Claus Wall

Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial

Objective To compare breast cancer incidence and mortality up to 25 years in women aged 40-59 who did or did not undergo mammography screening. Design Follow-up of randomised screening trial by centre coordinators, the study’s central office, and linkage to cancer registries and vital statistics databases. Setting 15 screening centres in six Canadian provinces,1980-85 (Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia). Participants 89 835 women, aged 40-59, randomly assigned to mammography (five annual mammography screens) or control (no mammography). Interventions Women aged 40-49 in the mammography arm and all women aged 50-59 in both arms received annual physical breast examinations. Women aged 40-49 in the control arm received a single examination followed by usual care in the community. Main outcome measure Deaths from breast cancer. Results During the five year screening period, 666 invasive breast cancers were diagnosed in the mammography arm (n=44 925 participants) and 524 in the controls (n=44 910), and of these, 180 women in the mammography arm and 171 women in the control arm died of breast cancer during the 25 year follow-up period. The overall hazard ratio for death from breast cancer diagnosed during the screening period associated with mammography was 1.05 (95% confidence interval 0.85 to 1.30). The findings for women aged 40-49 and 50-59 were almost identical. During the entire study period, 3250 women in the mammography arm and 3133 in the control arm had a diagnosis of breast cancer, and 500 and 505, respectively, died of breast cancer. Thus the cumulative mortality from breast cancer was similar between women in the mammography arm and in the control arm (hazard ratio 0.99, 95% confidence interval 0.88 to 1.12). After 15 years of follow-up a residual excess of 106 cancers was observed in the mammography arm, attributable to over-diagnosis. Conclusion Annual mammography in women aged 40-59 does not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available. Overall, 22% (106/484) of screen detected invasive breast cancers were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial.

The Canadian national Breast screening study-1: Breast cancer mortality after 11 to 16 years of follow-up a: Randomized screening trial of mammography in women age 40 to 49 years

Context Seven- and 10-year results of the Canadian National Breast Screening Study (CNBSS) showed no reduction in breast cancer mortality from five annual mammographies and breast examinations for 40- to 49-year-old women. Some authors have argued that longer follow-up would reveal important benefits. Contribution After 11 to 16 years, the cumulative rate ratios for mammography versus usual care were 0.97 (95% CI, 0.74 to 1.27) for breast cancer mortality without adjustment for nonstudy mammography and 1.06 (CI, 0.80 to 1.40) with adjustment. Clinical Implications The CNBSS suggests that screening 40- to 49-year-old women is unlikely to reduce breast cancer by 20% or more. Controversy will persist because other studies suggest that screening causes small reductions in breast cancer mortality. The Editors The Canadian National Breast Screening Study-1 (CNBSS-1), an individually randomized trial in women 40 to 49 years of age at study entry, evaluated the efficacy of annual mammography, breast physical examination, and instruction on breast self-examination in reducing breast cancer mortality (1). The 7-year (2) and preliminary 10-year (3) mortality results were previously reported. At 7 years, 38 women in the mammography group and 28 women in the usual care group had died of breast cancer, for a rate ratio of 1.36 (95% CI, 0.84 to 2.21) (2). At 10 years, there were 82 breast cancer deaths in the mammography group and 72 in the usual care group (rate ratio, 1.14 [CI, 0.83 to 1.56]) (3). This article reports CNBSS-1 results after an average 13-year follow-up from study entry. Methods Patient Selection and Recruitment Participants were recruited through media publicity, personal invitation letters using population lists (municipal registers and provincial health insurance registers), group mailings, and physicians (4). Eligibility criteria were age 40 to 49 years, no previous diagnosis of breast cancer, not being pregnant, no mammography in the previous 12 months, and signed informed consent. The Human Experimentation Committee of the University of Toronto (Toronto, Ontario, Canada) and Human Experimentation Committees at 15 CNBSS collaborating centers approved the study. A total of 50 430 women age 40 to 49 years were enrolled from January 1980 through March 1985. Randomization Before randomization, all participants received an initial breast physical examination and instruction on breast self-examination. They were then immediately randomly assigned to receive mammography and, thereafter, either annual screening with mammography and breast physical examination (25 214 women in the mammography group were available for analysis) or usual care in the context of the Canadian health care system (25 216 women in the usual care group were available for analysis). Center coordinators randomly assigned participants using prepared allocation lists, independent of breast physical examination findings. This sequence ensured that the conduct and interpretation of the breast physical examination would be unbiased by knowledge of whether mammography would follow. Intervention Screening Schedule In the mammography group, 62% of women received five annual screenings. The remainder, recruited later, received four. Each screening examination comprised mammography, breast physical examination, and instruction and evaluation on breast self-examination. Women in the mammography group completed questionnaires at each rescreening visit. Women in the usual care group were not recalled for rescreening but were mailed annual questionnaires. We expected that these participants would continue their normal pattern of medical care as delivered through Canadas universal health care coverage, including access to mammography for diagnosis. Study Procedures Two-view mammography was done on dedicated mammography units (5), and second readers reviewed mammograms deemed abnormal. Systematic audit procedures were used (6). Nurses provided breast physical examination in 12 centers and physicians in 3 centers in Qubec (7). These providers taught and evaluated breast self-examination while conducting their own examination (8). If findings on breast physical examination or mammography were abnormal, participants were referred to a CNBSS review clinic. The study surgeon discussed mammography findings with the study radiologist, examined the participant, and decided whether further diagnostic procedures should be recommended to the womans physician. The womans physician determined whether and how to implement the study surgeons recommendations. Data Collection Protocol During the screening period, the center coordinators collected surgery and pathology reports for breast-related diagnostic and therapeutic procedures. The CNBSS pathologists reviewed all slides. If the community and CNBSS pathologist disagreed, a panel of three to five CNBSS pathologists blindedly and independently reviewed the slides. Extensive quality control procedures were used during data collection. After the screening centers closed in 1988, the central CNBSS central office annually followed all women known to have breast cancer until 30 June 1996, the cut-off for this analysis. Passive follow-up of all participants through linkage with the National Cancer Registry identified new diagnoses of breast cancer in study participants through 31 December 1993. The central office collected pathology reports for postscreening cases of breast cancer. The community diagnosis was accepted for study purposes. Family members responding to the annual mailed questionnaire identified deaths that occurred before completion of a participants screening schedule. Thereafter, women not known to have cancer were followed only through registry linkage; their mammography experience was not traced. However, for women known to have breast cancer, attending physicians received annual requests for updated clinical information, including death. Attending physicians, who received annual requests for information on women with breast cancer, reported deaths until 30 June 1996. Linkage with the Canadian Mortality Database at Statistics Canada (including deaths in Canadians who resided in the United States at the time of death) identified causes of death in the entire cohort until 31 December 1993. The procedures used to verify deaths from breast cancer were described previously (2). Investigative procedures were initiated for women dying with breast cancer; those whose death certificates mentioned breast cancer; and those whose cause of death was described as unknown, unknown primary, lung cancer, colon cancer, or liver cancer. The reviewers were blinded to study group allocation. All other causes of death were accepted as certified. For the most recent record linkage, more stringent confidentiality requirements exercised by many hospitals hindered verification. Thus, of the breast cancer deaths reported in this paper, a panel reviewed 67% in the mammography group and 77% in the usual care group. The remaining deaths are as reported on death certificates. Study Outcomes Death due to or probably due to breast cancer was the major study outcome. A previous report of the CNBBS-1 noted axillary node status, as assessed by community pathologists, through 7 years of follow-up (2). Subsequently (1993 to 1997), to achieve consistent reporting of tumor size, all available material for screening-detected cancer and cancer detected between screenings was re-collected from originating institutions and reviewed by one of the CNBSS pathologists or a colleague. Slides were obtained for review for nearly 80% of requested cases. For the current analysis, pathologists measured the size of small tumors as observed on the slide or the size of the invasive component for mixed invasive and in situ tumors. Statistical Analysis Sample Size The CNBSS-1 was planned to evaluate whether breast cancer mortality would decrease by 40% in the mammography group compared with the usual care group after 5 years of follow-up, with a required sample size of 50 000 women ( = 0.05; power, 80%) (1). At 5 years, however, too few women had died of breast cancer for the study to achieve the planned power. Thus, for the first report on breast cancer mortality, we extended follow-up to 7 years (2). CNBSS Database The database includes records for 50 430 women, including demographic and risk factor variables and results of screening examinations, diagnostic and therapeutic procedures, pathology results, and causes of death. CNBSS Terminology The terms screen 1, screen 2, through screen 5 denote events associated with screening examinations in the mammography group. The initial breast physical examination received by the usual care group is called screen 1. Screening-detected cancers are those diagnosed after a recommendation made by the study surgeon at the CNBSS review clinic. Interval cancers are cases of cancer that occurred less than 12 months after a screening examination at which no recommendation for diagnostic procedures was made. Incident cancers are cases of cancer that occurred more than 12 months after the previous CNBSS screening examination. Statistical Tests The statistical significance of differences in proportions was determined by using the chi-square test (two-sided = 0.05). For all observed-to-expected ratios, 95% CIs were computed. Death rates were computed by using person-years based on stratification by quinquennium of age; we assumed that all women not known to be dead are alive. Age was defined as age at entry. Because all eligible participants were included in the analysis and follow-up, this is an intention-to-treat analysis. Cox proportional-hazards regression was done to examine variables with the most significant independent influence on survival (9), using the PHREG program in SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Because the variable allocation to screening was our primary interest, it was fo

Women's attitudes to screening after participation in the national breast screening study. A questionnaire survey

A self‐administered questionnaire study exploring womens attitudes to breast screening after participation in the Canadian National Breast Screening Study (NBSS) achieved an 82% response rate. Of active respondents (AR) attending two to five screening examinations, 1582 had received annual mammography (MA) and physical examination (PE) of the breasts and 548 received annual PE alone. Of 139 dropouts after the first screening, 105 received MA and PE and 34 received PE alone. Dropout respondents (DR) were significantly less likely than AR to report receiving very prompt (46% versus 66%), very courteous (73% versus 92%), or very competent examinations (74% versus 95%). Although 35% of those allocated to PE expressed disappointment with PE allocation compared with 9% of those allocated to MA, fewer of those allocated PE were prepared to accept MA in the future than those allocated MA (59% versus 73%). Of those who had MA, 36% reported moderate and 9% extreme discomfort from mammography. Almost half of each subgroup–MA allocations, PE allocations, and DR–preferred mammography every 2 to 3 years and 30% preferred mammography restricted to diagnostic purposes. Only 5% of AR reported anxiety after screening. National Breast Screening Study participation was a positive experience for 93%. An intention to do breast self‐examination (BSE) was reported by 89% of AR and 79% of DR. Forgetfulness was a major impediment to BSE. Disincentives for screening were excessive distance to center, painful mammography, fear of radiation, lack of time, and preference for own physician. Convenient location, punctual appointments, and courteous and supportive staff should enhance screening compliance.

Incidence and mortality from breast cancer in the mama program for breast screening in Finland, 1973–1986

Background. A cohort of women enrolled in the Mama breast self‐examination‐(BSE) containing breast screening program in Finland from 1973 through 1975 (with BSE used for screening and mammography for diagnosis) was studied.

Changes in breast self-examination behavior in a cohort of 8214 women in the Canadian National Breast Screening Study.

A study cohort of 8214 women was formed from all participants in the Canadian National Breast Screening Study who attended their first three screens after the introduction of a structured evaluation protocol involving eight criteria for breast self‐examination (BSE). Self‐reported BSE frequency was collected by questionnaire at all three screens. Breast self‐examination instruction preceded breast exam at each screen but BSE evaluation occurred only at the second and third screen. Reported monthly BSE frequency increased from 18% to 51% to 55% on first, second, and third screens, respectively. The proportion claiming to do no BSE fell correspondingly: 52%, 16%, and 11%. Compliance with each of the seven other BSE criteria was significantly greater at the third screen than at the second. The mean number of these criteria performed at screen 3 was 5.1 compared with 4.4 at screen 2; older women performed as well as younger. The mean number of criteria performed was associated with BSE frequency at screen 3. The authors conclude that womens BSE behavior can be altered, and that integration of BSE evaluation and instruction into routine medical exams seems feasible and potentially useful.

Chronic disease prevalence in women and air pollution — A 30-year longitudinal cohort study

BACKGROUND Air pollution, such as fine particulate matter (PM2.5), can increase risk of adverse health events among people with heart disease, diabetes, asthma and chronic obstructive pulmonary disease (COPD) by aggravating these conditions. Identifying the influence of PM2.5 on prevalence of these conditions may help target interventions to reduce disease morbidity among high-risk populations. OBJECTIVES The objective of this study is to measure the association of exposure of PM2.5 with prevalence risk of various chronic diseases among a longitudinal cohort of women. METHODS Women from Ontario who enrolled in the Canadian National Breast Screening Study (CNBSS) from 1980 to 1985 (n = 29,549) were linked to provincial health administrative data from April 1, 1992 to March 31, 2013 to determine the prevalence of major chronic disease and conditions (heart disease, diabetes, asthma, COPD, acute myocardial infarction, angina, stroke and cancers). Exposure to PM2.5 was measured using satellite data collected from January 1, 1998 to December 31, 2006 and assigned to resident postal-code at time of entry into study. Poisson regression models were used to describe the relationship between exposure to ambient PM2.5 and chronic disease prevalence. Prevalence rate ratios (PRs) were estimated while adjusting for potential confounders: baseline age, smoking, BMI, marital status, education and occupation. Separate models were run for each chronic disease and condition. RESULTS Congestive heart failure (PR = 1.31, 95% CI: 1.13, 1.51), diabetes (PR = 1.28, 95% CI: 1.16, 1.41), ischemic heart disease (PR = 1.22, 95% CI: 1.14, 1.30), and stroke (PR = 1.21, 95% CI: 1.09, 1.35) showed over a 20% increase in PRs per 10 μg/m(3) increase in PM2.5 after adjusting for risk factors. Risks were elevated in smokers and those with BMI greater than 30. CONCLUSIONS This study estimated significant elevated prevalent rate ratios per unit increase in PM2.5 in nine of the ten chronic diseases studied.

Long-term Exposure to Fine Particulate Matter Air Pollution and Mortality Among Canadian Women.

Background: Long-term exposure to fine particulate matter (PM2.5) has been associated with increased mortality, especially from cardiovascular disease. There are, however, uncertainties about the nature of the exposure–response relation at lower concentrations. In Canada, where ambient air pollution levels are substantially lower than in most other countries, there have been few attempts to study associations between long-term exposure to PM2.5 and mortality. Methods: We present a prospective cohort analysis of 89,248 women who enrolled in the Canadian National Breast Screening Study between 1980 and 1985, and for whom residential measures of PM2.5 could be assigned. We derived individual-level estimates of long-term exposure to PM2.5 from satellite observations. We linked cohort records to national mortality data to ascertain mortality between 1980 and 2005. We used Cox proportional hazards models to characterize associations between PM2.5 and several causes of death. The hazard ratios (HRs) and 95% confidence intervals (CIs) computed from these models were adjusted for several individual and neighborhood-level characteristics. Results: The cohort was composed predominantly of Canadian-born (82%) and married (80%) women. The median residential concentration of PM2.5 was 9.1 &mgr;g/m3 (standard deviation = 3.4). In fully adjusted models, a 10 &mgr;g/m3 increase in PM2.5 exposure was associated with elevated risks of nonaccidental (HR: 1.12; 95% CI = 1.04, 1.19), and ischemic heart disease mortality (HR: 1.34; 95% CI = 1.09, 1.66). Conclusions: The findings from this study provide additional support for the hypothesis that exposure to very low levels of ambient PM2.5 increases the risk of cardiovascular mortality.

Dysplasia and the natural history of cervical cancer: Early results of the Toronto cohort study

A sample of 176,808 Pap smears, taken from 70,236 women, was constructed from the records of a large cytopathology laboratory between 1962 and 1981. The prevalence of cervical dysplasia, based on the distribution of initial smear results, rose from 42.7 to 94.9 per 1000 during the study period. The relative risks (RR) for the manifestation of a malignancy (carcinoma in situ or worse) in a subsequent cervical smear were 1.48, 3.42, 20.9 and 71.5 for women with minimal, mild, moderate and severe dysplasia, respectively, compared with the entire cohort. The initial degree of dysplasia for women developing a malignancy was much more likely to be interpreted as moderate (RR = 5.0) or severe (RR = 42.3) than were those for controls. These results are strongly supportive of the hypothesis that the degree of dysplasia is related to the risk of development of cancer of the cervix.

Is carcinoma in situ a precursor lesion of invasive breast cancer

This study measures the probability of development of invasive breast cancer (BC) following the diagnosis of carcinomas in situ (CIS). A 25‐year prospective follow‐up was conducted by linking the Canadian National Breast Screening Study (CNBSS) to cancer registries and a national vital statistics database. Subsequent BC incidence was identified in CNBSS women who were diagnosed with CIS. CIS was classified into ductal (DCIS) and lobular carcinoma in situ (LCIS). Cumulative cancer incidence probabilities were calculated and a 1:5 matched nested case control study was conducted to estimate the odds of BC development. Of the 146 women diagnosed with CIS, 26 developed invasive BC (17.8%) and 12 died of BC (8.2%). The average time from the diagnosis of CIS to invasive BC was 6.3 years (±5.6). The 20‐year cumulative incidence probabilities for DCIS and LCIS were 19.0% (95%CI: 11.2, 26.8) and 21.3% (95%CI: 7.1, 35.4) respectively. The odds of development of BC in CIS women was significantly elevated compared with controls (OR = 2.6, 95% CI: 1.5, 4.5). While women with CIS had a higher odds of development of BC compared to those without CIS, at 20‐year post CIS diagnosis, more than 80% of them remained free of invasive BC. This low probability of developing invasive BC post CIS diagnosis does not support the notion that CIS of the breast is an obligate precursor lesion of invasive BC.

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/m3. In total, 932 participants developed lung cancer. In fully adjusted models, a 10 µg/m3 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.