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creening for Hereditary Breast Cancerebecca Dent and Ellen Warner
Most women at risk for hereditary breast cancer opt for intensive breast screening ratherthan risk-reducing mastectomy. For this to be a rational choice, the vast majority of tumorsmust be detected either while still in situ or at a very early stage of invasion. Annualscreening mammography has low sensitivity in this population, in part due to the greaterbreast density of younger women, resulting in cancers being detected at a suboptimalstage. In six prospective comparative studies, the addition of annual contrast-enhancedmagnetic resonance imaging (MRI) of the breast to mammography demonstrated greaterthan 90% sensitivity, more than twice that of mammography alone. In those studies thatincluded ultrasound and clinical breast examination, additional cancers were rarely de-tected by these modalities. False positive rates were higher with the addition of MRI, butspecificity improved on successive rounds of screening. Although long-term survival dataare still lacking, there is mounting evidence that the addition of screening MRI to mam-mography detects hereditary breast cancers at an earlier stage and is thus estimated to becost-effective, at least for women with BRCA mutations. This review will examine theliterature and current screening recommendations.Semin Oncol 34:392-400 © 2007 Elsevier Inc. All rights reserved.
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pproximately 1% to 2% of women are at very high riskfor developing breast cancer due to a proven or sus-
ected inherited predisposition. One extremely effective op-ion for these women is bilateral mastectomy, which virtuallyliminates any future risk of breast cancer. However, thisutilating procedure is unacceptable to most women withroven BRCA1 or BRCA2 gene mutations.1 It is even lesscceptable to women who decline genetic testing, or for thoseith a strong family history but indeterminate mutation sta-
us,2 who have no means of ascertaining whether their life-ime risk for breast cancer is as low as that of the generalopulation (�12%)3 or as high as that of a woman with aRCA mutation (�85%).4 Furthermore, accumulating evi-ence for the effectiveness of strategies such as chemopreven-ion and premenopausal oophorectomy at reducing risk bypproximately 50%,5-8 makes the case for bilateral mastec-omy less compelling for many women. However, with anyisk reduction strategy other than bilateral mastectomy, theelative risk of breast cancer compared to the general popu-ation remains sufficiently high for these women to require a
ore intensive screening regimen. Moreover, a recommen-
epartment of Medical Oncology, Sunnybrook Health Sciences Center andUniversity of Toronto, Ontario, Canada.
ddress correspondence to Ellen Warner, MD, Sunnybrook Health SciencesCenter, T Wing, 2075 Bayview Ave, Toronto ON, Canada M4N 3M5.
wE-mail: [email protected]
92 0093-7754/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1053/j.seminoncol.2007.07.002
ation for screening as an alternative to mastectomy can onlye ethically justified if the vast majority of tumors can beetected either before invasion (ductal carcinoma in situDCIS]) or at an early stage of invasion (node-negative can-ers �1 cm in diameter) for which the systemic recurrenceate is less than 10%.9
Since the annual risk of hereditary breast cancer is signif-cant from the age of 25 or 30 onwards and remains higherhan that of age-matched women in the general populationor life, screening for hereditary breast cancer differs fromcreening the general population in several important ways:1) screening must be started no later than age 30; (2) thecreening regimen must have adequate sensitivity in youngomen; and (3) the screening regimen must be more sensi-
ive at all ages than that used for screening the general pop-lation, even at the expense of somewhat lower specificity.his is because although the relative number of false neg-tives and suboptimal stage true positives does not dependn cancer risk, the absolute number will vary directly withancer incidence. With the widespread use of screeningammography, 2% to 3% of women in the general popu-
ation die of breast cancer, with most of these deaths oc-urring after age 65.3 In contrast, assuming a threefoldreater cancer incidence and similar prognosis in the high-isk population, there would be at least three times asany deaths and these deaths would on average occur in
omen 20 years younger.
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Screening for hereditary breast cancer 393
ammography-Based Screeningor Hereditary Breast Cancerntil recently, consensus guidelines for screening womenith an inherited predisposition to breast cancer have relied
hiefly on mammography, the only screening modalityroven to reduce mortality in any population, as there hadever been a screening trial directed at the “very-high-risk”opulation. As late as 2004, the American National Compre-ensive Cancer Network (NCCN) recommended monthlyreast self-examination (BSE) starting at age 18, and semian-ual clinical breast examination (CBE) plus annual mam-ography from age 25 onwards. Unfortunately, studies ofomen with BRCA mutations undergoing conventionalammography-based screening have been extremely disap-ointing. In three prospective10-12 and one retrospective13
eries, very few cases of DCIS were detected, 40% to 78% ofhe invasive cancers were greater than 1 cm in size, 20% to6% had lymph node involvement, and the interval cancerate ranged from 35% to 50%.
The relatively poor performance of mammography inhese studies can be attributed to three factors as follows,reast density, tumor doubling time, and the pathobiology ofRCA1-related tumors.
reast Densityn general, the proportion of radiodense fibroglandular tissuen the breast relative to radiolucent fat is inversely propor-ional to patient age.14 Invasive cancers are usually detectabley mammography when there is contrast between the x-ray–ttenuating tumor (which appears white) and the surround-ng normal fatty tissue (which appears black), but they areften missed when the surrounding normal tissue is predom-nantly fibroglandular and also appears white. Thus mammo-raphic sensitivity also is inversely proportional to age.15
umor Doubling Timeiven the consistent observation that breast cancers inounger women are more commonly high grade than inlder women,16-18 it is not surprising that formal studies ofumor doubling time have shown shorter doubling time (ie,ore rapid growth) in younger women than in older women
or “hereditary” cancers,19 as well as for “sporadic” cancers.20
his factor, together with breast density, likely explains whyhe reduction in breast cancer mortality conferred by screen-ng mammography in the general population is significantlyower in women ages 40 to 49 than in older women.17 SinceRCA1-related tumors are particularly likely to be highrade,21,22 doubling time may be even faster in this subgroup.
athobiology of BRCA1-Related Tumorshree studies23-25 have demonstrated that even among womenf a given age group, BRCA1-related cancers are more oftenither mammographically occult or misinterpreted as benign.he authors of these studies attributed this to the tendency of
hese tumors to be cellular and fleshy with round pushing
argins (rather than scirrhous with irregular infiltrating mar- tins) and to be associated with less DCIS21,22 (which oftenevelops microcalcifications that lead to detection by mam-ography).Also, as mentioned above, even if one could match the
ensitivity and cancer stage distribution achieved withcreening mammography in the general population ofomen over age 50 (80% sensitivity, 78% of cancers node-egative, and 35% of cancers 1 cm or less in size),18 the ratesould not be adequate for the very-high-risk population,ecause of the higher cancer incidence and the muchounger average age of onset. For these reasons, there haseen a major focus on developing a screening regimen that isubstantially more sensitive than mammography and is notffected by breast density.
creeningltrasound of the Breast
n several nonrandomized studies in the general popula-ion, screening ultrasound was found to add to the sensi-ivity of mammography, particularly for women with densereasts.26,27 Thus, despite its relatively poor specificity, ultra-ound as an adjunct to screening mammography for very-igh-risk women has been considered. Indeed, the 2004 up-ate of the French Guidelines for the management ofereditary breast cancer recommended that ultrasound beombined with mammography (and CBE) for high-riskomen with 50% or greater breast density.28 However, inrospective studies the sensitivity of this combination haseen inadequate (see below).
agnetic Resonancemaging of the Breastagnetic resonance imaging (MRI) uses magnetic fields to
roduce detailed cross-sectional (tomographic) images of tis-ue structures. Differences in the mobility and magnetic en-ironment of the hydrogen atoms in various breast tissuesfat, glandular tissue, fibrous tissue, lesions, etc) create sig-als of varying intensity that determine the brightness of the
mage. To help distinguish tumors from surrounding stromalnd fatty tissues, a paramagnetic small molecular contrastgent gadolinium diethylenetriamine-penta-acetic acid (Gd-TPA) is injected intravenously. The enhancement of areast lesion reflects local tissue changes in blood flow, cap-
llary permeability, and extracellular volume,29 which arearticularly characteristic of tumor-related angiogenesis andumor growth. Because the high signal from enhancing le-ions may still be difficult to separate from fat or from normalbroglandular tissue, techniques such as image subtractionr fat suppression or both are often used. Generally a pre-njection image and sequential sets of images after contrastnjection are collected (dynamic contrast-enhanced MRI).he appearance of a lesion (morphology), as well as its con-
rast uptake and washout pattern (contrast kinetics), can besed to discriminate malignant lesions from benign condi-
ions. Malignant lesions often enhance rapidly with maximal
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394 R. Dent and E. Warner
ontrast uptake in the first 1 to 2 minutes and may alsoemonstrate rapid contrast washout (Fig. 1). Benign lesionsnd normal parenchyma generally demonstrate a slower in-rease in enhancement sustained over time30 (Fig. 2). How-ver, contrast kinetics are only an adjunct to morphology andot a reliable means of distinguishing benign from malignant
esions, particularly DCIS.31 Unlike mammography, mag-etic resonance image quality is not influenced by breastensity (Fig. 3). Contrast-enhanced MRI has been reported toave 94% to 100% sensitivity in the diagnostic setting.32
Despite its outstanding sensitivity, MRI has several signif-cant drawbacks. MRI costs approximately 10 times morehan mammography. Its specificity is lower and more vari-ble than its sensitivity, ranging from 37% to 97%.32 Thisowered specificity translates into a large number of recallsnd benign biopsies with their attendant costs to the patientn time, anxiety, and deformity, as well as their economicurden.33 For premenopausal women, MRI should be per-ormed during the second week of the menstrual cycle toptimize sensitivity and specificity. Not all women can un-ergo MRI. It is contraindicated in the following situations:omen with pacemakers or aneurysm clips; women whoecome too claustrophobic to lie prone for 30 minutes in theagnet, even after sedation; and obese women (particularly
hose with broad shoulders) who may not fit into the magnet.hile MRI is too costly and insufficiently specific to consider
or screening the general population, it is a logical choice fortudy in the relatively small population of women at high riskor hereditary breast cancer.
RI Screening Studiesn the mid to late 1990s, six prospective, nonrandomizedtudies were initiated in Germany,34 Canada,35 Nether-ands,36 United Kingdom,37 United States,38 and Italy39 toetermine the benefit of adding annual MRI to mammogra-
Figure 1 A 51 year-old woman who recently tested positi(2) MRI images; (a) taken 90 seconds after contrast injelater shows early central washout. Lesion was not palpafound on MRI-guided biopsy. Lumpectomy revealed areceptor–negative, sentinel node–negative, invasive ducfollow-up.
hy for women at increased risk for breast cancer based on C
ither a known BRCA mutation or a strong family history.ach group of investigators has published at least preliminaryesults (Table 1). In all of these studies patients underwentnnual mammography and MRI within a very short timeeriod, thereby enabling assessment of the relative perfor-ance of the two modalities in terms of sensitivity and spec-
ficity. In all studies biopsy-confirmed cancer was consideredhe definitive positive result for calculating sensitivity. Thereere notable differences between the studies that affect their
omparability, including patient population (age, risk status,nd history of previous cancer); the number and experiencef participating centers; the MRI technique itself (eg, whethermaging was done in the sagittal, axial, or coronal plane); usef additional screening modalities such as ultrasound andBE that could affect the interval cancer rates; and criteria forefining positive and negative screening results (eg, sometudies considered an American College of Radiology Breast
igure 2 Arrows point to two fibroadenomas in the same breast.
BRCA1 mutation. (1) Normal mammogram left breast.hows a tiny early enhancing mass; (b) taken 5 minutesd was invisible on targeted ultrasound, but cancer was, grade III, estrogen receptor–negative, progesterone
noma. The patient remains disease-free after 8 years of
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ontrast uptake was slow and delayed enhancement was persistent.
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Screening for hereditary breast cancer 395
maging Reporting and Data System (BIRADS) 0 and/or 3core to be “positive” while others did not).
Despite these differences, the study results were remark-bly similar. Interval cancer rates were uniformly less than0%. All studies found the sensitivity of MRI to be substan-ially higher than that of the other modalities, with MRI sen-itivity ranging from 71% to 100% compared to 16% to 40%or mammography. Three studies included ultrasound,hich had overall sensitivity similar to mammography with
omewhat better sensitivity than mammography for invasiveancer but negligible sensitivity for detecting DCIS. In all buthe German study,34 the specificity of MRI in terms of bothecalls and biopsies was inferior to that of mammography.owever, MRI specificity was substantially better on the sec-nd and subsequent rounds of screening than on the firstound.35,40
Sardanelli and Podo41 recently performed a combinednalysis of the five largest studies.34-37,39 Overall, 3,571omen were screened for a total of 9,652 rounds; 168 can-
ers were diagnosed, of which eight were interval cancers, forn annual cancer detection rate of 1.7%. Only 19% weressociated with nodal involvement. The pooled sensitivityas 16% for CBE, 40% for mammography, 43% for ultra-
ound, and 81% for MRI. Corresponding positive predictivealues were 33%, 47%, 18%, and 53%, respectively.
Based on the previously described studies comparing di-
Figure 3 A 47-year-old woman recently found to have airregular, early enhancing mass. Right: Mammogram of lewas not palpable and screening ultrasound was normal,underwent lumpectomy for a 1.5-cm, grade III, estrogcarcinoma. The tumor could not be seen even on spefollow-up.
gnostic mammography in women with and without BRCA1 a
utations,23-25 one would expect the difference in sensitivityetween MRI and mammography to be particularly large forRCA1-related cancer. Indeed, in the UK study, the sensi-ivity of MRI was significantly higher than that of mammog-aphy only for women who had a BRCA1 mutation but not foromen with BRCA2 mutations or no known mutation.37
owever, the numbers in each subgroup were small, and theesults may have been confounded by the very low rate ofCIS in the BRCA1 group (see below). In our Toronto study,
he sensitivity advantage of MRI over mammography wasdentical for women with BRCA1 or BRCA2 mutations. Alsoontrary to our expectations was the finding that the differ-nce in sensitivity between MRI and mammography was noreater for women under 50 than for women ages 50 andlder.42 Finally, while as expected mammography performedomewhat better in women with less dense breasts than inhose with greater breast density, even in the low-densityroup the sensitivity of mammography was less than 50%.43
n fact, in the Dutch study, there was an unexplained greaterensitivity advantage of MRI over mammography in womenith low breast density than in those with high breastensity.44
There is evidence of a learning curve for radiologists con-ucting MRI breast screening, with the sensitivity of MRIising with experience45 and the number of benign lesionsnvestigated falling with experience.46 This learning curve
1 mutation. Left: First MRI scan of left breast showingst showing dense tissue with no abnormality. The lesione biopsy was performed under targeted ultrasound. Sheptor–positive, sentinel node–negative, invasive ductalradiograph. She remains disease-free after 9 years of
BRCAft brea
but coren rececimen
ppears to be particularly steep for DCIS. In the two largest
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396 R. Dent and E. Warner
ulticenter studies (the Dutch and UK studies36,37) the sen-itivity of MRI was significantly higher than that of mammog-aphy for the detection of invasive cancer, but the reverse waseen for DCIS. In our study we were initially unable to detectny cases of DCIS with MRI, but in our more recent cohort ofatients, the sensitivity of MRI for detecting DCIS greatlyxceeded that of mammography (Fig. 4).45 Similar resultsave been reported by others.47 The results of the Dutch andK studies reflect the likely initial effectiveness of this modal-
ty in a population context, and it is expected that with trainingnd advances in technology, sensitivity will increase further andpproach that reported by experienced single centers.
RI Screeningnd Mortality Reductionhile the significantly greater sensitivity of MRI is unques-
ionable, like any screening intervention its ultimate clinicalffectiveness is dependent on its ability to reduce mortality,s opposed to simply increasing diagnostic lead time. Thereatest challenge in reviewing the evidence for the effective-ess of MRI screening is the lack of any randomized trials.his phenomenon likely resulted from the fact that oncereliminary evidence from comparative pilot studies of MRI
able 1 Published Results of Six Prospective Studies Using Coigh-Risk Women
Single-Center Studies
Kuhl et al,200534
Warner et al,200445
emographicsScreened women 529 236Mean age at entry (range) 42 (27–59) 47 (26–65)Patients enrolled who are
mutation carriers8.1% 100%
Mean no. of screens perwoman
3.2 1.9
Total no. of tumorsdetected (invasive �DCIS)
43 (34 � 9) 22 (16 � 6)
est characteristicsSensitivity (%)
CBE 4.7% 9.1%Mammography 33% 36%Ultrasound 40% 33%MRI 91% 77%
Tumors only MRIdetected†
48% 32%
Interval cancers 1 (2.3%) 1 (4.5%)Invasive tumor
characteristicsSize <1 cm (%) 58% 56%Node-negative (%) 84% 87%
bbreviations: NR, not reported; NA, not applicable.Includes women with a BRCA mutation and their relatives.Denominator is tumors detected through imaging.
nd mammography was available, randomized studies were D
o longer considered to be feasible or even ethical. Thus, theffectiveness of MRI will have to be determined by comparinghe long-term outcomes of well-matched cohorts of high riskomen who differ only with respect to whether or not they
eceived MRI screening.Even though follow-up of the six comparative MRI screen-
ng studies discussed above is still too short for recurrencend survival data to be available, it is highly likely that MRIcreening does lower breast cancer mortality. This arguments based on the “proof of principle” that the tumor downstag-ng observed with screening mammography in the generalopulation has resulted in a corresponding reduction inreast cancer mortality. It would follow that any interventionhat significantly downstages breast cancer in the high-riskopulation should also lower mortality. The tumor stage dis-ribution reported in the six screening trials generally appearsore favorable than the reports for mammography withoutRI10-13 but is still suboptimal, with a node-positive rate of
3% to 21% and relatively few cases of DCIS (Table 1). How-ver, early study results reflect center inexperience, as well asdisproportionate number of prevalent cancers that may
ave been present for years, occult to mammography. In ouroronto study the vast majority of cancers detected on theecond or subsequent screen (incident cancers) were either
-Enhanced MRI and Other Imaging Modalities for Screening
Multicenter Studies
ege et al,200436
Leach et al,200537
Lehman et al,200538
Sardanelliand Podo,
200641
1909 619 367 278(19–72) 40 (31–55) 45 (26–86) 46 (25–77)
19% 19% NR 63%*
2.7 3.0 1 1.4
(39 � 6) 35 (29 � 6) 4 (3 � 1) 18 (14 � 4)
18% — NR 50%40% 40% 25% 59%— — — 65%71% 77% 100% 94%49% 58% 75% NR
(8.9%) 2 (5.7%) NA 0
43% 46% 67% 57%79% 81% 100% 77%
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CIS or node-negative cancers less than 1 cm in diameter.45
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Screening for hereditary breast cancer 397
ost-Effectivenessf MRI Screening
wo recent studies, one in the United States and one in thenited Kingdom, have examined the cost-effectiveness of
creening MRI for high-risk women. Plevritis et al48 used aomputer simulation model to estimate the survival benefitor a range of screening strategies for women with BRCA1 orRCA2 mutations. Using the assumption that MRI reducesreast cancer mortality by 23% relative to screening with mam-ography alone and applying a cost-effectiveness threshold of100,000 per quality-adjusted life-year (QALY), these investi-ators48 found significant variation by age and mutation. Theost of adding annual breast MRI for women with BRCA1 mu-ations ages 35 to 54 was $55,420 per QALY and for ages 25 to9, it was $88,651. The corresponding costs for BRCA2 were130,695 and $188,034, respectively. However, MRI screeningas cost-effective for women ages 35 to 54 with BRCA2 muta-
ions who had dense breasts ($98,454 per QALY). The mostmportant determinants of cost-effectiveness were breast cancerisk, mammographic sensitivity, MRI cost, and quality of lifeained from the greater reassurance of a negative MRI. As a pointf comparison, the cost-effectiveness of beginning annualcreening mammography in the general population at age 40nstead of age 45 is $58,000 per QALY.49
Griebsch et al50 looked at the cost per cancer detected by
Figure 4 Right breast of a 47-year-old woman with a stronnormal mammogram. Right: MRI showing clumped sbenign parenchymal enhancement. Breast examinationMRI-guided localization and surgical excisional biopsy. Aof microinvasion was found. Sentinel node biopsy was
ither adding MRI to mammography or replacing mammog- f
aphy with MRI in the UK study,37 which only screenedomen ages 35 to 49. For all women in the study the incre-ental cost of adding MRI to mammography was £28,284er cancer detected and for the subgroup of women withRCA mutations, this cost dropped to £15,302 (£11,731 forRI v mammography). Using a cost-effectiveness threshold
f £20,000 per QALY, the authors50 concluded that thereould only have to be a gain of 1.4 QALYs for the whole
tudy group in order to demonstrate cost-effectiveness.
sychological Effectsf Intensive Screening
n the general population of women undergoing screeningor breast or cervical cancer, abnormal test results have beenound to have a large short-term impact on psychosocialealth and well-being. While these effects are generally tran-ient and resolve if the test is proven to be a false-positive, inome studies anxiety and increased sense of susceptibility toancer persisted for 6 months or more.51 Given the muchigher rates of both cancer and false positive scans in a high-isk population undergoing MRI-based screening, the psy-hological health of these women merits study.
In a subgroup of 611 women in the UK MRI screeningtudy,37 89% reported that they definitely intended to return
ly history of breast cancer but no known mutation. Left:tal enhancement, which was originally thought to beargeted ultrasound were normal. DCIS was found onectomy, a 6-cm area of grade II DCIS with a 2-mm focuse.
g famiegmen
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eturn. However, 4% found breast MRI “extremely distress-ng,” and 47% reported still having intrusive thoughts abouthe examination 6 weeks afterwards.52
In a sample of 357 women from the Dutch study, psycho-ogical distress remained within normal limits throughoutcreening for the group as a whole. However, elevated breastancer specific distress related to screening was found inxcessive (at least once per week) breast self-examiners, riskver-estimators, and women closely involved in the breastancer case of a sister. At least 35% of the total sample be-onged to one of these subgroups. It was recommended thatatients in one of these vulnerable subgroups be approachedor additional psychological support.53
In a small sample of women from the Toronto study fol-owed over a course of 2 years, there was no evidence of anyffect on global anxiety, depression, or breast cancer–relatednxiety.54 In another sample of 57 women, a nonsignificantncrease in general anxiety and breast cancer–related anxietyas found in the subset of women recalled for further imag-
ng or biopsies.55 Follow-up time is still insufficient to deter-ine whether anxiety scores return to baseline once theork-up has been completed.
urrentcreening Recommendations
he 2006 guidelines of the National Comprehensive Canceretwork (NCCN) state that annual mammography andreast MRI should be started at age 25 (along with semian-ual CBE and monthly BSE) for women known or likely toarry BRCA1 or BRCA2 mutations. No upper age limit istated.56
A recently updated American Cancer Society guideline57
ecommends MRI screening starting at age 30 for womenith BRCA mutations (or other rare genetic disorders confer-
ing a similar lifetime risk), untested first-degree relatives ofomen with BRCA mutations, and any patient with a familyistory predictive of a lifetime cancer risk of at least 25%.hese recommendations were based on published evidence.he authors also believed MRI screening should be offered toomen who received radiation therapy to the chest between
ges 10 and 30. A guideline with similar recommendationsas recently published online in Ontario, Canada.The rationale for recommending mammography along
ith MRI is that the sensitivity of MRI was less than 80% in allut one of the screening studies with more than 1 year ofollow-up. In a large recent, multicenter study of diagnostic
RI, its sensitivity was only 88%.31 In addition, mammogra-hy is the only breast screening modality to date proven toeduce mortality in any population. There is no consensus aso whether it is preferable to perform mammography and
RI at the same time or separated by 6 months.Recent UK screening guidelines58 have taken a slightly
ifferent approach, recommending MRI either in addition to,r as an alternative to, mammography for: (1) women withnown BRCA1 or BRCA2 mutations ages 30-49; (2) women
ith known TP53 mutations ages 20 or older; (3) women wges 30-39 with a 10-year risk greater than 8%; and (4)omen ages 40-49 with a 10-year risk greater than 20% or10-year risk greater than 12% and a dense breast pattern.
echnical Considerationshere are numerous effective methods of MR image acquisi-
ion and no single method has proven superior to another.owever, certain minimum requirements are recommendedy most experts in order to achieve high spatial resolution for
dentification of morphology and high temporal resolutionor interpretation of kinetics. A magnet with a minimumtrength of 1.5 Tesla and a dedicated breast surface coil,ither unilateral or bilateral, should always be used. Bilateraloils have the advantage in terms of cost, time, and patientonvenience. The set-up must be “open” to allow access forRI-guided biopsy for lesions that are occult on mammo-
ram and targeted ultrasound.59 When technically possible,RI-guided vacuum-assisted biopsies should be performed
s they are highly accurate60,61 and result in significantly lessatient morbidity than MRI-localized open biopsies. Due tohe steep learning curve for MRI, results will be optimal in aenter staffed with experienced MRI technologists and radi-logists who have had special training in breast MRI inter-retation.
reas for Further Researchhile annual screening MRI is currently recommended for
ery high risk women from the age of 25 or 30 onwards, thege at which MRI screening can be safely discontinued is notnown, nor is the optimal screening schedule known forpecific ages and risk categories. Increasing the specificity ofRI would significantly improve its cost-effectiveness. Sev-
ral approaches to this are currently under study includingomputer-assisted detection and proton magnetic resonancepectroscopy.62 With this latter technique malignant lesionsan be distinguished from benign ones due to the presence orbsence of a detectable composite choline signal. Novel con-rast agents and the increasing availability of 3.0 Tesla mag-ets may lead to improvements in sensitivity as well as spec-
ficity.Tomosynthesis is a promising new variation on mammog-
aphy that gives three-dimensional cross-sectional (tomo-raphic) slices of the breast without an increase in themount of ionizing radiation.63 The addition of a contrastgent64 could conceivably result in sensitivity approachinghat of MRI at a much lower cost.
onclusionsnnual MRI plus mammography should now be considered
he standard of care for screening women age 30 or older whore known or likely to have inherited a strong predispositiono breast cancer. Physical examination of the breasts (CBEnd BSE) and ultrasound rarely detect additional cancers.owever, most high-risk women given this information
ould still opt to undergo CBE and BSE.65 Ultrasound should
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Screening for hereditary breast cancer 399
e reserved for the diagnostic evaluation of lesions detectedy other screening modalities but, if MRI is not feasible,ltrasound should probably be added to mammography,articularly for women with dense breasts. Over time thepecificity of MRI is likely to improve and costs to decrease.urther research is necessary to define the optimal screeningchedule for different subgroups, as well as long-term sur-ival rates. While it is tempting to extrapolate results fromereditary cancer studies to other populations of women atigh risk for breast cancer (eg, radiation therapy to chestefore age 30; biopsy showing lobular neoplasia or atypicaluctal hyperplasia; very dense breasts), studies of these spe-ific populations should be done. At present there is noroven role for MRI in screening women at average or mod-rately increased risk for breast cancer.
Finally, in counseling very-high-risk women who are try-ng to choose between risk-reducing mastectomy and screen-ng, the point should be made that, although the sensitivity of
RI is excellent, it is less than 100%. Therefore, women whopt for screening should strongly consider other risk-reduc-ng measures (eg, chemoprevention and/or oophorectomy)nd must be able to accept some risk.
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mutation: prophylactic surgery and screening behavior in women 2years post testing. Am J Med Genet A 118:201-209, 2003
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3. Ries LAG, Harkins D, Krapcho M, et al: SEER Cancer Statistics Review,1975-2003. Bethesda, MD, National Cancer Institute, 2006
4. Wooster R, Weber BL: Genomic medicine: Breast and ovarian cancer.N Engl J Med 348:2339-2347, 2003
5. Narod SA, Brunet JS, Ghadirian P, et al: Hereditary Breast Cancer Clin-ical Study Group. Tamoxifen and risk of contralateral breast cancer inBRCA1 and BRCA2 mutation carriers: A case-control study. Lancet356:1876-1881, 2000
6. King MC, Wieand S, Hale K, et al: Tamoxifen and breast cancer inci-dence among women with inherited mutations in BRCA1 and BRCA2:National Surgical Adjuvant Breast and Bowel Project (NSABP P-1)Breast Cancer Prevention Trial. JAMA 286:2251-2256, 2001
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