Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs X-ray mammography of women at a high familial risk of breast cancer.

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 pound28 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to pound11 731 (CE MRI vs mammography) and pound15 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.

Screening younger women with a family history of breast cancer--does early detection improve outcome?

Women with a family history are often offered mammographic surveillance at an earlier age and with greater frequency than those in the National Breast Screening Programme. In this study, we compared the survival of 62 breast cancer patients diagnosed in the context of a family history clinic offering 12-18 monthly mammographic screening with that of 1108 patients of the same age range but having no exposure to screening. We subtracted the expected additional observation time due to lead time from the survival of the screen-detected cases. Survival was significantly better in the family history group with relative hazards of 0.19 (95% CI 0.07-0.52, P<0.001) for breast cancer death and 0.19 (95% CI 0.08-0.43, P<0.001) for disease-free survival. After correcting for lead-time, the relative hazards were 0.24 (95% CI 0.09-0.66, P=0.005) for breast cancer death and 0.25 (95% CI 0.11-0.57, P<0.001) for disease-free survival. These results strongly suggest that screening younger women with a family history of breast cancer leads to improved survival. More precise estimates of the benefit will accrue from further follow-up and other such studies.

Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS).

BACKGROUND: Women genetically predisposed to breast cancer often develop the disease at a young age when dense breast tissue reduces the sensitivity of X-ray mammography. Our aim was, therefore, to compare contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening. METHODS: We did a prospective multicentre cohort study in 649 women aged 35-49 years with a strong family history of breast cancer or a high probability of a BRCA1, BRCA2, or TP53 mutation. We recruited participants from 22 centres in the UK, and offered the women annual screening with CE MRI and mammography for 2-7 years. FINDINGS: We diagnosed 35 cancers in the 649 women screened with both mammography and CE MRI (1881 screens): 19 by CE MRI only, six by mammography only, and eight by both, with two interval cases. Sensitivity was significantly higher for CE MRI (77%, 95% CI 60-90) than for mammography (40%, 24-58; p=0.01), and was 94% (81-99) when both methods were used. Specificity was 93% (92-95) for mammography, 81% (80-83) for CE MRI (p<0.0001), and 77% (75-79) with both methods. The difference between CE MRI and mammography sensitivities was particularly pronounced in BRCA1 carriers (13 cancers; 92%vs 23%, p=0.004). INTERPRETATION: Our findings indicate that CE MRI is more sensitive than mammography for cancer detection. Specificity for both procedures was acceptable. Despite a high proportion of grade 3 cancers, tumours were small and few women were node positive. Annual screening, combining CE MRI and mammography, would detect most tumours in this risk group.

Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme.

INTRODUCTION: Accurate individualised breast cancer risk assessment is essential to provide risk-benefit analysis prior to initiating interventions designed to lower breast cancer risk. Several mathematical models for the estimation of individual breast cancer risk have been proposed. However, no single model integrates family history, hormonal factors, and benign breast disease in a comprehensive fashion. A new model by Tyrer and Cuzick has addressed these deficiencies. Therefore, this study has assessed the goodness of fit and discriminatory value of the Tyrer-Cuzick model against established models namely Gail, Claus, and Ford. METHODS: The goodness of fit and discriminatory accuracy of the models was assessed using data from 1933 women attending the Family History Evaluation and Screening Programme, of whom 52 developed cancer. All models were applied to these women over a mean follow up of 5.27 years to estimate risk of breast cancer. RESULTS: The ratios (95% confidence intervals) of expected to observed numbers of breast cancers were 0.48 (0.37 to 0.64) for Gail, 0.56 (0.43 to 0.75) for Claus, 0.49 (0.37 to 0.65) for Ford, and 0.81 (0.62 to 1.08) for Tyrer-Cuzick. The accuracy of the models for individual cases was evaluated using ROC curves. These showed that the area under the curve was 0.735 for Gail, 0.716 for Claus, 0.737 for Ford, and 0.762 for Tyrer-Cuzick. CONCLUSION: The Tyrer-Cuzick model is the most consistently accurate model for prediction of breast cancer. The Gail, Claus, and Ford models all significantly underestimate risk, although the accuracy of the Claus model may be improved by adjustments for other risk factors.

Uptake of screening and prevention in women at very high risk of breast cancer.

Management of women at high lifetime risk of familial breast cancer is hampered because of limited data concerning the appropriateness of treatment options. Over the past 8 years women at very high (>40%) lifetime risk of breast cancer have had the option of entering two chemoprevention treatment trials, a magnetic resonance imaging (MRI) breast screening study, or a risk-reducing mastectomy (RRM) study. Only 10% of eligible women have entered one of the chemotherapy trials with a similar proportion opting for RRM (>50% in mutation carriers) compared with 60% opting for MRI screening. Future chemotherapy trials will have to be designed to address this poor recruitment.

Development of a protocol for evaluation of mammographic surveillance services in women under 50 with a family history of breast cancer.

BACKGROUND: Preliminary retrospective data suggest it is possible to identify impalpable breast cancer in women presenting with a family history of breast cancer under the age of 50, by using regular mammography. In consequence, this service is offered in a number of centres in the UK. The effectiveness of such a service, however, has not been fully evaluated. METHODS: We propose to perform such an evaluation in a cohort of 20000 women under the age of 50 with a significant family history of breast cancer, given regular mammographic surveillance over 5 years. Comparison of surgical and pathological data with completed and ongoing population screening trials using analysis techniques of varying complexity will be performed to obtain an accurate prediction of future breast-cancer mortality reduction. The formal aims are: i) to estimate the difference in breast-cancer mortality in women under the age of 50 with a significant family history of breast cancer having regular mammography, compared with those not being screened; ii) to estimate the cost-effectiveness of regular mammography in this group of women, compared with no screening. The increase in health service resource use attributable to such a policy will be compared with no screening, and costed. Incremental cost-effectiveness ratios of implementing the standardised mammography strategy compared with no screening will be presented in terms of the additional cost per cancer detected, per life saved and per life-year saved.

Initial results of a study into the effectiveness of breast cancer screening in a population identified to be at high risk.

BACKGROUND: Women are frequently referred to genetic clinics because of a family history of breast or ovarian cancer, conferring a moderate increased risk of the disease, but not sufficient in itself to indicate gene mutation analysis. One possible management strategy is to offer regular mammographic screening, possibly earlier in life and more frequently than in the general population. This strategy is used in many parts of the UK, although it has not been formally evaluated. METHODS: In this paper we present some early results on the effectiveness of a programme of mammography in 2,998 women aged 19-71 with a moderate family history of breast cancer in Manchester. We estimated the test and programme sensitivity and sojourn time, using different statistical methods. RESULTS: Fifty breast cancers were diagnosed. The incidence rate observed was 4.46 per thousand person-years. The incidence expected from the segregation analysis of Claus et al. was 3.75 per thousand person-years. Screen-detection rates at first and subsequent screens were 5.00 and 4.93 per thousand respectively. Interval cancer incidence in the first year following a negative screen was 0.91 per thousand person-years. Screening test sensitivity was estimated conservatively as 83%, programme sensitivity as 70%. CONCLUSIONS: Early indications are that the programme is likely to be effective. Further follow-up, analysis of tumour size, node status and malignancy grade, and subsequent mortality from breast cancer is required to confirm this.

Computer-assisted mammographic imaging.

Computer-assisted mammography imaging comprises computer-based analysis of digitized images resulting in prompts aiding mammographic interpretation and computerized stereotactic localization devices which improve location accuracy. The commercial prompting systems available are designed to draw attention to mammographic abnormalities detected by algorithms based on symptomatic practise in North America. High sensitivity rates are important commercially but result in increased false prompt rates, which are known to distract radiologists. A national shortage of breast radiologists in the UK necessitates evaluation of such systems in a population breast screening programme to determine effectiveness in increasing cancer detection and feasibility of implementation.

Breast cancer diagnosis using scattered X-rays.

Small-angle X-ray diffraction data has been collected from 99 ;core-cut' breast tissue specimens representing a number of different pathologies. Data in the range 75-1390 A have been compared with controls from patients with no breast disease. Bessel functions and Bragg maxima resulting from the fibrillar structure of collagen have been identified. The Bragg maxima indexed onto a 649 A lattice. Systematic differences in the intensities and D-spacings between the collagen of malignant, benign and normal tissue groups have been clearly demonstrated and quantified. These differences appear to be due to a significantly lower structural order within the malignant tissues. Possible explanations for this are discussed and the potential for utilizing this observation in cancer diagnosis is considered.

Model-based detection of spiculated lesions in mammograms.

Computer-aided mammographic prompting systems require the reliable detection of a variety of signs of cancer. In this paper we concentrate on the detection of spiculated lesions in mammograms. A spiculated lesion is typically characterized by an abnormal pattern of linear structures and a central mass. Statistical models have been developed to describe and detect both these aspects of spiculated lesions. We describe a generic method of representing patterns of linear structures, which relies on the use of factor analysis to separate the systematic and random aspects of a class of patterns. We model the appearance of central masses using local scale-orientation signatures based on recursive median filtering, approximated using principal-component analysis. For lesions of 16 mm and larger the pattern detection technique results in a sensitivity of 80% at 0.014 false positives per image, whilst the mass detection approach results in a sensitivity 80% at 0.23 false positives per image. Simple combination techniques result in an improved sensitivity and specificity close to that required to improve the performance of a radiologist in a prompting environment.

Screening by mammography, women with a family history of breast cancer.

The aim of this study was to describe the experience of screening women under the age of 50 years with a family history of breast cancer. 1259 women attended the Family History Clinic in Manchester for their first and subsequent consultations between 30 September 1992 and 30 April 1997. All women were under the age of 50 years at the initial consultation and had a lifetime risk of breast cancer of 1 in 6 or greater. Seven prevalent, seven incident and two interval cancers were detected. The number of invasive cancers expected to occur if this high risk population had not been screened was 8.45 (in 2722 person years at risk). 12 invasive cancers were detected, giving a ratio of 1.42 (95% confidence interval 0.73-2.48). The overall cancer detection rates in this young, at risk population were similar to those in older women in the National Health Service Breast Screening Programme. The number of cancers detected in the study was greater than expected in this population. As the numbers were small, a national trial needs to be undertaken to confirm these results and to determine the long term effects of screening.

The influence of previous films on screening mammographic interpretation and detection of breast carcinoma.

AIM: To establish if the availability of previous mammograms improves the detection rate of carcinomas and reduces supplementary examinations in the National Health Service Breast Screening Programme (NHSBSP). METHOD: Eight radiologists with varying experience but an interest in reporting mammograms reported 100 mammograms on two occasions, at least 1 month apart. In this selection of 100 mammograms we randomly inserted 12 abnormal films, with both benign and malignant changes present. These were chosen retrospectively with histological correlation of the abnormality. On the first occasion only the current films were reviewed, however, on the second occasion previous films were available for comparison. The films were viewed under standard viewing conditions, and the participants were asked to comment if they required further views or would refer the patient for either an ultrasound examination or surgical referral. RESULTS: Receiver operating curves (ROC) were constructed for the group's overall performance on each of the occasions and there was no difference in the curves. This indicates that the presence of previous films did not improve diagnostic accuracy. The presence of previous films did, however, lead to a significant reduction in the number of additional views and ultrasound examinations that would have been requested. The most significant reductions occurred in the group of normal mammograms. CONCLUSION: The presence of previous mammograms does not lead to an improvement in diagnostic accuracy. However, the presence of previous films led to significant reduction in additional examinations and ultrasound examinations.

A comparison of axillary node status between cancers detected at the prevalence and first incidence breast screening rounds.

Screen-detected breast cancers are smaller than those detected in symptomatic populations and, for any given size, they are associated with fewer lymph node metastases. The management of axillary lymph nodes in patients with screen-detected breast cancer remains controversial. We have previously reported that prevalence (initial screen)-detected cancers are associated with nodal metastases in 17.4% of cases overall. Cancers < or = 10 mm, of any grade, are associated with metastases in only 5% of cases, and grade I cancers <30 mm are not associated with metastases. This led to our recommendation that axillary surgery is unnecessary for these groups of women. The present study compared the nodal status of cancers detected at the prevalence and first incidence (second) screens in order to determine whether our recommendation is appropriate for cancers detected at the first incidence screen. Overall, 30.1% of cancers detected in the first incidence screen presented axillary nodal metastases. At all size ranges, cancers detected at the first incidence screen were associated with significantly more lymph node metastases than prevalence-detected cancers. In particular, cancers < or = 10 mm were associated with metastases in 14.3% of cases. With the possible exception of grade I cancers, we believe that surgical staging of the axilla is essential for cancers detected at the first incidence screen, irrespective of size.

Is the three year breast screening interval too long? Occurrence of interval cancers in NHS breast screening programme's north western region.

OBJECTIVE: To report the detection rate of interval cancers in women screened by the NHS breast screening programme. DESIGN: Detection of interval cancers by computer linkage of records held by the screening centres in the North Western Regional Health Authority with breast cancer registrations at the regional cancer registry. SETTING: North Western Regional Health Authority. SUBJECTS: 137,421 women screened between 1 March 1988 and 31 March 1992 who had a negative screening result. RESULTS: 297 invasive interval cancers were detected. The rate of detection of interval cancers expressed as a proportion of the underlying incidence was 31% in the first 12 months after screening, 52% between 12 and 24 months, and 82% between 24 and 36 months. CONCLUSION: The incidence of interval cancers in the third year after breast screening approaches that which would have been expected in the absence of screening and suggests that the three year interval between screens is too long.

Non-invasive ultrasound localization of impalpable breast lesions.

Thirty patients presenting through the Breast Screening Programme with impalpable breast abnormalities clearly visible on ultrasound, underwent non-invasive ultrasound localization. The patient was scanned so that the ultrasound abnormality lay below the probe and the skin at this site marked with a skin marker. In all cases the abnormality was easily identified and removed at surgery. All the surgical biopsies contained either a carcinoma (17 cases) or fibroadenoma (13 cases). This non-invasive technique is a simple and accurate method for localizing small ultrasonically visible breast abnormalities.