Cornelia J. Baines

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

Clinical Breast Examination: Practical Recommendations for Optimizing Performance and Reporting

Clinical breast examination (CBE) seeks to detect breast abnormalities or evaluate patient reports of symptoms to find palpable breast cancers at an earlier stage of progression. Treatment options for earlier‐stage cancers are generally more numerous, include less toxic alternatives, and are usually more effective than treatments for later‐stage cancers. For average‐risk women aged 40 and younger, earlier detection of palpable tumors identified by CBE can lead to earlier therapy. After age 40, when mammography is recommended, CBE is regarded as an adjunct to mammography. Recent debate, however, has questioned the contributions of CBE to the detection of breast cancer in asymptomatic women and particularly to improved survival and reduced mortality rates. Clinicians remain widely divided about the level of evidence supporting CBE and their confidence in the examination. Yet, CBE is practiced extensively in the United States and continues to be recommended by many leading health organizations. It is in this context that this report provides a brief review of evidence for CBEs role in the earlier detection of breast cancer, highlights current practice issues, and presents recommendations that, when implemented, could contribute to greater standardization of the practice and reporting of CBE. These recommendations may also lead to improved evidence of the nature and extent of CBEs contribution to the earlier detection of breast cancer.

Physical examination. Its role as a single screening modality in the Canadian National Breast Screening Study.

Although often recommended as an important component in screening for breast cancer, physical examination of the breasts (PE) by medical professionals has not been well evaluated. The Canadian National Breast Screening Study (NBSS) permits estimation of sensitivity, specificity, and positive predictive value (PPV) of PE alone as performed by screen‐examiners because 50% of the 89,835 NBSS participants did not receive mammography. There were 19,965 women aged from 50 to 59 years who were eligible to receive four or five annual PEs from 77 nurse‐examiners, in 12 screen centers outside Quebec province and 58 physician‐examiners in three screen centers in Quebec. The gold standard was histologically proven breast cancer. When a test was positive the participant was referred to the study surgeon for review. For screens one to five, sensitivity was 83, 71, 57, 83, and 77; specificity was 88, 94, 96, 96, and 96; and PPV was 3,3,4,3, and 4, respectively. For 25,620 women aged 40 to 49 years who were eligible to receive only one PE, sensitivity was 71, specificity 84, and PPV 1.5. Using a binomial regression model, X2 for heterogeneity suggested there was no difference between nurse and physician examiners (P = 0.6879). Similar estimates made for the surgeons who performed 8914 reviews showed that sensitivity and PPV were higher than for the screen examiners and specificity was lower. These results support the conclusion that physical examination of the breasts by trained nurses is a useful component in screening for breast cancer.

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.

The role of the reference radiologist. Estimates of inter-observer agreement and potential delay in cancer detection in the national breast screening study.

The Canadian National Breast Screening Study (NBSS) is a randomized controlled trial to assess the effect of screening on breast cancer mortality. The NBSS designated a single reference radiologist who blindly reviewed over the course of the study 5200 randomly selected two-view mammographic examinations of women not known to have breast cancer. He also reviewed 575 screening-detected breast cancer (SBC) cases and 102 interval breast cancer (IBC) cases. All cancers were histologically proven. As a result of the reviews, comments on inter-observer agreement, interpretation, and technical quality were conveyed on an ongoing basis to radiologists appointed to 15 NBSS screening centers. Agreement of the reference radiologist with center radiologists was better for breast cancer cases (kappa = 0.511, P less than .002) than for those not known to have breast cancer (kappa = 0.307, P less than .002). Observer error and technical problems led to delayed detection in 22% of SBCs and 35% of IBCs. Another 11% of SBCs and 58% of IBCs were probably mammographically occult. No similarly comprehensive review of mammography during a screening program has been published. Suggestions arising from the NBSS review were sometimes resisted by center radiologists. Measures are suggested which might facilitate acceptance of recommendations arising from audit mechanisms in mammography screening programs, thereby enhancing opportunities for mammographic excellence.

Impact of menstrual phase on false-negative mammograms in the canadian national breast screening study

The efficacy of breast carcinoma screening should be enhanced if false‐negative mammography were reduced. Prospectively collected data from the Canadian National Breast Screening Study were used to examine whether menstrual cycle phase was associated with false‐negative outcomes for mammographic screening.

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.

Multiple chemical sensitivity: Discriminant validity of case definitions

Abstract In this study, the authors used the University of Torontos Health Survey self-administered questionnaire to determine discriminant validity of multiple chemical sensitivity definitions. The authors distributed a total of 4,126 questionnaires to adults who attended general, allergy, occupational, and environmental health practices. The authors then matched responses to features selected from existing case definitions posited by Thomson et al.; the National Research Council; Cullen; Ashford and Miller; Randolph; Nethercott et al.; and the 1999 Consensus (references 4–7, 2, 9, and 10, respectively, herein). The overall response rate was 61.7%. The prevalence of reported symptoms was lowest in general practices, was intermediate in occupational health and allergy practices, and was highest in environmental health practices. Features from the definitions presented by Nethercott et al. and the 1999 Consensus (references 9 and 10, respectively, herein) correctly identified more than 80% of environmental health practice patients and more than 70% of general practice patients. Combinations of 4 symptoms (i.e., having a stronger sense of smell than others, feeling dull/groggy, feeling “spacey,” and having difficulty concentrating) also discriminated successfully. In summary, features from 2 of 7 case definitions assessed by the University of Toronto Health Survey achieved good discrimination and identified patients with an increased likelihood of multiple chemical sensitivity.

Selection of women at high risk of breast cancer for initial screening.

Selective breast cancer screening refers to the intentional restriction of screening to only a high-risk subgroup of the total population of women at risk. Using data from the Canadian National Breast Screening Study, we explored methods of defining such subgroups. Discriminants were based on risk factor information collected prior to screening and were constructed using a training group of 77 cases and 400 controls. They were then tested on a separate group of 38 cases and 200 controls. Both simple risk factor counts and logistic models were utilized and separate analyses were performed for pre- and post-menopausal women. Using a logistic model, we were able to define a high-risk subgroup encompassing less than 40% of the test controls and over 85% of the test cases. Such a selection strategy, if implemented, might reduce initial visit mammography rates by up to 60% with only a small reduction in case detection. Other uses as determining the optimal age for initiation of screening are also discussed.