is important to provide them with information that will help them make a decision with which they are comfortable. Any screening test involves some risk, as there is always the possibility that a false positive test will result in unnecessary, invasive tests, or that a false negative test will inappropriately reassure a woman when a cancer is present. For women in their 40s, the risk of a false positive test over a decade of biennial screening is estimated to be about 30%, and for 10 screening mammograms in this period about 56%.  Thus, thFor the past year, the debate has taken on another form, however. A reanalysis published in the Lancet in 2001 suggested that mammography was not beneficial in any age group.  Because Another screening procedure, BSE, has also been revisited in the past couple of years. A recent update found that there is no evidence of benefit and some evidence of risk, and so recommended that it not be routinely advised.  This agaAs early as 1989, there were recommendations in Canada that mammographic screening be done in the context of organized screening programs,  a sugges• a population-based outcome goal• information about the target population• attention to those hard to reach• meticulous quality assurance, including equipment and interpretation• outcome data and analysis• a woman-centred focus• information systems and linkages• coordination with high-quality diagnosisBetween 1988 and 1991, five provinces and one territory inaugurated programs; they are now in place in all 10 provinces and in 2 territories.  There haOne of the quality determinants for screening is a recommended minimum number of readings of3,000 films per radiologist per year,  a standaUnfortunately, in most provinces and territories, the majority of women do not receive screening through such organized programs  Figure , and mucAnother measure of quality is the time between screening and diagnosis. Recent studies have shown average delays of about 3.7 weeks from screening to diagnosis in Canada, increasing to 6.9 weeks if a biopsy is involved.  Within tThere are still differences in the ability of organized programs to reach some women for screening. The Canadian population health survey of 1996–1997 showed that only 29% of Newfoundland and Labrador women aged 50 to 69 reported undergoing screening mammography in the previous two years, as compared with 59% in Ontario and 60% in New Brunswick  (Figure Regional or provincial variations in treatment practices and access to radiotherapy have been found. ,55 It isThe data presented represent high-quality population-based data available from a number of sources. However, surveillance in Canada could be enhanced by various initiatives. First, there is no readily available data on the staging of cancer across the country, as stage is not routinely collected by cancer registries; this would be valuable in interpreting whether there are differences in time or place in the diagnosis or stage-specific survival of breast cancer. Further, there is no specific information on Aboriginal or other groups, as ethnic origin is not collected on Canadian registries. Finally, while the National Population Health Survey and the Canadian Community Health Survey provide excellent self-report data on screening, enhanced data from actual screening providers in addition to those currently reporting from the screening programs would allow us to get more accurate data on screening prevalence and outcomes across the country.There are several areas, particularly in screening, in which the guidelines are unclear and there is a need to develop ways to involve women fully in informed decision making. Several policy issues need to be addressed to prevent disparities in access to high-quality services:• The patenting issues of genetic tests and thus the availability of testing for women with high-risk histories need to be clarified.• There should be leadership to ensure that all screening occurs in the context of high-quality, coordinated programs.• The key components of organized screening programs, identified well over a decade ago, should be put in place.• When clinical guidelines are known, there is a requirement for health services research or ongoing monitoring by the provincial cancer agencies to assess the adherence levels to guidelines and to ensure equity of access within provinces.If attention is paid to these issues, we have some hope of minimizing the rates of breast cancer in Canada and further reducing the burden for the over 20,000 women who will develop breast cancer in Canada this year.The views expressed in this report do not necessarily represent the views of the Canadian Population Health Initiative, the Canadian Institute for Health Information or Health Canada.


Multiple primary cancer of the breast and ovary were investigated as part of a survey being undertaken at the Birmingham and West Midlands Regional Cancer Registry. Population-based data relating to 17,756 registrations for breast and 3470 for ovarian cancer between 1950 and 1964 were analysed. On the basis of person-years at risk and incidence rates for the Region (1960-1962), an increased risk of a second primary tumour in the ovary was observed in patients diagnosed with a first primary in the breast before 45 years of age . No excess was found in patients diagnosed after 45 years of age . In patients with an index tumour of the ovary, the observed number of second primary tumours of the breast was not significantly different from the expected number . Complementary analysis (a combined assessment for the 2 sites) showed that the development of a first primary at either site before 45 years of age carried a 2.8-fold risk of a second primary tumour at the other site . After 45 years of age no increased risk was found . Over all ages a 1.3-fold risk was observed . No evidence of subfertility was found in the 9 patients in the high-risk premenopausal group who developed the 2 tumours. The results are more consistent with an aetiology of early exposure to an external carcinogen than with one of abnormal hormone production.


CYP1B1) polymorphisms and breast cancer risk have been inconsistent. We set out to ascertain whether there might be an association between polymorphisms in exon 2  and exon 3  of CYP1B1 and breast cancer in a Chinese Han population in the rural region of Ningxia. Using an allele-specific polymerase chain reaction method and direct DNA sequencing, the presence or absence of the two CYP1B1 polymorphisms was investigated. Genotype and allele frequencies were analyzed in breast cancer cases (n = 152) and healthy age-matched controls (n = 156). The odds ratio (OR) of 119G→T or 432G→C in breast cancer cases and controls was 3.3 (95% CI: 1.28 to 8.28) and 2.8 (95% CI: 1.04 to 7.51), respectively. In addition, the OR for people with both polymorphisms (119T and 432C) was 4.69 (95% CI: 1.97 to 11.19). Our results suggest that certain polymorphisms in the CYP1B1 gene might increase risk for breast cancer among Han Chinese, perhaps because they influence the efficiency of CYP1B1 bio-transformation of oestrogens or pro-carcinogens into DNA-reactive electrophiles that may act as cancer-initiating agents.Studies investigating possible associations between cytochrome P4501B1 ( BRCA1/2.CYP1B1) catalyzes the formation of genotoxic 4-hydroxy oestradiol (4-OH E2), and bio-activates environmental pro-carcinogens .CYP1B1 and the formation of 4-OH E2 have been associated with oestrogen-related tumours in multiple tissues and species.OHE2 catechol metabolite has the highest carcinogenic as well as oestrogenic activity and is found in higher quantities in breast cancer tissue than other 17β-oestradiol (E2) metabolites.11Breast cancer remains a major cause of morbidity and mortality worldwide with incidence rates ranging from 27/100,000 in Asian countries to 97/100,000 among US Causcasian women, but its aetiology remains unclear. Only a small proportion of cases (<10%) may be due to germline mutations in highly-penetrant susceptibility genes e.g. CYP1B1 is genetically polymorphic, and sequence variations in the gene may be related to risk of breast cancer in some populations.CYP1B1 gene, located at the 2p21–22 region, consists of three exons, one of which is noncoding, and two introns.CYP1B1 in exon 2  and exon 3  encode the heme-binding domain; variant alleles probably exhibit altered activity.CYP1B1 may explain why individuals vary in their susceptibility to the carcinogenic effects of environmental chemicals.CYP1B1 polymorphisms and breast cancer have involved different populations but, have given rise to often inconsistent and/or contradicting findings even within the same ethnic groups.CYP1B1 polymorphisms [in exon 2  and exon 3 ] with breast cancer patients and healthy controls were determined. Our results point to an association between these two polymorphisms and breast cancer in this study population.Studies reporting the association between From May 2005 to June 2006, a total of 152 sporadic breast cancer patients and 156 healthy controls were recruited at Affiliated Hospital of Ningxia Medical University. All participants provided written informed consent before participating in the study. This research programme was approved by the local ethics approvals board at Ningxia Medical University.The 152 breast cancer cases were verified by histopathology with a single pathologist. A cohort of 156 controls confirmed to be free of any cancer based on a health examination were randomly matched to the breast cancer arm of the study, with an age difference that was no greater than 5 years (y). The status for oestrogen receptor (ER) and progesterone receptor (PR) was also collected. The controls were not related in any way with the patients and they had no family history of breast cancer. All participants were long-term residents of Ningxia who had no prior history of cancer.Blood samples (3–5 ml) were collected in Vacutainer tubes containing ethylenediaminetetraacetic acid (EDTA). Genomic DNA was extracted using standard phenol/chloroform methods. The sequences of primers for polymerase chain reaction (PCR) at each locus were synthesized by SBS-Biology (Beijing) and are listed in CYP1B1 were conducted using allele-specific (AS) PCR methods in a Biometra T Gradient Thermocycler (Bio-Rad Laboratories). Each PCR mixture (25 μl) contained 10 ng DNA, 1 × PCR buffer with 1.5 mmol/L MgCl2, 0.16 mmol/L of each dNTP, 0.4 μmol/L of each primer, and 1 unit of Hotstart Taq DNA polymerase (SBS-Biology). The reaction mixture was initially denatured at 95 °C for 5 min, followed by 30 cycles at 94 °C for 30 sec, 60 °C for 30 sec, and 72 °C for 45 sec. The PCR was completed by a final extension cycle at 72 °C for 5 min. The DNA fragments were then separated and visualized by electrophoresis on 2% agarose gels containing ethidium bromide.Genotyping assays for the two SNPs for CYP1B1 genotype frequencies were in Hardy-Weinberg equilibrium using standard χ2-statistics. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using SPSS . ORs were used to measure the strength of the association between CYP1B1 genotypes and breast cancer risk. The χ2 test was used to compare the distributions of CYP1B1 alleles and genotypes in cases and controls.We determined whether The breast cancer patients had an age range between 28 y and 75 y, with a mean (M) and standard deviation (SD) of 52.27 (10.28) y. The control cohort had an age range between 30 y and 70 y, with a M (SD) of 52.69 (11.25) y. There was no significant difference in the age distribution between the patient and control arms of the study.CYP1B1 are shown in CYP1B1, the appearance of only the “a” band was identified with GG based on DNA fragment size, the appearance of both “a” and “b” bands was identified with GT, and the appearance of only a “b” band was identified with TT , which results in a substitution of alanine (Ala) at codon 119 by a serine (Ser) (CYP1B1 (GenBank accession No. rs1056836), which causes a substitution of the valine  at codon 432 by a leucine (Leu) (Representative samples for genotyping codons 119 and 432 of  with TT . For gened to CC . Reversene (Ser) . Direct ne (Leu) .CYP1B1 in breast cancer patients and the controls (CYP1B1 differed significantly between the two cohorts (P = 0.000) with an OR of 2.20 (95% CI: 1.49 to 3.26). The frequencies of G and C alleles on codon 432C/G of CYP1B1 also showed significant differences between the two cohorts (P = 0.003), with an OR of 1.97 (95% CI: 1.25 to 3.11). The genotype frequencies at codons 119 and 432 for all subjects in this study are shown in P > 0.05). There were significant differences in the GG, GT, and TT genotypes between the two cohorts (P = 0.001). The risk of breast cancer in individuals with genotypes of the homozygous TT mutation and heterozygous GT mutation was increased 3.26- and 2.32-fold, respectively, compared to the risk in individuals with the wild-type GG. There were significant differences in frequencies of the genotype GG, GC, CC between the two cohorts (P = 0.038) (We compared the distribution frequencies of the two SNPs for controls . The fre= 0.038) . The risCYP1B1 codons 119 and 432 are not in linkage disequilibrium. The OR for individuals possessing both 119T and 432C was nearly five times the OR for those possessing 119G/G-432G/G. No associations were found between these two variations and with ER or PR status.20We analyzed the effect of the combined 119/432 genotypes on breast cancer risk in the Ningxia Han population . In our CYP1B1, which are involved in oestrogen and xenobiotic metabolism, may contribute to the different risks of breast cancer observed for different populations.CYP1B1 polymorphisms in a Ningxia Han Chinese population, and observed that the genotypes 119T/T and G/T are present at a significantly higher frequency (P = 0.001) in breast cancer patients than in control participants. A difference between breast cancer patients and healthy participants was also found in the allelic distributions of codon 432. The combination of the two polymorphisms of CYP1B1 investigated [in exon 2  and exon 3 ] further increases the risk of breast cancer in this Ningxia Han (China) ethnic group.Individual susceptibility to cancer is likely to be influenced by the genotype for enzymes involved in the activation or detoxification of carcinogens. Polymorphic alleles of key candidate genes such as CYP1B1 codon 119(G→T) and codon 432(G→C) and breast cancer in different populations have often given rise to conflicting or contradicting results. Our results on CYP1B1 codon 119(G→T) confirm those of a study in a Japanese population.CYP1B1 codon 119(G→T) “T” allele among controls (0.16) and cases (0.29) in the Ningxia Han than were reported among controls (0.12) and cases (0.16) in the Japanese study.CYP1B1 codon 119(G→T), which is thought to participate in the substrate recognition site 1 of CYP1B1 protein, is significantly associated with breast cancer in both the Ningxia Han (China) population and the Japanese. This contradicts the protective effect reported for this polymorphism in studies carried out among Chinese women in Shanghai, Caucasian and African in U.S.  and Polish women.24Previous studies on the association between CYP1B1 Val432Leu polymorphism and breast cancer was observed in Asians . An inverse association was observed in a population of mixed/African origin . The pooled analysis suggested a possible association in Caucasians , with effect modification across age categories.CYP1B1 codon 432 (G→C) and breast cancer is consistent with the results of several studies in Caucasians.Val/Leu genotype was associated with a 2.15-fold higher risk (95% CI: 1.31–3.52). In a study of a Shanghai population, Zheng et alLeu/Leu genotype had a 2.3-fold  higher risk of breast cancer. Our study in the Ningxia Han population confirms these results, although we measured lower frequencies of the CYP1B1 codon 432(G→C) “C” allele among controls (0.11) and cases (0.19) compared to those reported among controls (0.46) and cases (0.53) in the Shanghai Han population, respectively. Some studies in Caucasian populations and Asian populationsCYP1B1 Val/Leu genotype and breast cancer risk. However, others have found a significant increase in the breast cancer risk for smoking women in a Finnish population , especially for smokers homozygous for the Leu allele .13The valine substitution is reported to be present at an allele frequency of 0.43 in Caucasians, 0.75 in African-Americans and 0.23 in Asians. cases 0. comparedCYP1B1 codon 119 (Ala→Ser) and codon 432  and risk of breast cancer. Our results show that the risk of breast cancer increases significantly  proportional to the number of variant alleles individuals possess. Han women living in the Ningxia province are relatively homogeneous in ethnic background, therefore eliminating some confounding effects. On the other hand, our study investigates a relatively small sample size in a case-control setting, which may make our risk estimates unstable. Nevertheless, our results are consistent with recent findings from in vitro and animal experiments implicating a potentially important role of CYP1B1 in the aetiology of human breast cancer.29Certain genotypes may contribute to variation in risk for breast cancer observed in different populations or ethnic groups. To evaluate this in a rural Ningxia Han population of P. R. China, we analysed the association between CYP1B1 may be a risk factor for breast cancer in the Ningxia Han population of China, and in at least some other populations. Further investigations involving larger sample sizes and other ethnic populations are needed in order to establish more completely the relationship between these CYP1B1 SNPs and breast cancer risk.Other factors such as the expressed profile of ER splice variants may play a hitherto under-recognised role in the modulation of breast cancer risk.


Association between breast cancer risk and the intake of vitamins C and E, retinol, beta (beta)-carotene, dietary fibre, vegetables, fruit and potatoes was examined in The Netherlands Cohort Study, for 62,573 women aged 55-69 years. After 4.3 years of follow-up, 650 incident breast cancer cases were identified. After adjusting for traditional risk factors, breast cancer risk was not influenced by the intake of beta-carotene, vitamin E, dietary fibre, supplements with vitamin C, vegetables or potatoes. Fruit consumption showed a non-significant inverse association with breast cancer risk . A small reduction in risk was also observed with increasing intake of dietary vitamin C . For retinol, a weak positive association was observed . Among subjects with a high intake of polyunsaturated fatty acids (PUFAs), both beta-carotene and vitamin C intake showed a non-significant inverse association with breast cancer risk (P-trend = 0.15 and 0.16 respectively). Our findings do not suggest a strong role, if any, for intake of vitamins C and E, beta-carotene, retinol, dietary fibre, vegetables, fruit and potatoes in the aetiology of breast cancer.


In a case-control study of testis cancer 259 cases with testicular cancer, 238 controls treated at radiotherapy centres and 251 non-radiotherapy hospital in-patient controls were interviewed about some possible prenatal and familial risk factors for the tumour. For firstborn men, the risk of testis cancer increased significantly according to maternal age at the subject's birth, and this effect was most marked for seminoma. The association with maternal age was not apparent for cases other than firstborn. The risk of testis cancer was also significantly raised for men from small sibships and of early birth order. These results accord with the theory that raised maternal levels of available oestrogen during the early part of pregnancy are aetiological for testicular cancer in the son, although other explanations are possible; there is evidence that seminoma risk may particularly be affected.


British Journal of Cancer (2002) 87, 1195–1196. doi:10.1038/sj.bjc.6600633www.bjcancer.com© 2002 Cancer Research UK The first published report of an association between alcohol consumption and breast cancer risk was by Since these initial reports, a substantial number of epidemiological investigations have assessed these hypotheses. The overall evidence from the epidemiological data published so far seems to indicate that alcohol intake may be associated with a slight increase in the risk of breast cancer. By contrast, the evidence for smoking has been rather inconsistent, with some studies showing a slight increase in risk and others reporting no association or, even, a protective effect. Most of these studies have been based on relatively small numbers of breast cancer cases, however, thus yielding rather imprecise estimates of the true effects of these exposures. In addition many of them were unable to take account of the fact that alcohol and tobacco consumption are correlated, as smokers are more likely to drink alcohol than non-smokers.Clarification of the independent effects, if any, of these exposures on the risk of breast cancer is of epidemiological relevance for various reasons. First, for populations where the prevalence of alcohol and/or tobacco consumption is high, even if the relative risk associated with these exposures is small, the effect of these exposures could still account for a substantial number of breast cancer cases. Second, unlike most of the known risk factors for breast cancer, alcohol and tobacco consumption are potentially modifiable behaviours and hence offer some scope for prevention. Third, clarification of the aetiological role of these exposures might shed light on the biology of breast cancer.−1 intake of alcohol, i.e. for each extra unit  consumed on a daily basis. Relative to women who reported drinking no alcohol, the risk of developing breast cancer was 32% higher among those who reported drinking 35–44 g day−1 and 46% higher among those who reported consuming 45 g day−1 or more (average 57 g day−1). The effect of alcohol was not found to be confounded by smoking or by any other known risk factor for breast cancer. The authors estimated that in developed countries the cumulative incidence of breast cancer by age 80 would be 8.8 per 100 women in non-drinkers and 9.4, 10.1, 10.8, 11.6, 12.4 and 13.3, respectively, per 100 women among women consuming an average of 1, 2, 3, 4, 5 and 6 alcoholic drinks each day. By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol and when the analysis was restricted to non-drinkers, no association was found between smoking and breast cancer.In this issue, the So, can we now finally pass judgement on the alcohol- and tobacco-breast cancer hypotheses and lay them to rest? Unfortunately, the answer is not yet. As acknowledged by the authors the quality and validity of their exposure data were, to a certain extent, limited, as most of the individual studies were not set up with the primary purpose of addressing these hypotheses. Despite this caveat, the results strongly argue against an association between smoking and breast cancer but are in favour of a true positive association between alcohol and this tumour. Given the impossibility of conducting a randomised trial on this issue a causal relation between alcohol and breast cancer can never be established beyond any doubt, but the evidence provided by this reanalysis of practically all the available worldwide data, and the consistency of the findings across the various studies, strongly suggest that something is going on. As the relative risks involved are modest, it could be argued that the observed relationship between alcohol and breast cancer might be due to confounding by unknown risk factors, but it is hard to envisage an as yet unknown risk factor, which is consistently associated with alcohol intake in the relatively diverse populations studied.Even if causal, the exact relationship with duration, timing, or indeed amount, of alcohol intake remains unclear. Self-reported information on alcohol consumption is known to be prone to measurement error and it is uncertain to what extent this might have affected the magnitude and shape of the dose–response relationship. Thus, a degree of uncertainty remains about the true quantitative effect of a given amount of alcohol on the risk of developing breast cancer, and in particular, whether there may be a threshold dose below which alcohol has no effect. The tendency for underestimation of the amount drunk and concerns that non-drinkers may differ in some relevant, but unmeasured, ways from those who occasionally drink alcohol, precludes an accurate estimation of the risks associated with low levels of alcohol intake.−1. On the basis of the observed dose–response relationship, and assuming causality, the authors estimated that about 4% of all breast cancer cases in developed countries are attributable to alcohol. In developing countries, where the average alcohol consumption is very low (only 0.4 g day−1), alcohol would make a negligible contribution to the total number of cases of breast cancer. To put these figures into perspective, up to 90% of all lung and cervical cancers can be attributed to smoking and infection with human papillomavirus (HPV), respectively.Should the advice to women change in the light of the findings from this reanalysis? After assimilating the new findings the answer is probably no. In terms of public health, both factors are already known to be important for women's health. Smoking has already been shown to cause many fatal diseases, particularly lung cancer and coronary heart disease. The implications of the findings for alcohol are less straightforward. In this reanalysis, the average consumption of alcohol reported by controls from developed countries was 6.0 g dayComplete elimination of alcohol consumption is neither feasible nor justified in health terms. We know from other studies that women who drink alcoholic beverages regularly have higher death rates from injuries, violence, suicide, poisoning, cirrhosis, certain cancers , and possibly haemorrhagic stroke, but lower death rates from coronary heart disease and thrombotic stroke compared with those who abstain completely , a net pThe answer to the initial question ‘Should alcohol be condemned and tobacco acquitted?’ will depend on whether this is primarily an aetiological or a public health question. In terms of breast cancer aetiology, this reanalysis provides strong evidence that alcohol, rather than smoking, is the culprit. And yet, in public health terms, there is no doubt that tobacco should be condemned as it was responsible for an average of about 3 million deaths per year worldwide during the 1990s and, if nothing is done to change current smoking patterns, this figure may well rise to 10 million deaths per year by the 2020s (


Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome  and breast cancer risk. Reactive oxygen species, a by-product of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study . We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele . However, we were unable to replicate these findings in the Women's Health Study , although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk. Mitochondria are very important cellular organelles, playing active roles in various functions, such as energy balance and cell cycle control. In addition, by transforming energy into a form that the cell can use, mitochondria produce reactive oxygen species (ROS) that can lead to damage of key components of the cell, particularly proteins and DNA. All of these facets of mitochondrial biology make them of interest with respect to cancer biology.As mitochondria were once symbiotic bacteria living within early eukaryotes, they still carry their own genome, separate from the nuclear genome. While many genes have been shared between the mitochondrial and nuclear genomes of humans over evolutionary history, the mitochondrial genome still retains many of the genes required for its proper functioning. Like the nuclear genome, the mitochondrial genome carries polymorphic sequences. Interestingly, it is hypothesized that polymorphisms in the mitochondria that cause the mitochondria to be less efficient in energy exchange, therefore creating more heat and reactive oxygen species, allowed early humans an adaptive advantage when migrating to cooler climates, such as from Africa to Europe The nonsynonymous A10398G (T114A) polymorphism in the ND3 (NADH dehydrogenase subunit) gene of the mitochondrial genome is one of the most extensively studied mitochondrial polymorphisms. There is no prior knowledge of this polymorphism affecting mitochondrial function, however it has been associated with neurodegenerative diseases such as Parkinson'sBaseline characteristics of both the NHS and WHS are reported in Major ancestry was asked in the Nurses' Health Study by questionnaire in 1992 and 98% of the participants who responded to this question are self described Caucasians. Furthermore, 659  of the subjects described themselves as South European/Mediterranean, 260  as Scandinavian, and 2603 as Other Caucasian . In these sub-categories, the G allele of A10398G is present at 18.5, 18.1, and 19.7% respectively. 28 subjects described themselves as African-American, 11 as Hispanic and 14 as Asian. In these sub-categories, the G allele of A10398G is present at 89.3, 9.1, and 64.3% respectively.We did observe, however, an interaction between A10398G and alcohol consumption  in the NHS. P-values from both the Wald and Likelihood Ratio Tests (LRT) were similar , as expected. In cross-tabulated analyses, women carrying the variant G allele and not consuming alcohol were at decreased risk of breast cancer as compared to women not carrying the variant and not consuming alcohol  describe themselves, or how the participants were described in prior publications. It should be noted that the A10398G polymorphism is of great importance with respect to mitochondrial phylogeny, being relatively less frequent in West Eurasian populations as opposed to African or Asian lineagesa priori hypothesis of an interaction between alcohol consumption and the A10398G polymorphism on breast cancer risk is relatively strong.One limitation of this study is that having genotyped only one mitochondrial variant, we are unable to categorize the participants of this study into well defined mitochondrial haplogroups as done by Bai et al.The A allele of the A10398G polymorphism has been associated with an increase in risk of breast cancer in African-Americans , but not among Caucasians  The Nurses' Health Study has greater than 80% power to detect a 26% increase (OR = 1.26) in risk between the A10398G polymorphism and breast cancer at an alpha of 0.05. Therefore, we can exclude any association between this polymorphism and breast cancer risk with an odds ratio above 1.26, such as those first observed in African-Americans (OR = 1.60) and Indians (OR = 1.73) in our study population. We have limited power to detect, however, more moderate (OR<1.26) associations between this polymorphism and breast cancer risk.Our findings of an interaction between alcohol consumption and A10398G in the Nurses' Health Study are of interest. Alcohol is a well established breast cancer risk factor in vitro evidence to date to support this hypothesis. Therefore the interaction that we have observed between this polymorphism, which may well be nothing more than a marker of other mitochondrial variation and have no functional relevance specifically, and alcohol consumption on breast cancer risk could be due to other mitochondrial polymorphisms which occur in common with A10398G. Epidemiologic studies are generally ill-suited to describe a causal marker when multiple correlated markers, all with little if any known functional relevance to the phenotype in question, exist.Further examination of the interaction between alcohol consumption and the A10398G polymorphism of the mitochondrial genome on breast cancer risk could refine our observations. While it is hypothesized that A10398G alters the production of reactive oxygen species in the mitochondria, there is no Additional epidemiologic evidence such as evidence for interactions between this polymorphism and/or other variants with which it is correlated and alcohol consumption in other breast cancer studies would also be of interest. However, the studies would need to have sufficient power to detect such an interaction. Similarly, as alcohol consumption is associated with other diseases (presumably through increased oxidative stress), including other cancer sites, it is possible that similar interactions could be observed with risk of these diseases and should be explored. Alternatively, interactions between this polymorphism and alcohol consumption on markers of oxidative stress would also provide biological evidence supporting our observations.In conclusion, we have detected an interaction between the A10398G polymorphism in the human mitochondrial genome and alcohol consumption associated with breast cancer risk. In the Nurses' Health Study, drinkers who carry the 10398G allele are at a 56% higher risk of breast cancer than non-drinkers with the same allele. This interaction was not observed in the Women's Health Study; however there was insufficient power to detect this association in this study. Upon combining results from the NHS and WHS, the risk of breast cancer associated with alcohol consumption among carriers of the G allele of A10398G was reduced to 33%  Further examination of the possible interaction between alcohol consumption and the A10398G polymorphism, or other variants for which it is a marker, on breast cancer risk is needed to further define this association. Additionally, understanding of the biological significance, if any, related to the A10398G polymorphism  and how it/they could interact with alcohol consumption would also be of great interest.The Nurses' Health Study nested breast cancer case control study  is derived from 32,826 women who were free of diagnosed breast cancer at blood collection in 1989 and 1990, and were followed for incident disease until May 31, 2004. Medical records were used to confirm the diagnoses in women who reported a diagnosis of breast cancer on the biennial questionnaires. Control subjects were matched to cases based on age, menopausal status, recent hormone replacement therapy, and blood-draw specific variables (such as date and time of day). Questionnaires were used to determine the subject's major ethnic group , as well as further detail within Europe . The nested breast cancer case control study in the Harvard Women's Health Study began in 1993 when 28,263 women provided blood samples and were followed for incident disease until March 7, 2000, with 702 cases and 703 controls selected using the same criteria as in the NHS. Detailed descriptions of these cohorts have been published previously, and a brief summary of the subjects in these analyses are in The A10398G polymorphism in the mitochondrial genome was genotyped using Taqman technology . Primer and probe sequences as well as cycling conditions are available from the authors. Internal blinded quality control (QC) samples were 100% concordant, and greater than 95% of samples yielded genotypes. Hardy-Weinberg equilibrium tests are not valid for mitochondrial SNPs, and therefore were not assessed, and no heteroplasmy (detected as heterozygous samples) was observed.We included possible confounding factors, including body mass index (BMI), family history of breast cancer, self reported history of benign breast disease, age, and menopausal status in all models in the Nurses' Health Study. We also used unconditional logistic regression with the Women's Health Study, controlling for age, family history of breast cancer, and self reported history of benign breast disease. Tests for interactions were performed using Wald tests that include main effects and interaction terms in the model, and likelihood ratio testing, comparing the fit of the model with only main effects to the fit of the model with both main effects and interaction terms. All statistical analyses were carried out using SAS 9.1 , with the exception of power calculations which were performed in the Quanto softwareInformed written consent was obtained from all participants, and this study was approved by the Institutional Review Board of the Brigham and Women's Hospital.