The precautionary principle implies the need for research paradigms that contribute to “strength of the evidence” assessments of the plausibility of health effects when scientific uncertainty is likely to persist and prevention is the underlying goal. Previous discussions of science that inform precautionary decision making are augmented by examining three activist-initiated breast cancer and environment studies—the Long Island, New York, and Cape Cod, Massachusetts, studies and the National Institute of Environmental Health Sciences breast cancer and environment centers. These studies show how the choice of research questions affects the potential of results to inform action. They illustrate a spectrum of public involvement, population- and individual-level epidemiologic study designs, and the crucial importance of developing and applying new exposure assessment methods. The exposure studies are key because they are critical in assessing plausibility , are prerequisite to health studies, and identify preventable exposures that could be reduced by precautionary policies, even in the absence of strong evidence of harm. The breast cancer studies have contributed to environmental and biological sampling programs for endocrine-disrupting compounds in drinking water and household air and dust and the application of geographic information systems for surveillance and historical exposure assessment. They leave unanswered questions about when to invest in large epidemiologic studies, when negative results are sufficient, and how to pursue ambiguous positive results in further research and policy. Finally, strategies for aggregating effects of mixtures have yet to be developed.The design of epidemiologic studies to address activist concerns is problematic, however, particularly because the exposure assessments themselves pose challenges . Self-reGiven these challenges, as activist-generated breast cancer research unfolded, tensions emerged from the mismatch between what investigators can achieve through prevailing epidemiologic research paradigms and what activists had hoped to accomplish in time to help their daughters. Lessons from these conflicting perspectives carry many parallels with, and can inform, other health issues for which relevant exposures are similarly difficult to assess and where disease has multifactorial causation . In this commentary, we seek to draw out these lessons by discussing the relationship between activist goals and scientific methods in reference to the precautionary principle, because it provides a framework for generalizing from the breast cancer studies to other public health issues where scientific uncertainty is likely to persist. We focus particularly on the Cape Cod Breast Cancer and Environment Study, because two of us have been involved for nearly a decade in its development and implementation . We also comment on the Long Island study and the NIEHS breast cancer and environment research centers program. The Bay Area Breast Cancer and the Environment Study Group and research in Marin County, California, which offers another early example, is now affiliated with the NIEHS centers program.a) taking preventive action in the face of uncertainty, b) placing responsibility on those who create risks to study and prevent them, c) considering alternatives to potentially harmful activities, and d) increasing public participation and transparency in decision making. In contrast, current U.S. chemical regulations require substantial evidence of harm before regulatory action is taken, regardless of the availability of alternatives.The precautionary principle calls for preventive action in the face of uncertain but suggestive evidence of risk, especially when safer alternatives exist. The 1998 Wingspread Statement on the Precautionary Principle  identifiPrevious discussions have outlined how the precautionary principle calls for changes in research process, questions, interpretations, and policy applications , 2003. BMany breast cancer activist organizations, including groups involved in the Long Island and Cape Cod studies, have explicitly endorsed the precautionary principle {examples come from New York , CaliforIncreased public participation and transparency in decision making are a logical starting point for applying the precautionary principle to breast cancer studies because democratizing scientific research opens the door for activists’ priorities to influence study design. Breast cancer activists, following the example of AIDS activists, have become leaders in helping to drive research agendas by catalyzing federal and state legislation and appropriations and participating in research design , 2004. IThe LIBCSP was the first of the activist-generated studies to become nationally visible. Mandated by Congress in 1993, it grew to encompass > 10 studies totaling > $30 million. Beyond winning funds, the Long Island activists specified in the Congressional mandate several aspects of the research design, including a case–control study using biologic markers and the development of a geographic information system (GIS) . The graThe Cape Cod Breast Cancer and Environment Study also began from a legislative mandate , althougThe founders’ vision transcended “science as usual” and gave activists governance roles on the scientific team. As a nonprofit organization, the institute has a public-interest board of directors (including three directors chosen as MBCC representatives) with the authority to hire and fire the study’s principal investigator. The board’s authority is tempered by grant requirements for funder approval before key personnel can be replaced, however, and the Silent Spring Institute board developed additional mechanisms to ensure that it exercises its authority responsibly. The board convened a science advisory committee of outside experts, frequently sent a representative to co-investigator meetings, gave added weight to input from board members trained in biology and medicine, and supported publication of research results in peer-reviewed scientific journals even when MDPH disallowed use of state funds for this purpose. This activist-governed research model is particularly notable at a time when government increasingly relies on industry science in regulatory decisions and academic science is growing more dependent on industry funding . FurtherThe NIEHS Centers program began as an initiative of the National Breast Cancer Coalition, which, along with NIEHS, convened a series of invitational brainstorming sessions for researchers and activists. These sessions, coupled with public meetings, shaped the request for applications (RFA). The RFA specified a multidisciplinary approach, including laboratory and epidemiologic components, and required ongoing public involvement .Among these three examples of activist-initiated research, the Cape Cod and NIEHS models have extended the democratization of science in ways that can offer models for the development of new norms for environmental health research: public empowerment that goes beyond mere involvement on advisory boards, a shift away from purely investigator-defined research to joint activist–scientist definition of research problems, and integration across disciplines and across institutions. The Cape Cod study is perhaps unique even in the history of community-based participatory research in that activists govern the research team.If democratization in science makes a difference, we would expect to see activist-initiated studies that differ in design from the typical investigator-initiated studies funded by the National Cancer Institute, Department of Defense, and major foundations. Consistent with breast cancer activists’ support for the pre-cautionary principle, we expect study designs that will inform preventive public health policies in the face of uncertainty [the first principle of the Wingspread Statement on the Precautionary Principle ]. The reThe Breast Cancer and the Environment on Long Island case–control study, the centerpiece of the LIBCSP, applied a typical hypothesis-testing framework to investigate whether an association exists between breast cancer risk and organochlorine compounds , which are EDCs, and poly-cyclic aromatic hydrocarbons (PAHs), which are mammary carcinogens , 2002b. Aside from the choice of target compounds, case–control studies can serve public health decision making by generating an estimate of relative risk and its confidence interval. However, we consider this a high-risk strategy in both the Long Island and Cape Cod studies from a precautionary perspective, because of the considerable expense coupled with the likelihood of generating inconclusive negative findings, which are common in case–control studies of hard-to-assess exposures to pollutants in the general population. Several factors favored the potential in the LIBCSP to produce persuasive evidence that organochlorines increase breast cancer risk: the biologically plausible hypothesis that EDCs affect breast cancer, several earlier studies showing an association between breast cancer and serum organochlorines, a large sample size , rapid case ascertainment (so serum measures could not be affected by breast cancer treatment), extensive interviews about established and hypothesized breast cancer risk factors (to control for confounding and investigate effect modification), and individual-level biologic markers of exposure. On the other hand, results that failed to show an association could contribute little, because study design limitations mean we cannot conclude from null results that no association exists. For example, no one in the study can reasonably be considered unexposed, raising questions about whether there is adequate exposure variability to detect effects. In addition, the one-time exposure measures do not accord well with the evidence that timing in the life cycle is important in breast cancer etiology. Specifically, serum measures taken near the time of diagnosis may not represent early life exposures or even total lifetime exposure, because recent levels are influenced by variables related to mobilization and excretion, such as weight gain/loss and lactation, and by intake of breakdown products in food that have different toxicologic properties from the parent compound  . Resultsp < 0.05 level, but with no linear dose response  or by funding agencies (in RFAs). Thus, the development of the research ideas, goals, and methods precedes formal funding of the study, making it more difficult for scientists and the community members to debate together the research agenda at this crucial design stage.The Cape Cod study team reviewed nine issue areas—ranging from local food distribution systems to military facilities—as candidates for study and set priorities based on three criteria: scientific literature showing a plausible link to breast cancer; evidence of exposure on Cape Cod, particularly distinctive exposure; and community concern. Scientific evidence included laboratory studies of animal models and cellular mechanisms and epidemiologic studies. These criteria and types of evidence provide widely applicable guidelines for selecting research questions under the precautionary principle, because they emphasize assessing plausibility in situations in which proof is unlikely to be achievable. Including community concern as a decision-making criterion helps avoid studies that, although elegantly designed, do not answer relevant questions, a pitfall sometimes referred to as a type III error .The scoping process also incorporated surveillance and ecologic epidemiology to refine the definition of the problem and generate hypotheses. This process illustrates how a precautionary approach can generate evidence that appropriately reduces public concern in some areas and focuses attention on more promising hypotheses. Using GIS technology, we integrated breast cancer and environmental data and searched for geographic and temporal patterns. We geocoded home addresses from the Massachusetts Cancer Registry of about 2,600 Cape Cod women diagnosed between 1982 and 1994 and used U.S. Census data and population growth models to estimate age-adjusted standardized incidence ratios annually by census block group .Results showed consistently higher incidence rates on Cape Cod than in the rest of the state; rates of “early” stage 1 diagnosis and mammography could not account for the higher incidence rates , 2004. Min vitro bioassay of estrogen-sensitive cells—the E-Screen bioassay—to assess total estrogenicity  What is the history of exposure to wastewater contaminants (particularly EDCs) in public and private drinking water (b) What is the history of exposure to pesticides from wide-area application (c) What EDCs are women exposed to at home (d) How do EDCs from septic systems travel in groundwater, which supplies drinking water (e) After controlling for established risk factors, is living longer on Cape Cod associated with breast cancer risk (f ) Is exposure to pesticides from wide-area application associated with breast cancer risk (g) Is exposure to drinking water contaminants associated with breast cancer risk ?Nevertheless, the study retained many elements of a scientific approach focused on pre-cautionary strength-of-evidence goals. The study’s scientific publications have addressed seven core research questions, more than half of which focus on exposure assessment: ng water ? b) Whatlication ? c) What at home ? d) How ng water ? e) Aftecer risk ? f ) Is cer risk ? g) Is eThe exposure questions are key because they are critical in assessing plausibility , they are prerequisite to health studies, and they identify preventable exposures that could be reduced by precautionary policies, even in the absence of strong evidence of harm.Ideally, a breast cancer study would estimate exposures years before diagnosis and at particular times in the life cycle. Retrospective self-reporting can offer this standard for exposures that women themselves can identify and are likely to report without bias, such as the year and their age at the births of their children, which reveals that pregnancy within 5 years of diagnosis and older age at the birth of a first child both increase breast cancer risk . To apprAlthough the GIS exposure assessment is valuable for developing new methods for public health studies, its application in the Cape Cod study shares with the Long Island study the risk of generating findings that are difficult to interpret because of uncertainties in the exposure assessment. Indeed, the results have been ambiguous. We found no consistent association between pesticides and breast cancer and weak evidence of associations with certain types of pesticide use . After cParallel to the drinking water sampling in phase 1, phase 2 included monitoring of EDC exposures in homes with these goals: identify common exposures, including mixtures, for toxicologic and epidemiologic study and regulation; identify the products or practices that lead to common exposures; identify factors that contribute to high-end exposures; test methods to reduce contaminant levels by changing product use and other practices; and develop methods of exposure assessment for future health studies.The household exposure study has not been linked to health outcomes in the epidemiologic study because of low statistical power for that purpose, and information on the health significance of these exposures is not available. This strategy of broadly studying exposure without an identified health outcome is atypical in public health studies—perhaps because health officials are uncomfortable dealing with the uncertain action implications of reporting on exposure without an established tie to health—but it has received strong scientific and public interest e.g., . This apState funding for environmental sampling in the Cape Cod study resulted from advocacy by MBCC, and breast cancer activist organizations also have provided financial support for the work. Recently, the household exposure study has become a point of connection between breast cancer advocacy and other health-affected groups. For example, the study team is currently collaborating with Brown University researchers and Communities for a Better Environment , a community-based environmental justice organization, to apply the methods in a low-income, ethnic-minority fenceline community, where the immediate focus will be on whether exposure data can be useful in evaluating emissions limits, flare rules, and emergency procedures.Still in a relatively early stage of development, the NIEHS Breast Cancer Centers and the Environment Research Centers were initiated with several important elements consistent with the precautionary principle. First, the RFA specified girls’ development through puberty as the health outcome, which represents a breakthrough in moving “upstream” in breast cancer research. Early age at puberty is a well-established risk factor for breast cancer, and age at puberty is falling, particularly among African-American girls, a group at greater risk than whites for breast cancer mortality, though not incidence . In addiBy including a laboratory research component as well, the centers elucidate biologic mechanisms, an important element in assessing plausibility, and develop tools for screening and testing chemicals for possible regulation. The laboratory component also facilitates research on a longer list of chemicals than the epidemiologic study. The RFA did not, however, specifically call for an investment in exposure assessment, although the lack of such methods is a significant barrier to studying EDCs , 2001. TThe centers’ steering committee, composed of scientist and advocate representatives, integrates epidemiologic and laboratory work, scientist and activist perspectives, and the interests of the different centers. This management approach represents innovation in both science and public involvement. The centers program recently held its first scientist–advocate conference , at whicAs the continuing increase in breast cancer incidence sparked activist demands for prevention-oriented research, laboratory evidence that many common pollutants are mammary carcinogens and/or EDCs provided new hypotheses about environmental factors. But the challenges in assessing relevant exposures to pollutants in a breast cancer study meant a mismatch between activist goals and the scientific methods typically used in investigator-initiated epidemiologic studies. By examining recent research—the Long Island and Cape Cod breast cancer and environment studies and the new NIEHS Centers—we can draw lessons for many public health problems for which scientific uncertainty is likely to persist.Each of these studies contributes novel public involvement methods and increases transparency in public health science, providing new models for community-based participatory research. Activists used legislation and appropriations processes to direct scientific inquiry and, in Massachusetts, founded the Silent Spring Institute as a scientific team with activist participation in governance. The 3-year scoping process in the Cape Cod study provided an opportunity to review scientific plausibility of multiple hypotheses, allowing activist and scientist perspectives to converge.Far from hindering science, the involvement of breast cancer activists has helped drive scientific innovation, particularly in the development and application of exposure assessment methods. Environmental and biologic sampling methods can identify common mixtures for further study and inform precautionary exposure reduction. GIS methods can assess historical exposures that women cannot report. The suggestive positive result for PAHs in the Long Island study provides the impetus for policies to reduce ubiquitous PAH exposure. At the same time, however, unresolved weaknesses in exposure assessment methodologies have hindered the success of epidemiologic components of the research programs, because they mean that negative results are insufficient to conclude that no relationship exists.Breast cancer activists were among the first and most powerful health-affected groups to make environmental research and prevention a priority. The resulting studies provide paradigmatic models for public health science for diseases whose links to environmental factors are difficult to prove. They argue for greater emphasis on exposure studies before undertaking health studies and on laboratory research on questions that do not lend themselves to human research. Yet they leave unanswered questions about when to invest in traditional epidemiologic studies, when negative results are sufficient, and how to pursue ambiguous positive results in further research and policy.


This study had three aims: to establish the incidence of ipsilateral breast tumour recurrence (IBTR) in a community treatment setting, to evaluate known factors – in particular younger age (< 40 years) – predictive for local recurrence, and to assess the impact of local recurrence on disease-specific survival (DSS).A consecutive series of 1,540 women with node-negative breast cancer, diagnosed between the ages of 18–75 years, were prospectively accrued between September 1987 and September 1999. All had undergone a resection of the primary breast cancer with clear margins, an axillary lymph node dissection with a minimum of four sampled nodes, and breast-conserving surgery (of any type).During the study follow-up period, 98 (6.4%) IBTRs and 117 (7.6%) deaths from or with breast cancer were observed. The median time to IBTR was 3.1 years and to death from or with disease was 4.3 years. In the multivariate Cox proportional hazards (PH) regression model for IBTR with adjuvant therapy factors, independent risk factors included age < 40 years (relative risk (RR) = 1.89, 95% confidence interval (CI) of 1.00 – 3.58), presence of intraductal disease  and histological grade . In the multivariate Cox PH regression model for DSS with adjuvant therapy factors, independent risk factors included previous IBTR , tumor size , progesterone receptor status , lymphatic invasion , and histological grade . The effects of competing risks could be ignored.The Cox PH analyses confirmed the importance of known risk factors for IBTR and DSS in a community treatment setting. This study also revealed that the early occurrence of an IBTR is associated with a relatively poor five-year survival rate. Breast-conserving surgery (BCS) has been a standard of care for some considerable time ,2. LocalIn comparison with clinical trial participants, community-based observational patient cohorts may provide enhanced generalizability. Beginning in 1987, we have followed a consecutive series of 1,540 women with node-negative breast cancer treated at eight Toronto hospitals . Women iWomen aged 18 to 75 years with node-negative breast cancer were accrued from September 1987 until September 1999. To be eligible for this prospective study, women had to have undergone a resection of a primary breast cancer with clear margins, and an axillary lymph node dissection with a minimum of four sampled nodes, based on pathology review. The median number of nodes removed was 11; the number of nodes removed ranged from 4 to 38 nodes. All patients with T2 tumours underwent staging with the use of bone scan, abdominal ultrasound/abdominal computed tomographic scan and chest X-ray. Eligible women were invited to participate by their treating physician. Written informed consent was obtained and final eligibility was based on chart review. Exclusion criteria included inadequate assessment of histological grade, inadequate staging, synchronous breast primary tumours, surgeon or patient refusal, or previous malignancies. For the purposes of this present report we included only women who had undergone BCS (of any type) and had any follow-up information.in situ disease.Patient and pathological features recorded, as reported previously , includeTreatment and subsequent follow-up data were collected in a standardized format. Charts were reviewed every 3 months during the first 2 years after diagnosis, every 6 months until 5 years after diagnosis, and every year thereafter. Follow-up for this report was terminated as of 10 January 2002, with an additional 6 months allowed for verification purposes. The time interval from the median participant entering the study to the termination date for analysis was 10.9 years. Follow-up data collected for each patient included treatment received, local and distant recurrences, and cause of death, with the corresponding dates. Local and distant recurrences were confirmed by review of reports or imaging conducted by MEB.A total of 1,540 women met the eligibility criteria for this report. Descriptive statistics compared the frequency distribution of measured patient and pathological features between groups defined by age (age < 40 years versus age ≥ 40 years).The two outcomes of interest in this study are time to local recurrence  and time to death with or from disease. Both invasive and intraductal IBTRs were included as events for the analysis of local recurrence. Deaths from and with disease defined events for DSS. Only prognostic factors previously identified in the literature were evaluated in the statistical analyses. Univariate survival analysis of each measured prognostic factor was conducted via the log-rank test with Kaplan–Meier curves and via the likelihood ratio statistic for Cox proportional hazards (PH) models -14.n = 26) were censored at their last known follow-up time for either event of interest. Censoring for IBTR could also occur for three reasons. IBTR-free women were censored at their death date (death from any cause) or at the study termination date. In addition, women who experienced a distant metastasis within 12 weeks before a diagnosis of IBTR (n = 10) were censored for IBTR at their diagnosis date for the distant metastasis [n = 80) were censored at their death times.Patients currently lost to follow-up (tastasis . This tip ≤ 0.05) or borderline significant (p < 0.1) prognostic factors identified from the univariate survival analyses, together with factors selected for hypothesis testing, were evaluated in multivariable survival models. Because any form of treatment  can be a confounding factor with patient and pathological features, all forms of treatment were forced into the final model. To evaluate the hypothesis that younger women (age < 40 years) experienced a higher rate of IBTR than older women (age ≥ 40 years), this factor was included in the multivariate modelling process for IBTR outcome as well. Pairwise interactions between the factor for young age and each of the other factors associated with IBTR were assessed separately in bivariate models that also included both variables. However, because very few younger women (age < 40 years) experienced a local recurrence (12 of 98), most interactions could not be evaluated because of inadequate power (results not shown).Using a Cox PH model, statistically significant (n = 8) or were censored (n = 12).The effect of time dependence of an IBTR on survival was taken into account in the statistical analyses of DSS by modelling IBTR as a time-dependent covariate in the multivariable Cox PH models. In addition, the landmark method  was used2 distribution for testing for a trend between the scaled Schoenfeld residuals and survival time.The proportional hazards assumption was assessed graphically and formally with a trend test statistic . Scaled In this study, women could experience one or both of the events of interest during follow-up: an IBTR, and death from or with breast cancer. If a woman does experience an IBTR, her risk for dying can be altered. Similarly, if a woman experiences a distant recurrence and subsequently dies from or with breast cancer, she is not really at risk for IBTR and so should not be treated as simply censored in any time-to-IBTR analyses. The competing risks between developing an IBTR and dying from or with disease were evaluated by modelling the cumulative incidence function for each event of interest  and fitt® software (Version 8.2) SAS System for Unix [All analyses were conducted with SAS/STATfor Unix  and R sofor Unix .Nearly two-thirds of the 1,540 eligible patients were postmenopausal at diagnosis . Just under 50% received adjuvant hormonal therapy and 15.5% received adjuvant chemotherapy; the proportion receiving adjuvant systemic therapy increased over time. Tamoxifen was the sole hormone therapy for 741 of the 758 women who received this adjuvant therapy. The predominant (196 of 239) chemotherapy regimen was CMF (cyclophosphamide–methotrexate–5-fluorouracil). The type of systemic adjuvant therapy differed with age, with younger women receiving less hormonal therapy (18% versus 52%) and more chemotherapy (43% versus 13%) than the older women. Younger women who were oestrogen receptor-positive were about half as likely to receive hormone therapy as older women who were oestrogen receptor-positive .n = 98) in this community-based study. The median time to IBTR was 3.1 years (SD 2.4), with nearly two-thirds (62 of 98) occurring within 4 years from surgery .The incidence of an isolated local recurrence was 6% , but this was apparently due to the association between IBTR and unknown histological grade. The variable multicentricity lost significance in the multivariate model, but because 11 of 12 women who experienced an IBTR and had areas of multicentricity were also classified as having ductal carcinoma in situ, the separate effects of these variables on IBTR could not be evaluated in these data.Although the age < 40 years variable was not statistically significant in the univariate Cox PH model, to assess the hypothesis about the increased incidence of local recurrence in this age group, this variable was also evaluated in a multivariate model adjusting for the effects of other relevant factors. In a multivariate model, age at diagnosis < 40 years and presence of intraductal disease were found to be independently associated with IBTR, whereas adjuvant therapy (particularly radiotherapy) was associated with reduced risk Table . HistoloThe diagnosis of an isolated IBTR significantly affected DSS. In a univariate Cox PH model for DSS, IBTR had a RR of 3.04  = 1.72 to 5.35). This risk diminished only slightly  in a multivariable Cox PH model for DSS. In addition, we found that an early IBTR diagnosis (within 1.7 years of surgery) resulted in a very poor 5-year survival rate.n = 15). In contrast to this poor survival outcome, women diagnosed with an IBTR more than 1.7 years from surgery (n = 83) or not diagnosed with an IBTR  so far and alive at 1.7 years from surgery had 5-year survival rates of 0.94. At the latest time of death (7.6 years) for the early IBTR group, 38% were alive, which was significantly less (log-rank test p ≤ 0.0001) than the 91% surviving in the non-IBTR or IBTR > 1.7 years group. Inspection of the pointwise test statistics reveals strong evidence that the group with an IBTR diagnosed within 1.7 years from surgery has a hazard rate different from that expected (χ2 = 47.2), with many more observed deaths (7) than expected (0.81).Twelve percent of the 117 women who died from or with disease during this study were diagnosed with a previous IBTR, with an overall median time to death of 4.3 years (SD 2.5). Five years after surgery, 67 of 117 deaths had occurred and the percentage surviving was 95%. This percentage decreased to 87% by 12 years from surgery. With stratification on IBTR status at the landmark time point , Figure p < 0.1) as well as the three treatment variables. In contrast with the analysis of IBTR-free survival, age at primary diagnosis < 40 years was not significant in the multivariate model. The diagnosis of IBTR increased the risk of death with or from breast cancer by 2.6. In this model, histological grade '2' or 3 was most strongly associated with the risk of mortality, with a RR 8.6-fold that of histological grade 1. Increasing tumour size and negative progesterone receptor status also retained significance in the multivariate model. However, the estimated RRs for the adjuvant treatment variables changed with adjustment for other factors in the multivariate model, owing to the association of treatment received with known prognostic factors [A multivariate Cox PH model for DSS (right side of Table  factors .p = 0.47). Patient age at diagnosis was statistically significant at the 5% level in a multivariable Cox PH model for IBTR, with a RR of 1.89 (95% CI = 1.00 to 3.58) but not in a univariate Cox PH model for IBTR .Our investigation of patient age at diagnosis as a prognostic factor for IBTR and DSS found that age was an important risk factor for IBTR but not for DSS. The Kaplan–Meier survival estimates of time to IBTR suggested differences between the older (age ≥ 40 years) and younger (age < 40 years) women after 5 years of follow-up but the difference was not significant on the basis of a log-rank test statistic .p values were compared with those obtained from the standard Cox PH model. Generally, results were identical to two decimal places and there were no real differences in the significance of the variables in the final models (results not shown). Thus, the effects of the competing risks could safely be ignored in this study.We also fitted proportional subdistribution hazards regression models of the final multiple variable models for time to IBTR and DSS. The estimated parameters (coefficients and their standard errors) and Wald statistic A summary plot of the curves for the competing risks can show how changes in the probability of one event can impact the probability of the other event. In Figure The global test of proportional hazards for the IBTR multivariate regression model was non-significant, as were univariate tests for non-proportionality for each prognostic factor in this model. Hence, there was no evidence that the proportional hazards assumptions were not met. For the disease-specific multivariate regression model, however, the global test of proportional hazards was significant, indicating evidence against this assumption. Two variables in this final model, oestrogen receptor status and hormone therapy, also showed evidence of non-proportionality. Plots of the scaled Schoenfeld residuals along with a fitted linear spline indicated that being negative or equivocal for oestrogen receptor status was associated with higher death rates for about the first 5 years after surgery but not thereafter. Hormone therapy also had a negative trend in these plots; the apparent benefit of this therapy developed slowly and did not appear until nearly 5 years from surgery. Thus, the estimated RRs for these time-dependent factors represent an average effect over the follow-up time (results not shown).Our study adds to the literature on local recurrence after BCS in four respects. First, the incidence of local recurrence (6%) in this community setting is comparable to that seen in clinical trial data. This level was achieved despite the fact that 15% of our patients did not receive radiotherapy. Because therapy was at the discretion of the treating physician, we assume that radiotherapy was not thought necessary or suitable for these women. Second, the median time to IBTR of 3.1 years closely parallels that (46 months) seen in a similarly treated, node-negative cohort as published by Cowen and colleagues . Third, The 5-year overall survival after IBTR in women treated with BCS is between 50 and 75% ,23-27. OYoung women have previously been found to have a worse prognosis than older women, in terms of increased rates of both local recurrence -30 and mThe competing risk analysis revealed that, in this study, the effects of the competing risks could be ignored. The summary plot of the cumulative incidences of IBTR and death from or with breast cancer Figure  showed hOur results support published data on factors associated with local recurrence, including the impact of early-onset breast cancer. We also demonstrate that the early occurrence of IBTR is associated with a relatively poor 5-year DSS of only 57%. The repeated identification of this adverse effect suggests that women with early local recurrence should be targets for clinical studies of 'pseudo-adjuvant' systemic therapy.BCS = breast-conserving surgery; CI = confidence interval; DSS = disease-specific survival; IBTR = ipsilateral breast tumour recurrence; PH = proportional hazards; RR = relative risk.The authors declare that they have no competing interests.MKN and MEB conceived of the study. KAK and AT performed the statistical analyses. The manuscript was drafted by MKN and KAK. SBB provided oversight of the data analyses and critical revision of the manuscript for its intellectual content. MEB, ILA and SBB designed the original study and continue to coordinate follow-up data collection. All authors read and approved the final manuscript.


A population-based case-control study was conducted in Sweden and Norway to analyse possible associations between breast cancer occurring before the age of 45 and several different characteristics of the women's reproductive life. A total of 422 (89.2%) of all eligible patients, and 527 (80.6%) of all eligible controls were interviewed. In univariate analyses, different characteristics of child-bearing , measures of the fertile or ovulating period  and symptoms of anovulatory cycles or infertility were all seemingly unrelated to, or at most weakly associated with breast cancer. Adjustment for possible confounding factors in multivariate analyses resulted in largely unaltered risk estimates with odds ratios close to unity and without any significant trends when the exposure variables were studied in categorised or in continuous form. We conclude that reproductive factors did not explain the occurrence of breast cancer before the age of 45 in this population.


COX-2 .926, COX-2 .5209, and COX-2 .8473) may reduce overall breast cancer risk or risk for subtypes of breast cancer by modulating the inflammatory response and may interact with aspirin or any NSAID use.The association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer risk remains unclear. Inconsistencies in previously reported findings may be partly due to differences in expression of cyclooxygenase (COX)-2. We hypothesized that genetic polymorphisms . There was no corresponding interaction for aspirin use, possibly because of limited power.No major effects of the three COX-2 .8473 may interact with NSAIDs to reduce risk for hormone receptor positive breast cancer.These data provide modest evidence that the C allele of  In recent years, several relatively large studies have examined the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer. A meta-analysis of 14 studies (six prospective studies and eight case-control studies)  observedCOX-2 encodes one of two COX enzymes that catalyze the synthesis of prostaglandins (PGs) from the dietary fatty acid arachidonic acid [2, have an organ-site-specific effect of increasing the levels of aromatase, thereby increasing estrogen and progesterone synthesis [P < 0.002) but not in ER/PR-negative ones [The anticancer activity of NSAIDs is believed to be due to inhibition of cyclooxygenase (COX)-2, which is over-expressed in many types of cancer, including breast cancer, and plays a major role in tumorigenesis ,9. COX-2nic acid . Increasnic acid . In breaynthesis -12. COX-ynthesis ,13, and ynthesis . COX-2 eive ones . Therefoive ones -18.COX-2 gene expression or be limited to certain subtypes of breast cancer. Thus, we hypothesized that potential functional genetic polymorphisms  in COX-2 that result in altered expression and/or activity of the protein may modulate the inflammatory response, modifying overall breast cancer risk or risk for subtypes of breast cancer. Single nucleotide polymorphisms (SNPs) in the promoter and 3'-untranslated region (UTR) of COX-2 were previously reported to modulate the risks for prostate, colorectal, esophageal, gastric, bladder, biliary tract, and non-small-cell lung cancer [COX-2 .926 G→C polymorphism examined here can result in higher COX-2 expression and lead to an approximate 30% reduction in promoter activity in vitro [COX-2 polymorphisms potentially associated with cancer risks have been reported. Little is known regarding COX-2 polymorphism and breast cancer risk and its potential interactions with aspirin and NSAID use [The previous inconsistent findings on the association between NSAIDs and breast cancer risk might be explained by interindividual differences in g cancer ,19-31. Ain vitro ,18. No fSAID use -35.in situ or invasive breast cancer between 1 August 1996 and 31 July 1997. Control individuals were frequency matched to the expected age distribution of the cases and were identified through random digit dialing for women aged under 65 years and through the Center for Medicare and Medicaid Services rosters for women aged 65 years and older. Eligible control individuals were women who spoke English and who resided in the same Long Island counties as the cases, but who had no personal history of breast cancer. The study was conducted with approval from participating institutional review boards, and in accordance with an assurance filed with and approved by the US Department of Health and Human Services.The study population of the Long Island Breast Cancer Study Project has been described in detail previously . In brien = 1,508) and 62.8% , respectively. Of those who completed the 100-minute main questionnaire, 73.1% of cases  and 73.3% of controls  donated a blood sample [Interview response rates among eligible cases and controls were 82.1%  a minor allele frequency of 5% or greater in Caucasians, according to literature data; and (b) more than 80% homology between human and rat/mouse genome, or (c) previous laboratory evidence indicating a significant functional effect, or (d) previous epidemiologic findings indicating associations with cancer susceptibility. Finally, three SNPs were selected and genotyped for the present study: COX-2 .926 G→C , which satisfies all four criteria; and COX-2 .5209 G→T  and COX-2 .8473 C→T , both of which satisfy three of the four criteria .The human ilobases . We collas dbSNP , UCSC Geas dbSNP , and Genas dbSNP . A totalCOX-2 gene sequence (GeneBank accession number D28235.1) and were (respectively) as follows: 5'-CAT TTA GCG TCC CTG CAA AT-3' and 5'-TAC CTT CAC CCC CTC CTT GT-3' for COX-2 .926; 5'-CAT GAT TAT GCC GCT TTC AA-3' and 5'-TCC ACC AAA GCT ACA AAC TGA-3' for COX-2 .5209; and 5'-TTC CAA TGC ATC TTC CAT GA-3' and 5'-TCA AAC AAG CTT TTA CAG GTG A-3' for COX-2 .8473. The sequences of TDI (Template-directed Dye-terminator Incorporation) probes were designed using Primer 3 software [COX-2 .926; reverse 5'-ACT TCA CTA TGA TGA TAT GGT AAT T-3' for COX-2 .5209; and reverse 5'-ATT TTT CTG TCA TCA AAC AAA AAC A-3' for COX-2 .8473. The three allele-specific dye terminators used for each of the three SNPs were G/C, C/A and G/A, respectively. The assay was validated by sequencing individuals with all three genotypes, and these known samples were used as positive controls on each plate.Genomic DNA was extracted  by standsoftware  as folloThe laboratory staff was blind to the case/control status of individuals. Based on 272 duplicated quality control samples randomly included in genotyping, an estimated error rate of 0.6% (5/816) was observed. Genotyping data were available for 1,067 (96.8%) cases and 1,110 (97.3%) controls who donated blood, which represent 70.8%  of eligible cases and 71.3%  of eligible controls.As part of the interviewer-administered main questionnaire, women were asked to report their intake of aspirin, ibuprofen, and acetaminophen. For 1,028 (96.3%) cases and 1,029 (92.7%) controls, both questionnaire data and DNA for genotyping were available. As previously described , 'ever uHardy-Weinberg equilibrium was tested to compare the observed and expected genotype frequencies among cases and controls, respectively . Bivaria2 test [Haplotype and diplotype frequencies were estimated from genotype data by PHASE version 2.1.1 ,47, base2 test . The mosGene-environment interactions were tested by evaluating departures from multiplicative interaction models by including main effect variables and multiplicative interaction terms in the logistic regression model with Wald statistic . BecauseCOX-2 .5209 and COX-2 .8473 genotypes were compatible with those expected from Hardy-Weinberg equilibrium, and the frequencies of the variant G and C alleles were respectively 20.0% and 34.1%. The genotype distribution for COX-2 .926 significantly deviated from Hardy-Weinberg equilibrium in both controls and combined cases and controls .The distributions of COX-2 SNPs, even when women were categorized by menopausal status  did not differ significantly from the controls, even when breast cancer groups were stratified based on hormone receptor status (data not shown).No main effects on reduced breast cancer risk were found for the three us Table . The freCOX-2 SNPs reconstructed using PHASE software [Haplotypes and diplotypes for the three software  resultedCOX-2 genotype, the decreased OR observed among ever users of aspirin who carried at least one variant C allele of COX-2 .8473  compared with nonusers carrying the wild-type TT genotype (Table P for interaction = 0.77). When restricted to hormone receptor positive cases, the reduction in breast cancer risk was slightly stronger for carriers of at least one variant C allele of COX-2 .8473 who ever used aspirin . No significant interaction between ever use of aspirin, ever use of NSAIDs, and variant C allele of COX-2 .8473 was observed in ER/PR-negative breast cancer  and 0.6 (95% CI = 0.2 to 1.4) compared with nonusers carrying all other diplotypes (data not shown). Ever use of any NSAID was associated with a pronounced reduction in OR among women carrying the diplotype of GTT/GGC  compared with nonusers with all other diplotypes, but numbers were small in these groups and no significant interaction was observed (data not shown).COX-2 in the initiation, promotion, and progression of cancers in different organs [COX-2 in breast cancer, and modification with NSAID use [COX-2 variant alleles and breast cancer risk were found. This finding is consistent with an observation from a nested case-control study conducted in Danish women (361 breast cancer cases and 361 matched controls) [COX-2 . 8473-CC genotype was associated with breast cancer risk  in an Austrian population (500 cases and 500 controls) [COX-2 genotypes to affect overall breast cancer risk. However, among women with hormone receptor positive breast cancer, there was some evidence to suggest that the reduction in risk associated with ever NSAID use (including both aspirin and nonaspirin NSAID use) was limited to women who carried the variant C allele for COX-2 .8473; however, there was no corresponding interaction between this polymorphism and ever aspirin use alone in this subgroup.The COX-2 pathway is now recognized to be important in human cancer development and progression . Numerout organs -52. HoweSAID use -35. In tontrols) . The freontrols) ,35. We fCOX-2 .8473 variant C allele in the 3'-UTR in Caucasian populations to range between 31.4% and 46.5% [COX-2 .8473 variant C allele had a significantly increased risk for lung cancer (ORs 2.12 for CT genotype and 4.28 for CC genotype), an expanded study in the same population [Several previous studies, including the SNP500 database , have rend 46.5% -21, whicnd 46.5%  found thCOX-2 .8473 polymorphism and NSAIDs among women with hormone receptor positive breast cancer are biologically plausible. Polymorphisms present in the regulatory 3'-UTR of COX-2 might hinder the binding of RNA-binding proteins and modulate mRNA stability and degradation, and finally decrease the production of protein [COX-2 .8473 polymorphism, located downstream of the stop codon in the adenylate/uridylate-rich 3'-UTR region [2 and aromatase synthesis. The consequent reduction in the local production of estrogen, in turn, is associated with the reduced breast cancer risk [COX-2 .8473 polymorphism may increase the likelihood of a spurious association or indicate the presence of some other functional SNPs in strong linkage disequilibrium with this SNP.Our findings on the roles of  protein -56. TherR region , could pcer risk -13,57,58COX-2 .8473 polymorphism and ever NSAID use in ER-positive or PR-positive tumors than that in ER/PR-negative tumors is of particular interest. This might be an indication that different mechanisms are involved in subtypes of breast cancer. The lower frequency of COX-2 over-expression in hormone receptor positive tumors may make it easier to observe a significant protective effect of NSAID use among carriers of the variant C allele of COX-2 .8473. This is consistent with the observation that elevated expression of COX-2 was statistically significantly associated with poor survival in ER-positive or PR-positive tumors but not in ER/PR-negative ones [2 and aromatase synthesis, and decreasing estrogen production. However, there are also several discrepant reports showing that long-term daily use of aspirin significantly increased risk for ER/PR-negative breast cancer [COX-2 .8473 in ER/PR-negative breast cancer, perhaps because of limited power . This is consistent with the results from our analysis of the interactions between nonaspirin NSAID use alone, aspirin use alone, and COX-2 .8473 polymorphism (data not shown). Thus, the difference in interaction between ever aspirin use, ever NSAID use, and the COX-2 .8473 polymorphism might well be the result of limited power for subgroup analyses rather than lack of a true association.The more pronounced interaction between the ive ones . The samt cancer . We did The relatively large sample size, population-based study design, and availability of both genotyping and NSAID information are the strengths of the study. The NSAID data were obtained from retrospective reporting of medication use, which might lead to recall bias. However, in order to explain our findings, cases should under-report more than controls or the accuracy of reporting should be related to genotype status or ER/PR status. Thus, it is unlikely that recall bias played a major role in explaining the present findings. Previous sensitivity analysis also indicated that the missing data would not have altered the overall conclusion of a protective effect between aspirin use and breast cancer .COX-2 genotype limited power to evaluate dose-response effects.Another consideration was that our NSAIDs information did not include the use of prescription drugs containing NSAIDs . The presumed 'unexposed' women who used prescription NSAIDs would be included in the nonuser category and lead to an underestimation of inverse associations. Such a misclassification of users as nonusers would tend to bias estimates of NSAID effects toward the null. The extensive information collected in the study for evaluating confounding factors and effect modifiers allowed us to assess confounding in the data analysis. ORs changed less than 10% when considering potential confounding factors individually or in multivariate models, indicating that the effects of confounding are limited. Inclusion of age at reference in logistic models minimized any possible residual confounding effect of age. Although our questionnaire also included variables on duration and frequency of aspirin and other NSAID use, providing some information on dose, the small sample size in some subgroups when categorized by COX-2 .8473 variant C allele may be a genetic modifier for ever use of NSAIDs and reduced breast cancer risk among hormone receptor positive cases, but we observed no corresponding interaction with aspirin use alone, which may be due to reduced power in this subgroup. Because there has been no laboratory evaluation of the biologic function of COX-2.8473 polymorphism, additional studies to examine the functionality of the polymorphism and the potential interactions with various inflammation-related genes are warranted.This population-based case-control study provided some evidence to support our hypothesis that the CI = confidence interval; COX = cyclooxygenase; ER = estrogen receptor; NSAID = nonsteroidal anti-inflammatory drug; OR = odds ratio; PG = prostaglandin; PR = progesterone receptor; SNP = single nucleotide polymorphism; UTR = untranslated region.The authors declare that they have no competing interests.JS was responsible for genotyping polymorphisms, data analyses and interpretation, and drafting of the manuscript. MG contributed to study design, sample collection and manuscript preparation, and provided expertise in data analyses. MBT, SL, and AN contributed to the study design, sample collection, and manuscript preparation. RS was responsible for supervising laboratory work, and contributed to study design, biospecimen processing and manuscript preparation. All authors read and approved the final manuscript.


MnSOD gene results in a Val → Ala change at the -9 position of the mitochondrial targeting sequence , which alters the protein secondary structure and thus affects transport of MnSOD into the mitochondria.It has been suggested that oxidative stress and mitochondrial DNA damage play important roles in breast cancer carcinogenesis. Manganese superoxide dismutase (MnSOD) is a major enzyme that is responsible for the detoxification of reactive oxygen species in the mitochondria. A T → C substitution in the MnSOD Val-9Ala polymorphism was examined in 1125 breast cancer cases and 1197 age-frequency-matched control individual.We evaluated this genetic polymorphism in association with breast cancer risk using data from the Shanghai Breast Cancer Study, a population-based case–control study conducted in urban Shanghai from 1996 to 1998. The Breast cancer risk was slightly elevated in women with Ala/Ala genotype , particularly among premenopausal women , as compared with those with Val/Val genotype. The increased risk with the Ala/Ala genotype was stronger among premenopausal women with a higher body mass index  and more years of menstruation . The risk among premenopausal women was further increased twofold to threefold among those with a low intake of fruits, vegetables, vitamin supplements, selenium, or antioxidant vitamins, including carotenes and vitamins A, C, and E. However, the frequency of the Ala allele was low (14%) in the study population, and most of the ORs provided above were not statistically significant.MnSOD gene may be associated with increased risk of breast cancer among Chinese women with high levels of oxidative stress or low intake of antioxidants. Studies with a larger sample size are needed to confirm the findings.The present study provides some evidence that genetic polymorphism in the  For all participants, current weight, circumference of the waist and hips, and height while sitting and standing were measured. Blood samples were obtained from 1193 (82%) cases and 1310 (84%) control individuals who completed in-person interviews. These samples were processed on the same day, typically within 6 hours of sample collection, and stored at -70°C until bioassays were performed.Usual dietary habits over the past 5 years were assessed by in-person interview, using a validated quantitative food frequency questionnaire ,23. The MnSOD genotypes were determined with PCR–restriction fragment length polymorphism methods, as reported previously [Ile58Thr polymorphism were 5'-AGCTGGTCCCATTATCTAATAG-3' (forward) and 5'-TCAGTGCAGGCTGAAGAGAT-3' (reverse). The PCR was performed in a PTC-200 Peltier Thermal Cycler . Each 20 μl of PCR mixture contained 5 ng DNA, 1× PCR buffer with 1.5 mmol/l MgCl2, 0.16 mmol/l each of dNTP, 0.5 μmol/l of each primer, and 1 unit of HotStarTaq™ DNA polymerase . The reaction mixture was initially denatured at 95°C for 15 min, followed by 35 cycles of 94°C for 30 s, 60°C for 30 s, and 72°C for 30 s. The PCR was completed by a final extension cycle at 72°C for 7 min. The PCR products were digested by the NgoMIV and EcoRV restriction endonucleases for the Val-9Ala and Ile58Thr polymorphisms, respectively. The DNA fragments were then separated using 3% Nusieve/Agarose gel and visualized by ethidium bromide staining.Genomic DNA was extracted from buffy coat fractions. The eviously ,25 but wNgoMIV. For the Ile58Thr polymorphism the PCR product (139 bp) with T allele (Ile) was digested to two fragments (117 bp and 22 bp), whereas the PCR product with C allele (Thr) cannot be cut by EcoRV. No Ile58Thr polymorphism was found in 400 individuals in our study, and we did not perform genotyping for this polymorphism in all participants.For the Val-9Ala polymorphism, the PCR product (107 bp) with C allele (Ala) was digested to two fragments (89 bp and 18 bp), whereas the PCR product with T allele  cannot be cut by The laboratory staff was blind to the identity of the participants. Quality control (QC) samples were included in the genotyping assays. Each 96-well plate contained one water, two CEPH 1347-02 DNA, two blinded QC DNA, and two unblinded QC DNA samples. The blinded and unblinded QC samples were taken from the second tube of study samples included in the study. The Val-9Ala genotypes determined for the blinded QC samples were in complete agreement with the genotypes determined for the study samples. Genotyping data were obtained from 1125 cases and 1197 control individuals. The major reasons for incomplete genotyping were insufficient DNA and unsuccessful PCR amplification.2 test and t-test were used, respectively. Conditional logistic regression models adjusted for age were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to measure the strength of the association between the MnSOD gene Val-9Ala polymorphism and breast cancer risk [MnSOD genotypes and breast cancer risk. A composite dietary antioxidant index was derived to incorporate information on intake of four antioxidant nutrients  [To evaluate case–control differences for categorical data, including genotype distribution and continuous variables, χcer risk ,27. Anal, and E) . Intake , and E) . All staThe distribution of selected demographic characteristics and major risk factors for breast cancer are shown in Table MnSOD Val-9Ala polymorphism was in Hardy–Weinberg equilibrium for both cases and control individuals. No Ile58Thr polymorphism was found in our study population. Thus, we report here the results for the Val-9Ala polymorphism.The frequencies of the Ala allele were 14.3% and 14.0% in cases and control individuals, respectively. Genotype frequencies were 73.9% , 23.6 , and 2.5% (Ala/Ala) for cases, and the respective frequencies were 73.9%, 24.2%, and 1.9% for control individuals  of menstruation and BMI, factors that are related to the duration and level of estrogen exposure  and 2.2 (95% CI 0.5–9.4) among premenopausal and postmenopausal women, respectively, who had a lower dietary antioxidant index.We further evaluated the association of the ke Table . IntriguAmbrosone and colleagues previously reported that Val/Val genotype was significantly associated with an increased risk of breast cancer among premenopausal Caucasian women, particularly those who had a low intake of fruits and vegetables and of dietary ascorbic acid and α-tocopherol . In thisWe observed in this study that women carrying the Ala/Ala genotype who had a higher BMI or a longer duration of menstruation were at higher risk of breast cancer, particularly among premenopausal women. Some ROS may be generated from estrogen metabolism through catechol redox cycling ,4. MitruMnSOD Val-9Ala polymorphism with other cancers, although the results were inconsistent among cancer sites. Recently, Woodson and coworkers [MnSOD Val-9Ala polymorphism with lung cancer risk in a case–control study conducted in Taiwan. Interestingly, Wang and coworkers [MnSOD genotype with breast and lung cancers suggest that the role played by MnSOD in carcinogenesis may vary for different tumors. The mechanism underlying this tumor type difference remains to be investigated.Several studies have evaluated the association of the oworkers  reportedoworkers . Recentloworkers  reportedoworkers  reported2•- radical. It was predicted that MnSOD Val-9Ala polymorphism might alter transfer of the MnSOD enzyme into mitochondria [in situ carcinomas or non-neoplastic breast epithelial cells.The SODs are the first and most important line of antioxidant enzyme defense against ROS and particularly Ochondria ,12. Recechondria  reportedchondria ,35. MnSOchondria . Over-exchondria . Recentlchondria  reportedSOD genes are polymorphic. It would be interesting to analyze jointly all of the three genes to evaluate any gene–gene interaction in relation to breast cancer risk. O2•-, if not scavenged by SOD, may react with nitric oxide radical (NO•) to form the strong oxidant peroxynitrite (ONOO-) [2•- to H2O2, which is further detoxified by GPX1 in mitochondria. If not be quenched, H2O2 will be converted to the more toxic hydroxyl radical (•OH). Thus, study of the joint effect of the MnSOD, nitric oxide synthase, and GPX1 gene polymorphisms might provide further information on the role played by oxidative stress in cancer risk.Three distinct isoforms of SOD have been identified in mammals. These three isoforms are encoded by three distinct genes located on different chromosomes . All thr (ONOO-) . MnSOD dMnSOD Val-9Ala polymorphism in our control population were 86.0% and 14.0%, respectively. The minor allele (Ala) frequency (14.0%) is comparable with that in Japanese (14.1%) [Frequencies of the Val and Ala alleles of the  (14.1%)  and Chin (14.1%)  populati (14.1%) -20. The The current study has many strengths. First, the high participation rate and the population-based study design substantially reduce selection bias. Second, Chinese women living in Shanghai are relatively homogenous in their ethnic background; over 98% are from a single ethnic group (Han Chinese). Therefore, the potential confounding effect of ethnicity is not a major concern in this study. Third, the extensive information collected on lifestyle factors allowed comprehensive evaluation of their interaction with genetic polymorphisms. The risk estimates derived from age-adjusted and multivariable adjusted analyses were similar, indicating that a confounding effect is unlikely to be a concern in this study.MnSOD Ala/Ala genotype was associated with a slightly but nonsignificantly elevated risk of breast cancer. The positive association was more evident among premenopausal women, particularly among those who consumed a low level of antioxidant vitamins or with high levels of oxidative stress. However, the study is limited by the low frequency of the Ala allele in the Chinese population, and most of the ORs were not statistically significant. Studies with a larger sample size are needed to confirm the findings.In this population-based case–control study conducted in Chinese women, we found that the QC, X-OS, and WZ participated in interpretation of results and writing the manuscript. QC participated in laboratory assays. WW conducted the statistical analyses. J-RC, QD, and Y-TG participated in field operation.The authors declare that they have no competing interests.BMI = body mass index; bp = base pairs; CI = confidence interval; GPX = glutathione peroxidase; MnSOD = manganese superoxide dismutase; OR = odds ratio; PCR = polymerase chain reaction; QC = quality control; ROS = reactive oxygen species.


The relationship between Quetelet's index and subsequent risk for cancer of endocrine target organs was studied in a cohort of 47,003 women, examined for height and weight in the years 1963-65, and followed up in the Swedish Cancer Register until 1987. High Quetelet's index was associated with a decreased risk for breast cancer among women less than 55 years of age at risk, while a high Quetelet's index predicted an increased risk among older women. Among women > or = 55 years of age, the excess relative risk for breast cancer associated with high Quetelet's index declined significantly during the follow-up period. Cancer of the ovaries and the uterine cervix were not significantly related to Quetelet's index in any age group. In women > or = 55 years of age, the relative risk for cancer of the uterine corpus associated to Quetelet's index was higher than that for breast cancer, and this association persisted during the entire follow-up period of more than 20 years. In spite of the fact that endometrial cancer is less common than breast cancer, because of the stronger relation between overweight and endometrial cancer, more endometrial cancer would be attributable to obesity than breast cancer.


To examine the hypothesis that radiotherapy for breast cancer can cause myocardial infarction, cause-specific mortality by laterality of the primary tumour was analysed among 54,617 breast cancer patients reported to the Swedish Cancer Registry during 1970-1985. The rationale was that radiotherapy for a left-sided breast cancer invariably results in higher doses of radiation to the myocardium than a similar treatment given for a right-sided tumour whereas other possible risk factors for cardiovascular disease probably are unrelated to the laterality of the tumour. The median follow-up was 9 years (range 1-17 years). Patients with left-sided tumours were found to have a higher mortality due to myocardial infarction than patients with right-sided tumours (P less than 0.01) but there was no difference in regard to total intercurrent mortality. Further analyses of individual radiotherapy studies are warranted to quantify the excess risk associated with radiation and to study the significance of the type of radiation, portal arrangements, total dose and fractionation. It seems reasonable to assume that adverse effects of radiation are dose-related and may thus be minimised or prevented by the use of appropriate treatment techniques.


Information was obtained on the health status or cause of death in the mothers of a population-based series of 143 children with soft tissue sarcomas. Among these mothers there were 6 cases of breast cancer. All 6 women were pre-menopausal and 2 had bilateral disease. This represents a significant 3-fold excess risk of breast cancer. Malignant disease had occurred in 6 other women whose ages at diagnosis ranged from 33 to 58 years. This was not significantly in excess of expectation. The incidence of cancer among mothers of various sub-groups of children was computed. For breast cancer mothers of: boys, children who were less than the median age at diagnosis, and children who had pelvic tumours had a greater excess risk than the group as a whole. Among those sub-groups of mothers the highest excess risk was 13.5. For other cancers, no sub-group showed an incidence which was significantly above the expected. A high proportion of infiltrating lobular carcinoma was found among the breast cancers, and histological type may indicate familial disease. These findings are consistent with the cancer family syndrome described by Li & Fraumeni in 1969, but the present results suggest that a higher proportion of childhood soft tissue sarcoma than was hitherto suspected may have a genetic aetiology. Further pedigree and laboratory studies may help to identify familial cases at the time of the child's diagnosis.


It has recently been found by various authors that despite a normal serum concentration of oestradiol (E2), the percentage of non-protein-bound or free E2 is abnormally high in breast cancer patients. Since it is the free E2 which is considered to be biologically active, confirmation of this finding would be most relevant to the pathogenesis of breast cancer. Using Hammond's centrifugal ultrafiltration dialysis method we have measured free E2 in heparinized plasma from 68 premenopausal women (a) at high familial risk of breast cancer (n = 18), (b) with benign breast disease (n = 17), (c) cured of T1N0M0 breast cancer at least 6 months previously (n = 17) and (d) normal controls matched for age, parity and Quetelet index (n = 16). Sex hormone binding globulin (SHBG) was measured as [3H]-dihydrotestosterone binding capacity. Free E2 and SHBG were also measured in the serum of (e) postmenopausal patients having breast cancer (n = 38) and (f) matched control cancer patients (n = 67). We confirmed a very good inverse correlation between log free E2 per cent and log SHBG (P less than 0.0001). The regression lines for groups (a)-(d) were not statistically different. The regression lines for groups (e) and (f) were identical and ran nearly parallel to those for groups (a)-(d) though somewhat lower. This small difference may be ascribed to menopausal status. Therefore, we found no difference in free E2 percentage, calculated free E2 concentration or SHBG between premenopausal women at risk, women with benign breast disease, patients cured for early breast cancer or having breast cancer and matched controls. However, postmenopausal breast cancer patients had a significantly higher total serum E2 concentration and, by consequence a higher calculated free E2 concentration compared to the carefully matched control group.


N-acetyltransferase 2 is a polymorphic enzyme in humans. Women who possess homozygous polymorphic alleles have a slower rate of metabolic activation of aryl aromatic amines, one of the constituents of tobacco smoke that has been identified as carcinogenic. We hypothesized that women with breast cancer who were slow acetylators would be at increased risk of breast cancer associated with active and passive exposure to tobacco smoke.We used a case-only study design to evaluate departure from multiplicativity between acetylation status and smoking status. We extracted DNA from buccal cell samples collected from 502 women with incident primary breast cancer and assigned acetylation status by genotyping ten single-nucleotide polymorphisms. Information on tobacco use and breast cancer risk factors was obtained by structured interviews.We observed no substantial departure from multiplicativity between acetylation status and history of ever having been an active smoking  or ever having had passive residential exposure to tobacco smoke . The estimates for departure from multiplicativity between acetylation status and various measures of intensity, duration, and timing of active and passive tobacco exposure lacked consistency and were generally not supportive of the idea of a gene–environment interaction.In this, the largest case-only study to evaluate the interaction between acetylation status and active or passive exposure to tobacco smoke, we found little evidence to support the idea of a departure from multiplicativity. N-acetylated in the liver by N-acetyltransferase-2 (NAT2) or N-acetyltransferase-1 (NAT1) [N-oxidized by P450 enzymes in the liver or in extrahepatic tissues [N-acetylation for aromatic amines but not for heterocyclic amines. The product of the oxidation is then either O-acetylated by NAT2 or NAT1, a reaction that yields the activated electrophile, or detoxified by competing enzymatic pathways [The aromatic and heterocyclic amines are among the constituents of tobacco smoke that have been identified as carcinogens ,2. These1 (NAT1) . This ispathways . The NATNAT2 is a polymorphic enzyme in humans ,7-10. ThMost epidemiologic studies that have examined the relation between active cigarette smoking and breast cancer have found weak or null associations ,18. A meWe collected genetic and behavioral information from incident primary breast cancer cases arising in five different sites across the United States. We used a case-only design to examine the potential interaction between acetylation status – as assigned by NAT2 genotype – and self-reported active or passive smoking status. We hypothesized that slow acetylators would be at increased risk of breast cancer associated with both active and passive smoking, and that these risks would be more pronounced among women whose exposure began before their first pregnancy or at an early age. The case-only design is optimal for assessing multiplicative interaction when the genotype and environmental exposure are independent of one another. This investigation is the largest case-only study to examine the interaction between NAT2 acetylation status and history of tobacco exposure as it relates to the risk of breast cancer.The cases of female breast cancer included in this analysis were identified as parts of two study populations ,27. The Introductory letters were mailed to breast cancer patients in 2001 and 2002. A trained interviewer followed the letter with a telephone call to answer questions and solicit participation. Patients who agreed to participate were sent an enrollment package containing an introductory letter, summary information about the study, an informed consent form, instructions for submitting a mouthwash sample, a safety-sealed sample of mouthwash, and a wide-mouth sample-collection bottle. Participants collected the sample and returned it in a postage-paid box along with their informed consent form. Buccal cells were precipitated by centrifugation and stored at -70°C until a batch of 90 samples had been collected. Batches were sent by overnight delivery on dry ice to Qiagen Genomics  for DNA extraction and genotyping.Qiagen Genomics applied proprietary Masscode technology to measure Masscode tags, which are low-molecular-weight compounds linked to the DNA via a photocleavable linker. The tag is cleaved in flow into a mass spectrometer, and a Microsoft Access database converts the raw analytical data into statistically generated genotype calls. The assay has been validated in over one million genotypes. Existing primers were used to characterize NAT2 genotypes at ten single-nucleotide polymorphisms (SNPs) in each buccal cell sample., and the predicted haplotypes with the highest probability were used for the primary analyses.The Qiagen genotyping data characterized each participant as homozygous wild-type, heterozygous, or homozygous polymorphic at each SNP. Inferred haplotypes were estimated from the genotyping data using an expectation-maximization algorithm implemented in the software program SNPHAP Patients who were included in the study were interviewed on the telephone by trained interviewers using a structured interview to obtain information on demographic characteristics, history of active and passive exposure to tobacco smoke, and known or suspected risk factors for breast cancer. Patients from the Cape Cod study population were interviewed between March 1997 and March 1998. Patients from the second study population were interviewed approximately 40 months after their date of diagnosis to gather the variables primarily used in this analysis.The literature on the expression of specific SNPs in the NAT2 gene guided the phenotypic assignments for each haplotype used in this study ,28-34. WWe considered a woman an active smoker if she reported smoking 100 or more cigarettes in her lifetime, and a passive smoker if she was not herself a smoker but reported living with someone who was a smoker. Women who were neither active nor passive smokers were considered separately. For women who reported having smoked 100 or more cigarettes in their lifetime or who lived with someone who smoked, information on the duration, intensity, and timing of exposure to tobacco smoke (active or passive) was also collected.2). A woman was considered to have a first-degree family history of breast cancer if she reported that her mother, sister(s), or daughter(s) had been diagnosed with breast cancer. We defined alcohol use according to the number of drinks a woman reported 'usually' having: nondrinker, ≤ one drink/month, few drinks/month, few drinks/week, almost every day, and unknown.In addition to information about smoking, we collected information on health and behavioral risk factors, including alcohol use, body mass index (BMI), family history of breast cancer (yes or no), history of benign breast disease, and parity. BMI was calculated as weight divided by the square of height (kg/mN-acetyltranferase activity groups do not differ in their phenotypic expression (acetylation status). Based on this finding and others [Ambrosone and colleagues  found thd others ,36, we cd others  to quantWe also evaluated departure from multiplicativity for variables describing the duration, intensity, and timing of active smoking or exposure to passive smoking. For active smokers, we examined the ORs in categories of the number of packs of cigarettes smoked per day, duration of smoking, age at onset of smoking, when a woman began smoking in relation to the first live birth of a child, and time since cessation of smoking. For passive smokers, we examined the duration of passive exposure, age when first passive exposure began, and when this first passive exposure occurred in relation to the first live birth of a child.P = 0.0001; and 74 versus 73 in the second study population, P = 0.03), reflecting greater losses to follow-up among older women. Age was not associated with genotype among the participants. The proportion of participants who were slow acetylators, active smokers, and passive smokers did not vary significantly with their site of enrollment. Among the genotyped controls in the Cape Cod study, the OR for association of acetylation status (fast versus slow) with exposure to tobacco smoke  was 1.06 (P = 0.90). This finding is consistent with those of earlier studies [Among the Cape Cod population, 330 of 483 eligible women agreed to receive a sample collection kit; the remainder refused or could not be contacted. Of the 330 who received a kit, 272 returned a sample and 269 samples yielded DNA that could be genotyped. Among the second study population , 372 of 410 eligible women agreed to receive a sample collection kit and the remainder refused or were unable to be contacted. Of the 372 who received a kit, 321 returned a sample and 233 had samples that yielded DNA that could be genotyped and had the requisite interview data. In both studies, 56% of eligible participants were genotyped and included in the analysis. The proportion of smokers among nonparticipants was not significantly different from that among participants in either study population. The mean age was greater among nonparticipants than among participants  = 0.9) or of ever having experienced passive residential exposure to tobacco smoke (AOR = 0.7) Table . These rEstimates for the departure from multiplicativity between acetylation status and the various measures of intensity, duration, and timing of active and passive tobacco exposure are presented in Table The estimates for departure from multiplicativity between acetylation status and the measures of duration and timing of passive exposure to tobacco also lacked consistency. For the variable describing the duration of passive exposure to tobacco in the residence, we observed null and less than null associations with slow acetylation status: AOR = 1.0 for <20 years, 0.6 for 20 to <40 years, and 0.8 for 40+ years. We observed a departure from multiplicativity between slow acetylation status and passive exposure occurring exclusively before a woman's first live birth (AOR = 1.9), and a positive departure for women whose first passive exposure to tobacco smoke occurred between the ages of 12 and 20 (AOR = 2.4).In this, the largest case-only study to evaluate the interaction between acetylation status and exposure to tobacco smoke, we found little evidence to support a departure from multiplicativity between acetylation status and a history of active smoking for women with breast cancer. There is some suggestion that women who were slow acetylators were at higher risk from passive exposure to tobacco smoke before their first live birth than women who had never been either passive or active smokers. A similar positive departure was observed for women who were first passively exposed between the ages of 12 and 20. The effect estimates observed in this study for measures of intensity, duration, and timing of exposure showed no consistent pattern and in some instances were statistically unstable.Our study is one of only a few to assess the interaction between exposure to tobacco smoke and acetylation status in relation to breast cancer risk. Hunter and colleagues , in addiIn the only other case-only analysis, Ambrosone and colleagues  found a To date, numerous polymorphisms on the NAT2 gene have been identified Table , which hMisclassification of either the genetic or environmental variables involved in an assessment of interaction by case–control design can give rise to the appearance of interaction when, in fact, there is none . Our anaWeighing against this advantage of the case-only design is the limitation that only departure from multiplicativity can be assessed. Many epidemiologists weigh departure from additive interaction more heavily, arguing that the additive scale corresponds better to the biologic meaning of synergistic effects . A furthThese results must be interpreted with the following additional limitations in mind. First, only 56% of eligible cases were available for analysis. Participation was not related to smoking status and although participation was related to age, age was not related to genotype. We expect that the selection of participants introduced no substantial bias, although we acknowledge that our study of breast cancer survivors may have influenced the estimates of effect in ways that we are unable to anticipate. Second, haplotypes were inferred from genotyping data by assigning the haplotype with the maximum probability to each case. Forty-one percent of haplotype assignments had probabilities of 100% and 91% had probabilities of 80% or better. Less than 5% had probabilities of less than 50%. We expect that the procedure used to infer haplotypes introduced little error.This large case-only analysis is the first to be able to assign acetylation status on the basis of ten SNPs. No previous analysis assigned acetylation status on the basis of more than four. In addition, the study involved the largest number of breast cancer cases used to investigate the interaction between NAT2 acetylation status and exposure to tobacco smoke as related to breast cancer risk. The combination of the most complete genotyping data and the large case-only design provides important advantages, the results of which do not suggest any substantial interaction between acetylation status and exposure to tobacco smoke in the etiology of breast cancer. Weighing against the null result is the potential for an unanticipated bias towards the null to have arisen by selection of breast cancer survivors from among the incident cases.N-acetyltransferase; OR = odds ratio; PCR–RFLP = polymerase chain reaction–restriction fragment length polymorphism; SNPs = single-nucleotide polymorphisms.AOR = adjusted odds ratio estimate of departure from multiplicativity; BMI = body mass index; CI = confidence interval; NAT = The author(s) declare that they have no competing interests.TL conceived of the study, collected genotyping samples, participated in data analysis, and drafted the manuscript. BB conducted data analysis and drafted the manuscript. JW inferred haplotypes from the genotyping data using SNPHAP and drafted the manuscript. AA collected interview data from the Cape Cod population and drafted the manuscript. All authors read and approved the final manuscript.


Female breast cancer incidence rates in Utah are among the lowest in the U.S. The influence of the Church of Jesus Christ of Latter-day Saint (LDS or Mormon) religion on these rates, as well as on disease-specific survival, will be explored for individuals diagnosed with breast cancer in Utah from 1985 through 1999.Population-based records for incident female breast cancer patients were linked with membership records from the LDS Church to determine religious affiliation and, for LDS Church members, level of religiosity. Incidence rates were age-adjusted to the 2000 U.S. standard population using the direct method. Cox proportional hazards model was used to compare survival among religiously active LDS, less religiously active LDS, and non-LDS with simultaneous adjustment for prognostic factors.Age-adjusted breast cancer incidence rates were consistently lower for LDS than non-LDS in Utah from 1985 through 1999. Rates were lower among LDS compared with non-LDS across the age span. In 1995–99, the age-adjusted incidence rates were 107.6 (95% CI: 103.9 – 111.3) for LDS women and 130.5 (123.2 – 137.9) for non-LDS women. If non-LDS women in Utah had the same breast cancer risk profile as LDS women, an estimated 214 (4.8%) fewer malignant breast cancer cases would have occurred during 1995–99. With religiously active LDS serving as the reference group, the adjusted death hazard ratio for religiously less active LDS was 1.09 (0.94 – 1.27) and for non-LDS was 0.86 (0.75 – 0.98).In Utah, LDS lifestyle is associated with lower incidence rates of female breast cancer. However, LDS experience poorer survivability from breast cancer than their non-LDS counterparts. Parity and breastfeeding, while protective factors against breast cancer, may contribute to poorer prognosis of female breast cancer in LDS women. Breast cancer is the most frequently diagnosed cancer among women in the United States . Of 668,About 70% of the 2.3-million population in Utah is affiliated with the Latter-day Saint (LDS or Mormon) religion ,5. HenceThe current study updates the findings of Lyon et al.  to the yUtah Cancer Registry (UCR) data were linked to LDS Church membership records to estimate breast cancer survival according to LDS (religiously active and less active) and non-LDS populations in Utah during 1985–99.th Revision, as 174.0 – 174.9 [th Revision, which uses an alphanumeric system and codes them as C50 [The UCR, established in 1966, has continuously participated in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute since 1973. UCR staff members and local cancer registrars identify incident cases of cancer among Utah residents through routine and systematic review of pathology reports, medical records, radiation therapy records, hospital discharge lists, and vital records. Tumor characteristics including histology, grade, and primary site are coded according to the International Classification of Disease for Oncology-Second Edition (ICDO-2) . Breast  – 174.9 , and 10tm as C50 . Registrm as C50 .In order to provide valid estimates of cancer survival, a high percentage of cancer cases must be routinely followed to ascertain both vital status and date of last contact. UCR records are linked four times each year with records of death certificates from the Office of Vital Records and Health Statistics from the Utah Department of Health. Results from these routine linkages identify cancer patients who have died, regardless of their cause of death. Registry staff members work closely with cancer registrars in local hospitals to document, through systematic review of medical records, the date of last contact for those cancer patients not known to be deceased. Records for these patients are also linked annually with administrative databases, including Medicaid reimbursement claims, Utah driver license records, and Utah voter registration lists; these databases are often a source of updated information regarding vital status and/or date of last contact. According to SEER Program standards, follow-up is considered to be current when the Registry documents that a patient has died, or when the Registry documents that a patient was alive within 18 months of the annual anniversary of the date of original cancer diagnosis. By this definition, 97.9% of the patients in the present study were determined to have complete follow-up at the time data were captured for analysis.UCR records were linked to LDS church membership records to determine membership in the LDS church. A person was identified as a member of the LDS church if the membership record included a baptismal date. The linkage process took place under direct supervision of the Church and the UCR and was conducted in the Church's Member and Statistical Records Department. After the records were linked, all personal identifying information was stripped from the database to ensure confidentiality.Records were linked using the probabilistic linking program LinkPro . The proIn addition to information about baptism, LDS church membership records include information on whether born in the church and whether endowed in the temple. To receive one's temple endowment requires conscientious effort toward obedience to the lifestyle prescribed by LDS doctrine . This inThe present study was based on 9,619 female microscopically confirmed, actively followed malignant breast cancer cases (ICDO-2 site code C50.0:C50.9) diagnosed in Utah from 1985 through 1999. There were 5,234 (54.4%) religiously active LDS, 1,369 (14.2%) less religiously active LDS, and 3,015 (31.4%) non-LDS. In addition to LDS membership and level of religiosity, the following variables were considered: age, marital status, summary stage , histological grade, number of primary cancers in one individual, and treatment. Because of the high percentage of whites in Utah [Age was categorized as 0–34, 35–44, 45–54, 55–64, 65–74, and 75 years and older; marital status was categorized into four groups: never married, married/cohabitating, previously married, and unknown; and calendar years were categorized into four groups: 1985–88, 1989–92, 1993–96, and 1997–99. Number of primary cancers in an individual describes the chronology of diagnosis of all primary malignant cancers over the entire lifetime of the person ,19. ThesCases who had died but had unknown date of death, whose cause of death was determined by death certificate or autopsy only, or who represented a second or later primary cancer were excluded from the survival analysis. After these exclusions, there were 8,731 cases available for this portion of the study.SEER registries were included in the study if they provided data to the National Cancer Institute during all the years from 1985 through 1999. These registries are as follows: San Francisco-Oakland, Connecticut, Metropolitan Detroit, Hawaii, Iowa, New Mexico, Seattle (Puget Sound), Utah, and Metropolitan Atlanta.1/2 [Age-adjusted rates were derived using the direct method and standardized to the 2000 U.S. population. Counts used in the rate calculations were microscopically confirmed. LDS and non-LDS breast cancer incidence rates were compared with SEER incidence rates. Ninety-five percent confidence intervals for the incidence rate calculations were based on standard error estimates from the formula SE(rate) ≈ rate/(cancer cases)1/2 . PopulatAmong LDS, population values were not available by level of religiosity. Hence, rates are presented for LDS and non-LDS. However, level of religiosity among LDS could be estimated among the cases such that the survival analysis considered religiously active LDS, religiously less active LDS, and non-LDS.Survival time was calculated as the time interval between diagnosis and date of last information. For deceased cases, the date of last information was the date of death. For cases not known to be deceased, the date of last information was the date that the case was last known to be alive. Cases with death from breast cancer (the outcome of interest), and all other cases were censored at the time of last information. We estimated breast cancer-specific survival for cases where breast cancer is a single cancer primary or the first of multiple cancer primaries.Bivariate comparisons were evaluated using the chi-square test. Survival estimates were calculated by the Cox proportional hazards method with one-month intervals ,27. StatBivariate analyses of the association between religion and selected variables for female malignant breast cancer patients in Utah, 1985–99 are displayed in Table Age-adjusted female malignant breast cancer incidence rates among white women in Utah are presented by LDS status and calendar year in Figure For the combined years 1995 through 1999, lower female malignant breast cancer incidence rates among LDS compared with non-LDS women in Utah were observed across the age span Figure . Age-adjA proportional hazards model was used to estimate the death hazard for female malignant breast cancer among patients, with religiously active LDS as the referent group. The death hazard ratio for religiously less active LDS was 1.09 (0.94 – 1.27) and for non-LDS was 0.86 (0.75 – 0.98). Adjusted hazard ratios for age and marital status were also computed for patients based on their already having survived 0 months, 6 months, 12 months, 18 months, and 24 months Figure . ReligioUtah presents a unique area for breast cancer studies because of the relatively low incidence of breast cancer among its residents, and the lower risk of breast cancer among members of the LDS church compared with non-LDS in the state. Lifestyle behaviors common among members of the LDS church, such as higher birthrates, higher prevalence and duration of breastfeeding, and lower alcohol consumption have been associated with lower incidence rates of breast cancer. The significantly lower risk of breast cancer among LDS shows the potential preventive effect certain behaviors may have against breast cancer. Yet this study also showed poorer survivability among a population with a traditionally lower incidence rate of breast cancer. It appears that the same factors that are associated with a lower incidence rate of breast cancer are also associated with poorer prognosis once breast cancer is diagnosed. This paradoxical finding is consistent with the results of a study by Korzeniowski and Dyba who reported that "reproductive factors known to decrease the risk of breast cancer development have an adverse effect on prognosis" .Results in the current paper confirm those found by Lyon et al. . SpecifiNot only did LDS women in Utah experienced lower breast cancer incidence rates than did women in SEER, non-LDS women in Utah also had lower rates. This may be attributed to a conforming effect wherein the non-LDS minority approximates the lifestyle behaviors of the LDS majority to increase their social acceptability . Social It should be noted that the linked data did not provide information about religious preference or religiosity among the nearly 30% non-LDS women. However, if the women in the study represent a similar representation as those identified in a recent cross-sectional survey of Utah adult women, approximately 26% of the non-LDS women were religiously active, 41% were less religiously active, and 34% had no religious preference . DanielsThe population attributable-risk percent was presented to indicate the amount of breast cancer that could have been avoided under the hypothetical situation that everyone in Utah experienced the same breast cancer risk profile as LDS women. If everyone in SEER had the same breast cancer risk profile as LDS women in Utah, this percentage was 22.4%. In other words, approximately 22.4% of all breast cancer in SEER could have been avoided had women in SEER experienced a similar breast cancer risk profile as LDS women in Utah. Applying this percentage to the U.S. female population in 2004, an estimated 48,382 new cases could have been avoided had women in the U.S. displayed similar breast cancer risk behaviors as LDS women in Utah.There was not a significant difference in death hazard rates between religiously active and less active LDS. However, there was a significant difference in death hazard rates between religiously active LDS and non-LDS. Lower death hazard rates in non-LDS became more pronounced as we conditioned on months already survived from diagnosis. Two possible explanations may help explain this, proximity to last childbirth and diagnosis during the lactation period.New studies have indicated that a more recent birth prior to the diagnosis of breast cancer is associated with poorer survivability -33. OldeA less conclusive, yet possible contributor to poorer survivability among active LDS, is diagnosis during the lactation period. One study noted that breast cancer diagnosed during the lactation period has been associated with poorer survival among women younger than 45 years . This reThe temple endowment was used as a surrogate marker for religiosity among LDS women. Although receiving one's temple endowment requires conscientious effort toward obedience to the lifestyle prescribed by LDS doctrine, which includes certain health practices like not smoking or consuming alcohol and abstention from sexual relationships outside of marriage, the data did not allow us to identify whether a previously endowed individual continued to adhere to the doctrine of the church. Yet we assume that given the high level of religious commitment required to receive one's temple endowment, the tendency was for these individuals to continue adherence to the health practices of the LDS religion. A related religiosity measure to the temple endowment was not available for non-LDS women.We were concerned with the degree of accurate assignment of the cause of death, but the influence of inaccurate specification of cancer death appeared to be very small. Bias may result when considering multiple cancer primaries because religiously active LDS are less likely to smoke cigarettes. Hence, they are less likely to get a cancer related to smoking, where these cancers tend to be more lethal . There would have been a selection bias if we had considered death from any cancer. However, limiting disease-specific death to breast cancer made the groups more comparable with respect to smoking history.2(4) = 1.71, p = .789). There is no reason to believe that the "unknown" grade would have been distributed differently among the religious groups.It was not possible to explore the association between histological grade and survivability because of the large number of patients in the "unknown" category. Nevertheless, the difference in distribution of histological grade among patients with known grade information was very similar and not statistically different  declare that they have no competing interests.Ray M. Merrill conceptualized the study, analyzed the data, and drafted the manuscript. Jeffrey A. Folsom assisted in interpreting the data and writing the manuscript.The pre-publication history for this paper can be accessed here: