Age-specific sensitivities of mammographic screening for breast cancer

Summary The sensitivity of the mammographic screening test in the biennial screening program of Nijmegen is assessed by analyzing the occurrence of interval cancers, i.e. cancers surfacing clinically in the interval between a negative screening examination and the subsequent scheduled examination. The difference between the observed number of interval cancers and the expected number of clinically manifest cancers in the absence of screening for the interval period reflects the number of cancers detected by screening. The expected number should be limited by the number of those cancers that were not detectable at the time of the screening examination because their size was under the threshold of mammographic detectability (5 mm). In contrast to other sensitivity studies we took these fast growing cancers into consideration, the numbers of which are estimated in each of the six-month periods of the two-year interval using age-specific tumor volume growth rates for three age groups: < 50, 50–69, and 70 years. In patients under age 50, the sensitivity was 64% for cancers which would become clinically manifest within one year after screening. This sensitivity was lower than those obtained from the 50–69 and 70 age groups, being 85% and 80%, respectively. For cancers that would become clinically manifest 12–18 months after screening, sensitivity decreases to 22% in the under age 50 group, and to 56% and 65% in the two above age 50 groups, respectively. We conclude that even when adjusted for growth rate, the mammographic screening test has a poor performance in the under age 50 group.     

Randomized mammographic screening for breast cancer in Stockholm

In March 1981 a randomized single-view mammographic screening for breast cancer was started in the south of Stockholm. The screened population in the first round numbered 40,318 women, and 20,000 women served as a well-defined control group. The age groups represented were 40–64 years, and 80.7% of the invited women participated in the study. The first round disclosed 128 breast cancers (113 invasive and 15 noninvasive), or 4.0 per 1,000 women. Mean tumour size was 14.1 mm and axillary lymph node metastases were found in 21.8%. Fifty-five per cent of the tumours were small (10 mm) or non-invasive, and 71% were stage I.Participation rates are high in all Swedish trials. The present results differ only slightly from other screening programs; the percentages of patients with axillary metastases and stage II tumours are similar in the Stockholm, Malmö and Kopparberg/Östergötland studies. Comparisons of cancer prevalence in the various Swedish screening trials show that, in comparable age groups, there are some differences, even when the differences in the natural cancer incidence are taken into account.A decreased mortality was found recently in a Swedish trial in ages above 50 years but not below. In the Stockholm study more than one-third of the participants were aged 40–49 years.     

Radiogenic breast cancer effects of mammographic screening

The radiocarcinogenic implications of published breast-screening policies were compared. With the use of radioepidemiologic data published recently by the National Institutes of Health, expected excess breast cancers were projected. With a base-line mammogram at age 35 and annual mammography after age 40, as few as 150 or as many as 1,000 radiogenic breast cancers were projected for a screening population of 1 million women, depending on the mammographic system employed and the screening schedule.     

Smoking and survival after breast cancer diagnosis

We examined whether a history of smoking is associated with an increased risk of death from any cause or from breast cancer, among women diagnosed with breast cancer. This was a prospective observational study among 5,056 women from the Nurses' Health Study with Stages I-III invasive breast cancer diagnosed between 1978 and 2002 and for whom we had information on smoking, and who were followed until January 2002 or death, whichever came first. Subjects were classified as current, former or never smokers based upon smoking status at the biennial questionnaire immediately preceding the breast cancer diagnosis. In multivariate-adjusted analyses, compared with never smokers, women who were current smokers had a 43% increased adjusted relative risk (RR) [95% confidence interval (95% CI): 1.24-1.65] of death from any cause. A strong linear gradient was observed with the number of cigarettes per day smoked, p-trend <0.0001; the RR (95% CI) for 1-14, 15-24 and 25 or more cigarettes per day was 1.27 (1.01-1.61), 1.30 (1.08-1.57) and 1.79 (1.47-2.19). In contrast, there was no association with current smoking and breast cancer death; the RR (95% CI) was 1.00 (0.83-1.19). Current and past smokers were more likely than never smokers to die from primary lung cancer, chronic obstructive pulmonary disease and other lung diseases. We conclude that a history of smoking increased mortality following diagnosis with breast cancer, but did not increase mortality from breast cancer.     

Body size, mammographic density, and breast cancer risk.

BACKGROUND: Greater weight and body mass index (BMI) are negatively correlated with mammographic density, a strong risk factor for breast cancer, and are associated with an increased risk of breast cancer in postmenopausal women, but with a reduced risk in premenopausal women. We have examined the associations of body size and mammographic density on breast cancer risk. METHOD: We examined the associations of body size and the percentage of mammographic density at baseline with subsequent risk of breast cancer among 1,114 matched case-control pairs identified from three screening programs. The effect of each factor on risk of breast cancer was examined before and after adjustment for the other, using logistic regression. RESULTS: In all subjects, before adjustment for mammographic density, breast cancer risk in the highest quintile of BMI, compared with the lowest, was 1.04 [95% confidence interval (CI), 0.8-1.4]. BMI was associated positively with breast cancer risk in postmenopausal women, and negatively in premenopausal women. After adjustment for density, the risk associated with BMI in all subjects increased to 1.60 (95% CI, 1.2-2.2), and was positive in both menopausal groups. Adjustment for BMI increased breast cancer risk in women with 75% or greater density, compared with 0%, increased from 4.25 (95% CI, 1.6-11.1) to 5.86 (95% CI, 2.2-15.6). CONCLUSION: BMI and mammographic density are independent risk factors for breast cancer, and likely to operate through different pathways. The strong negative correlated between them will lead to underestimation of the effects on risk of either pathway if confounding is not controlled.     

Clinical, mammographic, and sonographic determination of preoperative breast cancer size

Clinical, mammographic, and sonographic preoperative size measurements were correlated with the values obtained at pathologic examination in a series of 31 patients with pathologically T1 (n = 23) and T2 (n = 8) breast carcinomas. Sonographic measurements demonstrated the highest correlation coefficient (r = 0.84), with the lowest residual standard deviation calculated in relation to the regression line. As a result, real-time sonography yielded the most accurate determination of breast cancer size in this series. Sonographic tumor size determination has proved valuable when mammography failed to delineate the tumor, particularly in patients with dense breasts. It may also be recommended in the evaluation of tumor response to nonsurgical conservative treatment.     

Diabetes and cancer I: risk, survival, and implications for screening

Type 2 diabetes mellitus (DM) and cancer are common diseases that are frequently diagnosed in the same individual. An association between the two conditions has long been postulated. Here, we review the epidemiological evidence for increased risk of cancer, decreased cancer survival, and decreased rates of cancer screening in diabetic patients. The risk for several cancers, including cancers of the pancreas, liver, colorectum, breast, urinary tract, and endometrium, is increased in patients with DM. In a pooled risk analysis weighting published meta-analytic relative risk (RR) for individual cancer by differences in their incidence rates, we found a population RR of 0.97 (95?% CI, 0.75-1.25) in men and 1.29 (95?% CI, 1.16-1.44) in women. All meta-analyses showed an increased relative risk for cancer in diabetic men, except studies of prostate cancer, in which a protective effect was observed. The relationship between diabetes and cancer appears to be complex, and at present, a clear temporal relationship between the two conditions cannot be defined. DM also impacts negatively on cancer-related survival outcomes and cancer screening rates. The overwhelming evidence for lower cancer screening rates, increased incidence of certain cancers, and poorer prognosis after cancer diagnosis in diabetic patients dictates a need for improved cancer care in diabetic individuals through improved screening measures, development of risk assessment tools, and consideration of cancer prevention strategies in diabetic patients. Part two of this review focuses on the biological and pharmacological mechanisms that may account for the association between DM and cancer.     

Body mass index and breast cancer survival in relation to the introduction of mammographic screening

Aims

Mammographic screening reduces mortality in breast cancer. It is not known if this reduction is more pronounced in certain groups. Obesity has been associated with worse survival following breast cancer diagnosis. This study investigates BMI in relation to breast cancer mortality, and if this association is affected by invitation to mammographic screening.

Methods

In 1976, a randomised mammographic screening trial, inviting 50% of all women aged 45–69 years (n = 42?283), was set up in Malmö, Sweden. BMI in relation to breast cancer mortality was examined separately in women invited or not invited to screening in the trial. The analyses also included a historical control-group diagnosed before the screening trial. The study included 2974 women diagnosed in 1961–1991. Relative risks (RR) with a 95% confidence interval was obtained from a Cox proportional hazard analysis and in the analysis of all women, follow-up was limited to 10 years.

Results

Obese women (BMI ≥ 30) not invited to mammographic screening had a higher adjusted RR of dying of breast cancer as compared to normal weight women (2.08:1.13–3.81) in the 10-year follow-up. In women invited to screening there was no association between BMI and breast cancer mortality. In the historical control group, mortality was increased in overweight women (BMI: 25–30), RR = 1.27:0.99–1.62, and obese women, RR = 1.32:0.94–1.84, but these associations totally disappeared in the multivariate analysis, following adjustment for tumour size and stage.

Conclusions

Overweight and obese women may be a group that profit from mammographic screening to more than normal weight women.     

Social networks and survival after breast cancer diagnosis

Introduction  

Evidence has been inconsistent regarding the impact of social networks on survival after breast cancer diagnosis. We prospectively examined the relation between components of social integration and survival in a large cohort of breast cancer survivors.     

Advanced breast cancer incidence following population-based mammographic screening

BackgroundBreast cancer mortality is declining in many Western countries. If mammography screening contributed to decreases in mortality, then decreases in advanced breast cancer incidence should also be noticeable.Patients and methodsWe assessed incidence trends of advanced breast cancer in areas where mammography screening is practiced for at least 7 years with 60% minimum participation and where population-based registration of advanced breast cancer existed. Through a systematic Medline search, we identified relevant published data for Australia, Italy, Norway, Switzerland, The Netherlands, UK and the USA. Data from cancer registries in Northern Ireland, Scotland, the USA (Surveillance, Epidemiology and End Results (SEER), and Connecticut), and Tasmania (Australia) were available for the study. Criterion for advanced cancer was the tumour size, and if not available, spread to regional/distant sites.ResultsAge-adjusted annual percent changes (APCs) were stable or increasing in ten areas (APCs of -0.5% to 1.7%). In four areas (Firenze, the Netherlands, SEER and Connecticut) there were transient downward trends followed by increases back to pre-screening rates.ConclusionsIn areas with widespread sustained mammographic screening, trends in advanced breast cancer incidence do not support a substantial role for screening in the decrease in mortality.     

Mammography screening in the Netherlands: delay in the diagnosis of breast cancer after breast cancer screening

In a prospective study we determined the frequency and causes of delay in the diagnosis of breast cancer after suspicious screening mammography. We included all women aged 50-75 years who underwent biennial screening mammography in the southern breast cancer screening region of the Netherlands between 1 January 1996 and 1 January 2002. Clinical data, breast imaging reports, biopsy results and breast surgery reports were collected of all women with a positive screening result with a minimum of 2-year follow-up. Of 153 969 mammographic screening examinations, 1615 (1.05%) were positive screens. Breast cancer was diagnosed in 770 (47.9%) of 1607 women for whom follow-up information was available, yielding a cancer detection rate of 5.0 per 1000 women screened. Breast cancer was diagnosed within 3 months following a positive screen in 722 cases (93.8%). The diagnostic delay was 4-6, 7-12 and 13-24 months, respectively, in 11 (1.4%), 24 (3.1%) and nine (1.2%) patients. In four other patients (0.5%), breast cancer was diagnosed after a repeat positive screen, resulting in a diagnostic delay of 25-27 months. Reasons for a diagnostic delay >3 months were erroneous mammographic interpretation of suspicious lesions as benign or probably benign lesions (33 cases), benign biopsies from a malignant lesion (10), and omission to biopsy or remove a lesion that was suspicious at breast imaging (4) or core biopsy (1). We conclude that there is room for improvement in the workup of patients with a positive screening mammography, as seen from data in this screening region. To improve the workup, we suggest that other breast cancer screening programmes also identify delay in breast cancer diagnosis after a positive screen.     

Weight, weight gain, and survival after breast cancer diagnosis.

PURPOSE: To determine whether weight prior to diagnosis and weight gain after diagnosis are predictive of breast cancer survival. METHODS: Patients included 5,204 Nurses' Health Study participants diagnosed with incident, invasive, nonmetastatic breast cancer between 1976 and 2000; 860 total deaths, 533 breast cancer deaths, and 681 recurrences (defined as secondary lung, brain, bone, or liver cancer, and death from breast cancer) accrued to 2002. We computed the change in body mass index (BMI) from before to the first BMI reported > or = 12 months after the date of diagnosis. Cox proportional hazards models were used to evaluate associations of categories of BMI before diagnosis and of BMI change with time to event. We stratified by smoking, menopausal status, and breast cancer-related variables. RESULTS: In multivariate-adjusted analyses, weight before diagnosis was positively associated with breast cancer recurrence and death, but this was apparent only in never smokers. Similarly, among never-smoking women, those who gained between 0.5 and 2.0 kg/m(2) (median gain, 6.0 lb; relative risk [RR], 1.35; 95% CI, 0.93 to 1.95) or more than 2.0 kg/m(2) (median gain, 17.0 lb; RR, 1.64; 95% CI, 1.07 to 2.51) after diagnosis had an elevated risk of breast cancer death during follow-up (median, 9 years), compared with women who maintained their weight (test for linear trend, P = .03). Associations with weight were stronger in premenopausal than in postmenopausal women. Similar findings were noted for breast cancer recurrence and all-cause mortality. CONCLUSION: Weight and weight gain were related to higher rates of breast cancer recurrence and mortality, but associations were most apparent in never-smoking women.     

Current status and goals of mammographic screening for breast cancer in japan

In Europe and the United States, the proportion of women receiving mammographic screening for breast cancer has increased to 60-80%, resulting in an increase in the detection of early-stage cancer and a reduction in the mortality rate. The objectives of breast cancer screening have thus already been achieved there. In Japan, both the incidence and mortality of breast cancer have increased recently. Breast cancer screening has long been performed by clinical breast examination (CBE) alone. A reduction in the mortality of breast cancer cannot be expected from CBE. Mammographic screening for breast cancer was recommended in a notification issued by Ministry of Health, Labour and Welfare in 1999. An important aspect of mammographic screening is quality control. The Central Committee on Quality Control of Mammographic Screening(Central Committee)was organized by six screening-related societies, and attempts have since been made to establish a quality control system. Both the social recognition of the Central Committee and its cooperation with the "Quality Control Committee " of each community will become important. The cover rate of nationwide breast cancer screening by CBE alone is 12-13%, while the implementation rate of mammographic screening is presently very low and its cover rate is considered to be about 2%. With such a low cover rate, it is absolutely impossible to reduce the mortality of breast cancer. To achieve this, the administration and clinicians will be required to cooperate with each other to increase the spread and cover rate of high-quality mammographic screening.     

Overdiagnosis and overtreatment of breast cancer: Estimates of overdiagnosis from two trials of mammographic screening for breast cancer

Randomised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality. This has often been accompanied, however, by an increase in breast cancer incidence, particularly during the early years of a screening programme, which has led to concerns about overdiagnosis, that is to say, the diagnosis of disease that, if left undetected and therefore untreated, would not become symptomatic. We used incidence data from two randomised controlled trials of mammographic screening, the Swedish Two-county Trial and the Gothenburg Trial, to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ (DCIS) in the study groups, to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of 'real' and non-progressive 'overdiagnosed' tumours from the study groups of the trials. We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters. After taking into account the effect of lead time, we estimated that less than 5% of cases diagnosed at prevalence screen and less than 1% of cases diagnosed at incidence screens are being overdiagnosed. Overall, we estimate overdiagnosis to be around 1% of all cases diagnosed in screened populations. These estimates are, however, subject to considerable uncertainty. Our results suggest that overdiagnosis in mammography screening is a minor phenomenon, but further studies with very large numbers are required for more precise estimation.     

Dietary patterns and survival after breast cancer diagnosis.

PURPOSE: There is little prior study of major dietary patterns and breast cancer survival. METHODS: Patients included 2,619 Nurses' Health Study participants who were diagnosed with invasive breast cancer between 1982 and 1998 and completed a dietary questionnaire more than 1 year after diagnosis. Participants were followed through 2002 (median = 9 years). During follow-up, 414 patients died of any cause, 242 patients died of breast cancer, and 172 patients died from causes other than breast cancer. Women with in situ or metastatic disease at diagnosis were excluded. We used Cox proportional hazards models to evaluate prospective associations of prudent and Western dietary patterns assessed both before and after diagnosis with time to event after diagnosis. RESULTS: In multivariate-adjusted analyses assessed after diagnosis, the Western and prudent dietary patterns were unrelated to all-cause or breast cancer mortality. However, compared with women with the lowest intake of the prudent dietary pattern, the relative risks (and 95% CIs) of death from causes other than breast cancer were 0.85 (95% CI, 0.53 to 1.35), 0.74 (95% CI, 0.45 to 1.21), 0.70 (95% CI, 0.42 to 1.17), and 0.54 (95% CI, 0.31 to 0.95; P = .03, from lowest to highest quintile of intake). In contrast, the Western dietary pattern was positively associated with this outcome (P = .04). Results for the assessment of dietary patterns before diagnosis were similar, except the prudent dietary pattern was unrelated to mortality. CONCLUSION: A higher intake of the prudent pattern and a lower intake of the Western pattern may protect against mortality from causes unrelated to breast cancer.     

Association between mammographic breast density and breast cancer tumor characteristics.

OBJECTIVE: Few studies have examined the association between breast density and breast cancer tumor characteristics. We examined the association between hormonal, proliferative, and histologic tumor characteristics and mammographic breast density in women with breast cancer. METHODS: We conducted a cross-sectional analysis in 546 women diagnosed with invasive breast cancer to evaluate the associations between breast density and tumor size, lymph node status, lymphatic or vascular invasion, histologic grade, nuclear grade, tumor differentiation, mitotic index, tumor necrosis, Ki-67 proliferation, estrogen receptor, progesterone receptor, p53, p27, cyclin E, Bcl-2, and C-erb-B2 invasion. Breast density was classified as fatty (Breast Imaging Reporting and Data System code 1 or 2; n = 373) or dense (Breast Imaging Reporting and Data System code 3 or 4; n = 173) for the cancer-free breast. A single pathologist measured all tumor markers. We examined whether the relationships were modified by interval cancer or screen-detected cancer. RESULTS: Women with a tumor size >1.0 cm were more likely to have dense breasts compared with women with a tumor size < or =1.0 cm after adjusting for confounders (odds ratio, 2.0; 95% confidence interval, 1.2-3.4 for tumor sizes 1.1-2.0 cm; odds ratio, 2.3; 95% confidence interval, 1.3-4.4 for tumor sizes 2.1-10 cm). Tumor size, lymph node status, and lymphatic or vascular invasion were positively associated with breast density among screen-detected cancers. Histologic grade and mitotic index were negatively associated with breast density in women diagnosed with an interval cancer. CONCLUSIONS: These results suggest that breast density is related to tumor size, lymph node status, and lymphatic or vascular invasion in screen-detected cancers. Additional studies are needed to address whether these associations are due to density masking the detection of some tumors, a biological relationship, or both.     

Current status of screening for breast cancer and tasks for introduction of mammographic screening in Japan

In the United States and Europe the high mortality of breast cancer has been significantly reduced by mammographic screening of women aged over 50 years, the effectiveness of which has been documented in many reports. In contrast, the effectiveness of such screening in women aged from 40 to 49 remains controversial. In Japan, breast cancer screening has consisted of physical examination alone, with inspection and palpation. Thus, more than half of the patients with breast cancer detected by this screening system are already aware of their lumps, the detection rate has been a little less than 0.1%, and the proportion of early-stage disease among breast cancers is only about 50%. It is difficult to detect breast cancer consisting of non-palpable tumors by physical examination, and the low sensitivity of this screening method has been pointed out. In Japan, there is no difference in overall survival between cases detected by screening and those detected in outpatient clinics. The results of the mammographic screening trial performed in Miyagi and Tokushima, which were promising in terms of proportions of early-stage cancer and no nodal involvement, strongly suggest its usefulness in Japan as well as in other countries. However, long-term results are not yet available. It is advocated that screening for breast cancer should be performed by means of mammography to improve the screening sensitivity, and increase the proportion of early-stage breast cancers. Mammo-graphic screening, either mammography and physical examination separately or simultanously in combination, has been effective for women aged over 50 years in Japan. However, with regard to those aged under 49 years, further studies are needed.     

Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases

Two of the most important prognostic indicators for breast cancer are tumor size and extent of axillary lymph node involvement. Data on 24,740 cases recorded in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were used to evaluate the breast cancer survival experience in a representative sample of women from the United States. Actuarial (life table) methods were used to investigate the 5-year relative survival rates in cases with known operative/pathologic axillary lymph node status and primary tumor diameter. Survival rates varied from 45.5% for tumor diameters equal to or greater than 5 cm with positive axillary nodes to 96.3% for tumors less than 2 cm and with no involved nodes. The relation between tumor size and lymph node status was investigated in detail. Tumor diameter and lymph node status were found to act as independent but additive prognostic indicators. As tumor size increased, survival decreased regardless of lymph node status; and as lymph node involvement increased, survival status also decreased regardless of tumor size. A linear relation was found between tumor diameter and the percent of cases with positive lymph node involvement. The results of our analyses suggest that disease progression to distant sites does not occur exclusively via the axillary lymph nodes, but rather that lymph node status serves as an indicator of the tumor's ability to spread.     

Using mammographic density to improve breast cancer screening outcomes

It is possible that the performance of mammographic screening would be improved if it is targeted at women at higher risk of breast cancer or who are more likely to have their cancer missed at screening, through more intensive screening or alternative screening modalities. We conducted a case-control study within a population-based Australian mammographic screening program (1,706 invasive breast cancers and 5,637 randomly selected controls). We used logistic regression to examine the effects of breast density, age, and hormone therapy use, all known to influence both breast cancer risk and the sensitivity of mammographic screening, on the risk of small (15 mm) screen-detected and interval breast cancers. The risk of small screen-detected cancers was not associated with density, but the risk of large screen-detected cancers was nearly 3-fold for the second quintile and approximately 4-fold for the four highest density categories (third and fourth quintiles and the two highest deciles) compared with the lowest quintile. The risk of interval cancers increased monotonically across the density categories [highest decile odds ratio (OR), 4.65; 95% confidence interval (95% CI), 2.96-7.31]. The risk of small and large screen-detected cancers, but not interval cancers, increased with age. After adjusting for age and density, hormone therapy use was associated with a moderately elevated risk of interval cancers (OR, 1.43; 95% CI, 1.12-1.81). The effectiveness of the screening program could be improved if density were to be used to identify women most likely to have poor screening outcomes. There would be little additional benefit in targeting screening based on age and hormone therapy use.