National Breast Screening Study Research Articles

A plea for more careful scholarship in reviewing evidence: the case of mammographic screening.

To identify issues of principle and practice giving rise to misunderstandings in reviewing evidence, to illustrate these by reference to the Nordic Cochrane Review (NCR) and its interpretation of two trials of mammographic screening, and to draw lessons for future reviewing of published results. A narrative review of the publications of the Nordic Cochrane Review of mammographic screening (NCR), the Swedish Two-County Trial (S2C) and the Canadian National Breast Screening Study 1 and 2 (CNBSS-1 and CNBSS-2). The NCR concluded that the S2C was unreliable, despite the review's complaints being shown to be mistaken, by direct reference to the original primary publications of the S2C. Repeated concerns were expressed by others about potential subversion of randomisation in CNBSS-1 and CNBSS-2; however, the NCR continued to rely heavily on the results of these trials. Since 2022, however, eyewitness evidence of such subversion has been in the public domain. An over-reliance on nominal satisfaction of checklists of criteria in systematic reviewing can lead to erroneous conclusions. This occurred in the case of the NCR, which concluded that mammographic screening was ineffective or minimally effective. Broader and more even-handed reviews of the evidence show that screening confers a substantial reduction in breast cancer mortality. Those carrying out systematic reviews should be aware of the dangers of over-reliance on checklists and guidelines. Readers of systematic reviews should be aware that a systematic review is just another study, with the capability that all studies have of coming to incorrect conclusions. When a review seems to overturn the current position, it is essential to revisit the publications of the primary research.

Serious Scientific Flaws in the Canadian National Breast Screening Study Trials Revealed in a Report from Breast Cancer Screening Experts.

HomeRadiology: Imaging CancerVol. 4, No. 4 Previous Research HighlightsSerious Scientific Flaws in the Canadian National Breast Screening Study Trials Revealed in a Report from Breast Cancer Screening ExpertsBonnie N. Joe, Samantha Fung-LeeBonnie N. Joe, Samantha Fung-LeeBonnie N. JoeSamantha Fung-LeePublished Online:Jul 29 2022https://doi.org/10.1148/rycan.229017MoreSectionsFull textPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Highlighted ArticleSeely JM, Eby PR, Yaffe MJ. The fundamental flaws of the CNBSS trials: a scientific review. J Breast Imaging 2022;4(2):108–112.doi: https://doi.org/10.1093/jbi/wbab099 Crossref, Google ScholarArticle HistoryPublished online: July 29 2022 FiguresReferencesRelatedDetailsRecommended Articles Closing the Gap: Disparities in Breast Cancer Mortality among African American WomenRadiology: Imaging Cancer2020Volume: 2Issue: 5Non-BRCA Early-Onset Breast Cancer in Young WomenRadioGraphics2022Volume: 42Issue: 1pp. 5-22Lessons Learned from the Randomized Controlled TOmosynthesis plus SYnthesized MAmmography (TOSYMA) TrialRadiology2022Volume: 306Issue: 2Breast Cancer Screening in High-Risk Men: A 12-year Longitudinal Observational Study of Male Breast Imaging Utilization and OutcomesRadiology2019Volume: 293Issue: 2pp. 282-291Predicting Breast Cancer by Applying Deep Learning to Linked Health Records and MammogramsRadiology2019Volume: 292Issue: 2pp. 331-342See More RSNA Education Exhibits An Educational Perspective: Surveillance Following Breast Conservation TherapyDigital Posters2019Artificial Intelligence in an Era of Increasing Global Cancer Burden: Opportunities and Challenges for Breast Cancer in Low- and Middle-Income CountriesDigital Posters2020Let’s Talk about Next-Generation Breast Cancer Screening Programs: How Should We Do? What Should We Use?Digital Posters2020 RSNA Case Collection Male invasive Ductal Carcinoma RSNA Case Collection2022Lactating BreastRSNA Case Collection2022Recurrent breast cancer on CEUSRSNA Case Collection2021 Vol. 4, No. 4 Metrics Altmetric Score PDF download

How Did CNBSS Influence Guidelines for So Long and What Can That Teach Us?

The biased randomization and other quality concerns about the Canadian National Breast Screening Studies (CNBSS) were documented and criticized for decades, even by several individuals very close to the research. CNBSS were the outlier studies among several RCTs of the era and yet were given equal weighting and occasionally higher importance than the remainder of the canon of mammography RCTs. These studies have had an ongoing influence on subsequent evidence review, guideline formation, and, ultimately, patient access to screening. This article explores possible reasons for the ongoing inclusion of CNBSS in the body of mammography screening evidence, discusses the lack of expertise in critical healthcare guideline processes, and, ultimately, suggests several actions and reforms.

Errors in Conduct of the CNBSS Trials of Breast Cancer Screening Observed by Research Personnel.

To investigate why the Canadian National Breast Screening Study (CNBSS) did not show mortality reduction with mammography. This study explored long-standing concerns related to the validity of the randomization process, methods of recruiting women to participate in the trials, and training of the staff working in the CNBSS. Surviving former CNBSS personnel, whose roles involved direct recruitment, enrollment, randomization, clinical examination, image interpretation, and management of patients in the CNBSS were interviewed. Individuals were contacted and consented to provide firsthand accounts of daily operations and adherence to research protocols via standardized questions. Consistency of observational data with quantitative results from the CNBSS trials was evaluated. Eleven of 28 (39.3%) staff confirmed that women with preexisting symptoms of breast cancer were systematically recruited at some centers; 57.1% (16/28) confirmed that personnel performing screening in CNBSS had very limited training and experience; 39.3% (11/28) verified that imaging equipment was often substandard; 50% (14/28) indicated that mammography image quality was generally poor; and 28.6% (8/28) corroborated that in some cases surgeons were unwilling to perform biopsies or surgeries for women with suspicious abnormalities found only on screening mammography that lacked a palpable correlate. These firsthand accounts provide new information confirming that the CNBSS did not consistently and rigorously assess the true efficacy of screening mammography. The staff accounts clarify reasons why the CNBSS results were outliers compared with the six other randomized trials of screening mammography and should not be used as credible scientific evidence to inform health policy.

Problems With the Canadian National Breast Screening Studies.

Problems With the Canadian National Breast Screening Studies.

The Fundamental Flaws of the CNBSS Trials: A Scientific Review.

Although the two Canadian National Breast Screening Study (CNBSS) trials were performed 40 years ago, their negative findings continue to heavily influence screening policies around the world. These policies, based on underestimates of the mortality reduction attributable to mammography particularly for women in the 40-49-year age range, contribute to increased mortality and morbidity from breast cancer. This review summarizes principles of a randomized controlled trial (RCT) and evaluates the compliance of the CNBSS1 and CNBSS2 RCTs in the context of these principles. We describe the fundamental flaws of the CNBSS trials, which failed to demonstrate mortality benefit of screening mammography and contribute to their being the only two outlier studies of eight screening mammography RCTs. The most significant flaws of the trials are (1) inadequate power to detect significant differences in breast cancer mortality; (2) very poor quality mammography with low sensitivity and cancer detection rates; (3) inclusion of women with symptoms of breast cancer; and (4) study design that allowed for violation of the randomization of the allocation process. Finally, we demonstrate that the conditions of the screening intervention in the CNBSS do not reflect the environment of modern population-based screening mammography programs.

The randomized trial of mammography screening that was not-A cautionary tale.

Two randomized trials were conducted in Canada in the 1980s to test the efficacy of breast cancer screening. Neither of the trials demonstrated benefit. Concerns were raised regarding serious errors in trial design and conduct. Here we describe the conditions that could allow subversion of randomization to occur and the inclusion of many symptomatic women in a screening trial. We examine anomalies in data where the balance would be expected between trial arms. “Open book” randomization and performance of clinical breast examination on all women before allocation to a trial arm allowed women with palpable findings to be mis-randomized into the mammography arm. Multiple indicators raising suspicion of subversion are present including a large excess in poor-prognosis cancers in the mammography trial arm at prevalence screen. Personnel described shifting of women from the control group into the mammography group. There is compelling evidence of subversion of randomization in Canadian National Breast Screening Study. Mis-randomization of even a few women with advanced breast cancer could markedly affect measured screening efficacy. The Canadian National Breast Screening Study trials should not influence breast screening policies.

Major failings of trial procedures and quality of screening fatally compromise the results of the Canadian National Breast Screening Studies

Despite overwhelming evidence of a major reduction in deaths, the debate about the efficacy of breast cancer screening has continued for over 50 years. The poor results in the Canadian National Breast Screening Studies (CNBSS) have been used to challenge the benefits shown by the other randomized, controlled trials. They continue to be used in assessing the value of breast cancer screening despite their unblinded allocation process, which first identified women with breast abnormalities and then assigned them on open lists allowing for nonrandom assignment, compromising the trials and rendering their results unreliable. There were, statistically significantly, more women with advanced cancers who were assigned to the screening arm in CNBSS1. The early results for CNBSS1 showed an excess of women dying in the screening arm, and an (otherwise inexplicable) greater than 90%, 5-year survival for the control women. The failure of random assignment also explains why the clinically evident cancers were larger in the screening arms than the cancers in the "usual care" arms, despite the fact that the screened women underwent very intense clinical breast examinations each year by highly skilled examiners. The claim that balanced demographic factors prove random assignment is also false. Nonrandom allocation of a hundred or more women with clinically evident abnormalities would have no detectable influence on the distribution of demographic factors. In summary, policy decisions about mammography should not be influenced by the results of the CNBSS.

Recommendations for breast cancer screening – Author's reply

László Tabár and Peter Dean, Martin Yaffe and colleagues, and Daniel B Kopans have used my commentary 1 Miller AB Final results of the UK Age trial on breast cancer screening age. Lancet Oncol. 2020; 21: 1125-1126 Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar on the UK Age trial as a means to comment adversely on the Canadian National Breast Screening Study. Tabár and Dean rely on the International Agency for Research on Cancer 2016 evaluation of breast screening 2 International Agency for Research on Cancer Working Group on the Evaluation of Cancer Preventive StrategiesBreast Cancer Screening IARC Handbooks of Cancer Prevention. Volume 15. International Agency for Research on Cancer, Lyon2016: 254 Google Scholar to support their arguments, yet that evaluation did not consider the Canadian National Breast Screening Study. Yaffe and colleagues were impressed with the 25% reduction in breast cancer mortality at 10 years of follow-up in the UK Age trial (relative rate 0·75 [95% CI 0·58–0·97]), but acknowledge that this was attenuated on longer follow-up (0·98 [0·79–1·22]). They dismiss our determination of overdiagnosis in the Canadian National Breast Screening Study, casting doubt on the efficiency of our follow-up, which was in fact based on record linkage with the Canadian cancer and death registries. Only Kopans refers to the UK Age trial 3 Duffy SW Vulkan D Cuckle H et al. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol. 2020; 21: 1165-1172 Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar and suggests that the absence of a benefit from initiating mammography screening at age 40–41 years could be because single-view mammography was used in the trial. This suggestion is ironic, as single-view mammography was used in Tabár and colleagues' Two-County Swedish trial, 4 Tabár L Vitak B Chen TH et al. Swedish Two-County trial: impact of mammographic screening on breast cancer mortality during 3 decades. Radiology. 2011; 260: 658-663 Crossref PubMed Scopus (490) Google Scholar where a benefit of mammography screening in women from age 40 years was reported. Final results of the UK Age trial on breast cancer screening ageIn The Lancet Oncology, the findings from a 23-year follow-up of the UK Age trial are presented by Stephen Duffy and colleagues.1 No difference in mortality from breast cancer was found between the group that began yearly mammography screening at age 39–41 years until they entered the National Health Service (NHS) Breast Screening Programme at age 50–52 years, and a group that did not begin mammography screening until they entered the NHS Breast Screening Programme (126 deaths vs 255 deaths occurring after more than 10 years of follow-up; relative rate 0·98 [95% CI 0·79–1·22]; p=0·86). Full-Text PDF Open AccessRecommendations for breast cancer screeningDespite evidence confirming the benefits of detecting breast cancer before it becomes palpable, in his Comment, Anthony Miller1 advocates that women should not have mammography screening, but instead could wait until their breast cancers have grown large enough to become palpable. Contrary to his closing statement, Miller's argument against earlier diagnosis of breast cancer through mammography screening is not supported by the WHO recommendations, which review various methodologies available to bring care to patients as early as possible. Full-Text PDF Recommendations for breast cancer screeningIn his Comment on the UK Age trial, Anthony Miller1 stated that it could be argued that breast cancer screening with mammography should not be initiated at any age. We disagree with this assertion, given the overwhelming evidence from multiple randomised trials and observational studies showing the lifesaving benefits of mammography screening—benefits that have been acknowledged by guideline-setting bodies in several countries.2 Furthermore, recent publications have shown a reduced need for mastectomy, chemotherapy, and axillary dissection when breast cancers are detected by mammography screening. Full-Text PDF Recommendations for breast cancer screeningIn his Comment, Anthony Miller1 asserted that his trials showed “comparability of the study groups”. Although Miller states that women were randomly assigned in the Canadian National Breast Screening Studies, he did not mention that all women had a clinical breast examination before allocation and study coordinators with this information could assign women out of random order. Significantly more women with palpable, advanced cancers were allocated to the screening group than to the control group of the Canadian National Breast Screening Study-1. Full-Text PDF

Is mammography screening beneficial: An individual-based stochastic model for breast cancer incidence and mortality.

The benefits of mammography screening have been controversial, with conflicting findings from various studies. We hypothesize that unmeasured heterogeneity in tumor aggressiveness underlies these conflicting results. Based on published data from the Canadian National Breast Screening Study (CNBSS), we develop and parameterize an individual-based mechanistic model for breast cancer incidence and mortality that tracks five stages of breast cancer progression and incorporates the effects of age on breast cancer incidence and all-cause mortality. The model accurately reproduces the reported outcomes of the CNBSS. By varying parameters, we predict that the benefits of mammography depend on the effectiveness of cancer treatment and tumor aggressiveness. In particular, patients with the most rapidly growing or potentially largest tumors have the highest benefit and least harm from the screening, with only a relatively small effect of age. However, the model predicts that confining mammography to populations with a high risk of acquiring breast cancer increases the screening benefit only slightly compared with the full population.

Associations between incident breast cancer and ambient concentrations of nitrogen dioxide from a national land use regression model in the Canadian National Breast Screening Study

BackgroundAir pollution has been classified as a human carcinogen based largely on epidemiological studies of lung cancer. Recent research suggests that exposure to ambient air pollution increases the risk of female breast cancer especially in premenopausal women. MethodsOur objective was to determine the association between residential exposure to ambient nitrogen dioxide (NO2) and newly diagnosed cases of invasive breast cancer in a cohort of 89,247 women enrolled in the Canadian National Breast Screening Study between 1980 and 1985. Vital status and incident breast cancers through 2005 were determined through record linkage to the Canadian national mortality and cancer registries. Estimates of exposures to NO2 using participants’ addresses at time of entry into the study were derived from a national land use regression model. We classified women as reaching menopause according to information obtained at baseline. In addition, as we had no information from women on their menopausal status during the observation period, we conducted analyses using different cut-points for defining postmenopausal status (i.e., at 50 or at 52 years of age), and hence we had four non-independent cohorts. We computed rate ratios for the incidence of breast cancer and their 95% confidence intervals (CI) separately for premenopausal and postmenopausal women. Our Cox models used attained age as the time axis and the rate ratios were adjusted for several individual-level risk factors, including reproductive history, as well as census-based neighborhood-level characteristics. ResultsThe median concentration of NO2 was about 15 parts per billion (ppb). After adjusting for personal risk factors and contextual variables, we found no evidence of associations for the incidence of breast cancer in the postmenopausal cohorts. In premenopausal women, the rate ratio for an increase of 9.7 ppb (about the interquartile range) was 1.13 (95%CI: 0.94–1.37) for the 50 years of age cut-off for menopausal status and it was 1.17 (95%CI: 1.00–1.38) for the 52 years of age cut-off. ConclusionsOur findings suggest that exposure to low concentrations of NO2, a marker for traffic-related air pollution, increases the risk of premenopausal breast cancer, but not postmenopausal breast cancer.

Impact of regular Breast Self-Examination on breast cancer size, stage, and mortality in Thailand.

Impact of regular Breast Self-Examination on breast cancer size, stage, and mortality in Thailand.

Evidence based mammography screening: is evidence changing?

Population-based mammography screening programmes were launched by developed countries in the latter half of the twentieth century based on the promising evidence on mortality benefits reported by the earliest randomised control trials (RCTs). It was widely accepted that screening mammography significantly reduced breast cancer mortality in women invited for screening. However, since the first RCT in the 1960s, varying evidence has been tabled by many researchers, sometimes alarming the public, drawing attention to the harms of screening mammography, mainly identified as overdiagnosis and false positives. While overtreatment is recognised as a consequence of over diagnosis, a relatively newer set of harms categorized under psychological distress have been highlighted as resultant from false positive screening tests. Currently, the magnitude of the harms of screening mammography remains uncertain. The most turbulent reviews on breast screening, however, were the queries into the well and long believed mortality benefits of mammography screening first tabled in the 1970s by the Canadian national breast screening study. A Cochrane review by Gotzsche and Jorgensen further added to the negative attributes of mammography screening as they concluded that the actual current mortality benefits are nonsignificant and smaller than that claimed by many RCTs which were poorly randomised. Although heavily criticized, sparks ignited by these reports have led many countries worldwide to conduct their panel discussions on evidence on population screening mammography. While many countries have decided to continue their programmes understanding the harms involved, Switzerland in this light has discontinued their population-based mammography screening programme. The debate continues; currently while not overlooking the mortality benefits of mammography, it is also understood that the mortality benefits are not solely due to mammography but are also contributed by other factors such as advancement in therapeutic measures and awareness on breast cancer created among the females. In this regard, critical evaluation of global literature is imperative to make country-specific policy decisions for middle-income countries such as Sri Lanka, who are contemplating the options for expanding opportunistic mammography screening services to reach wider population screening targets.

Asthma and Chronic Obstructive Pulmonary Disease Overlap in Women. Incidence and Risk Factors.

Women with asthma are at a high risk of developing chronic obstructive pulmonary disease (COPD) or asthma and COPD overlap syndrome (ACOS) as they age, which is a condition associated with a high mortality rate, low quality of life, and high healthcare costs. However, factors influencing the development of ACOS remain unclear. To quantify the risk of developing COPD in women in Ontario with asthma and identify factors that are associated with increased risk. Data for women in Ontario with asthma who participated in the Canadian National Breast Screening Study from 1980 to 1985 were linked to health administrative databases, and participants were followed from 1992 to 2015. A competing risks survival model was used to measure the associations between sociodemographic, lifestyle, and environmental risk factors and time to COPD incidence, accounting for death as a competing risk. A total of 4,051 women with asthma were included in the study, of whom 1,701 (42.0%) developed COPD. The mean age at the study end date was 79 years. Low education, high body mass index, rurality, and high levels of cigarette smoking were associated with ACOS incidence, whereas exposure to fine particulate matter, a major air pollutant, was not. Individual risk factors appear to play a more significant role in the development of ACOS in women than environmental factors, such as air pollution. Prevention strategies targeting health promotion and education may have the potential to reduce ACOS incidence in this population.

Identification of the Fraction of Indolent Tumors and Associated Overdiagnosis in Breast Cancer Screening Trials.

It is generally accepted that some screen-detected breast cancers are overdiagnosed and would not progress to symptomatic cancer if left untreated. However, precise estimates of the fraction of nonprogressive cancers remain elusive. In recognition of the weaknesses of overdiagnosis estimation methods based on excess incidence, there is a need for model-based approaches that accommodate nonprogressive lesions. Here, we present an in-depth analysis of a generalized model of breast cancer natural history that allows for a mixture of progressive and indolent lesions. We provide a formal proof of global structural identifiability of the model and use simulation to identify conditions that allow for parameter estimates that are sufficiently precise and practically actionable. We show that clinical follow-up after the last screening can play a critical role in ensuring adequately precise identification of the fraction of indolent cancers in a stop-screen trial design, and we demonstrate that model misspecification can lead to substantially biased estimates of mean sojourn time. Finally, we illustrate our findings using the example of Canadian National Breast Screening Study 2 (1980-1985) and show that the fraction of indolent cancers is not precisely identifiable. Our findings provide the foundation for extended models that account for both in situ and invasive lesions.

Residential exposure to fine particulate matter air pollution and incident breast cancer in a cohort of Canadian women

Background: Air pollution has been classified as a human carcinogen based largely on epidemiological studies of lung cancer. Recent research suggests that exposure to ambient air pollution increases the risk of breast cancer. Methods: Our aim was to characterize associations between residential exposure to ambient fine particulate matter (PM2.5) and the incidence of breast cancer in a cohort of 89,247 women enrolled in the Canadian National Breast Screening Study between 1980 and 1985. Vital status and incident cancers were determined through record linkage to the national registry data through 2005. Individual-level estimates of exposures to PM2.5 at baseline were derived from satellite observations. Six thousand five hundred three incident breast cancers were identified during follow-up. We classified menopausal status using self-reported information collected at baseline and by attained age (50, 52, and 54 years) as women were followed-up. We computed hazard ratios (HRs) and their 95% confidence intervals (CI) using age as the time axis. Models were adjusted for several individual risk factors, including reproductive history, as well as census-based neighborhood-level characteristics. Results: The median residential concentration of PM2.5 was 9.1 μg/m3. In models adjusted for personal and contextual risk factors, a 10-μg/m3 increase in PM2.5 was associated with an elevated risk of premenopausal (HR = 1.26; 95% CI = 0.99, 1.61) but not postmenopausal breast cancer (HR = 1.01; 95% CI = 0.94, 1.10). The elevated risk of premenopausal breast cancer from PM2.5 was only evident among those randomized to the screening arm of the study. Conclusions: Our findings support the hypothesis that exposure to low concentrations of PM2.5 increase the risk of premenopausal breast cancer.

The Canadian National Breast Screening Studies are compromised and their results are unreliable. They should not factor into decisions about breast cancer screening

The Canadian National Breast Screening Studies were compromised by an unblinded allocation process and poor quality mammography. Contrary to the requirement that allocation in a randomized controlled trial (RCT) be blinded to avoid any possible intentional or unintentional subversion of a random allocation, all women in the CNBSS trials underwent a clinical breast examination prior to assignment to the study arm or the usual care arm. Women with abnormal clinical breast examinations were identified, and this information was available to the coordinators who then assigned the women on open lists. It was, therefore, possible to assign women to whichever arm the coordinator chose. Although subversion was likely unintended, a significant number of women with four or more positive axillary lymph nodes were assigned to the screening arm of CNBSS1. This explains why there were more breast cancer deaths among the screened women in the first ten years of the trial and why the 5 year survival of the control women was better than 90% when the background survival in Canada at the time was only 75%. The trials were further compromised by the poor quality of the mammography which was confirmed by a review conducted by the trials' organizers. These fundamental problems compromise the CNBSS and make their results, which are major outliers in the RCT's of breast cancer screening, unreliable. Consequently, they should not be used to establish guidelines for breast cancer screening.

Tumor size distribution of invasive breast cancers and the sensitivity of screening methods in the Canadian National Breast Screening Study.

This study set out to explore if breast cancers of different sizes are detected with varying sensitivity. In addition, we attempt to determine the effect of tumor size on screening detectability. Data arising from the Canadian National Breast Screening Study (CNBSS) was used to perform all analyses. The CNBSS consists of two randomized controlled trials, which includes data on detection methods, age, and allocation groups. We stratified tumor size by 5 mm; age into 40-49 and 50-59 years age groups; and cancer detection or presentation methods into mammography only, physical breast examination only, both mammography and physical breast examination, interval cancers, and incident cancers. This study revealed that a difference in tumor size exists for age (smaller tumor sizes are found in older women) and breast cancer detection or presentation modes. More specifically, breast cancers detected by mammography screening are statistically smaller than those detected by physical breast examination or those presenting as incident or interval cancers. This study also found that tumor size affects screening detectability for women in their 50's but not in their forties. That is, a statistically significant difference between mammography screening alone and physical examination alone was observed for women between the ages of 50-59 for tumor sizes up to 20 mm, including prevalent cases, and up to 15 mm when prevalent cases were excluded. The results of this study suggest that smaller breast cancers are more likely to be detected among women in their 50s.

Long-term exposure to fine particulate matter air pollution and the risk of lung cancer among participants of the Canadian National Breast Screening Study.

Recently, air pollution has been classified as a carcinogen largely on the evidence of epidemiological studies of lung cancer. However, there have been few prospective studies that have evaluated associations between fine particulate matter (PM2.5 ) and cancer at lower concentrations. We conducted a prospective analysis of 89,234 women enrolled in the Canadian National Breast Screening Study between 1980 and 1985, and for whom residential measures of PM2.5 could be assigned. The cohort was linked to the Canadian Cancer Registry to identify incident lung cancers through 2004. Surface PM2.5 concentrations were estimated using satellite data. Cox proportional hazards models were used to characterize associations between PM2.5 and lung cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) computed from these models were adjusted for several individual-level characteristics, including smoking. The cohort was composed predominantly of Canadian-born (82%), married (80%) women with a median PM2.5 exposure of 9.1 µg/m(3) . In total, 932 participants developed lung cancer. In fully adjusted models, a 10 µg/m(3) increase in PM2.5 was associated with an elevated risk of lung cancer (HR: 1.34; 95% CI = 1.10, 1.65). The strongest associations were observed with small cell carcinoma (HR: 1.53; 95% CI = 0.93, 2.53) and adenocarcinoma (HR: 1.44; 95% CI = 1.06, 1.97). Stratified analyses suggested increased PM2.5 risks were limited to those who smoked cigarettes. Our findings are consistent with previous epidemiological investigations of long-term exposure to PM2.5 and lung cancer. Importantly, they suggest associations persist at lower concentrations such as those currently found in Canadian cities.

Using Simulation to Model and Validate Invasive Breast Cancer Progression in Women in the Study and Control Groups of the Canadian National Breast Screening Studies I and II.

Modeling breast cancer progression and the effect of various risk is helpful in deciding when a woman should start and end screening, and how often the screening should be undertaken. We modeled the natural progression of breast cancer using a hidden Markov process, and incorporated the effects of covariates. Patients are women aged 50-59 (older) and 40-49 (younger) years from the Canadian National Breast Screening Studies. We included prevalent cancers, estimated the screening sensitivities and rates of over-diagnosis, and validated the models using simulation. We found that older women have a higher rate of transition from a healthy to preclinical state and other causes of death but a lower rate of transition from preclinical to clinical state. Reciprocally, younger women have a lower rate of transition from a healthy to preclinical state and other causes of death but a higher rate of transition from a preclinical to clinical state. Different risk factors were significant for the age groups. The mean sojourn times for older and younger women were 2.53 and 2.96 years, respectively. In the study group, the sensitivities of the initial physical examination and mammography for older and younger women were 0.87 and 0.81, respectively, and the sensitivity of the subsequent screens were 0.78 and 0.53, respectively. In the control groups, the sensitivities of the initial physical examination for older and younger women were 0.769 and 0.671, respectively, and the sensitivity of the subsequent physical examinations for the control group aged 50-59 years was 0.37. The upper-bounds for over-diagnosis in older and younger women were 25% and 27%, respectively. The present work offers a basis for the better modeling of cancer incidence for a population with the inclusion of prevalent cancers.