The Gothenburg breast screening trial: first results on mortality, incidence, and mode of detection for women ages 39-49 years at randomization.
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Biomedical subjects
Publications and source records attributed to C J Baines.
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In response to concerns about contamination of human breast milk from silicone gel-filled breast implants, and because silicon levels are assumed to be a proxy measurement for silicone, we compared silicon levels in milk from lactating women with and without implants. Two other sources of infant nutrition, cow's milk and infant formulas, were also analyzed for silicon. The survey took place at the Breast-feeding Clinic at Women's College Hospital in Toronto. A convenience sample of lactating women, 15 with bilateral silicone gel-filled implants and 34 with no implants, was selected. Women with foam-covered or saline implants or with medically related silicone exposures were ineligible. Collection of samples was scrupulously controlled to avoid contamination. Samples were prepared in a class 100 "ultraclean" laboratory and analyzed using graphite furnace atomic absorption spectrophotometry. Silicon levels were analyzed in breast milk, whole blood, cow's milk, and 26 brands of infant formulas. Comparing implanted women to controls, mean silicon levels were not significantly different in breast milk (55.45 +/- 35 and 51.05 +/- 31 ng/ml, respectively) or in blood (79.29 +/- 87 and 103.76 +/- 112 ng/ml, respectively). Mean silicon level measured in store-bought cow's milk was 708.94 ng/ml, and that for 26 brands of commercially available infant formula was 4402.5 ng/ml (ng/ml = parts per billion). We concluded that lactating women with silicone implants are similar to control women with respect to levels of silicon in their breast milk and blood. Silicon levels are 10 times higher in cow's milk and even higher in infant formulas.
OBJECTIVE: To measure the effect of breast self-examination (BSE) technique and frequency on the risk of death from breast cancer. DESIGN: Case-control study nested within the Canadian National Breast Screening Study (NBSS). SETTING: The Canadian NBSS, a multicentre randomized controlled trial of screening for breast cancer in Canadian women. SUBJECTS: The case subjects were 163 women who had died from breast cancer and 57 women with distant metastases. Ten control subjects matched by 5-year age group, screening centre, year of enrolment and random allocation group were randomly selected for each case subject. EXPOSURE MEASURES: Self-reported BSE frequency before enrolment in the NBSS, annual self-reports of BSE frequency during the program and annual objective assessments of BSE technique. OUTCOME MEASURES: Odds ratios (ORs) associated with BSE practice were estimated by conditional multiple logistic regression modelling, which permitted control of covariates. RESULTS: Relative to women who, when assessed 2 years before diagnosis, examined their breasts visually, used their finger pads for palpation and examined with their 3 middle fingers, the OR for death from breast cancer or distant metastatic disease for women who omitted 1, 2 or 3 of these components was 2.20 (95% confidence interval [CI] 1.30 to 3.71, p = 0.003). The OR for women who omitted 1 of the 3 components was 1.82 (95% CI 1.00 to 3.29, p = 0.05), for those who omitted 2 of the 3 components, 2.84 (95% CI 1.44 to 5.59, p = 0.003), and for those who omitted all 3 components, 2.95 (95% CI 1.19 to 7.30, p = 0.02). The results remained unchanged after adjustment for potential confounders. CONCLUSION: The results, obtained with the use of prospectively collected data, suggest that the performance of specific BSE components may reduce the risk of death from breast cancer.
BACKGROUND: 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. METHODS: Of 8887 women ages 40-44 years at the onset of screening, randomized to receive annual mammography and clinical breast examination, reporting menstruation no more than 28 days prior to their screening examination, and with a valid radiologic report, 1898 had never used oral contraceptives or replacement estrogen with or without progesterone. The remainder were past (6573) and current (416) estrogen users. Similar selection criteria were applied at subsequent screens. The distribution of false-negative and false-positive mammography in relation to true-negative and true-positive mammography was examined with respect to the follicular (Days 1 to 14) and luteal (Days 15-28) menstrual phases. RESULTS: Comparing luteal with follicular mammograms in 6989 patients who ever used estrogen, the unadjusted odds ratio (2-sided P-values) for false-negatives versus true-negatives was 2.16 (0.05) and the adjusted odds ratio was 1.47 (0.05). In 1898 never-users, parallel odds ratios for luteal false-negatives were 0.55 (1.0) and 0.74 (1.0), respectively. CONCLUSIONS: These results suggest that menstruating women who have used hormones may have an increased risk of false-negative results for screening mammograms performed in the luteal phase of the menstrual cycle. An increased risk of false-negative mammography might adversely affect screening efficacy. The impact of menstrual phase on mammographic interpretation, especially for women who ever used hormones, requires further investigation.
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Using published data from screening trials, this article compares two-modality (mammography and clinical examination) and single-modality (clinical examination alone) screening by evaluating cancer detection rates, program sensitivities, mode of cancer detection in two-modality screening, nodal status at time of detection, survival 10 years post-diagnosis, and breast cancer mortality 10 years after entry. Consistently, two-modality screening achieved higher cancer detection rates and program sensitivity estimates than either modality alone; mammography alone achieved higher rates than clinical examination alone; interval cancer detection rates between screening examinations were higher following clinical examination alone than mammography alone; single-modality screening with mammography failed to detect breast cancers identified by clinical examination alone; the sensitivity of mammography was lower in younger than older women, while the reverse was true for clinical examination; and mammography identified a higher proportion of node-negative breast cancer than clinical examination. We conclude that combining clinical breast examination with mammography is desirable for women age 40-49 because mammography is less sensitive in younger than older women. Careful training and monitoring are, however, as essential with clinical examiners as with mammographers.
The Canadian National Breast Screening Study (CNBSS), conducted on women age 40-49, was designed to evaluate the efficacy of combined annual mammography and physical examination of the breasts in reducing breast cancer mortality in comparison to usual care (UC) controls. From January 1980 through March 1985, 25,214 women were individually randomized to the mammography/physical exam (MP) arm and 25,216 to the UC. The integrity of the randomization has been reviewed and confirmed to be unbiased. During an average, follow-up of 10.5 years from entry (range: 8.75-13 years), 82 women died from breast cancer in the MP arm and 72 in the UC, for a rate ratio of 1.14 (95% confidence interval: 0.83-1.56). All-cause mortality was almost identical comparing the two groups; the nonsignificant excess of breast cancer deaths in the MP arm was balanced by an excess of other cancer deaths in the UC arm.
Why the National Breast Screening Study (NBSS)? In 1979, after reviewing the Breast Cancer Detection Demonstration Projects (BCDDP), the Beahrs Working Group made 11 recommendations. The NBSS protocol reflected a number of these recommendations, particularly the evaluation of screening women age 40-49 and the still unanswered question of the incremental benefit of mammography versus physical examination of the breasts among women age 50-59. Three years after publication of NBSS's 7-year results and in light of other published evidence from screening trials (as opposed to observational studies), it is reasonable to recommend screening with mammography and physical examination every 2 years for women age 50-59. In contrast, it is not reasonable to offer screening mammography to women age 40-49 other than in the context of a controlled trial, an opportunity currently available in the United Kingdom. The Beahrs recommendation, that "physical examinations should be continued in the Breast Cancer Detection Demonstration Projects as a routine screening modality for all ages," remains justifiable as long as so many women age 40-49 are having mammograms performed, given the relatively poor sensitivity of mammography in this age group. Criticism of the NBSS, mainly by radiologists, will continue until the NBSS yields results that support its critics' belief in the efficacy of screening. To date, responses to critics of the NBSS have focused on correcting misinformation and clarifying NBSS procedures. Useful critical commentary should await the results of a 10-year NBSS follow-up and the U.S. National Cancer Institute-sponsored meta-analysis of screening trials. Rigorous critical scrutiny should be directed at all trials.
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Recently published 7-year results from the Canadian National Breast Screening Study (NBSS) generated much controversy and criticism. In women aged 40 to 49 years at entry, no reduction in breast cancer mortality was observed when screened women were compared with virtually unscreened women. In women aged 50 to 59 years, breast cancer mortality was similar when annual screening with mammography and physical examination was compared with annual screening with physical examination alone. Although NBSS results in 40- to 49-year-old women are similar to those from previously published screening studies, critics have attacked the study's design, randomization, execution, mammography, follow-up procedures, contamination of controls, and analysis. The absence of benefit observed in mammographically screened women who were 50 to 59 years old has been used to support criticism of mammography. Important facts have been ignored. The NBSS controls, aged 50 to 59 years, unlike in other studies, received thorough annual physical examinations. Cancer detection rates in both age groups were higher in the mammography than the comparison groups. Screen and interval cancer detection rates, sensitivity and specificity estimates, and prevalence to incidence ratios at first screen met or exceeded standards established by other screening studies. Claims that randomization was flawed, in particular, that more symptomatic women were assigned to mammography, are not supported by the distribution of descriptive variables collected before randomization was done. As for the "contamination" of 26% of controls aged 40 to 49 years, who reported receiving mammography, it is improbable that single or occasional diagnostic mammograms in one quarter of the control group could obliterate the benefit of four or five annual mammograms in almost 100% of the mammography group. Much remains unknown about the efficacy of breast screening.
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OBJECTIVES: To evaluate the efficacy of the combination of annual screening with mammography, physical examination of the breasts and the teaching of breast self-examination in reducing the rate of death from breast cancer among women aged 40 to 49 years on entry. DESIGN: Individually randomized controlled trial. SETTING: Fifteen urban centres in Canada with expertise in the diagnosis and treatment of breast cancer. PARTICIPANTS: Women with no history of breast cancer and no mammography in the previous 12 months were randomly assigned to undergo either annual mammography and physical examination (MP group) or usual care after an initial physical examination (UC group). The 50,430 women enrolled from January 1980 through March 1985 were followed for a mean of 8.5 years. DATA COLLECTION: Derived from the participants by initial and annual self-administered questionnaires, from the screening examinations, from the patients' physicians, from the provincial cancer registries and by record linkage to the Canadian National Mortality Data Base. Expert panels evaluated histologic and death data. MAIN OUTCOME MEASURES: Rates of referral from screening, rates of detection of breast cancer from screening and from community care, nodal status, tumour size, and rates of death from all causes and from breast cancer. RESULTS: Over 90% of the women in each group attended the screening sessions or returned the annual questionnaires, or both, over years 2 to 5. The characteristics of the women in the two groups were similar. Compared with the Canadian population, the participants were more likely to be married, have fewer children, have more education, be in a professional occupation, smoke less and have been born in North America. The rate of screen-detected breast cancer on first examination was 3.89 per 1000 in the MP group and 2.46 per 1000 in the UC group; more node-positive tumours were found in the MP group than in the UC group. During years 2 through 5 the ratios of observed to expected cases of invasive breast cancer were 1.26 in the MP group and 1.02 in the UC group. Of the women with invasive breast cancer through to 7 years, 191 and 157 women in the MP and UC groups respectively had no node involvement, 55 and 43 had one to three nodes involved, 47 and 23 had four or more nodes involved, and 38 and 49 had an unknown nodal status. There were 38 deaths from breast cancer in the MP group and 28 in the UC group. The ratio of the proportions of death from breast cancer in the MP group compared with those in the UC group was 1.36 (95% confidence interval 0.84 to 2.21). The survival rates were similar in the two groups. The highest survival rate occurred among women whose cancer had been detected by mammography alone. CONCLUSION: The study was internally valid, and there was no evidence of randomization bias. Screening with yearly mammography and physical examination of the breasts detected considerably more node-negative, small tumours than usual care, but it had no impact on the rate of death from breast cancer up to 7 years' follow-up from entry.