Teresa To

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.

Congenital abnormalities and childhood cancer

The examination of specific characteristics of neoplasms diagnosed in children have suggested that a significant proportion can be attributed to a genetic mutation or genetic predisposition. Although the study of a genetic predisposition to cancer in children remains in the early stages, congenital abnormalities could provide essential information for mapping predisposing lesions in children with cancer.

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.

Mammography benefit in the Canadian National Breast Screening Study-2: A model evaluation†

The CNBSS‐2 among women aged 50–59 did not show any significant difference in breast cancer mortality between a control arm screened annually by CBE and a study arm screened by CBE and mammography. Because of this design, the benefit of screening compared to no screening could not be evaluated. We therefore conducted a modeling effort to estimate the benefit of mammography or CBE compared to no screening. We incorporated demographic, epidemiologic and screening characteristics of the CNBSS‐2 in MISCAN. Stage‐specific sensitivities of CBE, with and without mammography, and breast cancer incidence rate in the trial were estimated by comparing observed trial data with model predictions. We predicted the number of breast cancer deaths for both study arms of the CNBSS‐2 and in the absence of screening, assuming improvement in prognosis by early detection. We estimated a 24–29% higher breast cancer incidence rate in the CNBSS‐2 than the average Canadian rate. Estimated sensitivity of CBE (control arm) varied from 0.29 to 0.48 for stage T1c and from 0.6 to 0.65 for stage T2+. Estimated sensitivity of CBE supplemented with mammography (study arm) varied from 0.5 to 0.79 for stage T1c and was 0.95 for stage T2+. Expected breast cancer mortality reduction by annual CBE screening is 20.5% compared to no screening. Estimated breast cancer mortality reduction by mammography screening compared to no screening for the CNBSS‐2 fell within the range 13.6–34.1%. Enrolled women had above average risk. Screening sensitivity in both arms was high. A benefit of mammography screening is supported by our modeling of the CNBSS‐2 results.

Changes in breast self-examination behavior achieved by 89,835 participants in the canadian national breast screening study

Breast self‐examination (BSE) behavior was analyzed in 89,835 participants in the National Breast Screening Study (NBSS) of whom 64,619 were eligible for annual rescreening and 25,216 were followed by mail after a single screen exam. Among those eligible for rescreening, BSE competence scores based on seven BSE criteria significantly improved over time and correlated directly with reported BSE frequencies. Among all participants, the proportion reporting BSE frequencies of ⩾12/year increased over time from approximately 20% on entry to 50% to 64% at final screen. Similarly, reports of zero frequency diminished from 50% to 10% to 15%. Variables such as educational status, age (fifth versus sixth decades), eligibility for mammography, smoking history, and ethnic origin had negligible or no influence on BSE competence. However, women with first‐degree relatives with breast cancer had significantly higher BSE scores. NBSS experience suggests that most women who enter screening programs will upgrade their BSE skills if subjected to brief episodes of repeated BSE instruction.

Revised estimates of overdiagnosis from the Canadian National Breast Screening Study.

We have re-estimated overdiagnosis of breast cancer from mammography screening by age group in the Canadian National Breast Screening Study (CNBSS), a randomized screening trial. In the CNBSS, participants were recruited in 15 centers. 89,835 women were randomized with informed consent, 50,430 age 40-49 and 39,405 age 50-59. Women aged 40-49 received annual mammography and physical examination (MA+PX) versus a single physical examination and usual care in the community (UC). Women aged 50-59 received (MA+PX) versus (PX-alone) annually. Individual randomization resulted in 44 almost identically distributed demographic and risk factors. Annual compliance over the five or four scheduled screens was 86-95%. The cumulative numbers of invasive and in situ breast cancers ascertained by year during screening and subsequent follow-up to 25 years post entry to the CNBSS in the mammography arm have been compared to those in the control arm. Estimates of overdiagnosis were derived using post-screening cessation cut-off points from 1 to 20years.⋯Overdiagnosis of invasive breast cancer at five years post cessation of screening for women aged 40-49 was estimated to be 32%, and 16% for women aged 50-59; 20years post cessation of screening 48% for women 40-49 and 5% for those 50-59. Including ductal carcinoma in situ with invasive cancer, estimates were 41%, 25%, 55% and 16%, respectively. We conclude that approximately 30% of invasive screen-detected breast cancers in women age 40-49 were overdiagnosed, and 20% of those screen-detected in women age 50-59. Including ductal carcinoma in situ, the estimates are 40% and 30%, respectively.

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.

Twenty-Five–Year Follow-up for Breast Cancer Incidence and Mortality of the Canadian National Breast Screening Study: Randomized Screening Trial

The Canadian National Breast Screening Study was a randomized controlled trial that compared breast cancer incidence and mortality rates between screening mammography and physical breast examination in 89,835 women, aged 40 to 59 years. The study was initiated in 1980. The results of follow-up at 11 to 16 years were previously published. The present study compared the incidence of breast cancer and mortality up to 25 years in women aged 40 to 59 years who did or did not undergo mammography screening. Follow-up data for a mean of 22 years were obtained by center coordinators, the study’s central office, and record linkage to cancer registries and vital statistics databases. The study was conducted at 15 screening centers in six Canadian provinces, (Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia). Women aged 40 to 59 years were randomly assigned to a mammography group (1 screening every year for 5 years or control group [no mammography]). Women aged 40 to 49 years in the mammography group and all women aged 50 to 59 years in both groups received annual physical breast examinations. Women aged 40 to 49 years in the control group had a single examination followed by routine care. The primary study outcomemeasure was death from breast cancer. During the 5-year screening period, breast tumors were detected in 1190 women (666 in the mammography group [n = 44,925] and 524 in the control group [n = 44,910]); of these women, 180 in the mammography group and 171 in the control group died of breast cancer during the 25-year follow-up period. The 25-year cumulative mortality from breast cancers diagnosed during the screening period was similar in both groups (hazard ratio, 1.05; 95% confidence interval, 0.85–1.30; P = 0.63). There was no difference in the 25-year cumulative mortality between the women aged 40 to 49 and 50 to 59 years. During the entire 25-year study period, 3250 women in the mammography group and 3133 in the control group were diagnosed with breast cancer; of these, 500 in the mammography group and 505 in the control group died of breast cancer. Thus, the cumulative mortality rates were similar in both groups; the hazard ratio was 0.99, with a 95% confidence interval of 0.88 to 1.12, P < 0.87. During the 5-year screening period, an excess of 142 cancers were observed in the mammography group, with 106 excess cancers recorded after 15 years of follow-up. This indicates that 22% (106/484) of the cancers were overdiagnosed, representing 1 overdiagnosed breast cancer for every 424 women screened with mammography. It was concluded that annual mammography screening in women aged 40 to 59 years fails to reduce breast cancer– specific mortality compared with physical examination alone or routine care.