Mammographic density and breast cancer risk in breast screening assessment cases and women with a family history of breast cancer.

BACKGROUND: Mammographic density has been shown to be a strong independent predictor of breast cancer and a causative factor in reducing the sensitivity of mammography. There remain questions as to the use of mammographic density information in the context of screening and risk management, and of the association with cancer in populations known to be at increased risk of breast cancer. AIM: To assess the association of breast density with presence of cancer by measuring mammographic density visually as a percentage, and with two automated volumetric methods, Quantra™ and VolparaDensity™. METHODS: The TOMosynthesis with digital MammographY (TOMMY) study of digital breast tomosynthesis in the Breast Screening Programme of the National Health Service (NHS) of the United Kingdom (UK) included 6020 breast screening assessment cases (of whom 1158 had breast cancer) and 1040 screened women with a family history of breast cancer (of whom two had breast cancer). We assessed the association of each measure with breast cancer risk in these populations at enhanced risk, using logistic regression adjusted for age and total breast volume as a surrogate for body mass index (BMI). RESULTS: All density measures showed a positive association with presence of cancer and all declined with age. The strongest effect was seen with Volpara absolute density, with a significant 3% (95% CI 1-5%) increase in risk per 10 cm3 of dense tissue. The effect of Volpara volumetric density on risk was stronger for large and grade 3 tumours. CONCLUSIONS: Automated absolute breast density is a predictor of breast cancer risk in populations at enhanced risk due to either positive mammographic findings or family history. In the screening context, density could be a trigger for more intensive imaging.

Accuracy of Digital Breast Tomosynthesis for Depicting Breast Cancer Subgroups in a UK Retrospective Reading Study (TOMMY Trial).

PURPOSE: To compare the diagnostic performance of two-dimensional (2D) mammography, 2D mammography plus digital breast tomosynthesis (DBT), and synthetic 2D mammography plus DBT in depicting malignant radiographic features. MATERIALS AND METHODS: In this multicenter, multireader, retrospective reading study (the TOMMY trial), after written informed consent was obtained, 8869 women (age range, 29-85 years; mean, 56 years) were recruited from July 2011 to March 2013 in an ethically approved study. From these women, a reading dataset of 7060 cases was randomly allocated for independent blinded review of (a) 2D mammography images, (b) 2D mammography plus DBT images, and (c) synthetic 2D mammography plus DBT images. Reviewers had no access to results of previous examinations. Overall sensitivities and specificities were calculated for younger women and those with dense breasts. RESULTS: Overall sensitivity was 87% for 2D mammography, 89% for 2D mammography plus DBT, and 88% for synthetic 2D mammography plus DBT. The addition of DBT was associated with a 34% increase in the odds of depicting cancer (odds ratio [OR] = 1.34, P = .06); however, this level did not achieve significance. For patients aged 50-59 years old, sensitivity was significantly higher (P = .01) for 2D mammography plus DBT than it was for 2D mammography. For those with breast density of 50% or more, sensitivity was 86% for 2D mammography compared with 93% for 2D mammography plus DBT (P = .03). Specificity was 57% for 2D mammography, 70% for 2D mammography plus DBT, and 72% for synthetic 2D mammography plusmDBT. Specificity was significantly higher than 2D mammography (P < .001in both cases) and was observed for all subgroups (P < .001 for all cases). CONCLUSION: The addition of DBT increased the sensitivity of 2D mammography in patients with dense breasts and the specificity of 2D mammography for all subgroups. The use of synthetic 2D DBT demonstrated performance similar to that of standard 2D mammography with DBT. DBT is of potential benefit to screening programs, particularly in younger women with dense breasts. (©) RSNA, 2015.

Is computer aided detection (CAD) cost effective in screening mammography? A model based on the CADET II study.

BACKGROUND: Single reading with computer aided detection (CAD) is an alternative to double reading for detecting cancer in screening mammograms. The aim of this study is to investigate whether the use of a single reader with CAD is more cost-effective than double reading. METHODS: Based on data from the CADET II study, the cost-effectiveness of single reading with CAD versus double reading was measured in terms of cost per cancer detected. Cost (Pound (£), year 2007/08) of single reading with CAD versus double reading was estimated assuming a health and social service perspective and a 7 year time horizon. As the equipment cost varies according to the unit size a separate analysis was conducted for high, average and low volume screening units. One-way sensitivity analyses were performed by varying the reading time, equipment and assessment cost, recall rate and reader qualification. RESULTS: CAD is cost increasing for all sizes of screening unit. The introduction of CAD is cost-increasing compared to double reading because the cost of CAD equipment, staff training and the higher assessment cost associated with CAD are greater than the saving in reading costs. The introduction of single reading with CAD, in place of double reading, would produce an additional cost of £227 and £253 per 1,000 women screened in high and average volume units respectively. In low volume screening units, the high cost of purchasing the equipment will results in an additional cost of £590 per 1,000 women screened.One-way sensitivity analysis showed that the factors having the greatest effect on the cost-effectiveness of CAD with single reading compared with double reading were the reading time and the reader's professional qualification (radiologist versus advanced practitioner). CONCLUSIONS: Without improvements in CAD effectiveness (e.g. a decrease in the recall rate) CAD is unlikely to be a cost effective alternative to double reading for mammography screening in UK. This study provides updated estimates of CAD costs in a full-field digital system and assessment cost for women who are re-called after initial screening. However, the model is highly sensitive to various parameters e.g. reading time, reader qualification, and equipment cost.

Mammographic features of breast cancers at single reading with computer-aided detection and at double reading in a large multicenter prospective trial of computer-aided detection: CADET II.

PURPOSE: To evaluate the mammographic features of breast cancer that favor lesion detection with single reading and computer-aided detection (CAD) or with double reading. MATERIALS AND METHODS: The Computer Aided Detection Evaluation Trial II study was approved by the ethics committee, and all participants provided written informed consent. A total of 31,057 women were recruited from three screening centers between September 2006 and August 2007. They were randomly allocated to the double reading group, the single reading with CAD group, or the double reading and single reading with CAD group at a ratio of 1:1:28, respectively. In this study, cancers in the women whose mammograms were read with both single reading with CAD and double reading were retrospectively reviewed. The original mammograms were obtained for each case and reviewed by two of three experienced breast radiologists in consensus. The method of detection was noted. The size and predominant mammographic feature of the cancer were recorded, as was the breast density. CAD marking data were reviewed to determine if the cancer had been correctly marked. RESULTS: A total of 227 cancers were detected in 28,204 women. A total of 170 cases were recalled with both reading regimens. Lesion types were masses (66%), microcalcifications (25%), parenchymal deformities (6%), and asymmetric densities (3%). The ability of the reading regimens to correctly prompt the reader to recall cases varied significantly by lesion type (P < .001). More parenchymal deformities were recalled with double reading, whereas more asymmetric densities were recalled with single reading with CAD. There was no difference in the ability of either reading regimen to prompt the reader to correctly recall masses or microcalcifications. CAD correctly prompted 100% of microcalcifications, 87% of mass lesions, 80% of asymmetric densities, and 50% of parenchymal deformities. CAD correctly marked 93% of spiculated masses compared with 80% of ill-defined masses (P = .054). There was a significant trend for cancers detected with double reading to occur only in women with a denser mammographic background pattern (P = .02). Size had no effect on lesion detection. CONCLUSION: Readers using either single reading with CAD or double reading need to be aware of the strengths and weaknesses of reading regimens to avoid missing the more challenging cancer cases.

Increasing participant recruitment into large-scale screening trials: experience from the CADET II study.

OBJECTIVES: Multicentre randomized trials frequently encounter difficulties in meeting their recruitment targets, resulting in extension of the trial and delays in implementation of the findings. We report on recruitment strategies implemented in a randomized evaluation of computer-aided detection in women attending routine screening in the UK Breast Screening Programme. SETTING: The target population for the trial was identified from an existing NHS database of women aged 50-70 invited for routine mammography in Coventry, Manchester and Nottingham, UK. Women were asked to consent to their mammograms being randomly allocated (in a ratio of 28:1:1) to one of three film-reading protocols. Trial information was mailed to women, along with the invitation to attend screening, and informed consent was obtained at the mammography appointment. Several strategies were implemented to increase recruitment rates. RESULTS: Recruitment rate increased significantly over time in the study (P < 0.0010 in all centres) with an overall acceptance rate of 46% of those attending screening. Mailing of the trial information sheet separate from the screening invitation in Coventry and Nottingham increased the recruitment rate, even after adjustment for the trend over time and for socioeconomic status of the attendees (P < 0.001). Extension of recruitment to mobile screening units in Nottingham, and the presence of an additional member of staff also improved recruitment (P < 0.001). Simplification of the trial information sheet had little effect. Increases in recruitment rate were not attributable to socioeconomic status of the attendees. CONCLUSIONS: In multicentre trials, monitoring of local recruitment protocols is required to ensure that each centre can maximize accrual targets.

Single reading with computer-aided detection for screening mammography.

BACKGROUND: The sensitivity of screening mammography for the detection of small breast cancers is higher when the mammogram is read by two readers rather than by a single reader. We conducted a trial to determine whether the performance of a single reader using a computer-aided detection system would match the performance achieved by two readers. METHODS: The trial was designed as an equivalence trial, with matched-pair comparisons between the cancer-detection rates achieved by single reading with computer-aided detection and those achieved by double reading. We randomly assigned 31,057 women undergoing routine screening by film mammography at three centers in England to double reading, single reading with computer-aided detection, or both double reading and single reading with computer-aided detection, at a ratio of 1:1:28. The primary outcome measures were the proportion of cancers detected according to regimen and the recall rates within the group receiving both reading regimens. RESULTS: The proportion of cancers detected was 199 of 227 (87.7%) for double reading and 198 of 227 (87.2%) for single reading with computer-aided detection (P=0.89). The overall recall rates were 3.4% for double reading and 3.9% for single reading with computer-aided detection; the difference between the rates was small but significant (P<0.001). The estimated sensitivity, specificity, and positive predictive value for single reading with computer-aided detection were 87.2%, 96.9%, and 18.0%, respectively. The corresponding values for double reading were 87.7%, 97.4%, and 21.1%. There were no significant differences between the pathological attributes of tumors detected by single reading with computer-aided detection alone and those of tumors detected by double reading alone. CONCLUSIONS: Single reading with computer-aided detection could be an alternative to double reading and could improve the rate of detection of cancer from screening mammograms read by a single reader. (ClinicalTrials.gov number, NCT00450359.)

Visually assessed breast density, breast cancer risk and the importance of the craniocaudal view.

INTRODUCTION: Mammographic density is known to be a strong risk factor for breast cancer. A particularly strong association with risk has been observed when density is measured using interactive threshold software. This, however, is a labour-intensive process for large-scale studies. METHODS: Our aim was to determine the performance of visually assessed percent breast density as an indicator of breast cancer risk. We compared the effect on risk of density as measured with the mediolateral oblique view only versus that estimated as the average density from the mediolateral oblique view and the craniocaudal view. Density was assessed using a visual analogue scale in 10,048 screening mammograms, including 311 breast cancer cases diagnosed at that screening episode or within the following 6 years. RESULTS: Where only the mediolateral oblique view was available, there was a modest effect of breast density on risk with an odds ratio for the 76% to 100% density relative to 0% to 25% of 1.51 (95% confidence interval 0.71 to 3.18). When two views were available, there was a considerably stronger association, with the corresponding odds ratio being 6.77 (95% confidence interval 2.75 to 16.67). CONCLUSION: This indicates that a substantial amount of information on risk from percentage breast density is contained in the second view. It also suggests that visually assessed breast density has predictive potential for breast cancer risk comparable to that of density measured using the interactive threshold software when two views are available. This observation needs to be confirmed by studies applying the different measurement methods to the same individuals.

Using postal randomization to replace telephone randomization had no significant effect on recruitment of patients.

OBJECTIVE: To test the effect of postal randomization on recruitment of patients into a randomized trial in primary care. STUDY DESIGN AND SETTING: General practices used a telephone service to randomize patients in our trial. Delays in the start of recruitment at some sites led us to modify the randomization procedure. When new practices took part patients completed and posted baseline materials to the Trial Secretary in York who performed the randomization and informed those concerned of the allocation. RESULTS: Of the 647 practices who were invited to take part, 130 (45%) of 288 agreed to participate using telephone randomization and 155 (43%) of 359 using the postal method. These practices recruited 553 patients from November 2002 to October 2004 across 11 sites in the United Kingdom. The postal method reduced the number of patients recruited by a factor of 0.86 (95% confidence interval=0.62-1.20), or 14%. The number of general practitioners working in a practice significantly increased patient recruitment by a factor of 1.12 (1.05-1.20), whereas practice distance from hospital significantly decreased recruitment by a factor of 0.98 (0.97-0.99). CONCLUSION: Postal randomization had no significant effect on recruitment of patients into our trial.

Improving response rates using a monetary incentive for patient completion of questionnaires: an observational study.

BACKGROUND: Poor response rates to postal questionnaires can introduce bias and reduce the statistical power of a study. To improve response rates in our trial in primary care we tested the effect of introducing an unconditional direct payment of 5 pounds for the completion of postal questionnaires. METHODS: We recruited patients in general practice with knee problems from sites across the United Kingdom. An evidence-based strategy was used to follow-up patients at twelve months with postal questionnaires. This included an unconditional direct payment of 5 pounds to patients for the completion and return of questionnaires. The first 105 patients did not receive the 5 pounds incentive, but the subsequent 442 patients did. We used logistic regression to analyse the effect of introducing a monetary incentive to increase the response to postal questionnaires. RESULTS: The response rate following reminders for the historical controls was 78.1% (82 of 105) compared with 88.0% (389 of 442) for those patients who received the 5 pounds payment (diff = 9.9%, 95% CI 2.3% to 19.1%). Direct payments significantly increased the odds of response (adjusted odds ratio = 2.2, 95% CI 1.2 to 4.0, P = 0.009) with only 12 of 442 patients declining the payment. The incentive did not save costs to the trial--the extra cost per additional respondent was almost 50 pounds. CONCLUSION: The direct payment of 5 pounds significantly increased the completion of postal questionnaires at negligible increase in cost for an adequately powered study.

The DAMASK trial protocol: a pragmatic randomised trial to evaluate whether GPs should have direct access to MRI for patients with suspected internal derangement of the knee.

BACKGROUND: Though new technologies like Magnetic Resonance Imaging (MRI) may be accurate, they often diffuse into practice before thorough assessment of their value in diagnosis and management, and of their effects on patient outcome and costs. MRI of the knee is a common investigation despite concern that it is not always appropriate. There is wide variation in general practitioners (GPs) access to, and use of MRI, and in the associated costs. The objective of this study was to resolve uncertainty whether GPs should refer patients with suspected internal derangement of the knee for MRI or to an orthopaedic specialist in secondary care. METHODS/DESIGN: The design consisted of a pragmatic multi-centre randomised trial with two parallel groups and concomitant economic evaluation. Patients presenting in general practice with suspected internal derangement of the knee and for whom their GP was considering referral to an orthopaedic specialist in secondary care were eligible for inclusion. Within practices, GPs or practice nurses randomised eligible and consenting participants to the local radiology department for an MRI examination, or for consultation with an orthopaedic specialist. To ensure that the waiting time from GP consultation to orthopaedic appointment was similar for both trial arms, GPs made a provisional referral to orthopaedics when requesting the MRI examination. Thus we evaluated the more appropriate sequence of events independent of variations in waiting times. Follow up of participants was by postal questionnaires at six, twelve and 24 months after randomisation. This was to ensure that the evaluation covered all events up to and including arthroscopy. DISCUSSION: The DAMASK trial should make a major contribution to the development of evidence-based partnerships between primary and secondary care professionals and inform the debate when MRI should enter the diagnostic pathway.

Single reading with computer-aided detection and double reading of screening mammograms in the United Kingdom National Breast Screening Program.

PURPOSE: To retrospectively determine if the use of a computer-aided detection (CAD) system can improve the performance of single reading of screening mammograms to match that of double reading in the United Kingdom. MATERIALS AND METHODS: Local research ethics committee approval was obtained; informed consent was not required. This study included a sample of 10 267 mammograms obtained in women aged 50 years or older who underwent routine screening at one of two breast screening centers in 1996. Mammograms that were double read in 1996 were randomly allocated to be re-read by eight different radiologists using CAD. The cancer detection and recall rates from double reading and single reading with CAD were compared. Statistical significance and confidence intervals were calculated with the McNemar test to account for the matched nature of the data. RESULTS: Single reading with CAD led to a cancer detection rate that was significantly (P = .02) higher than that achieved with double reading: 6.5% more cancers were detected by means of single reading with CAD than by means of double reading. However, the recall rate was higher for single reading with CAD than for double reading (8.6% vs 6.5%, respectively; P < .001). This was equivalent to relative increases of 15% and 32% in the cancer detection and recall rates, respectively. CONCLUSION: Single reading with CAD leads to an improved cancer detection rate and an increased recall rate.

Low back pain: influence of early MR imaging or CT on treatment and outcome--multicenter randomized trial.

PURPOSE: To establish whether early use of magnetic resonance (MR) imaging or computed tomography (CT) influences treatment and outcome of patients with low back pain (LBP) and whether it is cost-effective. MATERIALS AND METHODS: In a multicenter randomized study, two imaging policies for LBP were compared in 782 participants with symptomatic lumbar spine disorders who were referred to orthopedists or neurosurgeons. Participants were randomly allocated to early (393 participants; mean age, 43.9 years; range, 16-82 years) or delayed selective (389 participants; mean age, 42.8 years; range, 14-82 years) imaging groups. Delayed selective imaging referred to imaging restricted to patients in whom a clear clinical need subsequently developed. Main outcome measures were Aberdeen Low Back Pain (ALBP) score, Short Form 36 (SF-36) score (for multidimensional health status), EuroQol (EQ-5D) score (for quality-adjusted life-year [QALY] estimates), and healthcare resource use at 8 and 24 months after randomization. Data were evaluated with analysis of covariance, ordinal logistic regression analysis, and chi(2) and Mann-Whitney tests. RESULTS: Both groups showed improvement in ALBP score, but this was greater in the early group (adjusted mean difference between groups, -3.05 points [95% CI: -5.16, -0.95; P =.005] and -3.62 points [95% CI: -5.92, -1.32; P =.002] at 8 and 24 months, respectively). Scores for SF-36 (bodily pain domain) and EQ-5D were also significantly better at 24 months. Clinical treatment was similar in both groups. Differences in total costs reflected cost of imaging. Imaging provided an adjusted mean additional QALY of 0.041 during 24 months at a mean incremental cost per QALY of $2,124. CONCLUSION: Early use of imaging does not appear to affect treatment overall. Decisions about the use of imaging depend on judgments concerning whether the small observed improvement in outcome justifies additional cost.