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.     

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.     

Breast cancer screening uptake in women at increased risk of developing hereditary breast cancer

This multicenter study assessed breast cancer screening uptake in 461 unaffected women at increased risk of developing breast cancer on the basis of family history who approached familial cancer clinics for advice about surveillance options. At the time of attending the clinic, 89% and 90% of participants were vigilant with respect to age- and risk-specific recommendations for mammography and clinical breast examination, respectively, and 51% reported practicing breast self-examination monthly or more frequently. The degree to which health outcomes are perceived to be under one's personal control (²=–2.09, p=0.0037) and breast cancer anxiety (²=8.11,p=0.044) were both associated with monthly or more frequent breast self-examination, while there were no associations with sociodemographic characteristics. A significantly lower percentage (56%) of women aged <30 were vigilant with respect to mammography recommendations, compared to 77%, 96% and 98% of women aged 30–39, 40–49 and >50, respectively (²=37.2,p<0.0001). These relatively low rates of mammographic screening in young women may reflect concerns about increased cancer risk associated with early and repeated radiation exposure or lack of sensitivity in young women with radiographically dense breasts. If mammographic screening is ultimately shown to lower mortality in women at high risk, there will be a strong case to promote screening in young women. The need for regular mammographic screening would then need to be highlighted and reinforced amongst young women and their referring physicians. Awareness amongst general practitioners, who are largely responsible for referral to screening services, would also need to be increased.     

Mammographic screening for young women with a family history of breast cancer: knowledge and views of those at risk

Although the effectiveness of mammography for women under the age of 50 years with a family history of breast cancer (FHBC) has not yet been proven, annual screening is being offered to these women to manage breast cancer risk. This study investigates women's awareness and interpretation of their familial risk and knowledge and views about mammographic screening. A total of 2231 women from 21 familial/breast/genetics centres who were assessed as moderate risk (17-30% lifetime risk) or high risk (>30% lifetime risk) completed a questionnaire before their mammographic screening appointment. Most women (70%) believed they were likely, very likely or definitely going to develop breast cancer in their lifetime. Almost all women (97%) understood that the purpose of mammographic screening was to allow the early detection of breast cancer. However, 20% believed that a normal mammogram result meant there was definitely no breast cancer present, and only 4% understood that screening has not been proven to save lives in women under the age of 50 years. Women held positive views on mammography but did not appear to be well informed about the potential disadvantages. These findings suggest that further attention should be paid to improving information provision to women with an FHBC being offered routine screening.     

Effectiveness of alternating mammography and magnetic resonance imaging for screening women with deleterious BRCA mutations at high risk of breast cancer

BACKGROUND:

Magnetic resonance imaging (MRI) has been used to supplement screening mammography and clinical breast examination (CBE) in women who are at high risk of developing breast cancer. In this study, the authors investigated the efficacy of alternating screening mammography and breast MRI every 6 months in women who had a genetically high risk of developing breast cancer.

METHODS:

A retrospective chart review was performed on all women who were seen in a high‐risk breast cancer clinic from 1997 to 2009. Patients with breast cancer gene (BRCA) mutations who underwent alternating screening mammography and breast MRI every 6 months were included in the study. Mammography, ultrasonography, MRI, and biopsy results were reviewed.

RESULTS:

Of 73 patients who met the study criteria, 37 had BRCA1 mutations, and 36 had BRCA2 mutations. Twenty‐one patients (29%) completed 1 cycle of mammography and MRI surveillance, 23 patients (31%) completed 2 cycles, 18 patients (25%) completed 3 cycles, and patients 11 (15%) completed ≥4 cycles. The median follow‐up was 2 years (range, 1‐6 years). Thirteen cancers were detected among 11 women (15%). The mean tumor size was 14 mm (range, 1‐30 mm), and 2 patients had bilateral cancers. Twelve of 13 cancers were detected on an MRI but not on the screening mammography study that was obtained 6 months earlier. One cancer (a 1‐mm focus of ductal carcinoma in situ) was an incidental finding in a prophylactic mastectomy specimen. One patient had ipsilateral axillary lymphadenopathy identified on ultrasonography but had no evidence of lymph node involvement after neoadjuvant chemotherapy and surgery.

CONCLUSIONS:

In women who were at genetically high risk of developing breast cancer, MRI detected cancers that were not identified on mammography 6 months earlier. Future prospective studies are needed to evaluate the benefits of this screening regimen. Cancer 2011;. © 2011 American Cancer Society.     

Digital breast tomosynthesis (3D mammography) for breast cancer screening and for assessment of screen-recalled findings: review of the evidence

Introduction: Digital breast tomosynthesis (DBT) addresses some of the limitations of digital mammography (DM) by reducing the effect of overlapping tissue. Emerging data have shown that DBT increases breast cancer (BC) detection and reduces recall in BC screening programs. Studies have also suggested that DBT improves assessment of screen-recalled findings.

Areas covered: Studies of DBT for population BC screening and those for assessment of screen-detected findings were reviewed to provide an up-to-date summary of the evidence on DBT in the screening setting. A systematic literature search was conducted for each of the topics; study-specific information and/or quantitative data on detection or accuracy were extracted and collated in tables.

Expert commentary: The evidence on DBT for BC screening reinforces that DBT integrated with DM increases cancer detection rates compared to DM alone, although the extent of improved detection varied between studies. The effect of DBT on recall rates was heterogeneous with substantial reductions evident noticeably in retrospective comparative studies. The evidence on DBT for workup was sparse and those studies had limitations related to design and methods. Even though the majority showed improved specificity using DBT compared with conventional imaging, there was little evidence on how DBT impacts assessment outcomes.     

First experiences in screening women at high risk for breast cancer with MR imaging

Women with a genetic predisposition for breast cancer are often advised surveillance with physical examination twice a year and mammography once a year from 25 years onwards. However, the sensitivity of the mammography decreases when breast tissue is dense and this is seen in 40–50% of women under 50 years. We therefore investigated whether magnetic resonance imaging (MRI) in addition to the normal surveillance could detect cancers otherwise missed. In 109 women with over 25% risk of breast cancer, MRI was performed because over 50% dense breast tissue was seen at mammography and no suspect lesion was seen at the previous screening. MRI detected breast cancers in three patients (2.8%) occult at mammography and with no new palpable tumor, twice at stage T1bN0 and T1cN0 once. Two cancers were expected. MRI was false positive in six women, resulting in two benign local excisions because ultrasound or fine needle examination confirmed suspicion. We had no false negative MRI results. MRI proved true benign in four BRCA 1/2 gene mutation carriers at histologic examination. Preoperative wire localization of the malignancies detected at MRI proved necessary as the tumor was not palpable in the lumpectomy specimen nor visible at specimen radiology. The extra cost of breast MRI in addition to mammography and physical examination was uro13.930 per detected cancer. The cost of the detection of one breast cancer patient in our national screening program is uro9000. During follow-up of patients with a familial risk in whom the first breast cancer was detected at MRI, MRI detected two recurrent cancers in stage T1bN0 and T1cN0 and one contralateral cancer T1aNo. Breast MRI is promising in screening young women at high risk for breast cancer, as it can advance the detection of cancers still occult at mammography and physical examination; but the cost may be considerable.     

A multi-centre randomised trial comparing ultrasound vs mammography for screening breast cancer in high-risk Chinese women

Background:

Chinese women tend to have small and dense breasts and ultrasound is a common method for breast cancer screening in China. However, its efficacy and cost comparing with mammography has not been evaluated in randomised trials.

Methods:

At 14 breast centres across China during 2008–2010, 13 339 high-risk women aged 30–65 years were randomised to be screened by mammography alone, ultrasound alone, or by both methods at enrolment and 1-year follow-up.

Results:

A total of 12 519 and 8692 women underwent the initial and second screenings, respectively. Among the 30 cancers (of which 15 were stage 0/I) detected, 5 (0.72/1000) were in the mammography group, 11 (1.51/1000) in the ultrasound group, and 14 (2.02/1000) in the combined group (P=0.12). In the combined group, ultrasound detected all the 14 cancers, whereas mammography detected 8, making ultrasound more sensitive (100 vs 57.1%, P=0.04) with a better diagnostic accuracy (0.999 vs 0.766, P=0.01). There was no difference between mammography and ultrasound in specificity (100 vs 99.9%, P=0.51) and positive predictive value (72.7 vs 70.0% P=0.87). To detect one cancer, the costs of ultrasound, mammography, and combined modality were $7876, $45 253, and $21 599, respectively.

Conclusions:

Ultrasound is superior to mammography for breast cancer screening in high-risk Chinese women.     

Cost-effectiveness of alternative strategies for integrating MRI into breast cancer screening for women at high risk

Background:

Magnetic resonance imaging (MRI) is recommended for women at high risk for breast cancer. We evaluated the cost-effectiveness of alternative screening strategies involving MRI.

Methods:

Using a microsimulation model, we generated life histories under different risk profiles, and assessed the impact of screening on quality-adjusted life-years, and lifetime costs, both discounted at 3%. We compared 12 screening strategies combining annual or biennial MRI with mammography and clinical breast examination (CBE) in intervals of 0.5, 1, or 2 years vs without, and reported incremental cost-effectiveness ratios (ICERs).

Results:

Based on an ICER threshold of $100 000/QALY, the most cost-effective strategy for women at 25% lifetime risk was to stagger MRI and mammography plus CBE every year from age 30 to 74, yielding ICER $58 400 (compared to biennial MRI alone). At 50% lifetime risk and with 70% reduction in MRI cost, the recommended strategy was to stagger MRI and mammography plus CBE every 6 months (ICER=$84 400). At 75% lifetime risk, the recommended strategy is biennial MRI combined with mammography plus CBE every 6 months (ICER=$62 800).

Conclusions:

The high costs of MRI and its lower specificity are limiting factors for annual screening schedule of MRI, except for women at sufficiently high risk.     

Use of hormone therapy and risk of breast cancer detected at screening and between mammographic screens

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer, but in women undergoing breast cancer screening it is not clear whether use of HT is associated with increased risk of breast cancer detected at screening or between screens (interval cancer). Further, it is unclear whether the use of the HTs that have been common in Scandinavia is associated with higher risk of breast cancer than the HTs used in other countries. Our study was based on data from 296,651 women aged 50-69 years, who participated in the Norwegian Breast Cancer Screening Program during 1995-2004. After a mean enrollment time of 3.8 years, 1,512 women were diagnosed with invasive screen detected breast cancer, and 814 with invasive interval breast cancer. Cox regression models were used to estimate hazard ratios (HRs) of breast cancer associated with HT use, after adjusting for confounders. Ever users of HT had a 58% increased risk of breast cancer, compared to never users. The HRs associated with HT use were 1.45 (95% confidence interval (CI) = 1.29-1.63) for screen detected and 1.89 (95% CI = 1.61-2.23) for interval cancer. The difference between screen detected and interval cancer was statistically significant (p = 0.011). The HR of breast cancer increased with duration of HT use, but significantly more so for interval than for screen detected cancer (use of HT for 5 or more years compared to never use; HR = 2.91, 95% CI = 2.10-4.04 and HR = 1.94, 95% CI = 1.51-2.50, respectively; p = 0.002). The population attributable fraction of breast cancer due to HT use was 19.8% overall. Ever users of HT tended to develop a cancer of lower grade. No other differences in histological tumor characteristics were observed between ever and never users of HT among screen detected or interval cancers. The estimated risks of either breast cancer overall with HT use are higher in Norway than reported in similar studies from the U.S. HT-use is a stronger risk factor for interval cancer than for screen detected cancer. The increased risk of interval cancer, which may partly be due to decreased sensitivity of mammograms in HT users, remains a challenge in breast cancer screening programs.     

Decision aids for breast and nodal surgery in patients with early breast cancer: development and a pilot study

Aim: As survival rates for aggressive and conservative breast and lymph node surgery are similar, surgical treatment decisions for patients with early‐stage breast cancer should take patient preference into account. Decision aids have been demonstrated to increase patient knowledge and satisfaction with decision making, while decreasing decisional conflict. Hundreds of decision aids exist; however, few address lymph node surgery in any detail, and none acknowledge that there is a choice comparable to that between mastectomy and breast‐conserving therapy. Methods: A systematic process was employed to develop decision aids for mastectomy versus breast‐conserving therapy, axillary dissection versus sentinel node biopsy, and options following a positive sentinel node biopsy. The first two of these decision aids were evaluated in a small pilot study. Choice of operation, knowledge and decisional conflict and satisfaction were compared with outcomes in an historical control group. Results: Women reported favorably on the decision aids. The numbers in the pilot group were too small to allow definitive conclusions to be drawn, but suggested a possible reduction in decisional conflict, and possibly increase in decisional satisfaction, knowledge and choice of axillary clearance (rather than sentinel node biopsy) in the intervention group. Conclusion: These decision aids could improve decision making for the surgical treatment of early breast cancer. A prospective randomized, control trial is needed to further evaluate the impact of these decision aids, particularly in the case of nodal surgery.     

Risk stratification in breast cancer screening: Cost-effectiveness and harm-benefit ratios for low-risk and high-risk women

In mammography screening programmes, women are screened according to a one-size-fits-all principle. Tailored screening, based on risk levels, may lead to a better balance of benefits and harms. With microsimulation modelling, we determined optimal mammography screening strategies for women at lower (relative risk [RR] 0.75) and higher (RR 1.8) than average risk of breast cancer, eligible for screening, using the incremental cost-effectiveness ratio (ICER) of current uniform screening in the Netherlands (biennial [B] 50-74) as a threshold ICER. Strategies varied by interval (annual [A], biennial, triennial [T]) and age range. The number of life-years gained (LYG), breast cancer deaths averted, overdiagnosed cases, false-positive mammograms, ICERs and harm-benefit ratios were calculated. Optimal risk-based screening scenarios, below the threshold ICER of €8883/LYG, were T50-71 (€7840/LYG) for low-risk and B40-74 (€6062/LYG) for high-risk women. T50-71 screening in low-risk women resulted in a 33% reduction in false-positive findings, a similar reduction in costs and improved harm-benefit ratios compared to the current screening schedule. B40-74 in high-risk women led to an increase in screening benefit, compared to current B50-74 screening, but a relatively higher increase in false-positive findings. In conclusion, optimal screening consisted of a longer interval and lower stopping age than current uniform screening for low-risk women, and a lower starting age for high-risk women. Extending the interval for women at lower risk from biennial to triennial screening reduced harms and costs while maintaining most of the screening benefit.     

Towards personalized screening: Cumulative risk of breast cancer screening outcomes in women with and without a first‐degree relative with a history of breast cancer

Several reviews have estimated the balance of benefits and harms of mammographic screening in the general population. The balance may, however, differ between individuals with and without family history. Therefore, our aim is to assess the cumulative risk of screening outcomes; screen‐detected breast cancer, interval cancer, and false‐positive results, in women screenees aged 50–75 and 40–75, with and without a first‐degree relative with a history of breast cancer at the start of screening. Data on screening attendance, recall and breast cancer detection were collected for each woman living in Nijmegen (The Netherlands) since 1975. We used a discrete time survival model to calculate the cumulative probability of each major screening outcome over 19 screening rounds. Women with a family history of breast cancer had a higher risk of all screening outcomes. For women screened from age 50–75, the cumulative risk of screen‐detected breast cancer, interval cancer and false‐positive results were 9.0, 4.4 and 11.1% for women with a family history and 6.3, 2.7 and 7.3% for women without a family history, respectively. The results for women 40–75 followed the same pattern for women screened 50–75 for cancer outcomes, but were almost doubled for false‐positive results. To conclude, women with a first‐degree relative with a history of breast cancer are more likely to experience benefits and harms of screening than women without a family history. To complete the balance and provide risk‐based screening recommendations, the breast cancer mortality reduction and overdiagnosis should be estimated for family history subgroups.     

Changes in mammographic density over time in breast cancer cases and women at high risk for breast cancer

High mammographic breast density is one of the strongest intermediate markers of breast cancer risk, and decreases in density over time have been associated with decreases in breast cancer risk. Using repeated measures of mammographic density in a cohort of high‐risk women, the Women at Risk (WAR) cohort at Columbia University Medical Center (N = 2670), we examined whether changes in prediagnostic mammographic density differed among 85 prospectively‐ascertained breast cancer cases and 85 age‐matched controls, using a nested case–control design. Median age at first mammogram was 51 years (range, 29–77 years), with a median of 4 years between first and second prediagnostic mammogram (range, 1–15 years). Using linear regression with change in percent density as the outcome, we found that in women who did not go on to be diagnosed with breast cancer, change in percent density decreased as time between first and second mammogram increased (β = ?1.62% per year, p = 0.004). However, in women who did go on to be diagnosed with breast cancer, there was no overall change in percent density associated with time between first and second mammogram (β = 0.29% per year, p = 0.61); the change over time was statistically significantly different between cases versus controls (p <0.009). If replicated in larger cohorts, these results suggest that within‐individual changes in mammographic density as measured by percent density may be a useful biomarker of breast cancer risk.     

Prospective study of electrical impedance scanning for identifying young women at risk for breast cancer

SummaryBackground One way to improve the cost-benefit ratio for breast cancer screening in younger women is to identify those at high-risk of breast cancer and manage them in an optimal manner. The purpose of this study is to evaluate the sensitivity and specificity of Electrical Impedance Scanning (EIS) for identifying young women who are at risk for having breast cancer and should be followed with directed imaging technologies.Methods A prospective, observational, two-arm, multi-site clinical trial was performed on women aged 30–45 years. The ‘Sensitivity Arm’ included Clinical Breast Examinations (CBE) and EIS (T-Scan™ 2000ED) on 189 women prior to scheduled breast biopsy. The ‘Specificity Arm’ included 1361 asymptomatic women visiting clinics for routine annual well-woman examination. Sensitivity and specificity were determined. Relative probability for a woman with a positive EIS examination was computed and compared with other approaches commonly used to define ‘high-risk’ in this population.Results Fifty of 189 women in the Sensitivity arm had verified cancers, 19 of whom had positive EIS examination resulting in sensitivity of 38% (19/50). Of the 1361 women in the Specificity arm, 67 had positive EIS examination resulting in a specificity of 95% (1294/1361). The relative probability of a woman with a positive EIS examination was 7.68, which compares favorably with other established risk identifiers (e.g. two first-degree relatives with breast cancer or atypical ductal hyperplasia).Conclusion EIS may have an important role as a screening tool for identifying young women that should be followed more closely with advanced imaging technologies for early detection of breast cancer.     

Recommendations for the surveillance of young women at increased risk for breast cancer

A review of the published reports regarding screening for breast cancer in young, at‐risk women has been undertaken. Draft recommendations for surveillance of these women with imaging methods such as mammography, ultrasound and MRI have been made.