Benefit of screening mammography in women aged 40-49: a new meta-analysis of randomized controlled trials

Eight randomized controlled trials (RCTs) of screening mammography have been conducted involving women aged 40-49 at entry. Current data are now available from these trials at 10.5 to 18 years of follow-up (average follow-up time: 12.7 years). Meta-analysis has been performed using a Mantel-Haenszel estimator method to combine current follow-up data from the eight RCTs of mammography that included women aged 40-49 at entry, including new follow-up data presented at the NIH Consensus Development Conference held January 21-23, 1997. Combining the most recent follow-up data on women aged 40-49 at entry into all eight RCTs yields a statistically significant 18% mortality reduction among women invited to screening mammography (relative risk: 0.82; 95% confidence interval: 0.71-0.95). Combining all current follow-up data on women aged 40-49 at entry into the five Swedish RCTs yields a statistically significantly 29% mortality reduction among women invited to screening (relative risk: 0.71; 95% confidence interval: 0.57-0.89). Meta-analysis including the most recent follow-up data from all eight RCTs involving women aged 40-49 at entry demonstrates for the first time a statistically significant mortality reduction due to regular screening mammography in women of this age group.     

Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit

In randomized controlled trials, screening mammography has been shown to reduce mortality from breast cancer about 25% to 30% among women aged 50 to 69 years after only five to six years from the initiation of screening. Among women aged 40 to 49 years, trials have reported no reduction in breast cancer mortality after seven to nine years from the initiation of screening; after 10 to 14 years there is a 16% reduction in breast cancer mortality. Given that the incidence of breast cancer for women aged 40 to 49 years is lower and the potential benefit from mammography screening smaller and delayed, the absolute number of deaths prevented by screening women aged 40 to 49 years is much less than in screening women aged 50 to 69 years. Because the absolute benefit of screening women aged 40 to 49 years is small and there is concern that the harms are substantial, the focus should be to help these women make informed decisions about screening mammography by educating them of their true risk of breast cancer and the potential benefits and risks of screening.     

Long-term survival of experimental calves with a left ventricular assist impeller pump

Screening with mammography in order to detect early curable breast cancer has been widely used during the last 2-3 decades. Especially an overview of 4 randomised trials in Sweden has shown a convincing short-term relative reduction of the breast cancer mortality while the long-term absolute effect on this mortality has been impossible to study due to screening of the control groups after some years. There is, however, rather general consensus about the value of screening in women above 50 years of age whereas screening in the age group 40-49 is still controversial due to the low rate of mammographically demonstrable cancers and the high rate of recalls for supplementary mammography, clinical examinations and biopsies in relation to cancers found. Recent follow-up of the pooled Swedish randomised trials have shown an about 20% almost significant reduction of the breast cancer mortality in women aged 40-49 at randomisation but the design of these trials does not allow an adequate estimation of the extra benefit obtained by starting periodical screening at age 40 instead of at age 50. The author proposes that screening in the age group 40-49 should be regarded as experimental and subject to proper randomised trials of a type on-going in UK and planned within UICC.     

Updated overview of the Swedish Randomized Trials on Breast Cancer Screening with Mammography: age group 40-49 at randomization

The purpose of this overview is to estimate more precisely the long-term effect of mammography screening by adding four more years of follow-up to women aged 40-49 years in the four Swedish trials on mammography screening. Data from the four, trials were merged and linked to the Swedish Cancer and Cause of Death Register for 1958-1993 and 1951-1993 respectively to identify date of breast cancer diagnosis and cause and date of death. The invited and control groups comprised 48,569 and 40,247 women respectively. At the December 1993 follow-up, 602 and 482 breast cancer cases were identified in the two groups respectively, of which 104 and 111 had breast cancer as the underlying cause of death. This corresponds to a relative risk (RR) of 0.77 (95% CI: 0.59-1.01) for the two groups. In the 40-44 age group at randomization, 94% of breast cancer patients in the study and 89% in the control group were diagnosed before the age of 50; however, among breast cancer deaths in this age group, only two in the invited and five in the control group died after age 50. At follow-up of women 40-44 years at randomization 208 women in the invited and 184 in the control group were reported to the Cancer registry with breast cancer. Out of these 195 (94%) and 163 (89%) respectively were reported before the age of 50. Further, the relative risk for the age group 40-44 years at randomization by age at follow-up was 1.11, 0.51 and 0.46 for the age groups 45-49, 50-54, and 55-59 at follow-up. This study shows a 23% reduction in the breast cancer mortality in women 40-49 years at randomization achieved from a median trial time of 7.0 years, a median follow-up time of 12.8 years, and a screening interval of 18-24 months. Almost all of the effect in the 40-44 year age group at randomization was due to screening before the age of 50.     

Recent results from the Swedish Two-County Trial: the effects of age, histologic type, and mode of detection on the efficacy of breast cancer screening

The effect of mammographic screening in reducing mortality from breast cancer is known to be smaller and more delayed in women aged 40-49 than in women over 50. In this study, we investigated how these phenomena relate to histology-specific breast cancer incidence and mortality. The data are from 2,468 women with breast cancer who participated in the Swedish Two-County Trial. The overall relative breast cancer mortality of invited to noninvited women aged 40-49 was 0.87, and the relative mortality from poorly differentiated (grade 3) ductal carcinoma was 0.95. These results were not statistically significant. The corresponding relative risks for invited women aged 50-74 were a statistically significant 0.65 and 0.61. We conclude that in this trial, with a two-year interscreening interval, the smaller and later effect of invitation to screening on breast cancer mortality in women 40-49 years old is due to the failure of screening to reduce mortality from grade 3 ductal carcinoma in this age group.     

Breast cancer screening among women in their forties: an overview of the issues

This article summarizes the issues prompting a recent NIH Consensus Conference on mammography screening for women in their forties. To date, eight randomized controlled trials of breast cancer screening have been conducted, and a reduction in breast cancer mortality has emerged after 10 to 15 years of follow-up among women offered screening in their forties. No effect appears for at least eight years, and the reason for the delay, compared to that seen in women aged 50-69, is not clear. Two possibilities include cancer-stage shift due to screening in younger women and the aging of women into their fifties during the course of screening. Possible adverse effects of screening include radiation risk, although this is low, false-negative and false-positive screening tests, and overdiagnosis due to detection of ductal carcinoma in situ (DCIS). In order to make appropriate decisions regarding mammography, women need age-related information about both the benefits and potential risks of screening.     

Markov models of breast tumor progression: some age-specific results

Researchers have noted that mammographic screening has a reduced effect on breast cancer mortality in women in their forties compared to older women. Explanations for this include poorer sensitivity in younger women due to denser breast tissue, as well as more rapid tumor progression, giving a shorter mean sojourn time (the average duration of the preclinical screen-detectable period). To test these hypotheses, we developed a series of Markov-chain models to estimate tumor progression rates and sensitivity. Parameters were estimated using tumor data from the Swedish two-county trial of mammographic screening for breast cancer. The mean sojourn time was shorter in women aged 40-49 compared to women aged 50-59 and 60-69 (2.44, 3.70, and 4.17 years, respectively). Sensitivity was lower in the 40-49 age group compared to the two older groups (83%, 100%, and 100%, respectively). Thus, both rapid progression and poorer sensitivity are associated with the 40-49 age group. We also modeled tumor size, node status, and malignancy grade together with subsequent breast cancer mortality and found that, to achieve a reduction in mortality commensurate with that in women over 50, the interscreening interval for women in their forties should be less than two years. We conclude that Markov models and the use of tumor size, node status, and malignancy grade as surrogates for mortality can be useful in design and analysis of future studies of breast cancer screening.     

The quality and interpretation of mammographic screening trials for women ages 40-49

Using MEDLINE and the bibliographies of retrieved articles and reviews, we identified and systematically reviewed the quality and results of all randomized trials of mammographic screening that included women less than 50 years of age. Eight randomized trials were identified, 7 of which included women less than 50. Identified trials were assessed for the following design features: (a) method of randomization, (b) documented comparability of baseline data, (c) standardized criteria for breast cancer death, (d) blinded review of cause of death, (e) completeness of follow-up, and (f) use of an "intention to treat analysis." The quality of trials was generally high, with a total of almost 160,000 women randomized. In women aged 40-49 at entry, the overall, absolute risk difference between those invited and those not was 0.0004 (95% CI: 0 to 0.0009). Yet, what does this mean to a 40-year-old women considering screening? If 10,000 women aged 40-49 years were screened regularly, then after a decade there would be about 4 less breast cancer deaths? Is that worthwhile? This is a difficult question, and it needs to be weighed against the problems arising from false positives and ductal carcinoma in situ. We recommend that women in this age group intending to be screened should be fully informed of these results in terms of absolute benefit.     

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The American Cancer Society recommends periodic mammography, clinical breast examination and breast self-examination beginning at age 40 years for asymptomatic women at average risk of breast cancer. Although there is substantial evidence from meta-analyses and non-randomized studies to support these recommendations, individual randomized clinical trials of breast cancer screening have not demonstrated mortality reduction in women aged 40-49 years. The opportunity to study this issue further in the United States has been diminished by the high prevalence of screening already being conducted in that population of younger women. The International Union Against Cancer, the American Cancer Society and the National Cancer Institute of the United States have convened a series of workshops and planning meetings to consider the available data and outline plans for future research. Plans are being developed to conduct a randomized trial of mammography in women younger than 50 years in multiple European sites. Successful completion of this trial may provide critical data on efficacy of breast cancer screening in younger women.     

Breast cancer screening outcomes in women ages 40-49: clinical experience with service screening using modern mammography

The several randomized controlled trials (RCTs) of breast cancer screening among women of ages 40 to 49 now collectively show a statistically significant reduction in breast cancer mortality. However, there have been numerous recent advances in mammography, such that it now is demonstrably better than when the RCTs were conducted. The use of surrogate measures of screening efficacy (tumor size, lymph node status, cancer stage), readily derived from modern service screening programs, demonstrates how the improved mammography of the 1990s should produce a greater degree of mortality reduction among women ages 40-49 than that already demonstrated in the RCTs. Indeed, these surrogate measures of mortality reduction are as favorable for women of ages 40-49 and 65+ as they are for women of ages 50-64, strongly suggesting that, since modern service screening is accepted as effectively reducing mortality among women of ages 50-64, it should also effectively reduce mortality among women in the 40-49 and 65+ age groups.     

Mammography versus clinical examination of the breasts

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 Edinburgh Randomized Trial of Breast Cancer Screening

This article presents additional follow-up analysis of women aged 45-49 from the Edinburgh Randomized Trial of Breast Cancer Screening. The screening protocol included four mammographic examinations at two-year intervals and seven annual clinical examinations. Altogether, 21,774 women aged 45-49 were recruited from 1978 to 1985 using cluster randomization. After 10-14 years of follow-up, breast cancer mortality has been reduced by 12% to 18% (rate ratios, with and without adjustment for socio-economic status, are 0.88 and 0.82 respectively, with 95% confidence intervals [CIs] of 0.55-1.41 and 0.51-1.32). These benefits are smaller than that reported previously with shorter follow-up. This article also presents data from an observational study that compared survival beyond baseline (50-52 years) of women first offered screening before and after age 50. Based on six-year data, the results suggest that earlier screening confers follow-up benefit (hazard ratio for later screening = 1.60; 95% CI: 0.96-2.67), but these findings are not statistically significant. The trial is too small to yield statistically significant results by itself, but can make useful contributions to overview and meta-analyses.     

The Gothenburg Breast Cancer Screening Trial: preliminary results on breast cancer mortality for women aged 39-49

We carried out a randomized trial of invitation to screening mammography in the city of Gothenburg, Sweden, to estimate the effect of screening on breast cancer mortality in women under age 50 years. A total of 11,724 women aged 39-49 were randomized to the study group, which was invited to mammographic screening every 18 months; 14,217 women in the same age range were randomized to a control group, which was not invited to screening until the fifth screen of the study group. Breast cancers diagnosed in both groups between randomization and immediately after the first screen of the control group were followed up for death from breast cancer to the end of December 1994. There was a significant 44% reduction in mortality from breast cancer in the study group compared to the control group (relative risk [RR] = 0.56, P = 0.042, 95% confidence interval [CI]: 0.32-0.98). A conservative estimate based on removal of the cancers detected at the first screen of the control group gave an RR = 0.59 (P = 0.069, 95% CI: 0.33-1.05). The true answer is likely to lie between the two estimates. These data suggest that mammographic screening can reduce breast cancer mortality in women under age 50, particularly if high-quality mammography is used and a short interscreening interval is adhered to.     

Effects of age, breast density, ethnicity, and estrogen replacement therapy on screening mammographic sensitivity and cancer stage at diagnosis: review of 183,134 screening mammograms in Albuquerque, New Mexico

PURPOSE: To examine how common patient factors affect screening mammographic sensitivity and cancer stage at diagnosis. MATERIALS AND METHODS: The authors used a population-based database of 183,134 screening mammograms and a statewide tumor registry to identify 807 breast cancers detected at screening mammography. RESULTS: Sensitivity varied significantly with ethnicity, use of estrogen replacement therapy, mammographic breast density, and age. Sensitivity was 54% (13 of 24) in women younger than 40 years, 77% (121 of 157) in women aged 40-49 years, 78% (224 of 286) in women aged 50-64 years, and 81% (277 of 340) in women older than 64 years. Sensitivity was 68% (162 of 237) for dense breasts and 85% (302 of 356) for nondense breasts and 74% (180 of 244) in estrogen replacement therapy users and 81% (417 of 513) in nonusers. Sensitivity was most markedly reduced with the combination of dense breasts and estrogen replacement therapy use; there was little difference when only one factor was present. Median cancer size and the percentage of early cancers showed little change with any factors. CONCLUSION: Age is a minor determinant of mammographic sensitivity in women aged 40 years or older. Sensitivity is substantially decreased with the combination of higher breast density and estrogen replacement therapy use. There was not a notable shift in cancer outcomes in the groups with lower mammographic sensitivity. These data do not support different screening recommendations in women aged 40-49 years or in estrogen replacement therapy users.     

Digital archival and exchange of events in a simple format for polygraphic recordings with application in event related potential studies

The relationship between sequential mammographic parenchymal patterns and breast cancer was estimated and the results were applied to selective screening. In a pilot screening program 4163 Finnish women aged 40-47 years at entry were invited to be screened every second year from 1982 to 1990. Mammographic parenchymal patterns (Wolfe's classification) were recorded at each screening round. The follow-up ended in 1993 and up until that time 68 new breast cancers were diagnosed. The age-adjusted relative risk of breast cancer was 2.5 (95% CI 1.5-4.0) among women with high-risk mammographic parenchymal patterns (P2,DY) at the screenings preceding cancer diagnosis compared with those with low-risk patterns (N1,P1). After further adjustment for body mass index, number of pregnancies and size of the breast, the relative risk increased to 2.8 (95% CI 1.7-4.9). The mammographic parenchymal pattern is an independent risk factor of breast cancer but not strong enough to be used as a criterion for selective screening.     

Does the proven benefit of mammography extend to breast cancer patients over age 70?

BACKGROUND: Prospective randomized studies show reduced breast cancer mortality among women offered mammographic screening; yet, few women 70 or older were represented in these trials. We examine the impact of mammography on stage at diagnosis of breast cancer, over the years when mammography came into general use, comparing women aged 40 to 69 with those aged 70 and older. METHODS: We reviewed the records of 1,001 consecutive patients 40 and older treated for invasive or in situ breast cancer in the surgical practice of one of us (H.S.C.) between 1979 and 1993, comparing trends in mammography use, means of diagnosis, tumor size, axillary node status, and pathology. RESULTS: The proportion of cases diagnosed by mammography increased over time to a comparable degree in both age groups, as did the proportion of T1 and DCIS or microinvasive cancers. This trend toward earlier stage appears entirely due to an increasing use of mammography. CONCLUSION: The potential benefit of regular mammography to healthy women aged 70 and older may equal that observed in their younger counterparts.     

Reduced breast cancer mortality in women under age 50: updated results from the Malm? Mammographic Screening Program

This article provides additional follow-up data of two cohorts from the Malm? Mammographic Screening Trial (MMST). The first cohort, MMST I, contained 7,984 women under age 50 at entry into MMST who were born between 1927 and 1932. Half were assigned to a control group and were not invited for examination until four years after the code was broken in the MMST in 1988. The second cohort, MMST II, contained 17,786 women born between 1933 and 1945. Fifty four percent of these women were randomly invited to screening between 1978 and 1990. The remaining 46%--the control group--was invited to screening between 1991 and 1994. Nine screening rounds were completed in MMST I, and a mean of five rounds were completed in MMST II; the screening interval ranged from 18 to 24 months. The effect of screening on breast cancer mortality was assessed by pooling the two cohorts. At the end of follow-up--December 1993 for MMST I and December 1995 for MMST II--there was a statistically significant 36% reduction in breast cancer mortality in the intervention groups (relative risk = 0.64; 95% CI: 0.45-0.89; P = 0.009). A harm-benefit analysis showed, however, that for every two breast cancer deaths prevented, one clinically insignificant cancer was diagnosed; for each breast cancer death prevented, 63 cancer-free women had been called back for further examinations; and for every 20 lives saved, one radiation-induced breast cancer death may have occurred. Recommendations for screening must therefore weigh mortality benefits against these negative effects.     

Survival of women with breast cancer in Europe: variation with age, year of diagnosis and country. The EUROCARE Working Group

Breast cancer is the most frequent malignancy among women in developed countries. Prognosis is better than for other major cancers, and an improvement in survival has been reported for several populations in recent decades. Within the framework of EUROCARE, a population-based project concerned with the survival and care of cancer patients in Europe, we analysed data from 119,139 women diagnosed with breast cancer between 1978 and 1985 in 12 countries and followed for at least 6 years. Multiple regression models of relative survival, which take mortality from all other causes in each area into account, were used to estimate the effect of age, period of diagnosis and country on survival. For the comparison between countries, survival rates were age-standardised to the age structure of the entire study population. Women aged 40-49 years at diagnosis had the best prognosis in all countries and throughout the study period. Women younger than 30 years at diagnosis had a worse prognosis than those aged 30-39. The highest relative survival at 5 years was in Finland and Switzerland (about 74%), intermediate levels were found for Italy, France, The Netherlands, Denmark and Germany (about 70%) and the lowest rates were in Spain, the United Kingdom, Estonia and Poland (55-64%). During the 6 months following diagnosis, survival was highly dependent on age and was sharply lower in women older than 49 years. For women surviving more than 6 months after diagnosis, survival was similar for all ages, although women aged 40-49 still had the better prognosis. The average rate of death from breast cancer fell by about 2.5% for each year of diagnosis between 1978 and 1985. This improvement manifested mainly in younger and older women, for whom survival was initially less good. The largest improvement was seen in Poland (-15% death risk per year). We suggest that the better survival of women aged 40-49 at diagnosis is related to lower levels of circulating sex hormones, resulting in reduced stimulation of tumour cell growth. Early diagnosis may also be important in the peri-menopausal period due to increased diagnostic attention. Low survival in the United Kingdom may be due to inadequate adherence to consensus treatment guidelines and greater variation in treatment.     

Outcomes of modern screening mammography

The University of California, San Francisco, Mobile Mammography Screening Program is a low-cost, community-based breast cancer screening program that offers mammography to women of diverse ethnic backgrounds (36% nonwhite) in six counties in northern California. Analysis of data collected on approximately 34,000 screening examinations from this program shows that the positive predictive value and sensitivity of modern screening mammography to be lower for women aged 40 to 49 years compared to women aged 50 and older. This lower performance is due to the lower prevalence of invasive breast cancer in younger women and possibly to age differences in breast tumor biology. Because of this lower performance, women in their forties may be subjected to more of the negative consequences of screening, which include additional diagnostic evaluations and the associated morbidity and anxiety, the potential for detecting and surgically treating clinically insignificant breast lesions, and the false reassurance resulting from normal mammographic results. Since the evidence is not compelling that the benefits of mammography screening outweigh the known risks for women aged 40 to 49 years, women considering mammography screening should be informed of the risks, potential benefits, and limitations of screening mammography, so that they can make individualized decisions based on their personal risk status and utility for the associated risks and potential benefits of screening.     

A systematic review of the effects of screening for colorectal cancer using the faecal occult blood test, hemoccult

OBJECTIVE: To review effectiveness of screening for colorectal cancer with faecal occult blood test, Hemoccult, and to consider benefits and harms of screening. DESIGN: Systematic review of trials of Hemoccult screening, with meta-analysis of results from the randomised controlled trials. SUBJECTS: Four randomised controlled trials and two non-randomised trials of about 330 000 and 113 000 people respectively aged >=40 years in five countries. MAIN OUTCOME MEASURES: Meta-analysis of effects of screening on mortality from colorectal cancer. RESULTS: Quality of trial design was generally high, and screening resulted in a favourable shift in the stage distribution of colorectal cancers in the screening groups. Meta-analysis of mortality results from the four randomised controlled trials showed that those allocated to screening had a reduction in mortality from colorectal cancer of 16% (relative risk 0.84 (95% confidence interval 0.77 to 0.93)). When adjusted for attendance for screening, this reduction was 23% (relative risk 0.77 (0.57 to 0.89)) for people actually screened. If a biennial Hemoccult screening programme were offered to 10 000 people and about two thirds attended for at least one Hemoccult test, 8.5 (3.6 to 13.5) deaths from colorectal cancer would be prevented over a period of 10 years. CONCLUSION: Although benefits of screening are likely to outweigh harms for populations at high risk of colorectal cancer, more information is needed about the harmful effects of screening, the community's responses to screening, and costs of screening for different healthcare systems before widespread screening can be recommended.