Magnetic resonance imaging screening in women at genetic risk of breast cancer: imaging and analysis...

Magnetic resonance imaging screening in women at genetic risk ofbreast cancer: imaging and analysis protocol for the UK multicentre

study

The UK MRI Breast Screening Study Advisory Group, Imaging Advisors and Staff:J. Browna, D. Buckleyb, A. Coulthardc, A.K. Dixond, J.M. Dixone, D.F. Eastonf, R.A. Eelesg,

D.G.R. Evansh, F.G. Gilberti, M. Gravesd, C. Hayesj, J.P.R. Jenkinsk, A.P. Jonesl,S.F. Keevilm, M.O. Leachj,*, G.P. Lineyn, S.M. Mosso, A.R. Padhanip, G.J.M. Parkerq,

L.J. Pointonj, B.A.J. Ponderr, T.W. Redpaths, J.P. Sloanet, L.W. Turnbulln, L.G. Walkeru,R.M.L. Warrenv

aHealth Economics Research Group, Brunel University, Middlesex, UKbCenter for Structural Biology, University of Florida, Gainesville, FL, USA

cVictoria Wing Radiology Department, Royal Victoria Infirmary, Newcastle, UKdDepartment of Radiology, Addenbrooke’s Hospital, Cambridge, UKeEdinburgh Breast Unit, Western General Hospital, Edinburgh, UK

fCRC Genetic Epidemiology Unit, Strangeways Research Laboratories, Cambridge, UKgCancer Genetics Clinic, The Institute of Cancer Research and The Royal Marsden NHS Trust, Sutton, UK

hCentral Manchester Healthcare NHS Trust, St Mary’s Hospital, Manchester, UKiDepartment of Radiology, University of Aberdeen, Aberdeen, UK

jCRC Clinical Magnetic Resonance Research Group, The Institute of Cancer Research and The Royal Marsden NHS Trust, Sutton, UKkDepartment of Clinical Radiology, Manchester Royal Infirmary, Manchester, UK

lNorth Western Medical Physics, Christie Hospital NHS Trust, Manchester, UKmDepartment of Radiological Sciences, Guy’s, King’s and St. Thomas’ Medical Schools, London, UK

nCentre for Magnetic Resonance Investigations, Hull Royal Infirmary, Hull, UKoCancer Screening Evaluation Unit, Institute of Cancer Research, Sutton, UK

pDiagnostic Radiology Department, The Royal Marsden NHS Trust, Sutton, UKqNMR Research Unit, Institute of Neurology, London, UK

rCRC Department of Oncology, Addenbrooke’s Hospital, Cambridge, UKsDepartment of Biomedical Physics, University of Aberdeen, Aberdeen, UK

tDepartment of Pathology, University of Liverpool, Liverpool, UKuInstitute of Rehabilitation, University of Hull, Hull, UK

vBreast Screening Centre, Addenbrooke’s Hospital, Cambridge, UK

Received 4 May 2000; received in revised form 3 June 2000; accepted 22 June 2000

Abstract

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breastcancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-viewx-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year forthree years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the firstyear to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhancedassessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morpho-logical assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospectiveanalysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic

* Corresponding author. Tel.:11-44-(0)208-661-3338; fax:11-44-(0)208-643-3812.E-mail address:[email protected] (M.O. Leach).

Magnetic Resonance Imaging 18 (2000) 765–776

0730-725X/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved.PII: S0730-725X(00)00167-3

impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeuticdecisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast ScreeningProgramme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.© 2000 Elsevier Science Inc. All rights reserved.

Keywords:Breast cancer; Genetic predisposition; Screening; Contrast agent; Mammography

1. Introduction

A study has commenced in the United Kingdom to testthe hypothesis that magnetic resonance imaging (MRI) canbe used with equal or better sensitivity and specificity thanx-ray mammography (XRM) for the screening of premeno-pausal women at high genetic risk of developing breastcancer. This group of women may develop breast cancer atan earlier age than in the general population [1,2], leading toan increased need for a breast cancer surveillance pro-gramme.

The purpose of this article is to describe the MRI mea-surement and analysis methodology employed in the UKMRI breast screening study. This is the first rigorouslycontrolled research study of MRI of the breast on a largenumber of young women and at multiple MRI facilities.Details of the interpretation criteria for lesion classificationare provided, with descriptions of both radiological andretrospective computer-assisted analysis. The quality assur-ance protocol is also outlined, with details of both technicaland radiological assessments.

2. Background/study rationale

It is estimated that about 5%–10% of breast cancer casesin the Western world occur in women with a family historyof the disease. Epidemiological studies and genetic linkageanalyses have shown that this susceptibility may be attrib-uted, in about 84% of cases [3], to the breast cancer sus-ceptibility gene mutations, BRCA1 and BRCA2. By impli-cation, a proportion of familial breast cancer cases are dueto unidentified mutations in genes other than BRCA1 andBRCA2, but these are at present largely unidentified. Thesestudies have also demonstrated that breast cancer in familialclusters develops at a relatively young age compared withthe general population. In the largest study published to dateof familial breast cancer [3], the Breast Cancer LinkageConsortium (BCLC) has estimated a cumulative risk ofbreast cancer of 45% at age 50 and 83% by age 70 forcarriers of the breast cancer gene, BRCA1, and 28% at age50 and 84% by age 70 for BRCA2 gene carriers.

Genetic testing for the BRCA1 and BRCA2 genes, andother diseases with a familial component, has generatedsubstantial controversy over the care and management ofgene carriers. Early detection, and/or preventative strategieshave been proposed. One option is chemoprevention andboth Tamoxifen and drugs of the retinoid family are being

evaluated in high risk women. Both drugs are teratogenicand thus are not normally given to women under 40 years.Another option is prophylactic mastectomy and Hartmannet al. [4] recently provided evidence that this is an effectivemeans of reducing the incidence of breast cancer amongwomen at high risk for the disease. However, the study didnot assess the benefit of prophylactic mastectomy for car-riers of BRCA1 or BRCA2 mutations.

Frequent screening has the potential to identify disease atan early stage. Although x-ray mammographic screening ofwomen aged over 50 years has reduced mortality [5], thebenefit of such screening to a younger age group is uncer-tain. The breasts of younger women are denser with theresult that mammograms are often difficult to interpret.Furthermore, there are concerns about repeated radiationexposure [6]. MRI of the breast is emerging as a verypowerful technique for the detection, diagnosis and moni-toring of breast abnormalities. However, its effectiveness asa screening tool is unproven, the current costs are high andunlike x-ray mammography, there are no standards for im-aging protocols, quality control and image interpretation.This screening study has therefore been designed to evalu-ate the sensitivity and specificity of both imaging modalitiesin this younger population, to determine the optimum imageanalysis methodology for MRI and to assess the biopsy rate,the number of interval cancers and the size and stage oftumours identified [7].

3. Study design

Three potential study designs were proposed for com-parison of the efficacy of MRI and XRM in high riskwomen: (1) a non-randomised comparison, in which womenare screened annually with both MRI and mammography,(2) a randomised trial, in which women are randomly allo-cated to either annual mammography or annual MRI and (3)a randomised cross-over trial in which individuals who arepositive on one arm are crossed over to the other arm.Design (1) was chosen in order to minimise the size and costof the study and because designs (2) and (3) require recruit-ment of a cohort of women, exceeding the number of eli-gible women that could be accrued in the UK.

The study will accrue approximately 500 women peryear for each of three years and run for five years withcontinuing clinical/mammographic follow-up for a furthertwo years. A cohort of women aged under 50 will berecruited who are either (1) confirmed as being carriers of

766 J. Brown et al. / Magnetic Resonance Imaging 18 (2000) 765–776

the BRCA1, BRCA2 or p53 genes or (2) at 1 in 2 risk ofcarrying one of these genes based on family history. Detailsof the genetic accrual criteria are given in reference [8]. Inall women, except p53 carriers, MRI and x-ray examinationwill be performed annually. The acceptability and psycho-logical costs of annual MRI and XRM screening to thesehigh-risk patients will also be evaluated [8].

The end points for the analysis will be detection andclassification of lesions at imaging as compared with thetrue incidence of cancer. The study design will allow (1)confirmation of the technical performance of the equipment;(2) determination of the most sensitive and/or specific di-agnostic parameters in breast MRI; (3) measurement ofdiagnostic performance against gold standards of pathologyand follow-up; (4) determination of diagnostic impact byexamining the effect of MRI on clinical decisions; (5) de-termination of therapeutic impact by assessing how thera-peutic decisions are affected by the availability of anddecisions arising from MRI measurements.

In order to develop expertise in analysis and reportingand to ensure common reporting practice and consistentcriteria for identifying and categorising abnormality at eachparticipating centre, a cohort of 240 women presenting atsymptomatic clinics will be examined using the study pro-tocol (symptomatic cohort). This will include those withabnormal or equivocal mammograms or ultrasound exami-nations. This study of symptomatic women will also assessthe value of MRI in identifying and categorising lesions ina non-screening population. Where possible, pre-meno-pausal women will be examined.

4. MRI methodology

High-sensitivity MRI screening requires that both breastsbe surveyed at high spatial resolution. Three-dimensional(3D) contrast-enhanced imaging techniques provide themost efficient and sensitive way of obtaining high-resolu-tion volume coverage, with many workers reporting sensi-tivities of 93–100% [9–13]. Although there is no standard-ised technique for MR imaging of the breast, a typicalprotocol includes imaging before and after intravenous in-jection of a gadolinium-based contrast agent, usually gado-pentetate dimeglumine. This agent tends to accumulate invascular tissues and with most breast cancers demonstratingneovascularity, a rapid increase in signal intensity is ob-served in the majority of malignant lesions within the firstfew minutes after contrast agent administration [14]. How-ever, it is also known that many benign lesions as well asnormal breast tissue may also enhance and that this en-hancement can vary during the different phases of the men-strual cycle [15]. Thus the differentiation of benign frommalignant enhancing lesions can be difficult, with the resultthat many studies have reported specificities of contrast-enhanced breast MRI ranging from 37–89%.

Developments in MR technology have enabled more

rapid MR imaging, allowing the uptake characteristics ofcontrast agents to be measured with improved temporalresolution. The degree of vascularity affects the enhance-ment pattern and many researchers have counselled that inorder to achieve sufficient specificity, images should berapidly acquired following contrast agent administration[16–21]. The evidence suggests therefore that the mosteffective strategy for achieving a high degree of accuracyshould use a high-resolution technique to achieve maximumsensitivity and a fast imaging contrast-enhanced techniqueto achieve maximum specificity. Given the capabilities ofcurrent equipment, satisfactory sensitivity can only beachieved at the expense of specificity. Thus, to achieveadequate overall sensitivity and specificity, a two-stage MRimaging procedure has been adopted for the screeningstudy-

Visit A , a high-sensitivity 3D contrast-enhanced MRIexamination of both breasts, carried out between days 6–16of the menstrual cycle, when the degree of parenchymalenhancement is more likely to be lower [15,22].

This is followed in women with lesions which aredeemed “equivocal” by-

Visit B , a high-specificity dynamic contrast-enhancedexamination of the equivocal area, carried out 2 or 6 weekslater.

This second examination will allow (1) imaging to becarried out at a different hormonal phase of the menstrualcycle; (2) the acquisition of high temporal resolution imagesof the area of abnormality; (3) more sophisticated analysisof high temporal resolution, dynamic data and (4) poten-tially improved specificity, thus optimising categorisation ofwomen and a possible reduction in the number of biopsies.If a lesion is still classed as equivocal after a Visit Bexamination and when conventional diagnostic methods(mammography, ultrasound, fine needle aspiration) are nothelpful, the woman may be invited back 3 months later fora third MR examination (Visit C). Visit C is carried out ondays 6 to 16 of the menstrual cycle using the Visit Aimaging protocol. Otherwise, localisation and biopsy will beperformed under MR guidance [23].

The MR imaging methodologies for Visits A and B aresummarised below and precise details of the sequence pro-tocols are given in Tables 1 and 2. The sequences have beenselected to enable the examinations to be performed oncurrent 1.0 T and 1.5 T systems at the collaborating centres,using dedicated bilateral breast coils. Measurement condi-tions vary slightly on different manufacturers’ systems, asstandard sequences are used.

4.1. Visit A

The annual (Visit A) screening examination uses 3Dspoiled gradient echo sequences, with all images beingacquired in the coronal plane. Using appropriate localiserimages, a high-resolution 3D image is obtained prior to

767J. Brown et al. / Magnetic Resonance Imaging 18 (2000) 765–776

contrast agent administration, with a sub-millimetre in-plane spatial resolution. This is followed by a proton den-sity-weighted acquisition, used to provide absolute T1 mea-surements for retrospective quantitative analysis (see thefollowing section). A series of two pre- and five post-contrast 3D data sets is then acquired, with 0.2 mmol ga-dopentetate dimeglumine (Magnevist, Schering HealthcareLtd., Burgess Hill, UK), per kilogram of body weight in-jected at the start of the third acquisition and followedimmediately with a 20 ml normal saline (0.9%) flush toensure complete delivery of the contrast agent. To ensurebolus delivery of contrast agent, it is recommended that bothinjections be completed, where possible, within 10 seconds.The temporal resolution of the dynamic series has been setto 90 seconds. On completion of the dynamic series ofacquisitions, a high-resolution 3D image is again acquired,using fat suppression if possible. This image will provide

high-resolution morphological information. To allow pool-ing of data from different sites, the following parameters arealso fixed for the entire Visit A examination: number ofslices: 64 or 60; slice thickness: 2.5 mm; field of view(FOV): 340 mm with the half FOV option (phase-encodingdirection); bandwidth: 244 Hz/pixel on 1.5 T systems, 150Hz/pixel on 1 T systems.

4.2. Visit B

In the event that a lesion is diagnosed as equivocal atVisit A, a second (Visit B) MR examination is recom-mended using a fast imaging contrast-enhanced gradientecho technique to obtain high-specificity information.Firstly, a 3D image of both breasts is acquired to allowlocalisation of the area(s) deemed equivocal in Visit A. Thisis followed by proton density-weighted 2D images oriented

Table 1Detailed description of the MR pulse sequences employed for Visit A, the screening examination

SequenceNumber Sequence type

RepetitionTime, TR(ms)

Echo Time,TE (ms)1.5 T systems

Echo Time,TE (ms)1 T systems

Flip angle(°) Matrix size

Pixel size(mm 3 mm)

Number ofaverages

Acquisitiontime(mins:secs)

(i) 3D T1-weighted 10-14 4.2-5 7 35 5123 384 0.663 0.89 1 ' 2-3(ii) 3D Proton

density-weighted10-14 4.2-5 7 6 2563 256a 1.333 1.33a 2 ' 3

(iii) 3D T1-weighted 10-14 4.2-5 7 35 2563 256a 1.333 1.33a 1 7 3 1:30(iv) 3D T1-weighted 10-14 4.2-5 7 35 5123 384 0.663 0.89 1 ' 2-3(v) 3D T1-weighted with

fat suppression20-40 4.2-5 7 35 5123 384 0.663 0.89 1 ' 5-8

a The matrix size is optimised to ensure that the acquisition time of sequence (iii) is 1.5 minutes.

Table 2Detailed description of the MR pulse sequences employed for Visit B, the high-specificity examination

SequenceNumber Sequence type

RepetitionTime, TR(ms)

Echo Time,(ms)1.5 T systems

Echo Time,TE (ms)1 T systems

Flipangle(°)

Slicethickness(mm)

Numberofslices Matrix size

Field ofview(FOV)(mm)

Pixel size(mm 3 mm)

Numberofaverages

Acquisitiontime(mins:secs)

(i) 3D T1-weighted 10-14 4.2-5 7 35 2.5 64 (60) 5123 384 340 0.663 0.89 1 ' 2-3(iia) 2D Proton

density-weightedb,sagittal slices

350 4.2-5 7 6 5 4-5 2563 256a 220 0.863 0.86a 2 ' 3

OR(iib) 2D Proton

density-weightedb,coronal slices

350 4.2-5 7 6 5 4-9 2563 256a 340 1.333 1.33a 2 ' 1:30

(iiia) 2D T1-weightedc,sagittal slices

9-14 4.2-5 7 35 5 4-5 2563 256a 220 0.863 0.86a 1 50 3 0:12

OR(iiib) 2D T1-weighted,

coronal slices9-14 4.2-5 7 35 5 4-9 2563 256a 340 1.333 1.33a 1 50 3 0:12

(iv) 3D T1-weighted 10-14 4.2-5 7 35 2.5 64 (60) 5123 384 340 0.663 0.89 1 ' 2-3(v) 3D T1-weighted

with fatsuppression

20-40 4.2-5 7 35 2.5 64 (60) 5123 384 340 0.663 0.89 1 ' 5-8

a The matrix size is optimised to ensure that the acquisition time of sequence (iii) per group of slices is 12 seconds.b Proton density-weighted images are acquired in an interleaved fashion.c T1-weighted images are acquired in a sequential fashion.


either coronally or sagittally at four or more slice locations,and used to provide absolute T1 measurements for retro-spective quantitative analysis (described below). The protondensity-weighted images are acquired in an interleavedfashion. A series of four pre-contrast and forty six post-contrast T1-weighted images is then acquired, with 0.1mmol/kg body weight gadopentetate dimeglumine injectedat the start of the fifth image acquisition. As for Visit A, thisis followed immediately with a 20 ml normal saline flush toensure complete delivery of the contrast medium, with therequirement that both injections be completed within 10seconds, if possible. Given the variability in different MRmanufacturer’s sequences, and in the technical performanceof machines, the number of slices may vary between fourand ten across sites. However, the temporal resolution of thefast dynamic acquisition has been set to 12 seconds andimages are acquired in a sequential fashion. The followingparameters are also fixed for the Visit B examination: slicethickness 5 mm, no inter-slice gap; bandwidth: 244 Hz/pixelon 1.5 T systems, 150 Hz/pixel on 1 T systems. All coronalslices are acquired with a 340 mm FOV, with the half FOVoption and all sagittal slices are acquired with a 220 mmFOV.

5. MRI analysis and lesion classification

Unlike x-ray mammography, MRI provides a large vol-ume of image information. Breast MR images have excel-lent soft tissue contrast, can provide high-resolution mor-phological information on enhancing lesions and theenhancement pattern can be analysed to study the tumourvascularisation and extravascular space. The relative diag-nostic value of individual or combinations of morphologicalor kinetic parameters is much debated in the literature anddiagnostic criteria remain poorly defined. Several investiga-tors recommend interpretation based on relative enhance-ment [16–18,24–26], while other workers advocate evalu-ation of morphological criteria [10,12,27]. However, morerecently, a number of analyses have suggested that theintegration of both kinetic and morphological informationcan provide the required sensitivity and specificity [11,28,29]. This study uses a multiparametric approach to imageanalysis and the protocol, which was prepared in 1996, iscompatible with recent guidelines on breast MR imageanalysis and reporting developed by the International Work-ing Group for Breast MRI [30].

The methods of image analysis proposed for this studyaim to

(1) ensure the systematic evaluation of screening exam-inations;

(2) minimise the number of women recalled for furtherexaminations;

(3) implement uniform processing, analysis of data and

robust quality assurance between all participatingcentres;

(4) maximise the information obtained from each visitby applying multi-parametric image analysis;

(5) retrospectively determine which parameters from thedata analysis give maximum sensitivity and speci-ficity;

(6) retrospectively develop an automated technique forimage analysis for routine use in a screening situa-tion.

The study protocol includes both radiological diagnosisand retrospective computer-assisted analysis of the imagedata. To maximise the specificity of the technique in differ-entiating benign from malignant tissue, the radiologicaldiagnosis is based on both morphological evaluation andcontrast agent uptake by the enhancing lesion. The guide-line cut-off values quoted in Tables 3 and 4 for the varioussemi-quantitative methods of analysis of the 3D, low-, and2D, high-temporal resolution dynamic studies, have beenobtained from the MR literature [17,21,31–33]. In thisstudy, recent improvements in data acquisition have beenimplemented and therefore cut-off values obtained using thestudy protocol may differ slightly from those derived fromthe literature. However, data obtained from the study ofsymptomatic women in the first phase of this study willallow appropriate correction and standardisation of cut-offvalues between all collaborating centres.

At the end of the study, the diagnostic efficacy of MRIand XRM will be measured in relation to a definitive diag-nosis, (“gold standard”), obtained at open biopsy/mastec-tomy, by tissue sampling using fine needle aspiration or corebiopsy or by clinical follow-up for a minimum of 2 years.Retrospective evaluation of the multiparametric analysiswill include ROC curve analysis of the high-risk cohort toverify cut-off points for sensitivity and specificity for MRIand for each method of analysis in order to determine therelative sensitivity and specificity of each parameter. Thesensitivity, specificity, positive and negative predictive val-ues for cancer detection will be calculated for MRI andcompared with XRM. For the purposes of this analysis,equivocal results will be included in the positive group.

Details of the image analysis methodologies for Visits Aand B are presented below together with the criteria forlesion classification.

5.1. Visit A MRI analysis

5.1.1. Radiological analysisThe initial radiological evaluation includes morphologi-

cal assessment, description of the pattern of contrast en-hancement and semi-quantitative analysis of contrast agentuptake in enhancing lesions. The series of dynamic 3D fastspoiled gradient echo images, performed with contrast agentadministration, can be used to perform further semi-quan-titative analysis of regions-of-interest (ROIs) within areas of


abnormality. The following recommendations have beenmade for region-of-interest selection:

(1) The maximum enhancing area of the lesion or theentire lesion if the pattern of enhancement is homo-geneous should be used. Non-enhancing areasshould be excluded.

(2) The ROI should be constant in position and size foreach image in the series under analysis. More than 9pixels are recommended if lesions allow, and vesselsshould be avoided.

It is also recommended that ROIs are placed on background(air surrounding breasts) away from phase-encoding arte-facts and that another ROI is placed on an area of fatadjacent to/or parallel with the enhancing region within thebreast if available. These two ROIs will help to scale thegraph in a consistent manner.

(1) Morphological assessment. Determination of themorphological appearance of a lesion has been standardisedfor both Visits A and B. The edge and contour of the lesionis described from the post-contrast image optimally demon-strating these features as follows: well defined (.50% ofthe lesion circumference clearly visible); poorly defined(,50% of the lesion circumference clearly visible) andspiculated or focal branching after contrast agent enhance-ment. Lesion contour is defined as irregular, rounded/ovoidor lobulated. Examples of lesions presenting these morpho-logical appearances are shown in Figure 1.

(2) Pattern of contrast enhancement. This is classified aseither no enhancement, centrifugal, homogeneous, hetero-geneous or ring-like. The pattern of enhancement is as-sessed from the series of post-contrast images. Examples areshown in Figure 1.

(3) Semi-quantitative analysis of multiple 3D-fast spoiled

Fig. 1. Contrast-enhanced MR images of typical breast lesions. All images were acquired in the coronal plane following contrast medium administration usingfast spoiled gradient echo sequences with T1-weighting and fat suppression. (a) A 35-year-old woman with a histologically proven fibroadenoma in the rightbreast: the MR image shows a homogeneously-enhancing lesion with a smooth border and a well-defined contour. (b) A 45-year-old woman withhistologically proven infiltrating ductal carcinoma in the left breast: the MR image shows a lesion (arrow) with an irregular contour, poorly-definededge anda heterogeneous enhancement pattern. (c) A 64-year-old woman with histologically proven infiltrating lobular carcinoma in the left breast: the MR imageshows a spiculated lesion and focal branching. (d) A 50-year-old woman with histologically proven infiltrating ductal carcinoma in the left breast: the MRimage shows irregular rim enhancement of a lesion with a poorly-defined edge.


gradient echo images. The mean signal intensity valueswithin the chosen regions of interest are measured on allpre- and post-contrast images. The signal intensity/time dataare evaluated as follows:

- % enhancement at maximum signal intensity

Smax 2 S0

S0p 100 (1)

where Smax is the maximum signal intensity measured in apost-contrast image and S0 is the average signal intensity ofthe two pre-contrast images.

-Maximum-intensity-time rate (MITR)

The temporal behaviour of the signal intensity changes isassessed by means of a maximum-intensity-time rate(MITR), which is defined as follows [32]:-

Smax 2 S0

Dt (seconds)p 100 (2)

whereDt is the time (in seconds) between contrast agentadministration and detection of maximum signal change inthe lesion. The MITR is not a normalised parameter and themaximum signal intensity change will depend on both bio-logical and imaging parameters. In order to remove thisdependency, image analysis in this study also includes de-termination of a normalised rate of enhancement (nMITR),which is defined as follows:

Smax 2 S0

S0 p Dt (seconds)p 100 (3)

(4) Wash-out of contrast agent. This is categorised as a)benign if there is a monotonic increase in signal intensityover the 7 minute examination period; b) suspicious if thepeak signal intensity achieved by 3 minutes is maintainedfor the remainder of the acquisition and c) malignant if thereis a decrease in signal intensity immediately after the peakis achieved [28,33]. The three categories of signal intensitycurves are shown schematically in Figure 2.

All data obtained are recorded in numerical format forsubsequent entry into and retrieval from the study database(Oracle™, Oracle Corporation, Redwood City, California,USA).

5.1.2. Diagnostic criteria for high-sensitivitymeasurements (Visit A)

Categorisation of women into high probability of carci-noma, low probability of carcinoma or equivocal is carriedout using the scoring system detailed in Table 3. Thissystem uses typical MRI appearances of common breastpathologies to weight the various scoring parameters de-scribed above for lesion morphology and the pattern ofcontrast uptake and washout [LW Turnbull, personal com-munication 1996]. Thus, a lobulated fibroadenoma whichdemonstrates rapid, extensive, centrifugal contrast uptake iscategorised as low probability, whereas a spiculated, irreg-ularly shaped carcinoma demonstrating rapid, and extensivecontrast uptake and fast washout is categorised as highprobability.

5.1.3. Retrospective analysisThe observation of rapid signal enhancement in T1-

weighted images acquired following contrast agent admin-istration has been shown by a number of workers to bestrongly indicative of malignancy [13,17,25,32,34–36].However, the degree of contrast enhancement is dependenton the initial longitudinal relaxation time, T1, of the tissue[20,37], the sequence parameters and the contrast agentconcentration. The imaging protocol for this study allowsthe change in absolute T1 values with time following con-

Fig. 2. Diagrams of patterns in contrast enhancement kinetics and theirtypical classification.

Table 3Diagnostic criteria for Visit A MRI examinations. Points scored are given in brackets. From the cumulative scores, women will be categorised as: A,high probability of malignancy (score5 22–35); B, equivocal (score5 14–21); C, low probability of malignancy (score5 0–13)

Morphology Pattern of enhancement

% Enhancement atmaximum signalintensity

Maximum intensity-time rate (MITR)%/min

Pattern of contrastwashout

lobulated, well-defined centrifugal/no enhancement ORminimal enhancement/homogeneous

,40% ,25% type “benign”(see Figure 2a)

(see example, Figure 1a) (see example, Figure 1a)(0) (0) (0) (0) (0)poorly defined heterogeneous enhancement 40-60% 25-49% type “suspicious”(see example, Figure 1b) (see example, Figure 1b) (see Figure 2b)(5) (3) (2) (4) (4)spiculated or focal branching ring-like enhancement .60% .50% type “malignant”(see example, Figure 1c) (see example, Figure 1d) (see Figure 2c)(10) (5) (4) (8) (8)


trast agent administration to be calculated and assessed fortime to maximum T1 change and the maximum T1 changeachieved. The calculation uses an adaptation [38] of thevariable flip angle technique described by Fram et al. [39] toestimate T1 values, determined as the ratio of a T1-weightedgradient echo image (sequence iii, detailed in Table 1) anda proton density-weighted gradient echo image (sequence ii,detailed in Table 1). Proton density is assumed to be invari-ant with the administration of contrast agent, therefore theproton density-weighted image is obtained once only, be-fore injection of the contrast agent. Reference samples areused to calibrate the T1 measurement procedure and detailsof this are given in references [38] and [40].

5.2. Visit B MR image analysis

Data analysis is carried out using (1) standard techniquesfor assessing morphology and pattern of contrast enhance-ment; (2) manual quantification of signal intensity-timecurves; (3) measurement of maximum concentration of con-trast agent achieved; (4) sophisticated pharmacokineticanalysis of contrast agent concentration-time curves and (5)computer-assisted image processing and analysis tech-niques. Methods (1) and (2) are carried out by radiologistsat all participating centres and are used to further categorisewomen as detailed for Visit A above. Determination of themaximum concentration of contrast agent achieved, phar-macokinetic analysis and the application of novel imageprocessing tools which involve the use of non-standardsoftware programmes and workstations, is performed retro-spectively on all data sets but at a limited number of sites.This involves data transfer by optical disc or tape to desig-nated sites for detailed analysis. A full description of theanalysis protocol for the Visit B MR examination is pre-sented below.

5.2.1. Radiological assessments(1) Morphological analysis. Lesion edge and contour is

determined from the 2D and 3D fast spoiled gradient echo

images orientated through the area of maximum enhance-ment of the lesion and is defined using the same criteria asdescribed above for Visit A image data.

(2) Pattern of contrast enhancementis determined as forVisit A.

(3) Manual Quantification. Measurements of signal en-hancement are calculated relative to the signal intensity ofthe baseline, which is defined as the average value of the 4pre-contrast data points. Enhancement is defined as an in-crease in signal intensity of 2 standard deviations or moreabove that obtained for the average baseline signal intensity.Measurements from enhancement curves include-

-% enhancement within the first 60 seconds, calculatedas described in reference [17]:-

S60 2 S0

S0p 100 (4)

where S60 is the signal intensity of the lesion 60 secondspost contrast agent administration.-% enhancement at the maximum signal intensity [21],assessed as described previously for Visit A;-maximum-intensity-time rate (MITR) and normalised max-imum intensity time rate (nMITR), determined as detailedfor Visit A.

(4) Wash-out of contrast agent. This is assessed as de-scribed previously for Visit A.

5.2.2. Diagnostic criteria for high specificitymeasurements (Visit B)

Women are categorised into high probability of tumour,low probability or equivocal on the basis of the morpholog-ical appearance and manual quantitation of the dynamicdata using the guideline scoring system detailed in Table 4.A similar approach to that detailed in Table 3 for Visit A isemployed. From current knowledge of the behaviour oftypical benign and malignant lesions, the results of dynamicimaging have been weighted such that typical lesions arescored appropriately. The scoring system for Visit B isbeing calibrated against data obtained from the study of

Table 4Diagnostic criteria for Visit B MRI examinations. Points scored are given in brackets. From the cumulative scores, women will be categorised as: A,high probability of malignancy (score5 32–46); B, equivocal (score5 20–31); C, low probability of malignancy (score5 0–19)

Morphology Pattern of enhancement% Enhancementwithin 60 secs

% Enhancement atmaximum signalintensity

Maximum intensity-time rate (MITR)%/min

Pattern of contrastwash-out

lobulated, well-defined centrifugal/no enhancement ORminimal enhancement/homogeneous(0)

,70% ,40% ,25% type “benign”(see Figure 2a)

(0) (0) (0) (0) (0)poorlydefined heterogeneous enhancement 70-100% 40-60% 25-49% type “suspicious”

(see Figure 2b)(5) (3) (5) (3) (4) (4)spiculated or focal branching ring-like enhancement .100% .60% .50% type “malignant”

(see Figure 2c)(10) (5) (10) (5) (8) (8)


another cohort of symptomatic women, examined using anidentical imaging protocol at Hull Royal Infirmary and TheRoyal Marsden NHS Trust, Sutton [41].

5.2.3. Retrospective data analysis(1) Maximum contrast agent concentration achieved.

Signal enhancement will be converted into tissue contrastagent concentrations using both the proton density-weightedand T1-weighted spoiled gradient echo images, the latterobtained before and after contrast agent administration.These images allow the calculation of T1 values accordingto the variable flip angle technique mentioned above, andthus calculation of contrast agent concentration, accordingto the following relationship:

Ct(t) 5

1

T1(t)2

1

T10

R1(5)

where Ct(t) is the tissue concentration of contrast agent attime t following contrast agent administration, T1(t) is thetissue longitudinal relaxation rate at time t, T10 is the T1 ofthe tissue prior to administration of contrast agent and R1 isthe longitudinal relaxivity of protonsin vivo due to contrastagent. Calibration of T1 measurements is carried out fromphantom studies for all systems.

(2) Pharmacokinetic analysis. Contrast agent concentra-tion—time curves determined according to the above equa-tion will be characterised by pharmacokinetic modellingusing software based on the models of Tofts and Kermode[42] and Brix et al. [43] developed by the CRC ClinicalMagnetic Resonance Research Group, Royal Marsden Hos-pital, Sutton, UK [38] and at the Centre for MR Investiga-tions, University of Hull, Hull Royal Infirmary, UK [44].The pharmacokinetic model is fitted to the data on a pixel-by-pixel basis to calculate the transfer coefficients of con-trast agent into, and out of, the lesion. These are well-established models and in the course of the study morerecent improvements in data analysis will be applied, whereappropriate [45].

(3) Timing of arterial enhancement. It is not possible inthis study to prospectively employ a cut-off time of 11.5 secbetween aortic and lesion enhancement, to differentiate be-tween benign and malignant lesions [16] due to the limitednumber of slices, the slice orientation and the slice position.However, image processing tools developed during thestudy will be used retrospectively to investigate the poten-tial for estimating with good time resolution (3 seconds), thearterial enhancement from normal tissue enhancement.

(4) Image processing and analysis. Computer pro-grammes are being developed to (a) register image data setsduring and between studies, (b) apply feature-mapping tech-niques and statistical shape analysis to identify significantdiagnostic and pre-clinical features and (c) implement in-telligent algorithms for detecting and classifying change.These techniques will be evaluated and validated on the data

sets obtained in the study, including symptomatic and high-risk cohorts.

6. Quality assurance

A quality assurance programme is important for themulticentre MRI breast screening study, not only to ensurethe stability and optimum performance of the MR systems,but also to allow data pooling across sites, assessment aftermanufacturer’s upgrades and, more especially, to ensurethat any quantitative image analysis is reliable and accurate.We have designed a quality assurance protocol (1) to makea comprehensive biannual evaluation of each MR system,(2) to allow verification, on a routine basis, of the stabilityof each system and (3) to monitor radiological image inter-pretation and analysis. We describe below the criteria forinclusion in the study, standardisation of the imaging meth-odology, system assessment and quality assurance in radi-ology.

6.1. MR system

For inclusion in the study, all centres must meet thefollowing requirements -

(1) a MR system with minimum field strength of 1T;(2) shielded gradients and a maximum gradient ampli-

tude of at least 10 mT/m, allowing four slices to beacquired in 12 seconds for rapid contrast-enhancedfast spoiled gradient echo imaging;

(3) a dedicated bilateral breast coil, providing adequatecoverage of the breast and axilla and which achievesa predetermined minimum signal-to-noise ratio(SNR) (Following an initial survey at ten sites andusing the breast phantom described below and theVisit A, sequence (iii) protocol, this value has beenset to 100).

(4) ability to produce calibration curves for T1 values,derived from pulse sequences appropriate to the par-ticular MR system, using a Eurospin phantom (Di-agnostic Sonar, Livingston, Scotland) with gels ofknown T1 value.

6.2. Standardisation of MRI acquisition

Strict MR imaging protocols have been established forthe study (Tables 1 and 2). These protocols have beendesigned to accommodate as many centres as possible.Where necessary, additional sequences have been providedby the MR manufacturer. Centres are requested to imple-ment the standard protocol ensuring that-

(1) images are acquired with fat and water in phase, thatis, with an appropriate echo time and voxel band-width;

(2) the 2D and 3D sequences used for quantitative anal-


ysis or image subtraction (pre- and post-contrastimage acquisitions) are performed with identical re-ceiver gain, frequency, transmitter reference voltageand image scale;

(3) a bolus injection of contrast agent is achieved. Thosestudies in which a bolus injection is not achievedwill be excluded from analysis.

6.3. Assessment of instrument performance and coilcalibration

6.3.1. Site testingEach MR system is assessed biannually by one of the

project physicists and assessment is repeated if the softwareor hardware is upgraded. The slice profile and spatial reso-lution of all pulse sequences employed in the study areverified using the Eurospin set of test objects. T1 values aredetermined from 2D and 3D fast spoiled gradient echosequences by determining the ratio of the signal intensity ina region of interest for T1-weighted and proton-densityweighted images. This ratio is matched against the absoluteT1 values and an empirical fit to the data allows values of T1

to be inferred from the ratios of signal intensities [38]. Thetemperature of the gels is recorded at the time of measure-ment. Breast phantoms have been constructed for all par-ticipating centres using two custom-made Perspex contain-ers [46]. These are filled with Esso Bayol 82 oil (WessexPetroleum, Southampton, UK) (T1 5 140 ms at 1.5 T) andBP dielectric 200T oil (Dominion Oils, Redhill, Surrey,UK) (T1 5 925 ms at 1.5 T) both of which have lowdielectric constants and are therefore suitable for radiofre-quency coil nonuniformity measurements. The phantom fitsall manufacturers’ breast coils and has been designed to fillas much of the coil as possible. A suitable support is pro-vided to ensure accurate and easy phantom positioning. Thebreast phantom is used (1) to determine the signal-to-noiseratio (2) to measure the percentage uniformity and (3) toallow visual examination for distortion and artefacts.

6.3.2. Routine quality controlRegular tests of machine performance may be performed

using the standard breast phantom. These include measure-ments of SNR, uniformity and T1 values and require record-ing of resonance frequency, receiver and transmitter set-tings.

6.4. Data interpretation

6.4.1. Dual reportingDual reporting of all examinations is carried out. At large

centres this is performed in-house. In smaller centres thisinvolves a radiologist from another centre, who examinesthe images within a 3–6 month period of the initial exam-ination. Data are transferred between centres with similarcommercial MR systems on optical disc or tape. The secondradiologist reanalyses all images from Visits A and B ac-

cording to the analysis protocol as detailed above. Theresults are retained in graphical and numerical format forretrospective analysis. Discrepancy in results is reviewed bya third radiologist, who also reviews a subset of randomlyselected data.

To assess systematic differences in reporting betweencentres, a set of 10 training examinations of common breastconditions of moderate/great difficulty is being prepared inconsultation, by 4 national experts in breast MR imaging,for circulation to named radiologists in all participatingcentres. Radiologists will be asked to report examinationsusing the methodologies detailed above and to categorisewomen appropriately.

6.5. Quality assurance in mammography

High quality mammograms are essential in the diagnosisof small cancers. The standards regarding mammographicdose and image quality laid down by the NHS BreastScreening Programme also apply to this study [47]. Allmammography units are used by radiographers with a Cer-tificate of Competence in Mammography to achieve well-positioned radiographs with adequate exposure (film densitymore than 1.4), processed on dedicated equipment. Theradiographs must have high-contrast spatial resolution (10line pairs/mm) and the minimal detectable contrast shouldbe approximately 1% (5–6 mm detail) and 5% (0.5 mmdetail). The radiation dose should be less than 2 mGy perfilm using a grid. Radiographs are reported by appropriatelytrained radiologists, preferably those involved with readingmore than either 1000 screening mammograms or 500symptomatic mammograms a year. Dual interpretation ofall mammograms is also performed.

7. Conclusions

The protocol described in this paper will allow the mea-surement of the diagnostic performance of MRI comparedwith XRM for screening premenopausal women for breastcancer. The two-stage examination protocol should improvethe specificity of MR screening and reduce the number ofunnecessary biopsies. The data acquired from the symptom-atic cohort and the retrospective analyses of all study im-ages will determine the most sensitive and the most specificimage interpretation parameters. This information will beessential if MR screening for breast cancer in young womenat high genetic risk were to be introduced as a service,following the results of this study.

Acknowledgment

This research study is supported by the Medical Re-search Council and the NHS National R&D Board. Theprotocol is based in part on developments supported by the


Cancer Research Campaign and the Yorkshire Cancer Re-search Campaign. Contributions towards training and edu-cation have been made by Schering Healthcare Ltd. andOracle Education.

EthicsThe study has gained approval from the North Thames

Multicentre Research Ethics Committee, and from 31 LocalResearch Ethics Committees in the UK.

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