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1.  Cancer Screening with Digital Mammography for Women at Average Risk for Breast Cancer, Magnetic Resonance Imaging (MRI) for Women at High Risk 
Executive Summary
Objective
The purpose of this review is to determine the effectiveness of 2 separate modalities, digital mammography (DM) and magnetic resonance imaging (MRI), relative to film mammography (FM), in the screening of women asymptomatic for breast cancer. A third analysis assesses the effectiveness and safety of the combination of MRI plus mammography (MRI plus FM) in screening of women at high risk. An economic analysis was also conducted.
Research Questions
How does the sensitivity and specificity of DM compare to FM?
How does the sensitivity and specificity of MRI compare to FM?
How do the recall rates compare among these screening modalities, and what effect might this have on radiation exposure? What are the risks associated with radiation exposure?
How does the sensitivity and specificity of the combination of MRI plus FM compare to either MRI or FM alone?
What are the economic considerations?
Clinical Need
The effectiveness of FM with respect to breast cancer mortality in the screening of asymptomatic average- risk women over the age of 50 has been established. However, based on a Medical Advisory Secretariat review completed in March 2006, screening is not recommended for women between the ages of 40 and 49 years. Guidelines published by the Canadian Task Force on Preventive Care recommend mammography screening every 1 to 2 years for women aged 50 years and over, hence, the inclusion of such women in organized breast cancer screening programs. In addition to the uncertainty of the effectiveness of mammography screening from the age of 40 years, there is concern over the risks associated with mammographic screening for the 10 years between the ages of 40 and 49 years.
The lack of effectiveness of mammography screening starting at the age of 40 years (with respect to breast cancer mortality) is based on the assumption that the ability to detect cancer decreases with increased breast tissue density. As breast density is highest in the premenopausal years (approximately 23% of postmenopausal and 53% of premenopausal women having at least 50% of the breast occupied by high density), mammography screening is not promoted in Canada nor in many other countries for women under the age of 50 at average risk for breast cancer. It is important to note, however, that screening of premenopausal women (i.e., younger than 50 years of age) at high risk for breast cancer by virtue of a family history of cancer or a known genetic predisposition (e.g., having tested positive for the breast cancer genes BRCA1 and/or BRCA2) is appropriate. Thus, this review will assess the effectiveness of breast cancer screening with modalities other than film mammography, specifically DM and MRI, for both pre/perimenopausal and postmenopausal age groups.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined whereas mortality is decreasing, though at a slower rate. The observed decreases in mortality rates may be attributable to screening, in addition to advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the Surveillance, Epidemiology and End Results (better known as SEER) cancer registry in the United States, indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20 year period, from 2.7 to 25 per 100,000.
There is a 4-fold lower incidence of breast cancer in the 40 to 49 year age group than in the 50 to 69 year age group (approximately 140 per 100,000 versus 500 per 100,000 women, respectively). The sensitivity of FM is also lower among younger women (approximately 75%) than for women aged over 50 years (approximately 85%). Specificity is approximately 80% for younger women versus 90% for women over 50 years. The increased density of breast tissue in younger women is likely responsible for the decreased accuracy of FM.
Treatment options for breast cancer vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy and/or radiotherapy. Surgery is the first-line intervention for biopsy-confirmed tumors. The subsequent use of radiation, chemotherapy or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is considered a noninvasive tumour.
Women at high risk for breast cancer are defined as genetic carriers of the more commonly known breast cancer genes (BRCA1, BRCA2 TP53), first degree relatives of carriers, women with varying degrees of high risk family histories, and/or women with greater than 20% lifetime risk for breast cancer based on existing risk models. Genetic carriers for this disease, primarily women with BRCA1 or BRCA2 mutations, have a lifetime probability of approximately 85% of developing breast cancer. Preventive options for these women include surgical interventions such as prophylactic mastectomy and/or oophorectomy, i.e., removal of the breasts and/or ovaries. Therefore, it is important to evaluate the benefits and risks of different screening modalities, to identify additional options for these women.
This Medical Advisory Secretariat review is the second of 2 parts on breast cancer screening, and concentrates on the evaluation of both DM and MRI relative to FM, the standard of care. Part I of this review (March 2006) addressed the effectiveness of screening mammography in 40 to 49 year old average-risk women. The overall objective of the present review is to determine the optimal screening modality based on the evidence.
Evidence Review Strategy
The Medical Advisory Secretariat followed its standard procedures and searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database. The subject headings and keywords searched included breast cancer, breast neoplasms, mass screening, digital mammography, magnetic resonance imaging. The detailed search strategies can be viewed in Appendix 1.
Included in this review are articles specific to screening and do not include evidence on diagnostic mammography. The search was further restricted to English-language articles published between January 1996 and April 2006. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters.
Digital Mammography: In total, 224 articles specific to DM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 5 health technology assessments (HTAs) (plus 1 update) and 4 articles specific to screening with DM.
Magnetic Resonance Imaging: In total, 193 articles specific to MRI were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 HTAs and 7 articles specific to screening with MRI.
The evaluation of the addition of FM to MRI in the screening of women at high risk for breast cancer was also conducted within the context of standard search procedures of the Medical Advisory Secretariat. as outlined above. The subject headings and keywords searched included the concepts of breast cancer, magnetic resonance imaging, mass screening, and high risk/predisposition to breast cancer. The search was further restricted to English-language articles published between September 2007 and January 15, 2010. Case reports, comments, editorials, nonsystematic reviews, and letters were not excluded.
MRI plus mammography: In total, 243 articles specific to MRI plus FM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 previous HTAs, and 1 systematic review of 11 paired design studies.
Inclusion Criteria
English-language articles, and English or French-language HTAs published from January 1996 to April 2006, inclusive.
Articles specific to screening of women with no personal history of breast cancer.
Studies in which DM or MRI were compared with FM, and where the specific outcomes of interest were reported.
Randomized controlled trials (RCTs) or paired studies only for assessment of DM.
Prospective, paired studies only for assessment of MRI.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which women had been previously diagnosed with breast cancer.
Studies in which the intervention (DM or MRI) was not compared with FM.
Studies assessing DM with a sample size of less than 500.
Intervention
Digital mammography.
Magnetic resonance imaging.
Comparator
Screening with film mammography.
Outcomes of Interest
Breast cancer mortality (although no studies were found with such long follow-up).
Sensitivity.
Specificity.
Recall rates.
Summary of Findings
Digital Mammography
There is moderate quality evidence that DM is significantly more sensitive than FM in the screening of asymptomatic women aged less than 50 years, those who are premenopausal or perimenopausal, and those with heterogeneously or extremely dense breast tissue (regardless of age).
It is not known what effect these differences in sensitivity will have on the more important effectiveness outcome measure of breast cancer mortality, as there was no evidence of such an assessment.
Other factors have been set out to promote DM, for example, issues of recall rates and reading and examination times. Our analysis did not show that recall rates were necessarily improved in DM, though examination times were lower than for FM. Other factors including storage and retrieval of screens were not the subject of this analysis.
Magnetic Resonance Imaging
There is moderate quality evidence that the sensitivity of MRI is significantly higher than that of FM in the screening of women at high risk for breast cancer based on genetic or familial factors, regardless of age.
Radiation Risk Review
Cancer Care Ontario conducted a review of the evidence on radiation risk in screening with mammography women at high risk for breast cancer. From this review of recent literature and risk assessment that considered the potential impact of screening mammography in cohorts of women who start screening at an earlier age or who are at increased risk of developing breast cancer due to genetic susceptibility, the following conclusions can be drawn:
For women over 50 years of age, the benefits of mammography greatly outweigh the risk of radiation-induced breast cancer irrespective of the level of a woman’s inherent breast cancer risk.
Annual mammography for women aged 30 – 39 years who carry a breast cancer susceptibility gene or who have a strong family breast cancer history (defined as a first degree relative diagnosed in their thirties) has a favourable benefit:risk ratio. Mammography is estimated to detect 16 to 18 breast cancer cases for every one induced by radiation (Table 1). Initiation of screening at age 35 for this same group would increase the benefit:risk ratio to an even more favourable level of 34-50 cases detected for each one potentially induced.
Mammography for women under 30 years of age has an unfavourable benefit:risk ratio due to the challenges of detecting cancer in younger breasts, the aggressiveness of cancers at this age, the potential for radiation susceptibility at younger ages and a greater cumulative radiation exposure.
Mammography when used in combination with MRI for women who carry a strong breast cancer susceptibility (e.g., BRCA1/2 carriers), which if begun at age 35 and continued for 35 years, may confer greatly improved benefit:risk ratios which were estimated to be about 220 to one.
While there is considerable uncertainty in the risk of radiation-induced breast cancer, the risk expressed in published studies is almost certainly conservative as the radiation dose absorbed by women receiving mammography recently has been substantially reduced by newer technology.
A CCO update of the mammography radiation risk literature for 2008 and 2009 gave rise to one article by Barrington de Gonzales et al. published in 2009 (Barrington de Gonzales et al., 2009, JNCI, vol. 101: 205-209). This article focuses on estimating the risk of radiation-induced breast cancer for mammographic screening of young women at high risk for breast cancer (with BRCA gene mutations). Based on an assumption of a 15% to 25% or less reduction in mortality from mammography in these high risk women, the authors conclude that such a reduction is not substantially greater than the risk of radiation-induced breast cancer mortality when screening before the age of 34 years. That is, there would be no net benefit from annual mammographic screening of BRCA mutation carriers at ages 25-29 years; the net benefit would be zero or small if screening occurs in 30-34 year olds, and there would be some net benefit at age 35 years or older.
The Addition of Mammography to Magnetic Resonance Imaging
The effects of the addition of FM to MRI screening of high risk women was also assessed, with inclusion and exclusion criteria as follows:
Inclusion Criteria
English-language articles and English or French-language HTAs published from September 2007 to January 15, 2010.
Articles specific to screening of women at high risk for breast cancer, regardless of the definition of high risk.
Studies in which accuracy data for the combination of MRI plus FM are available to be compared to that of MRI and FM alone.
RCTs or prospective, paired studies only.
Studies in which women were previously diagnosed with breast cancer were also included.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which there was insufficient data on the accuracy of MRI plus FM.
Intervention
Both MRI and FM.
Comparators
Screening with MRI alone and FM alone.
Outcomes of Interest
Sensitivity.
Specificity.
Summary of Findings
Magnetic Resonance Imaging Plus Mammography
Moderate GRADE Level Evidence that the sensitivity of MRI plus mammography is significantly higher than that of MRI or FM alone, although the specificity remains either unchanged or decreases in the screening of women at high risk for breast cancer based on genetic/familial factors, regardless of age.
These studies include women at high risk defined as BRCA1/2 or TP53 carriers, first degree relatives of carriers, women with varying degrees of high risk family histories, and/or >20% lifetime risk based on existing risk models. This definition of high risk accounts for approximately 2% of the female adult population in Ontario.
PMCID: PMC3377503  PMID: 23074406
2.  Screening Mammography for Women Aged 40 to 49 Years at Average Risk for Breast Cancer 
Executive Summary
Objective
The aim of this review was to determine the effectiveness of screening mammography in women aged 40 to 49 years at average risk for breast cancer.
Clinical Need
The effectiveness of screening mammography in women aged over 50 years has been established, yet the issue of screening in women aged 40 to 49 years is still unsettled. The Canadian Task Force of Preventive Services, which sets guidelines for screening mammography for all provinces, supports neither the inclusion nor the exclusion of this screening procedure for 40- to 49-year-old women from the periodic health examination. In addition to this, 2 separate reviews, one conducted in Quebec in 2005 and the other in Alberta in 2000, each concluded that there is an absence of convincing evidence on the effectiveness of screening mammography for women in this age group who are at average risk for breast cancer.
In the United States, there is disagreement among organizations on whether population-based mammography should begin at the age of 40 or 50 years. The National Institutes of Health, the American Association for Cancer Research, and the American Academy of Family Physicians recommend against screening women in their 40s, whereas the United States Preventive Services Task Force, the National Cancer Institute, the American Cancer Society, the American College of Radiology, and the American College of Obstetricians and Gynecologists recommend screening mammograms for women aged 40 to 49 years. Furthermore, in comparing screening guidelines between Canada and the United States, it is also important to recognize that “standard care” within a socialized medical system such as Canada’s differs from that of the United States. The National Breast Screening Study (NBSS-1), a randomized screening trial conducted in multiple centres across Canada, has shown there is no benefit in mortality from breast cancer from annual mammograms in women randomized between the ages of 40 and 49, relative to standard care (i.e. physical exam and teaching of breast-self examination on entry to the study, with usual community care thereafter).
At present, organized screening programs in Canada systematically screen women starting at 50 years of age, although with a physician’s referral, a screening mammogram is an insured service in Ontario for women under 50 years of age.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined, whereas mortality is decreasing, though at a slower rate. These decreasing mortality rates may be attributed to screening and advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the SEER cancer registry in the United States indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20-year period (from 2.7 to 25 per 100,000).
The incidence of breast cancer is lower in women aged 40 to 49 years than in women aged 50 to 69 years (about 140 per 100,000 versus 500 per 100,000 women, respectively), as is the sensitivity (about 75% versus 85% for women aged under and over 50, respectively) and specificity of mammography (about 80% versus 90% for women aged under and over 50, respectively). The increased density of breast tissue in younger women is mainly responsible for the lower accuracy of this procedure in this age group. In addition, as the proportion of breast cancers that occur before the age of 50 are more likely to be associated with genetic predisposition as compared with those diagnosed in women after the age of 50, mammography may not be an optimal screening method for younger women.
Treatment options vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy, and/or radiotherapy.
Surgery is the first-line intervention for biopsy confirmed tumours. The subsequent use of radiation, chemotherapy, or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is noninvasive.
With such controversy as to the effectiveness of mammography and the potential risk associated with women being overtreated or actual cancers being missed, and the increased risk of breast cancer associated with exposure to annual mammograms over a 10-year period, the Ontario Health Technology Advisory Committee requested this review of screening mammography in women aged 40 to 49 years at average risk for breast cancer. This review is the first of 2 parts and concentrates on the effectiveness of screening mammography (i.e., film mammography, FM) for women at average risk aged 40 to 49 years. The second part will be an evaluation of screening by either magnetic resonance imaging or digital mammography, with the objective of determining the optimal screening modality in these younger women.
Review Strategy
The following questions were asked:
Does screening mammography for women aged 40 to 49 years who are at average risk for breast cancer reduce breast cancer mortality?
What is the sensitivity and specificity of mammography for this age group?
What are the risks associated with annual screening from ages 40 to 49?
What are the risks associated with false positive and false negative mammography results?
What are the economic considerations if evidence for effectiveness is established?
The Medical Advisory Secretariat followed its standard procedures and searched these electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the International Network of Agencies for Health Technology Assessment.
Keywords used in the search were breast cancer, breast neoplasms, mass screening, and mammography.
In total, the search yielded 6,359 articles specific to breast cancer screening and mammography. This did not include reports on diagnostic mammograms. The search was further restricted to English-language randomized controlled trials (RCTs), systematic reviews, and meta-analyses published between 1995 and 2005. Excluded were case reports, comments, editorials, and letters, which narrowed the results to 516 articles and previous health technology policy assessments.
These were examined against the criteria outlined below. This resulted in the inclusion of 5 health technology assessments, the Canadian Preventive Services Task Force report, the United States Preventive Services Task Force report, 1 Cochrane review, and 8 RCTs.
Inclusion Criteria
English-language articles, and English and French-language health technology policy assessments, conducted by other organizations, from 1995 to 2005
Articles specific to RCTs of screening mammography of women at average risk for breast cancer that included results for women randomized to studies between the ages of 40 and 49 years
Studies in which women were randomized to screening with or without mammography, although women may have had clinical breast examinations and/or may have been conducting breast self-examination.
UK Age Trial results published in December 2006.
Exclusion Criteria
Observational studies, including those nested within RCTs
RCTs that do not include results on women between the ages of 40 and 49 at randomization
Studies in which mammography was compared with other radiologic screening modalities, for example, digital mammography, magnetic resonance imaging or ultrasound.
Studies in which women randomized had a personal history of breast cancer.
Intervention
Film mammography
Comparators
Within RCTs, the comparison group would have been women randomized to not undergo screening mammography, although they may have had clinical breast examinations and/or have been conducting breast self-examination.
Outcomes of Interest
Breast cancer mortality
Summary of Findings
There is Level 1 Canadian evidence that screening women between the ages of 40 and 49 years who are at average risk for breast cancer is not effective, and that the absence of a benefit is sustained over a maximum follow-up period of 16 years.
All remaining studies that reported on women aged under 50 years were based on subset analyses. They provide additional evidence that, when all these RCTs are taken into account, there is no significant reduction in breast cancer mortality associated with screening mammography in women aged 40 to 49 years.
Conclusions
There is Level 1 evidence that screening mammography in women aged 40 to 49 years at average risk for breast cancer is not effective in reducing mortality.
Moreover, risks associated with exposure to mammographic radiation, the increased risk of missed cancers due to lower mammographic sensitivity, and the psychological impact of false positives, are not inconsequential.
The UK Age Trial results published in December 2006 did not change these conclusions.
PMCID: PMC3377515  PMID: 23074501
3.  Personalizing Mammography by Breast Density and Other Risk Factors for Breast Cancer: Analysis of Health Benefits and Cost-Effectiveness 
Annals of internal medicine  2011;155(1):10-20.
Background
Current guidelines recommend mammography every 1 or 2 years starting at age 40 or 50 years, regardless of individual risk for breast cancer.
Objective
To estimate the cost-effectiveness of mammography by age, breast density, history of breast biopsy, family history of breast cancer, and screening interval.
Design
Markov microsimulation model.
Data Sources
Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and the medical literature.
Target Population
U.S. women aged 40 to 49, 50 to 59, 60 to 69, and 70 to 79 years with initial mammography at age 40 years and breast density of Breast Imaging Reporting and Data System (BI-RADS) categories 1 to 4.
Time Horizon
Lifetime.
Perspective
National health payer.
Intervention
Mammography annually, biennially, or every 3 to 4 years or no mammography.
Outcome Measures
Costs per quality-adjusted life-year (QALY) gained and number of women screened over 10 years to prevent 1 death from breast cancer.
Results of Base-Case Analysis
Biennial mammography cost less than $100 000 per QALY gained for women aged 40 to 79 years with BI-RADS category 3 or 4 breast density or aged 50 to 69 years with category 2 density; women aged 60 to 79 years with category 1 density and either a family history of breast cancer or a previous breast biopsy; and all women aged 40 to 79 years with both a family history of breast cancer and a previous breast biopsy, regardless of breast density. Biennial mammography cost less than $50 000 per QALY gained for women aged 40 to 49 years with category 3 or 4 breast density and either a previous breast biopsy or a family history of breast cancer. Annual mammography was not cost-effective for any group, regardless of age or breast density.
Results of Sensitivity Analysis
Mammography is expensive if the disutility of false-positive mammography results and the costs of detecting nonprogressive and nonlethal invasive cancer are considered.
Limitation
Results are not applicable to carriers of BRCA1 or BRCA2 mutations.
Conclusion
Mammography screening should be personalized on the basis of a woman’s age, breast density, history of breast biopsy, family history of breast cancer, and beliefs about the potential benefit and harms of screening.
Primary Funding Source
Eli Lilly, Da Costa Family Foundation for Research in Breast Cancer Prevention of the California Pacific Medical Center, and Breast Cancer Surveillance Consortium.
doi:10.7326/0003-4819-155-1-201107050-00003
PMCID: PMC3759993  PMID: 21727289
4.  Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs X-ray mammography of women at a high familial risk of breast cancer 
British Journal of Cancer  2006;95(7):801-810.
Contrast enhanced magnetic resonance imaging (CE MRI) is the most sensitive tool for screening women who are at high familial risk of breast cancer. Our aim in this study was to assess the cost-effectiveness of X-ray mammography (XRM), CE MRI or both strategies combined. In total, 649 women were enrolled in the MARIBS study and screened with both CE MRI and mammography resulting in 1881 screens and 1–7 individual annual screening events. Women aged 35–49 years at high risk of breast cancer, either because they have a strong family history of breast cancer or are tested carriers of a BRCA1, BRCA2 or TP53 mutation or are at a 50% risk of having inherited such a mutation, were recruited from 22 centres and offered annual MRI and XRM for between 2 and 7 years. Information on the number and type of further investigations was collected and specifically calculated unit costs were used to calculate the incremental cost per cancer detected. The numbers of cancer detected was 13 for mammography, 27 for CE MRI and 33 for mammography and CE MRI combined. In the subgroup of BRCA1 (BRCA2) mutation carriers or of women having a first degree relative with a mutation in BRCA1 (BRCA2) corresponding numbers were 3 (6), 12 (7) and 12 (11), respectively. For all women, the incremental cost per cancer detected with CE MRI and mammography combined was £28 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to £11 731 (CE MRI vs mammography) and £15 302 (CE MRI and mammography vs mammography). Results were most sensitive to the unit cost estimate for a CE MRI screening test. Contrast-enhanced MRI might be a cost-effective screening modality for women at high risk, particularly for the BRCA1 and BRCA2 subgroups. Further work is needed to assess the impact of screening on mortality and health-related quality of life.
doi:10.1038/sj.bjc.6603356
PMCID: PMC2360541  PMID: 17016484
cost-effectiveness analysis; breast MRI; screening; BRCA1 and BRCA2; breast cancer; high risk
5.  Cost-effectiveness of MRI compared to mammography for breast cancer screening in a high risk population 
Background
Breast magnetic resonance imaging (MRI) is a sensitive method of breast imaging virtually uninfluenced by breast density. Because of the improved sensitivity, breast MRI is increasingly being used for detection of breast cancer among high risk young women. However, the specificity of breast MRI is variable and costs are high. The purpose of this study was to determine if breast MRI is a cost-effective approach for the detection of breast cancer among young women at high risk.
Methods
A Markov model was created to compare annual breast cancer screening over 25 years with either breast MRI or mammography among young women at high risk. Data from published studies provided probabilities for the model including sensitivity and specificity of each screening strategy. Costs were based on Medicare reimbursement rates for hospital and physician services while medication costs were obtained from the Federal Supply Scale. Utilities from the literature were applied to each health outcome in the model including a disutility for the temporary health state following breast biopsy for a false positive test result. All costs and benefits were discounted at 5% per year. The analysis was performed from the payer perspective with results reported in 2006 U.S. dollars. Univariate and probabilistic sensitivity analyses addressed uncertainty in all model parameters.
Results
Breast MRI provided 14.1 discounted quality-adjusted life-years (QALYs) at a discounted cost of $18,167 while mammography provided 14.0 QALYs at a cost of $4,760 over 25 years of screening. The incremental cost-effectiveness ratio of breast MRI compared to mammography was $179,599/QALY. In univariate analysis, breast MRI screening became < $50,000/QALY when the cost of the MRI was < $315. In the probabilistic sensitivity analysis, MRI screening produced a net health benefit of -0.202 QALYs (95% central range: -0.767 QALYs to +0.439 QALYs) compared to mammography at a willingness-to-pay threshold of $50,000/QALY. Breast MRI screening was superior in 0%, < $50,000/QALY in 22%, > $50,000/QALY in 34%, and inferior in 44% of trials.
Conclusion
Although breast MRI may provide health benefits when compared to mammographic screening for some high risk women, it does not appear to be cost-effective even at willingness to pay thresholds above $120,000/QALY.
doi:10.1186/1472-6963-9-9
PMCID: PMC2630922  PMID: 19144138
6.  Detection of Breast Cancer with Addition of Annual Screening Ultrasound or a Single Screening MRI to Mammography in Women with Elevated Breast Cancer Risk 
Context
Annual ultrasound (US) may detect small, node-negative breast cancers not seen on mammography (M). MRI may depict additional breast cancers beyond mammography and ultrasound (M+US).
Objective
Determine supplemental cancer detection yield of ultrasound and MRI in women at elevated risk for breast cancer.
Design, Setting, Participants
From April 2004 to February 2006, 2809 women at 21 sites with elevated cancer risk and dense breasts consented to three annual independent screens with mammography and ultrasound in randomized order. After 3 rounds of mammography and US screening, 703 women from 14 sites consented to a single MRI.
Main Outcome Measures
Cancer detection rate (yield), sensitivity, specificity, positive predictive value of biopsies performed (PPV3 – rate of malignancy among cases positive on screening, who actually underwent biopsy), interval cancer rate. The diagnosis of breast cancer was based on a biopsy showing in situ or infiltrating ductal carcinoma or infiltrating lobular carcinoma in the breast or axillary lymph nodes. Reference standard was defined as a combination of pathology and 12-month follow-up and was available for 2662 women (7473 M+US screens) and 612 MRI participants.
Results
The 2662 patients underwent 7473 mammograms and US, with 110 women having 111 breast cancers detected, of which 33 were detected on mammography only, 32 on US only, 26 on both mammography and US, and 9 on MRI after mammography and US. Eleven were not detected by any imaging modality. Supplemental incidence-screening US identified 3.7 cancers per 1000 women-screens (95% CI 2.1 to 5.8, p<.001). Sensitivity, specificity, and PPV3 for M +US were 57/75 (0.76, 95% CI 0.65 to 0.85), 3987/4739 (0.84, 95% CI 0.83 to 0.85), and 55/339 (0.16, 95% CI 0.12 to 0.21); and for mammography alone 39/75 (0.52, 95% CI 0.40 to 0.64), 4325/4739 (0.91,95% 0.90 to 0.92), and 37/97 (0.38, 95% CI 0.28 to 0.49) (p<.001 all comparisons). Of 612 analyzable MRI participants, 16 (2.6%) had breast cancer diagnosed. Supplemental yield of MRI was 14.7 per 1000 (95% CI 3.5 to 25.9, p=.004). Sensitivity, specificity, and PPV3 for MRI+M+US were 16/16 (1.00, 95% CI 0.79 to 1.00), 390/596 (0.65, 95% CI 0.61 to 0.69), and 15/81 (0.19, 95% CI 0.11 to 0.29); and for M+US 7/16 (0.44, 95% CI 0.20 to 0.70, p=.004), 503/596 (0.84, 95% CI 0.81 to 0.87, p <.001), and 7/38 (0.18, 95% CI 0.08 to 0.34, p= .98) for M+US. Number of screens needed to detect one cancer was 127(95%CI 99 to 167) for mammography; 234(95%CI 173 to 345) for supplemental ultrasound, and 68 (95%CI 39 to 286) for MRI after negative M+US.
Conclusions
The addition of screening ultrasound or MRI to mammography in women at increased risk of breast cancer resulted in a higher cancer detection yield but also an increase in false positive findings.
doi:10.1001/jama.2012.388
PMCID: PMC3891886  PMID: 22474203
7.  Beyond Mammography: New Frontiers in Breast Cancer Screening 
The American journal of medicine  2013;126(6):472-479.
Breast cancer screening remains a subject of intense and, at times, passionate debate. Mammography has long been the mainstay of breast cancer detection and is the only screening test proven to reduce mortality. Although it remains the gold standard of breast cancer screening, there is increasing awareness of subpopulations of women for whom mammography has reduced sensitivity. Mammography has also undergone increased scrutiny for false positives and excessive biopsies, which increase radiation dose, cost and patient anxiety. In response to these challenges, new technologies for breast cancer screening have been developed, including; low dose mammography; contrast enhanced mammography, tomosynthesis, automated whole breast ultrasound, molecular imaging and MRI. Here we examine some of the current controversies and promising new technologies that may improve detection of breast cancer both in the general population and in high-risk groups, such as women with dense breasts. We propose that optimal breast cancer screening will ultimately require a personalized approach based on metrics of cancer risk with selective application of specific screening technologies best suited to the individual’s age, risk, and breast density.
doi:10.1016/j.amjmed.2012.11.025
PMCID: PMC4010151  PMID: 23561631
8.  Accuracy and Outcomes of Screening Mammography in Women With a Personal History of Early-Stage Breast Cancer 
Context
Women with a personal history of breast cancer (PHBC) are at risk of developing another breast cancer and are recommended for screening mammography. Few high-quality data exist on screening performance in PHBC women.
Objective
To examine the accuracy and outcomes of mammography screening in PHBC women relative to screening of similar women without PHBC.
Design and Setting
Cohort of PHBC women, mammogram matched to non-PHBC women, screened through facilities (1996–2007) affiliated with the Breast Cancer Surveillance Consortium.
Participants
There were 58 870 screening mammograms in 19 078 women with a history of early-stage (in situ or stage I-II invasive) breast cancer and 58 870 matched (breast density, age group, mammography year, and registry) screening mammograms in 55 315 non-PHBC women.
Main Outcome Measures
Mammography accuracy based on final assessment, cancer detection rate, interval cancer rate, and stage at diagnosis.
Results
Within 1 year after screening, 655 cancers were observed in PHBC women (499 invasive, 156 in situ) and 342 cancers (285 invasive, 57 in situ) in non-PHBC women. Screening accuracy and outcomes in PHBC relative to non-PHBC women were cancer rates of 10.5 per 1000 screens (95%CI, 9.7–11.3) vs 5.8 per 1000 screens (95%CI, 5.2–6.4), cancer detection rate of 6.8 per 1000 screens (95%CI, 6.2–7.5) vs 4.4 per 1000 screens (95% CI, 3.9–5.0), interval cancer rate of 3.6 per 1000 screens (95%CI, 3.2–4.1) vs 1.4 per 1000 screens (95% CI, 1.1–1.7), sensitivity 65.4% (95% CI, 61.5%–69.0%) vs 76.5% (95% CI, 71.7%–80.7%), specificity 98.3% (95% CI, 98.2%–98.4%) vs 99.0% (95% CI, 98.9%–99.1%), abnormal mammogram results in 2.3% (95% CI, 2.2%–2.5%) vs 1.4% (95% CI, 1.3%–1.5%) (all comparisons P <.001). Screening sensitivity in PHBC women was higher for detection of in situ cancer (78.7%;95% CI, 71.4%–84.5%) than invasive cancer (61.1%; 95% CI, 56.6%–65.4%), P<.001; lower in the initial 5 years (60.2%; 95% CI, 54.7%–65.5%) than after 5 years from first cancer (70.8%;95% CI, 65.4%–75.6%), P =.006; and was similar for detection of ipsilateral cancer (66.3%; 95% CI, 60.3%–71.8%) and contralateral cancer (66.1%; 95% CI, 60.9%–70.9%), P=.96. Screen-detected and interval cancers in women with and without PHBC were predominantly early stage.
Conclusion
Mammography screening in PHBC women detects early-stage second breast cancers but has lower sensitivity and higher interval cancer rate, despite more evaluation and higher underlying cancer rate, relative to that in non-PHBC women.
doi:10.1001/jama.2011.188
PMCID: PMC3799940  PMID: 21343578
9.  Screening for Breast Cancer 
Context
Breast cancer screening in community practices may be different from that in randomized controlled trials. New screening modalities are becoming available.
Objectives
To review breast cancer screening, especially in the community and to examine evidence about new screening modalities.
Data Sources and Study Selection
English-language articles of randomized controlled trials assessing effectiveness of breast cancer screening were reviewed, as well as meta-analyses, systematic reviews, studies of breast cancer screening in the community, and guidelines. Also, studies of newer screening modalities were assessed.
Data Synthesis
All major US medical organizations recommend screening mammography for women aged 40 years and older. Screening mammography reduces breast cancer mortality by about 20% to 35% in women aged 50 to 69 years and slightly less in women aged 40 to 49 years at 14 years of follow-up. Approximately 95% of women with abnormalities on screening mammograms do not have breast cancer with variability based on such factors as age of the woman and assessment category assigned by the radiologist. Studies comparing full-field digital mammography to screen film have not shown statistically significant differences in cancer detection while the impact on recall rates (percentage of screening mammograms considered to have positive results) was unclear. One study suggested that computer-aided detection increases cancer detection rates and recall rates while a second larger study did not find any significant differences. Screening clinical breast examination detects some cancers missed by mammography, but the sensitivity reported in the community is lower (28% to 36%) than in randomized trials (about 54%). Breast self-examination has not been shown to be effective in reducing breast cancer mortality, but it does increase the number of breast biopsies performed because of false-positives. Magnetic resonance imaging and ultrasound are being studied for screening women at high risk for breast cancer but are not recommended for screening the general population. Sensitivity of magnetic resonance imaging in high-risk women has been found to be much higher than that of mammography but specificity is generally lower. Effect of the magnetic resonance imaging on breast cancer mortality is not known. A balanced discussion of possible benefits and harms of screening should be undertaken with each woman.
Conclusions
In the community, mammography remains the main screening tool while the effectiveness of clinical breast examination and self-examination are less. New screening modalities are unlikely to replace mammography in the near future for screening the general population.
doi:10.1001/jama.293.10.1245
PMCID: PMC3149836  PMID: 15755947
10.  Performance of First Mammography Examination in Women Younger Than 40 Years 
Background
Few data have been published on mammography performance in women who are younger than 40 years.
Methods
We pooled data from six mammography registries across the United States from the Breast Cancer Surveillance Consortium. We included 117 738 women who were aged 18–39 years when they had their first screening or diagnostic mammogram during 1995–2005 and followed them for 1 year to determine accuracy of mammography assessment. We measured the recall rate for screening examinations and the sensitivity, specificity, positive predictive value, and cancer detection rate for all mammograms.
Results
For screening mammograms, no cancers were detected in 637 mammograms for women aged 18–24 years. For women aged 35–39 years who had the largest number of screening mammograms (n = 73 335) in this study, the recall rate was 12.7% (95% confidence interval [CI] = 12.4% to 12.9%), sensitivity was 76.1% (95% CI = 69.2% to 82.6%), specificity was 87.5% (95% CI = 87.2% to 87.7%), positive predictive value was 1.3% (95% CI = 1.1% to 1.5%), and cancer detection rate was 1.6 cancers per 1000 mammograms (95% CI = 1.3 to 1.9 cancers per 1000 mammograms). Most (67 468 [77.7%]) of the 86 871 women screened reported no family history of breast cancer. For diagnostic mammograms, the age-adjusted rates across all age groups were: sensitivity of 85.7% (95% CI = 82.7% to 88.7%), specificity of 88.8% (95% CI = 88.4% to 89.1%), positive predictive value of 14.6% (95% CI = 13.3% to 15.8%), and cancer detection rate of 14.3 cancers per 1000 mammograms (95% CI = 13.0 to 15.7 cancers per 1000 mammograms). Mammography performance, except for specificity, improved in the presence of a breast lump.
Conclusions
Younger women have very low breast cancer rates but after mammography experience high recall rates, high rates of additional imaging, and low cancer detection rates. We found no cancers in women younger than 25 years and poor performance for the large group of women aged 35–39 years. In a theoretical population of 10 000 women aged 35–39 years, 1266 women who are screened will receive further workup, with 16 cancers detected and 1250 women receiving a false-positive result.
doi:10.1093/jnci/djq090
PMCID: PMC2902813  PMID: 20439838
11.  Outcomes of Screening Mammography by Frequency, Breast Density, and Postmenopausal Hormone Therapy 
JAMA internal medicine  2013;173(9):807-816.
Importance
Controversy exists about the frequency women should undergo screening mammography and whether screening interval should vary according to risk factors beyond age.
Objective
To compare the benefits and harms of screening mammography frequencies according to age, breast density, and postmenopausal hormone therapy (HT) use.
Design
Prospective cohort.
Setting
Data collected January 1994 to December 2008 from mammography facilities in community practice that participate in the Breast Cancer Surveillance Consortium (BCSC) mammography registries.
Participants
Data were collected prospectively on 11 474 women with breast cancer and 922 624 without breast cancer who underwent mammography at facilities that participate in the BCSC.
Main Outcomes and Measures
We used logistic regression to calculate the odds of advanced stage (IIb, III, or IV) and large tumors (>20 mm in diameter) and 10-year cumulative probability of a false-positive mammography result by screening frequency, age, breast density, and HT use. The main predictor was screening mammography interval.
Results
Mammography biennially vs annually for women aged 50 to 74 years does not increase risk of tumors with advanced stage or large size regardless of women’s breast density or HT use. Among women aged 40 to 49 years with extremely dense breasts, biennial mammography vs annual is associated with increased risk of advanced-stage cancer (odds ratio [OR], 1.89; 95% CI, 1.06–3.39) and large tumors (OR, 2.39; 95% CI, 1.37–4.18). Cumulative probability of a false-positive mammography result was high among women undergoing annual mammography with extremely dense breasts who were either aged 40 to 49 years (65.5%) or used estrogen plus progestogen (65.8%) and was lower among women aged 50 to 74 years who underwent biennial or triennial mammography with scattered fibroglandular densities (30.7% and 21.9%, respectively) or fatty breasts (17.4% and 12.1%, respectively).
Conclusions and Relevance
Women aged 50 to 74 years, even those with high breast density or HT use, who undergo biennial screening mammography have similar risk of advanced-stage disease and lower cumulative risk of false-positive results than those who undergo annual mammography. When deciding whether to undergo mammography, women aged 40 to 49 years who have extremely dense breasts should be informed that annual mammography may minimize their risk of advanced-stage disease but the cumulative risk of false-positive results is high.
doi:10.1001/jamainternmed.2013.307
PMCID: PMC3699693  PMID: 23552817
12.  Prospective screening study of 0.5 Tesla dedicated magnetic resonance imaging for the detection of breast cancer in young, high-risk women 
BMC Women's Health  2006;6:10.
Background
Evidence-based screening guidelines are needed for women under 40 with a family history of breast cancer, a BRCA1 or BRCA2 mutation, or other risk factors. An accurate assessment of breast cancer risk is required to balance the benefits and risks of surveillance, yet published studies have used narrow risk assessment schemata for enrollment. Breast density limits the sensitivity of film-screen mammography but is not thought to pose a limitation to MRI, however the utility of MRI surveillance has not been specifically examined before in women with dense breasts. Also, all MRI surveillance studies yet reported have used high strength magnets that may not be practical for dedicated imaging in many breast centers. Medium strength 0.5 Tesla MRI may provide an alternative economic option for surveillance.
Methods
We conducted a prospective, nonrandomized pilot study of 30 women age 25–49 years with dense breasts evaluating the addition of 0.5 Tesla MRI to conventional screening. All participants had a high quantitative breast cancer risk, defined as ≥ 3.5% over the next 5 years per the Gail or BRCAPRO models, and/or a known BRCA1 or BRCA2 germline mutation.
Results
The average age at enrollment was 41.4 years and the average 5-year risk was 4.8%. Twenty-two subjects had BIRADS category 1 or 2 breast MRIs (negative or probably benign), whereas no category 4 or 5 MRIs (possibly or probably malignant) were observed. Eight subjects had BIRADS 3 results, identifying lesions that were "probably benign", yet prompting further evaluation. One of these subjects was diagnosed with a stage T1aN0M0 invasive ductal carcinoma, and later determined to be a BRCA1 mutation carrier.
Conclusion
Using medium-strength MRI we were able to detect 1 early breast tumor that was mammographically undetectable among 30 young high-risk women with dense breasts. These results support the concept that breast MRI can enhance surveillance for young high-risk women with dense breasts, and further suggest that a medium-strength instrument is sufficient for this application. For the first time, we demonstrate the use of quantitative breast cancer risk assessment via a combination of the Gail and BRCAPRO models for enrollment in a screening trial.
doi:10.1186/1472-6874-6-10
PMCID: PMC1553433  PMID: 16800895
13.  Evaluating the correlation between mammography and MRI for screening women with increased breast cancer risk 
Academic radiology  2009;16(11):1323-1328.
Rationale and Objectives
Breast magnetic resonance imaging (MRI) is increasingly being added to mammography for screening asymptomatic women at increased risk of breast cancer. Because the direction and extent of correlation between mammography and MRI could potentially result in over- or under-estimation of the diagnostic gain related to using MRI as an adjunct to mammographic screening, we performed an analysis to evaluate the extent of correlation between mammography and MRI.
Materials and Methods
We reviewed the published literature to identify multimodality breast cancer screening studies reporting the sensitivity of mammography and MRI, alone and in combination, for breast cancer diagnosis. After calculating the expected sensitivity of combined mammography and MRI under conditions of test independence (no correlation), we compared the calculated and observed sensitivities for combined mammography and MRI. We then calculated correlation coefficients for mammography and MRI.
Results
Seven studies of multimodality screening in women at increased risk of developing breast cancer were included for analysis. Of these studies, the correlation between film mammography and MRI was positive in three studies, negative in two studies, and not identified in two studies. The calculated correlation coefficients ranged from -0.38 to 0.18. In 6 of 7 studies, the 95% confidence interval for the correlation coefficient included 0.0, indicating no significant correlation.
Conclusion
Evidence from published trials of multimodality breast cancer screening identified no statistically significant correlation between film mammography and MRI. Using both tests for breast cancer screening is likely to improve the early detection of breast cancer in women at increased risk.
doi:10.1016/j.acra.2009.05.011
PMCID: PMC2763935  PMID: 19632865
Mammography; MRI; screening; technology assessment
14.  Screening for Breast Cancer: Systematic Evidence Review Update for the U. S. Preventive Services Task Force 
Annals of internal medicine  2009;151(10):727-W242.
Background
This systematic review is an update of evidence since the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation on breast cancer screening.
Purpose
To determine the effectiveness of mammography screening in decreasing breast cancer mortality among average-risk women age 40 to 49 and 70 and older; the effectiveness of clinical breast examination (CBE) and breast self examination (BSE); and harms of screening.
Data Sources
Cochrane Controlled Trials Registry and Database of Systematic Reviews (4th Quarter 2008), MEDLINE® (January 2001 to December 2008), reference lists, and Web of Science® for published studies; Breast Cancer Surveillance Consortium for screening mammography data.
Study Selection
Randomized controlled trials with breast cancer mortality outcomes for screening effectiveness; multiple study designs and data sources for harms.
Data Extraction
Investigators abstracted relevant data and rated study quality using established criteria.
Data Synthesis
Mammography screening reduces breast cancer mortality by 15% for women age 39 to 49 (relative risk 0.85; 95% CrI 0.75 to 0.96; 8 trials); data are lacking for age ≥70. Radiation exposure from mammography is low. Patient adverse experiences are common, transient, and do not impact screening practices. Estimates of overdiagnosis vary from 1% to 10%. Younger women have more false positive mammograms and additional imaging, but fewer biopsies than older women. Trials of CBE are ongoing; for BSE, trials showed no reductions in mortality but increased benign biopsies.
Limitations
Studies of older women, digital mammography, and MRI are lacking.
Conclusions
Mammography screening reduces breast cancer mortality for women age 39 to 69; data are insufficient for older women. False positive mammograms and additional imaging are common. No benefit has been shown for CBE or BSE.
doi:10.1059/0003-4819-151-10-200911170-00009
PMCID: PMC2972726  PMID: 19920273
15.  COST-EFFECTIVENESS OF DIGITAL MAMMOGRAPHY BREAST CANCER SCREENING: RESULTS FROM ACRIN DMIST 
Annals of internal medicine  2008;148(1):1-10.
Background
The Digital Mammography Imaging Screening Trial (DMIST) reported improved breast cancer detection with digital compared with film mammography in select population subgroups, but the economic value of digital relative to film mammography screening has not been assessed.
Objective
To evaluate the cost-effectiveness of digital mammography screening.
Design
Validated discrete-event simulation model.
Data Sources
DMIST data and publicly-available U.S. data.
Target Population
U.S. female population age 40 and older.
Time Horizon
Lifetime.
Perspective
Societal, Medicare.
Interventions
All-film mammography screening; All-digital screening and Targeted digital screening: Age-targeted (digital for women <50) and Age-density-targeted (digital for women <50 or ≥50 with dense breasts).
Outcome Measures
Cost per quality-adjusted life year (QALY) gained.
Results of Base-Case Analysis
All-digital screening cost $331,000 (95%CI: $268,000, $403,000) per QALY gained relative to All-film, but was more costly and less effective than targeted digital screening. Targeted digital screening resulted in more screen-detected cancers, and fewer cancer deaths than either All-film or All-digital screening with cost-effectiveness estimates ranging from $26,500 (95%CI: $21,000, $33,000) per QALY gained for Age-targeted digital to $84,500 (95%CI: $75,000, $93,000) per QALY gained for Age-density-targeted digital. In the Medicare population, Density-targeted digital screening cost-effectiveness varied from a base-case estimate of $97,000 (95% CI: $77,000, $131,000) to $257,000 per QALY gained (95%CI: $91,000, $536,000) in the alternative case analyses where assumptions about digital performance in women with non-dense breasts were dampened.
Results of Sensitivity Analysis
Results were sensitive to the cost of digital mammography and to the prevalence of dense breasts.
Limitations
Results dependent on model assumptions and DMIST findings.
Conclusions
Relative to film mammography, All-digital screening is not cost-effective. Age-targeted digital screening appears cost-effective while Density-targeted strategies are more costly and of uncertain value particularly among women age 65 and older.
PMCID: PMC2662630  PMID: 18166758
16.  Breast cancer detection using automated whole breast ultrasound and mammography in radiographically dense breasts 
European Radiology  2009;20(3):734-742.
Purpose
Mammography, the standard method of breast cancer screening, misses many cancers, especially in dense-breasted women. We compared the performance and diagnostic yield of mammography alone versus an automated whole breast ultrasound (AWBU) plus mammography in women with dense breasts and/or at elevated risk of breast cancer.
Methods
AWBU screening was tested in 4,419 women having routine mammography (Trial Registration: ClinicalTrials.gov Identifier: NCT00649337). Cancers occurring during the study and subsequent 1-year follow-up were evaluated. Sensitivity, specificity and positive predictive value (PPV) of biopsy recommendation for mammography alone, AWBU and mammography with AWBU were calculated.
Results
Breast cancer detection doubled from 23 to 46 in 6,425 studies using AWBU with mammography, resulting in an increase in diagnostic yield from 3.6 per 1,000 with mammography alone to 7.2 per 1,000 by adding AWBU. PPV for biopsy based on mammography findings was 39.0% and for AWBU 38.4%. The number of detected invasive cancers 10 mm or less in size tripled from 7 to 21 when AWBU findings were added to mammography.
Conclusion
AWBU resulted in significant cancer detection improvement compared with mammography alone. Additional detection and the smaller size of invasive cancers may justify this technology’s expense for women with dense breasts and/or at high risk for breast cancer.
doi:10.1007/s00330-009-1588-y
PMCID: PMC2822222  PMID: 19727744
Mammography; Ultrasound; Breast cancer; Screening; Automated
17.  Association of Mammographic Density with Pathologic Findings 
Background
Breast cancer is one of the most common cancers in the world and is the first cause of death due to cancer among women. Mammography is the best screening method and mammographic density, which determines the percentage of fibro glandular tissue of breast, is one of the strongest risk factors of breast cancer. Because benign and malignant lesions may present as dense lesions in mammography so it is necessary to take a core biopsy of any suspicious lesions to evaluate pathologic findings.
Objectives
The aim of this study was to assess the association between mammographic density and histopathological findings in Iranian population. Moreover, we assessed the correlation between mammographic density and protein expression profile. We indeed, determined the accuracy and positive predictive value and negative predictive value of mammographic reports in our center.
Patients and Method
This study is a cross-sectional study carried out among 131 eligible women who had referred to imaging center for mammographic examination and had been advised to take biopsy of breast tissue. All participants of the study had filled out the informed consent. Pathologic review was performed blinded to the density status. Patients were divided into low density breast tissue group (ACR density group 1-2) and high density breast tissue group (ACR 3, 4) and data was compared between these two groups. Statistical analysis performed using SPSS for windows, version 11.5. We used chi-square, t-test, and logistic regression test for analysis and Odds Ratio calculated where indicated.
Results
In patients with high breast densities, malignant cases (61.2%) were significantly more in comparison to patients with low breast densities (37.3%) (P= 0.007, OR=2.66 95% CI=1.29-5.49). After adjusting for age, density was associated with malignancy in age groups <46 years (P=0.007), and 46-60 years (P=0.024) but not in age group >60yrs (P=0.559). Adjusting for menopausal status, density showed association with malignancy in both pre-menopause (P=0.041) and menopause (P=0.010) patients. Using logistic regression test, only age and density showed independent association with risk of breast cancer. No association was found between density and protein profile expression. Mammographic method has a false negative percent of 10.3% for negative BI-RADS group and a Positive Predictive Value (PPV) of 69.6% for positive BI-RADS group. PPVs for BI-RADS 4a, 4b, 4c and 5 were 16%, 87.5%, 84.6%, and 91.5% respectively. NPVs for BI-RADS 1, 2 and 3 were 66.7%, 95.8% and 90.0% respectively.
Conclusions
In this study we found that increasing in mammographic density is associated with an increase in malignant pathology reports. Expression of ER, PR and HER-2 receptors didn't show association with density. Our mammographic reports had a sensitivity of 94.1% and a specificity of 55.6%, which shows that our mammography is an acceptable method for screening breast cancer in this center.
doi:10.5812/ircmj.16698
PMCID: PMC3955519  PMID: 24693404
Mammographic Density; Pathology; Receptors, Estrogen; Receptors, Progesterone
18.  Early detection of breast cancer: benefits and risks of supplemental breast ultrasound in asymptomatic women with mammographically dense breast tissue. A systematic review 
BMC Cancer  2009;9:335.
Background
Mammographic screening alone will miss a certain fraction of malignancies, as evidenced by retrospective reviews of mammograms following a subsequent screening. Mammographic breast density is a marker for increased breast cancer risk and is associated with a higher risk of interval breast cancer, i.e. cancer detected between screening tests. The purpose of this review is to estimate risks and benefits of supplemental breast ultrasound in women with negative mammographic screening with dense breast tissue.
Methods
A systematic search and review of studies involving mammography and breast ultrasound for screening of breast cancer was conducted. The search was performed for the period 1/2000-8/2008 within the data source of PubMed, DARE, and Cochrane databases. Inclusion and exclusion criteria were determined prospectively, and the Oxford evidence classification system for diagnostic studies was used for evidence level. The parameters biopsy rate, positive predictive value (PPV) for biopsy, cancer yield for breast ultrasound alone, and carcinoma detection rate by breast density were extracted or constructed.
Results
The systematic search identified no randomized controlled trials or systematic reviews, six cohort studies of intermediate level of evidence (3b) were found. Only two of the studies included adequate follow-up of subjects with negative or benign findings. Supplemental breast ultrasound after negative mammographic screening permitted diagnosis of primarily invasive carcinomas in 0.32% of women in breast density type categories 2-4 of the American College of Radiology (ACR); mean tumor size for those identified was 9.9 mm, 90% with negative lymph node status. Most detected cancers occurred in mammographically dense breast ACR types 3 and 4. Biopsy rates were in the range 2.3%-4.7%, with PPV of 8.4-13.7% for those biopsied due to positive ultrasound, or about one third of the PPV of biopsies due to mammography. Limitations: The study populations included wide age ranges, and the application to women age 50-69 years as proposed for mammographic screening could result in less striking benefit. Further validation studies should employ a uniform assessment system such as BI-RADS and report not only PPV, but also negative predictive value, sensitivity and specificity.
Conclusion
Supplemental breast ultrasound in the population of women with mammographically dense breast tissue (ACR 3 and 4) permits detection of small, otherwise occult, breast cancers. Potential adverse impacts for women in this intermediate risk group are associated with an increased biopsy rate.
doi:10.1186/1471-2407-9-335
PMCID: PMC2760575  PMID: 19765317
19.  Are there racial/ethnic disparities among women younger than 40 undergoing mammography? 
While the probability of a woman developing invasive breast cancer at age <40 is low (<1%), mammography use reported among younger women (age <40) is substantial, and varies by race/ethnicity. Little detail is known about mammography use among women aged <40, particularly by race/ethnicity. We describe racial/ethnic differences in: (1) mammography indication after considering underlying risk factors (breast symptoms and family history); (2) follow-up recommendations, and (3) mammography outcomes for first mammograms in women aged <40. These 1996–2005 Breast Cancer Surveillance Consortium data are prospectively pooled from seven U.S. mammography registries. Our community-based sample included 99,615 women aged 18–39 who self-reported race/ethnicity and presented for a first mammogram (screening or diagnostic) with no history of breast cancer. Multivariable analyses controlled for registry site, age, family history of breast cancer, symptoms, and exam year. Overall, 73.6% of the women in our sample were seen for a screening mammogram. Following screening mammography, African American (AA) women were more likely than white women to be recommended for additional workup [relative risk (RR): 1.15 (95% CI: 1.07–1.23)]. Following diagnostic mammography, AA [RR: 1.30 (95% CI: 1.17–1.44)] and Asian [RR: 1.44 (95% CI: 1.26–1.64)] women were more likely to be recommended for biopsy, fine-needle aspiration, or surgical consultation. Depending on race/ethnicity, and considering the rate of true positive to total first screening mammograms of younger women, a women has a likelihood of a true positive of 1 in 363–1,122; she has a likelihood of a false positive of 1 in 7–10. This study of community-based practice found racial/ethnic variability in mammography indication, recommendations, and outcomes among women undergoing first mammography before 40. These findings highlight important areas for future research to understand the motivating factors for these practice patterns and the implications of early mammography use.
doi:10.1007/s10549-010-0812-4
PMCID: PMC2927744  PMID: 20204501
Mammography; Breast neoplasms; Risk factors; Health services accessibility; Healthcare disparities
20.  Factors Associated with Annual-Interval Mammography for Women in Their 40s 
Cancer Epidemiology  2009;33(1):72-78.
Background
Evidence is mounting that annual mammography for women in their 40s may be the optimal schedule to reduce morbidity and mortality from breast cancer. Few studies have assessed predictors of repeat mammography on an annual interval among these women.
Methods
We assessed mammography screening status among 596 insured Black and Non-Hispanic white women ages 43 to 49. Adherence was defined as having a second mammogram 10 to 14 months after a previous mammogram. We examined socio-demographic, medical and healthcare-related variables on receipt of annual-interval repeat mammograms. We also assessed barriers associated with screening.
Results
44.8% of the sample were adherent to annual-interval mammography. A history of self-reported abnormal mammograms, family history of breast cancer and never having smoked were associated with adherence. Saying they had not received mammography reminders and reporting barriers to mammography were associated with non-adherence. Four barrier categories were associated with women's non-adherence: lack of knowledge/not thinking mammograms are needed, cost, being too busy, and forgetting to make/keep appointments.
Conclusions
Barriers we identified are similar to those found in other studies. Health professionals may need to take extra care in discussing mammography screening risk and benefits due to ambiguity about screening guidelines for women in their 40s, especially for women without family histories of breast cancer or histories of abnormal mammograms. Reminders are important in promoting mammography and should be coupled with other strategies to help women maintain adherence to regular mammography.
doi:10.1016/j.cdp.2009.03.001
PMCID: PMC2727566  PMID: 19481879
breast neoplasms; guideline adherence; health behavior; middle aged; attitude to health; patient compliance; mass screening; female; risk factor; health knowledge
21.  Multimodality Screening of High-Risk Women: A Prospective Cohort Study 
Journal of Clinical Oncology  2009;27(36):6124-6128.
Purpose
Mammography has been established as the primary imaging screening method for breast cancer; however, the sensitivity of mammography is limited, especially in women with dense breast tissue. Given the limitations of mammography, interest has developed in alternative screening techniques. This interest has led to numerous studies reporting mammographically occult breast cancers detected on magnetic resonance imaging (MRI) or ultrasound. In addition, digital mammography was shown to be more sensitive than film mammography in selected populations. Our goal was to prospectively compare cancer detection of digital mammography (DM), whole-breast ultrasound (WBUS), and contrast-enhanced MRI in a high-risk screening population previously screened negative by film screen mammogram (FSM).
Methods
During a 2-year period, 609 asymptomatic high-risk women with nonactionable FSM examinations presented for a prospective multimodality screening consisting of DM, WBUS, and MRI. The FSM examinations were reinterpreted by study radiologists. Patients had benign or no suspicious findings on clinical examination. The cancer yield by modality was evaluated.
Results
Twenty cancers were diagnosed in 18 patients (nine ductal carcinomas in situ and 11 invasive breast cancers). The overall cancer yield on a per-patient basis was 3.0% (18 of 609 patients). The cancer yield by modality was 1.0% for FSM (six of 597 women), 1.2% for DM (seven of 569 women), 0.53% for WBUS (three of 567 women), and 2.1% for MRI (12 of 571 women). Of the 20 cancers detected, some were only detected on one imaging modality (FSM, n = 1; DM, n = 3; WBUS, n = 1; and MRI, n = 8).
Conclusion
The addition of MRI to mammography in the high-risk group has the greatest potential to detect additional mammographically occult cancers. The incremental cancer yield of WBUS and DM is much less.
doi:10.1200/JCO.2009.24.4277
PMCID: PMC2793033  PMID: 19884532
22.  Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. 
OBJECTIVE: To evaluate the efficacy of annual mammography over and above annual physical examination of the breasts and the teaching of breast self-examination among women aged 50 to 59 on entry. DESIGN: Individually randomized controlled trial. SETTING: Fifteen urban centres in Canada with expertise in the diagnosis and treatment of breast cancer. PARTICIPANTS: Women with no history of breast cancer and no mammography in the previous 12 months were randomly assigned to undergo either annual mammography and physical examination (MP group) or annual physical examination only (PO group). The 39,405 women enrolled from January 1980 through March 1985 were followed for a mean of 8.3 years. DATA COLLECTION: Derived from the participants by initial and annual self-administered questionnaires, from the screening examinations, from the patients' physicians, from the provincial cancer registries and by record linkage to the Canadian National Mortality Data Base. Expert panels evaluated histologic and death data. MAIN OUTCOME MEASURES: Rates of referral from screening, rates of detection of breast cancer from screening and from community care, nodal status, tumour size and rates of death from all causes and from breast cancer. RESULTS: Over 85% of the women in each group attended the screening sessions after screen 1. The characteristics of the women in the two groups were similar. Compared with the Canadian population the participants were more likely to be married, have fewer children, have more education, be in a professional occupation, smoke less and have been born in North America. The rate of screen-detected breast cancer on first examination was 7.20 per 1000 in the MP group and 3.45 per 1000 in the PO group, more node-positive tumours were found in the MP group than in the PO group. At subsequent screens the detection rates were a little less than half the rates at screen 1. During years 2 through 5 the ratios of observed to expected cases of invasive breast cancer were 1.28 in the MP group and 1.18 in the PO group. Of the women with invasive breast cancer through to 7 years, 217 in the MP group and 184 in the PO group had no node involvement, 66 and 56 had one to three nodes involved, 32 and 34 had four or more nodes involved, and 55 and 46 had an unknown nodal status. There were 38 deaths from breast cancer in the MP group and 39 in the PO group. The ratio of the proportions of death from breast cancer in the MP group compared with those in the UC group was 0.97 (95% confidence interval 0.62 to 1.52). The survival rates were similar in the two groups. Women whose cancer had been detected by mammography alone had the highest survival rate. CONCLUSION: The study was internally valid, and there was no evidence of randomization bias. Screening with yearly mammography in addition to physical examination of the breasts detected considerably more node-negative, small tumours than screening with physical examination alone, but it had no impact on the rate of death from breast cancer up to 7 years' follow-up from entry.
PMCID: PMC1336544  PMID: 1423088
23.  Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years. 
OBJECTIVES: To evaluate the efficacy of the combination of annual screening with mammography, physical examination of the breasts and the teaching of breast self-examination in reducing the rate of death from breast cancer among women aged 40 to 49 years on entry. DESIGN: Individually randomized controlled trial. SETTING: Fifteen urban centres in Canada with expertise in the diagnosis and treatment of breast cancer. PARTICIPANTS: Women with no history of breast cancer and no mammography in the previous 12 months were randomly assigned to undergo either annual mammography and physical examination (MP group) or usual care after an initial physical examination (UC group). The 50,430 women enrolled from January 1980 through March 1985 were followed for a mean of 8.5 years. DATA COLLECTION: Derived from the participants by initial and annual self-administered questionnaires, from the screening examinations, from the patients' physicians, from the provincial cancer registries and by record linkage to the Canadian National Mortality Data Base. Expert panels evaluated histologic and death data. MAIN OUTCOME MEASURES: Rates of referral from screening, rates of detection of breast cancer from screening and from community care, nodal status, tumour size, and rates of death from all causes and from breast cancer. RESULTS: Over 90% of the women in each group attended the screening sessions or returned the annual questionnaires, or both, over years 2 to 5. The characteristics of the women in the two groups were similar. Compared with the Canadian population, the participants were more likely to be married, have fewer children, have more education, be in a professional occupation, smoke less and have been born in North America. The rate of screen-detected breast cancer on first examination was 3.89 per 1000 in the MP group and 2.46 per 1000 in the UC group; more node-positive tumours were found in the MP group than in the UC group. During years 2 through 5 the ratios of observed to expected cases of invasive breast cancer were 1.26 in the MP group and 1.02 in the UC group. Of the women with invasive breast cancer through to 7 years, 191 and 157 women in the MP and UC groups respectively had no node involvement, 55 and 43 had one to three nodes involved, 47 and 23 had four or more nodes involved, and 38 and 49 had an unknown nodal status. There were 38 deaths from breast cancer in the MP group and 28 in the UC group. The ratio of the proportions of death from breast cancer in the MP group compared with those in the UC group was 1.36 (95% confidence interval 0.84 to 2.21). The survival rates were similar in the two groups. The highest survival rate occurred among women whose cancer had been detected by mammography alone. CONCLUSION: The study was internally valid, and there was no evidence of randomization bias. Screening with yearly mammography and physical examination of the breasts detected considerably more node-negative, small tumours than usual care, but it had no impact on the rate of death from breast cancer up to 7 years' follow-up from entry.
PMCID: PMC1336543  PMID: 1423087
24.  Preventive health care, 2001 update: screening mammography among women aged 40–49 years at average risk of breast cancer 
Objective
A previous review by the Canadian Task Force on the Periodic Health Examination (now the Canadian Task Force on Preventive Health Care) in 1994 indicated fair evidence to exclude mammographic breast cancer screening of women aged 40–49 from the periodic health examination. This current review considers the available new and updated evidence regarding the effect of screening mammography on breast cancer mortality among women in this age group at average risk of breast cancer.
Options
Screening mammography starting at either age 40 or age 50.
Outcome
Reduction in breast cancer mortality.
Evidence
The MEDLINE and CANCERLIT databases were searched for relevant articles published from 1966 to January 2000. Of 68 references obtained, at least 22 were published after the 1994 review. To date, the only trial designed to assess the mortality benefits of screening mammography among women aged 40–49 did not have adequate power to exclude a clinically significant benefit. Other results from randomized controlled trials (RCTs) are post-hoc subgroup analyses of larger trials.
Benefits, harms and costs
Screening mammography offers the potential for significant benefits in addition to mortality reduction, including early diagnosis, less aggressive therapy and improved cosmetic results. However, the risks of screening include increased biopsy rates and the psychological effects of false reassurance or false-positive results. Although several of the trials reviewed constitute level I evidence (RCT), at present their conflicting results, methodologic differences and, most important, uncertainty about the risk:benefit ratio of screening precludes the assignment of a “good” or “fair” rating to recommendations drawn from them.
Values
The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. A high value was placed on changes in survival. When evidence was available, value was also placed on potential quality-of-life implications.
Recommendation
Current evidence regarding the effectiveness of screening mammography does not suggest the inclusion of the manoeuvre in, or its exclusion from, the periodic health examination of women aged 40–49 years at average risk of breast cancer (grade C recommendation). Upon reaching the age of 40, Canadian women should be informed of the potential benefits and risks of screening mammography and assisted in deciding at what age they wish to initiate the manoeuvre.
Validation
The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care.
Sponsors
The Canadian Task Force on Preventive Health Care is funded through a partnership between the Provincial and Territorial Ministries of Health and Health Canada.
PMCID: PMC80774  PMID: 11233866
25.  Do Social Network Characteristics Predict Mammography Screening Practices? 
Background
Many breast cancer screening programs are based on the assumption that dissemination of information through social networks and the provision of social support are effective strategies for promoting mammography use. This paper examines the prospective relationship between social network characteristics and breast cancer screening practices among employed women.
Methods
Women age 40 and over employed in 26 worksites participating in a randomized intervention trial completed baseline and two-year follow-up assessments. These analyses include women in the embedded cohort (n = 1,475). Measures included social network characteristics (size, social influences and support), breast cancer screening practices, and socio-demographic characteristics. Adherence to screening guidelines at follow-up (mammogram within the past two years) was modeled as a function of social network characteristics at baseline.
Results
The majority of women in this sample were adherent with mammography screening guidelines at baseline. Baseline adherence explained the vast majority of variation in screening practices at follow-up. Only after removing the effects of previous mammography screening did we find statistically significant relationships between network characteristics and screening status. Specifically, among women age 40–51, subjective norms and encouragement by family/friends to have a mammogram at baseline were each significantly associated with screening adherence at follow-up (OR = 2.20 and 1.18, respectively). For women age 52+, the perception that screening was normative among one’s peers was associated with increased likelihood of recent mammography at follow-up (OR = 1.46).
Conclusions
Previous mammography use is strongly predictive of future screening. Among employed women with high baseline screening rates, the impact of social network characteristics was modest. As previous use of screening is highly associated with future use, programs should focus on reaching those who have underutilized mammography in the past. In addition, further exploration of the prospective relationships between social network characteristics and mammography within more at-risk and disadvantaged populations is warranted.
doi:10.1177/1090198107303251
PMCID: PMC2859725  PMID: 17620665

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