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.     

Simultaneous differentiation and quantitation of erythroblasts and white blood cells on a high throughput clinical haematology analyser

Recently published evidence from two large-scale clinical trials conducted in England and in Denmark suggests that faecal occult blood screening for colorectal cancer significantly reduces mortality. However, before screening can be advocated as part of national health policy, its cost-effectiveness must be demonstrated. The English screening trial has been the subject of a detailed economic evaluation over the past 10 years In this paper, cost-effectiveness estimates of screening are presented, based on cost and outcome data combined in a mathematical model developed from the trial's clinical findings The estimates of cost per quality-adjusted life-year gained from colorectal cancer screening show the procedure to be of similar cost-effectiveness to breast cancer screening in the short term. Over the longer term, however, the estimates for colorectal cancer screening appear superior.     

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.     

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.     

Variation in the effectiveness of breast screening by year of follow-up

This meta-analysis assesses the effectiveness of breast screening by year from the start of screening for women aged 40-49 at study entry. Data from previous randomized controlled trials on breast cancer screening were combined, and cumulative and yearly breast cancer mortality rates and relative risks (RRs) were calculated for women offered screening compared to those not offered screening. At 7 years of follow-up, no reduction in breast cancer mortality from screening starting at ages 40-49 was found. At 10 years of follow-up, a nonsignificant reduction in breast cancer mortality was seen for women aged 40-49 at entry (RR = 0.93; 95% CI: 0.77-1.11). A nonsignificant excess of breast cancer mortality in those offered screening aged 40-49 was observed during the early years of follow-up in several trials. While the favorable effect of screening was observed within the first 5 years of study entry for women aged 50 or more, no similar effect was seen for women aged 40-49. The delayed effect for the 40-49 cohort may be attributable to 1) a biological difference in the effects of screening, which may be related to the onset of menopause, and 2) screening that occurred when women were aged 50 or more rather than before that age.     

Prevalence of self-reported screening mammography and impact on breast cancer mortality in Austria

Mammography for breast cancer screening has been available in Austria free of charge since 1974 and has been explicitly recommended for mass screening since 1980. The type of screening is opportunistic. Evaluation has to rely on population-based data (mortality, stage distribution, screening prevalence). In a representative cross-sectional study (women aged 40-79 years, n = 566, conducted in 1995) 58% reported at least one screening mammography; the lowest prevalence was found in the age group 70-74 years: 39.3%, the highest in the age group 50-54 years: 71.4%. 23.1% reported at least 2 mammograms within an interval of less than 2 years; lowest prevalence 70-74 years: 10.7%, highest 50-54 years: 35.7%. Age-standardized mortality rate has stabilized since 1985. Since 1980 age-specific rates have increased significantly in all age groups > 54 years, but a decreasing tendency in most groups has been noted since around 1990. The incidence rates of stage II or worse tumors have increased significantly since 1982, except in the age groups 40-44 and 55-59 years; however, during the past 3 to 6 years the absolute rates of incidence of advanced tumors has decreased in alle age groups. The reduction of advanced cancers at diagnosis, followed by a reduction of mortality rates is plausible related to screening prevalence. More uniform decreasing trends should be expected in the years to come. If not, discontinuation of the current opportunistic form of screening without monitoring and evaluation, financed by public money, has to be discussed.     

Evaluation of various screening and surveillance methods in colorectal carcinoma

Colorectal cancer is a common disease which is almost wholly preventable by early removal of adenomatous polyps. Screening should be offered to all persons without risk factors from the age of 50. Selection of the appropriate screening programme should take into account personal preference, local expertise and insurance coverage. Endoscopic screening and surveillance investigations should be strongly encouraged in all persons wit risk factors such as (1) previous treatment of colorectal adenomatous polyps or cancers, (2) ulcerative colitis, (3) patients with hereditary colorectal cancer syndromes and (4) first degree relatives of patients with colorectal cancer. The following four strategies are available for candidates > 50 years without risk factors: (1) faecal occult blood testing (annually), (2) flexible sigmoidoscopy (every 5 years), (3) a combination of both (1 + 2) strategies and (4) coloscopy (every 10 years). Coloscopy should be performed after a positive test result in strategy programs 1-3. Results from prospective randomized trials are available only for faecal occult blood testing, showing an approximately 15% reduction of mortality in the screening group. The potential for reduction of colorectal cancer mortality has been estimated at 30-70% and 60-90% for flexible sigmoidoscopy and coloscopy respectively. However, no results from prospective randomized trials are presently available. Cost-effectiveness analysis has not shown relevant differences between the four different screening strategies.     

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.     

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.     

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.     

Glycation accelerates the oxidation of low density lipoprotein by copper ions

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.     

Mass screening of colorectal cancer by general practitioners in France: what is the real target population?

OBJECTIVES: People at high risk of colorectal cancer, due to familial or personal history, or to specific symptoms, are considered not to be concerned by mass screening by Haemoccult test. The aim of this study was to investigate people aged 50 to 74 with high risk of colorectal cancer among general practitioners' practices in the department of Calvados (France). METHODS: A random sample of 200 general practitioners were asked to systematically fill out a questionnaire on Haemoccult II proposal for 50-74 year-old patients for a whole week. RESULTS: Participation rate of general practitioners was 58.5%. According to our findings, 13% of 50-74 years patients are considered not be concerned by mass screening, due to familial or personal history, or to specific symptoms. CONCLUSIONS: Colorectal cancer screening protocol have to be fit to level of risk of colorectal cancer. Involvement of general practitioners in colorectal cancer mass screening allows identification of high risk people who can then be managed with a more suitable screening protocol.     

Knee position error detection in closed and open kinetic chain tasks during concurrent cognitive distraction

OBJECTIVES: To estimate the number of breast cancer deaths induced by low dose radiation in breast cancer screening programmes compared with numbers prevented. METHODS: A computer simulation model on the natural history of breast cancer was combined with a model from BEIR-V on induced breast cancer mortality from low levels of radiation. The improvement in prognosis resulting from screening was based on the results of the Swedish overview of the randomised screening trials for breast cancer and the performance of screening in the Netherlands. Different scenarios (ages and intervals) were used to explore the objectives. Sensitivity analyses were carried out for latency period, dose of mammography, sensitivity of the screening test, early detection by screening of induced breast tumours, and new 1996 risk estimates by Howe and McLaughlin. RESULTS: For a screening programme, age group 50-69, two year interval, 2 mGy per view, the balance between the number of deaths induced versus those prevented was favourable: 1:242. When screening is expanded to the age group 40-49 with a one or two year interval the results may be less favourable, that is, 1:66 and 1:97. According to these scenarios and with the Dutch scenario as reference, one breast cancer death from radiation may be expected to occur to save eight extra deaths from breast cancer. If screening was equally effective in young women as in women aged 50-69, the marginal value was 1:+/- 30. Assuming detection of induced cancers by screening could influence the ratios by about 30%, but did not substantially change the conclusions. The new risk estimates by Howe and McLaughlin resulted in five times to eight times favourable ratios breast cancer deaths induced to prevented. Besides age group of screening, dose of mammography is the other determinant of risk. CONCLUSIONS: For screening under the age of 50, the balance between the number of breast cancer deaths prevented by screening compared with the number induced by radiation seem less favourable. Credibility intervals were however wide, because of many uncertainties of radiation risk at very low doses.     

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.     

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.     

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.     

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.     

Reduction in risk of mortality from colorectal cancer by fecal occult blood screening with immunochemical hemagglutination test. A case-control study

Fecal occult blood testing by immunochemical hemagglutination has been shown to be superior to the Hemoccult test, both in sensitivity and in specificity. The test has been widely used as a tool for population screening in Japan, but there has been no study to evaluate the efficacy of screening using this test. A case-control study to evaluate the screening was conducted in study areas where no previous and no other concomitant colorectal cancer screening had been performed. Case series in the study were 193 cases who died of colorectal cancer. Three controls were selected randomly from the list of individuals who were alive at the time of diagnosis of the corresponding case and had been living in the same area as the case, matched by gender and by age. Odds ratios (OR) of dying of colorectal cancer for those screened within 1, 2 and 3 years of case diagnosis vs. those not screened were 0.40 [95% confidence interval (CI) 0.17-0.92], 0.41 (95% CI 0.20-0.82), and 0.48 (95% CI 0.25-0.92), respectively. OR increased towards 1.0 as the duration during which screening histories were compared was extended, and showed similar tendencies when analyzed by number of years since the most recent screening history. These results suggest that colorectal cancer screening by the immunochemical fecal occult blood test would reduce mortality from colorectal cancer.     

Periodic examination of families with hereditary nonpolyposis colorectal carcinoma in The Netherlands: a study of 41 families

OBJECTIVE: To determine characteristics of hereditary nonpolyposis colorectal cancer (HNPCC) and the implications for screening and treatment. DESIGN: Longitudinal. SETTING: Nationwide. METHOD: Genealogic studies were performed in 114 families referred to the Netherlands Foundation for Detection of Hereditary Tumours because of a suspected inherited form of colorectal cancer. RESULTS: Forty-one families met the criteria for HNPCC: These families included 194 patients with colorectal cancer (84 females and 110 males). The mean age at diagnosis was 44 years (range: 16-74). In 92% the tumour was diagnosed before the age of 60 years. Fifty-eight per cent were located in the proximal colon. Twenty-three per cent of the patients had multiple primary colorectal cancer. The cumulative risk of developing a second colorectal cancer was 23% after 10 years of follow up. Cancer of the endometrium, stomach and urinary tract were the most frequent extracolonic cancers. CONCLUSIONS: Periodic examination of first-degree relatives of patients from HNPCC families should start between the ages of 20 and 25 years. The recommended interval between consecutive examinations is 2-3 years. After the age of 60 years screening may be performed at a lower frequency. The right colon in particular should be investigated. A subtotal colectomy is indicated at the time of diagnosis of the initial colon cancer, because of the risk of multiple primary tumours.     

Screening fundamentals

While researchers have established the value of screening for breast cancer with mammography, with and without clinical breast examination, age-specific analyses have led to differing opinions regarding the ages and the intervals that breast cancer screening should begin. This article, therefore, provides a detailed, age-specific evaluation of mammography screening by assessing the severity of breast cancer, the effectiveness of earlier versus later treatment, and the accuracy and reliability of mammography. Data from previous randomized trials and other sources are used to evaluate these criteria. The results indicate that screening programs must have high levels of participation, achieve acceptable sensitivity (85%) and specificity (90%), adopt age-specific screening intervals, and consider how disease stage influences diagnosis. In addition, as others have noted, the following benchmarks can be used to evaluate screening programs: (1) more than 50% of screen-detected cancers should be smaller than 15 mm; (2) 30% or more of grade 3 cancers detected on screening should be less than 15 mm; and (3) more than 70% of cancers detected on screening should be node negative.