Breast MRI as an Adjunct to Mammography for Breast Cancer Screening in High-Risk Patients: Retrospective Review
Abstract
OBJECTIVE. In July 2011, the provincial government of Ontario, Canada, approved funding for the addition of annual breast MRI to mammography screening for all women 30–69 years old considered to be at high risk for breast cancer. The purpose of this study was to evaluate the diagnostic performance of screening breast MRI as compared with mammography in a population-based high-risk screening program.
MATERIALS AND METHODS. A retrospective review identified 650 eligible high-risk women who underwent screening breast MRI and mammography between July 2011 and January 2013 at one institution. Results of 806 screening rounds (comprising both MRI and mammography) were reviewed.
RESULTS. Malignancy was diagnosed in 13 patients (invasive cancer in nine, ductal carcinoma in situ in three [one with microinvasion], and chest wall metastasis in one). Of the 13 cancers, 12 (92.3%) were detected by MRI and four (30.8%) by mammography. In nine of these patients, the cancer was diagnosed by MRI only, resulting in an incremental cancer detection rate of 10 cancers per 1000 women screened. MRI screening had significantly higher sensitivity than mammography (92.3% vs 30.8%) but lower specificity (85.9% vs 96.8%). MRI also resulted in a higher callback rate for a 6-month follow-up study (BI-RADS category 3 assessment) than mammography (119 [14.8%] vs 13 [1.6%]) and more image-guided biopsies than mammography (95 [11.8%] vs 19 [2.4%]).
CONCLUSION. MRI is a useful adjunct to mammography for screening in high-risk women, resulting in a significantly higher rate of cancer detection. However, this was found to be at the cost of more imaging and biopsies for lesions that ultimately proved to be benign.
Women with a predisposing genetic mutation (e.g., BRCA1 or BRCA2 mutation), those with a strong family history of breast cancer, and those who have received radiation therapy to the chest when younger than 30 years old have a significantly increased cumulative lifetime risk of breast cancer in comparison with the general population (20–65% vs ~11%) [1–7]. Unfortunately, this risk is also associated with diagnosis at a younger age, with a substantial proportion of cancers occurring in women younger than 50 years old [8]. These factors drive the need for an appropriate screening regimen. Although mammography has been shown to be an effective screening modality in the general population, particularly in women with mammographically nondense breasts, it is less effective in the population of women at higher risk [9, 10]. In part this is due to the increased mammographic density seen at a younger age [11] and the inherent biologic differences of BRCA-linked tumors that may make them mammographically occult or misread as benign [12, 13]. The faster doubling time of tumors in younger women and BRCA mutation carriers (relative to age-matched noncarriers) [14, 15] means that a small missed tumor will most likely present as a larger interval cancer before the next round of screening.
The ability of MRI to detect breast tumors is largely independent of breast density and instead relies on the enhancement characteristics of different tissues. Numerous studies have shown that breast MRI may be a useful adjunct to mammography for screening of high-risk patients, with greater cancer detection rates than mammography alone [5, 16–31]. In light of these emerging data, beginning in July 2011, the provincial government of Ontario, Canada began funding annual breast MRI as an adjunct to mammography for breast cancer screening of all eligible high-risk Ontario women. It was recommended to include women who received therapeutic chest radiation when younger than 30 years old, in addition to women with BRCA or other breast cancer–predisposing gene mutations and those with an estimated lifetime risk of breast cancer greater than 25% (based predominantly on personal or family cancer history), who have constituted the great majority of subjects in prior MRI screening studies. In contrast to other high-risk subgroups, this recommendation was based on expert consensus only, because the data regarding MRI screening in these women were at the time insufficient.
In this article, we retrospectively review our institution’s experience in the first 18 months with the addition of MRI to mammography in a population-based high-risk screening program. In addition, we compare the diagnostic performance of the two modalities.
Materials and Methods
Study Population
With research ethics board approval, a retrospective review of the radiology department database and electronic patient records was performed to find high-risk asymptomatic women who underwent breast cancer screening with MRI and mammography at a tertiary center (Sunnybrook Health Sciences Centre, University of Toronto) between July 1, 2011, and January 1, 2013. As per provincial funding guidelines, eligible women were 30–69 years old and were assessed as being at high risk for breast cancer according to the following criteria: was known carrier of a deleterious gene mutation (e.g., BRCA1 or BRCA2); had estimated lifetime risk of breast cancer greater than 25%, either as an untested first-degree relative of a mutation carrier or via assessment using International Breast Cancer Intervention Studies (IBIS) [32] or Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) [33] breast risk assessment tools; or received chest radiation when younger than 30 years old and at least 8 years previously.
Women meeting the aforementioned criteria for high risk who had a previous breast cancer (treated with breast conservative surgery or unilateral mastectomy) and were continuing breast screening were not excluded. Most women had had prior mammograms, and some had also had one or more prior diagnostic or screening breast MRI study in the years preceding initiation of the screening program. These were available as comparison studies for the radiologist interpreting the screening study. Only screening studies were included, and MRI referrals for follow-up of previously detected findings (e.g., a 6-month or 1-year follow-up) were not included. Screening rounds in which the interval between mammography and MRI exceeded 120 days were excluded.
Imaging Studies
Mammography—Conventional four-view full-field bilateral digital mammograms were obtained. Additional spot magnification views were acquired when judged to be necessary.
MRI—MRI examinations were performed on a 1.5-T system (Signa, GE Healthcare) using a standard dedicated bilateral breast coil (Sentinelle Vanguard, Sentinelle Medical). The MRI protocol was as follows: localizer axial T1-weighted fast spoiled gradient-echo imaging (TE/TR, 4.2/150) through the chest; sagittal T2-weighted fast spin-echo fat-saturated imaging (TE/TR, 88/3000) through both breasts; sagittal T1-weighted fast spoiled gradient-echo imaging (TE/TR, 4.2/9); simultaneous sagittal T1-weighted fat-saturated imaging (TE/TR, 3.2/6.6), including unenhanced and four contrast-enhanced dynamic runs through both breasts using Vibrant (volume imaging for breast assessment, GE Healthcare) (3-mm slices, < 90 s/dynamic run); contrast-enhanced axial 3D fast acquisition with multiphase Efgre3D (enhanced fast gradient-echo 3D) (FAME) with fat suppression (TE/TR, 1.8/7.8); and postprocessing imaging, including subtraction, maximum-intensity-projection (MIP), and 3D reformatted MIP images. Contrast-enhanced images were obtained after a bolus injection of 0.1 mmol/kg of gadodiamide (Omniscan, GE Healthcare). Whenever possible, premenopausal patients were scheduled in the 2nd week of their menstrual cycle.
Image Interpretation and Workup
All MRI and mammography studies were interpreted by one of seven radiologists in the breast imaging division, five of whom received fellowship training in breast imaging and had 1–20 years of experience and the other two of whom had more than 25 years of experience in breast imaging interpretation (but no fellowship training). Results were categorized in accordance with the BI-RADS classification as one of the following [34]: 0, incomplete (additional workup needed); 1, negative; 2, benign; 3, probably benign; 4, suspicious (indeterminate but possibly malignant); 5, highly suggestive of malignancy.
When a lesion was categorized as BI-RADS 3, a 6-month follow-up was recommended. For some MRI studies categorized as BI-RADS 3, a targeted ultrasound was initially recommended to correlate the MRI finding. If the lesion was seen on ultra-sound, additional workup depended on ultrasound characteristics; if it was not seen on ultrasound, follow-up MRI in 6 months was recommended.
Biopsy was recommended for all BI-RADS 4 and 5 lesions, using MRI, ultrasound, or stereotactic guidance. Whenever possible, ultrasound-guided biopsies were performed for MRI and mammographically detected findings. MRI-guided biopsies were performed for sonographically and mammographically occult lesions.
All ultrasound- and stereotactically guided biopsies were performed using a 14-guage core biopsy system. MRI-guided biopsies were performed using a 9-guage vacuum-assisted device.
Statistical Analysis
Results from imaging studies that received a final assessment of BI-RADS category 4 or 5 were considered positive findings. All other results were considered negative findings.
Electronic patient charts were reviewed at least 1 year after a negative result to corroborate the finding. If there was no interval cancer diagnosed, results were considered true-negative.
Results that received a final assessment of BI-RADS category 4 and 5 for which cancer was confirmed by image-guided biopsy or surgically excised specimen within 1 year were considered true-positive. Invasive carcinoma and ductal carcinoma in situ (DCIS) were accepted as positive for malignancy. Biopsy results necessitating surgical excision, such as atypical ductal hyperplasia, were correlated with histopathologic evaluation of the surgical specimen, and if malignancy was found, were considered true-positive. Otherwise, all other histopathologic results, including atypical ductal hyperplasia and lobular carcinoma in situ, were considered negative for malignancy.
False-negative results were those that received a final assessment of BI-RADS category 1, 2, or 3—and therefore considered negative—for which cancer was found within 1 year. False-positive results were those that received a final assessment of BI-RADS category 4 or 5 for which no cancer was found within 1 year.
The diagnostic performance of MRI and mammography was calculated, including sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratios, callback rates, and added cancer yield. Negative studies for which 1-year follow-up did not yet occur were not included in the calculation (part of the true-negative fraction). Comparisons of MRI and mammography were performed using the exact binomial test and Fisher exact test with the aid of a statistician.
Results
A total of 878 screening rounds with MRI and mammography were identified. Of these, 72 screening rounds were excluded because the interval between MRI and mammography exceeded 120 days. (No cancers were found in the 72 excluded MRI and mammography screening rounds.) Therefore, 806 MRI and mammography screening pairs in 650 women were eligible for analysis. The mean number of screening rounds per patient was 1.24.
The demographic characteristics of the study participants are summarized in Table 1. The mean age in our cohort was 45.3 years (range, 30–69 years). A total of 376 women (57.8%) had had at least one prior breast MRI at our institution that was available for comparison during image interpretation. The average number of days between mammography and MRI in the same screening round was 16.1 days (range, 0–120 days). In 328 of the 806 screening rounds (40.7%), the MRI and mammography were done on the same day; in 462 (57.3%), mammography preceded MRI; and in 16 (2.0%), MRI preceded mammography. The interpreting radiologist was not blinded and had full access to the results of any prior imaging investigation—including the screening mammogram if it was performed before MRI, and vice versa. A total of 11 cancers were detected on the first round of screening and two on the second round.
| Parameter | Result |
|---|---|
| Age (y) at first screening, mean (range) | 45.3 (30–69) |
| High-risk category | |
| Deleterious gene mutation | 287 (44.2) |
| BRCA1mutation | 141 (21.7) |
| BRCA2mutation | 144 (22.2) |
| PTENmutation (Cowden syndrome) | 2 (0.3) |
| > 25% estimated lifetime risk | 312 (48.0) |
| Chest radiation when younger than 30 years olda | 51 (7.8) |
| Prior breast cancer | 49 (7.5) |
| Prior MRI | 376 (57.8) |
| Screening rounds completed | |
| First round only | 650 (100) |
| First and second rounds | 156 (24) |
Note—Except where otherwise indicated, data are given as no. (%).
a
For treatment of Hodgkin lymphoma in all patients.
MRI Screening Studies
Of the 806 MRI screening rounds, a final assessment of BI-RADS category 1 or 2 was made in 608 studies (75.4%), BI-RADS 3 in 119 studies (14.8%), BI-RADS 4 in 78 studies (9.7%), and BI-RADS 5 in one study (0.1%) (Table 2). For the 119 BI-RADS 3 assessments, an initial targeted ultrasound was recommended in 80 cases (67.2%). This resulted in an ultrasound-guided biopsy in eight cases, on all of which the findings were benign (five lesions were upgraded to BI-RADS 4 assessment based on ultrasound findings, two were categorized as BI-RADS 3 lesions on ultrasound but the patients opted for biopsy; and in one case, an incidental mass was discovered that was unrelated to the MRI finding). At the 6-month follow-up MRI, seven lesions evolved or were new (two in one patient) and were biopsied. One of these revealed an invasive ductal carcinoma (counted as a false-negative for the purposes of statistical analysis because the initial MRI finding was “negative”), and the rest were benign.
| Parameter | MRI | Mammography |
|---|---|---|
| BI-RADS category | ||
| 1 or 2 | 608 (75.4) | 774 (96.0) |
| 3 | 119 (14.8)a | 13 (1.6) |
| 4 | 78 (9.7)b | 17 (2.1)c |
| 5 | 1 (0.1)d | 2 (0.2)e |
| No. of biopsies triggered | 95 (11.8) | 19 (2.4) |
| MRI guided | 68 (71.6) | |
| Ultrasound guided | 27 (28.4) | 13 (68.4) |
| Stereotactically guided | 6 (31.6) | |
| Cancers detected | ||
| DCIS or invasive cancer | 12 (1.5) | 4 (0.5) |
| Cancer yieldf | 15 | 5 |
Note—Except where otherwise indicated, data are shown as no. (%). US = ultrasound, DCIS = ductal carcinoma in situ.
a
Initially 80 patients received callback for ultrasound correlation, eight of whom were upgraded to ultrasound-guided biopsy. At 6-month follow-up, six patients were upgraded to MRI-guided biopsy one to ultrasound-guided biopsy.
b
61 MRI-guided biopsies (two-site biopsies in seven patients) and 18 ultrasound-guided biopsies triggered. Five MRI-guided biopsies were aborted because suspicious enhancement no longer seen, and one was canceled because patient did not return.
c
Six stereotactically guided and 11 ultrasound-guided biopsies triggered.
d
Single MRI-guided biopsy triggered.
e
Two ultrasound-guided biopsies triggered.
f
No. of cancers per 1000 women screened.
The 78 BI-RADS 4 assessments resulted in 61 MRI-guided biopsies (two-site biopsies in seven patients), 18 ultrasound-guided biopsies, five attempted MRI-guided biopsies that were aborted because previously identified suspicious enhancement was no longer seen (these were followed up with a 6-month MRI), and one patient who did not return for a biopsy. Pathology revealed seven invasive ductal carcinomas (three of which were also seen on mammography), three DCISs, one chest wall metastatic adenocarcinoma with features suggestive of a breast primary (in a BRCA2 mutation–positive patient with a history of ipsilateral breast and ovarian cancer), five ADH lesions, and the rest were benign. The only lesion given a BI-RADS 5 assessment was subsequently biopsied with MRI guidance and shown to be benign.
A previous MRI was available for comparison in 541 of the 806 screening rounds (67.1%) and unavailable for 265 (32.9%). This greatly influenced the rate of callbacks for follow-up imaging or biopsy. The call-back rate for a 6-month follow-up MRI (BI-RADS 3) or an image-guided biopsy (BI-RADS 4 or 5) was significantly lower for studies with a previous MRI for comparison (10.2% for BI-RADS 3, 7.4% for BI-RADS 4 and 5 [17.6% cumulative for BI-RADS 3–5]), as opposed to studies where no such comparison was available (24.2% for BI-RADS 3, 14.7% for BI-RADS 4 and 5 [38.9% cumulative for BI-RADS 3–5]).
Mammography Screening Studies
Of the 806 mammography screening studies, 707 (87.7%) received an initial assessment of BI-RADS category 1 or 2, and 99 (12.3%) received an initial assessment of BI-RADS category 0 and therefore required further workup. Of the latter, 67 were subsequently categorized as BI-RADS 1 or 2, 13 as BI-RADS 3, 17 as BI-RADS 4, and two as BI-RADS 5. The final BI-RADS assessments are given in Table 2.
The 17 BI-RADS 4 assessments resulted in 11 ultrasound-guided biopsies and six stereotactically guided biopsies. Of these, histology revealed two invasive carcinomas (one of which was also seen on MRI), and the rest of the lesions were benign.
Only two BI-RADS 5 assessments were given. Both resulted in a diagnosis of invasive carcinoma after an ultrasound-guided biopsy. (Both were also seen on MRI.)
MRI Versus Mammography
MRI resulted in a higher callback rate for a 6-month follow-up study (BI-RADS 3 assessment) than did mammography (119 [14.8%] vs 13 [1.6%] of studies). Similarly, there was a much higher rate of MRI-triggered biopsies (from pooled BI-RADS 3–5 assessments) than mammography-triggered biopsies. A total of 95 biopsies (11.8% of all MRI screening examinations) were performed as a result of findings on MRI screening, as compared with only 19 (2.4%) after mammography screening examinations. A diagnosis of malignancy was made in 12 of all MRI biopsies (12.6%), as compared with four (21.1%) of the mammography-triggered biopsies. The cancer yield from MRI was 1.5% versus only 0.5% for mammography (Table 2), resulting in an incremental cancer detection rate of 10 cancers per 1000 women screened for MRI in comparison with mammography.
Of the 806 screening rounds, 488 were included in the calculation of sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios. The studies that were excluded from analysis were studies with negative findings for which 1-year follow-up did not yet occur (i.e., such that the true-negative or false-negative status could not be confirmed). These results are shown in Table 3. The sensitivity of MRI was 92.3% (95% CI, 66.7–99.6%), and this was statistically significantly higher than the 30.8% (95% CI, 12.7–57.6%) sensitivity of mammography. However, the specificity of MRI (85.9% [95% CI, 82.5–88.7%]) was significantly lower than the specificity of mammography (96.8% [95% CI, 94.9–98.1%]).
| Parameter | MRI | Mammography | pa |
|---|---|---|---|
| Sensitivity | 92.3 (66.7–99.6) | 30.8 (12.7–57.6) | 0.0215 |
| Specificity | 85.9 (82.5–88.7) | 96.8 (94.9–98.1) | < 0.0001 |
| Positive predictive value | 15.2 (8.9–24.7) | 21.1 (8.5–43.3) | |
| Negative predictive value | 99.8 (98.6–100) | 98.1 (96.4–99) | |
| Positive likelihood ratio | 6.54 (4.99–8.59) | 9.74 (3.75–25.33) | |
| Negative likelihood ratio | 0.09 (0.01–0.59) | 0.71 (0.5–1.03) |
Note—Except where otherwise indicated, data are shown as % (95% CI).
a
p< 0.05 was considered threshold of statistical significance.
Breast Cancers
A total of 13 cancers (nine invasive cancers, three DCISs [one with microinvasion], and one chest wall metastasis) were found in 13 women. The characteristics of the patients, imaging findings, and tumor stage are summarized in Table 4. The mean age of the women was 45.3 years (range, 30–60 years). Only three of these women (23.1%) had a history of breast cancer. Six women (46.2%) were BRCA1 mutation carriers, three (23.1%) were BRCA2 mutation carriers, two (15.4%) had an estimated lifetime risk of breast cancer greater than 25%, and one (7.7%) had a history of prior chest radiation at age 29 years for treatment of Hodgkin lymphoma.
| Patient | Age (y) | High-Risk Category | Screen | Prior Breast Cancer? | Mammographic Breast Densitya | Prior MRI? | MRI Findings | Mammographic Findings | US Correlate | Image-Guided Biopsy | Histopathology | Tumor Size (cm) | Tumor Grade (I–III) | Lymph Node Status |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 35 | BRCA2mutation | 1 | No | 3 | Yes | − | Ca2+ | − | Stereo | ILC | 1.4 | II | − |
| 2b | 50 | > 25% lifetime risk | 1 | No | 3 | No | 0.6-cm mass | − | NP | MRI | IDC | 0.4 | II | − |
| 3 | 46 | Prior chest radiation | 2 | No | 3 | No | 0.6-cm mass | Spiculated mass | + | US | IDC | 0.6 | I | − |
| 4 | 58 | BRCA1mutation | 1 | No | 2 | No | 0.5-cm mass | − | + | US | IDC | 0.5 | III | − |
| 5 | 44 | BRCA1mutation | 2 | Yes (CL) | 3 | Yes | 2.8-cm clumped NME | − | − | MRI | IDC | 1.0 | III | 2/4 |
| 6 | 43 | BRCA2mutation | 1 | No | 3 | Yes | 2.8-cm linear NME | − | NP | MRI | DCIS | 2.2 | II | − |
| 7 | 36 | BRCA1mutation | 1 | No | 2 | No | 1.0-cm mass | − | + | US | IDC | 1.1 | III | − |
| 8 | 60 | BRCA1mutation | 1 | No | 3 | No | 2.8-cm mass | Distortion; Ca2+ | + | US | IDC | 1.6 | II | − |
| 9 | 30 | > 25% lifetime risk | 1 | No | 3 | No | 0.5-cm mass | − | NP | MRI | IDC | 0.3 | II | − |
| 10c | 59 | BRCA2mutation | 1 | Yes (IL) | 1 | Yes | Chest wall enhancement | − | NP | CT | ACA, breast primary | NA | NA | NA |
| 11d | 38 | > 25% lifetime risk | 1 | No | 3 | No | 0.6-cm mass | − | NP | MRI | DCIS | < 0.1 | I | − |
| 12e | 41 | BRCA1mutation | 1 | Yes (IL) | 1 | Yes | 1.3-cm linear NME | − | − | MRI | DCISf | 1.5f | IIIf | NA |
| 13 | 49 | BRCA1mutation | 1 | No | 2 | Yes | 1.1-cm mass | Mass | + | US | IDC | 1.0 | III |
Note—US = ultrasound, Stereo = stereotactic; CL = contralateral, IL = ipsilateral, NME = nonmass enhancement, Ca2+ = calcifications, NP = not performed, NA = not applicable, IDC = invasive ductal carcinoma, ILC = invasive lobular carcinoma, DCIS = ductal carcinoma in situ, ACA = adenocarcinoma. Dashes denote negative findings.
a
Scored from 1 to 4 as follows: 1, predominantly fatty; 2, scattered fibroglandular densities; 3, heterogeneously dense; 4, very dense.
b
Initial screening MRI was categorized as BI-RADS 3; at follow-up MRI at 6 months, cancer was diagnosed.
c
Suspicious chest wall enhancement at initial screening MRI, so correlation with chest CT and consideration for biopsy was suggested. CT-guided biopsy of the chest wall was eventually done at 6-month follow-up, and cancer was diagnosed.
d
Initial MRI-guided biopsy sample showed only atypical ductal hyperplasia at pathology. At subsequent lumpectomy, microscopic focus of DCIS was diagnosed.
e
Sentinel node sampling was attempted, but no axillary lymph nodes were identified; any lymph nodes were likely removed during prior sentinel node sampling as part of workup and treatment of ipsilateral breast cancer 3 years previously.
f
Microinvasion (< 0.1 cm) was detected at pathology. However, microinvasive focus was not assigned tumor grade.
Overall, MRI diagnosed 12 of the 13 cancers (92.3%) detected at screening, whereas only four of the 13 cancers (30.8%) were diagnosed by mammography. Nine of these cancers (69.2%) were seen on MRI alone (Figs. 1 and 2), one (7.7%) on mammography alone, and three (23.1%) on both MRI and mammography (Fig. 3). With the exclusion of the chest wall metastatic adenocarcinoma, of the other 11 MRI diagnosed cancers, eight (72.7%) were seen as an enhancing mass on MRI, with an average size of 0.9 cm (range, 0.5–2.8 cm). An initial targeted ultra-sound for correlation was performed in seven of the MRI-detected cancers and was able to identify the lesion in five of the seven patients (71.4%), all of whom had an enhancing mass on MRI. The two patients in whom ultrasound correlation was negative had nonmass enhancement on MRI. The one cancer that was only diagnosed on mammography was seen as microcalcifications (Fig. 4). All but two of the cancers (84.6%) were diagnosed in the first round of screening.
Fig. 1A —41-year-old woman with BRCA1 mutation. Screening mammogram findings were negative.
A, Mediolateral oblique view from digital mammography shows only peripherally calcified oil cyst.
Fig. 1B —41-year-old woman with BRCA1 mutation. Screening mammogram findings were negative.
B, Sagittal subtraction maximum-intensity-projection breast MR image obtained from first dynamic series shows linear nonmass enhancement (circle) in right upper outer quadrant. This was biopsied with MRI guidance and was diagnosed as ductal carcinoma in situ. Tiny (< 1 mm) focus of microinvasion was found on subsequent lumpectomy.
Fig. 2A —44-year-old woman with BRCA1 mutation. Screening mammogram findings were negative.
A, Mediolateral oblique view shows heterogeneously dense breast and metallic clip from previous biopsy.
Fig. 2B —44-year-old woman with BRCA1 mutation. Screening mammogram findings were negative.
B, Sagittal subtraction maximum-intensity-projection breast MRI obtained from first dynamic series shows large region of mass and clumped nonmass enhancement (arrows) in right upper breast.
Fig. 2C —44-year-old woman with BRCA1 mutation. Screening mammogram findings were negative.
C, ROI (circle) placed on central enhancing component shows washout kinetics. Subsequent MRI-guided biopsy and excision showed high-grade in situ and invasive ductal carcinoma.
Fig. 3A —46-year-old woman with history of Hodgkin lymphoma treated with chest radiation when 29 years old.
A, Mediolateral oblique view from digital mammography shows heterogeneously dense breast and new spiculated mass (circle) in posterior third.
Fig. 3B —46-year-old woman with history of Hodgkin lymphoma treated with chest radiation when 29 years old.
B, Sagittal subtraction maximum-intensity-projection breast MRI obtained from first dynamic series shows corresponding enhancing mass (circle) in upper breast.
Fig. 3C —46-year-old woman with history of Hodgkin lymphoma treated with chest radiation when 29 years old.
C, Targeted ultrasound image of left breast shows corresponding irregular solid hypoechoic mass (calipers) at 11 o’clock 5 cm from nipple. Mass was subsequently biopsied with ultrasound guidance and diagnosed as invasive ductal carcinoma.
Fig. 4A —35-year-old woman with BRCA2 mutation. Screening MRI findings were negative.
A, Mediolateral oblique view (A) and corresponding magnification view (B) from digital mammography show small new cluster of suspicious pleomorphic calcifications (circle) in left breast. Subsequent stereotactically guided biopsy of calcifications showed in situ ductal carcinoma, with invasive lobular carcinoma found on histopathology of excised sample.
Fig. 4B —35-year-old woman with BRCA2 mutation. Screening MRI findings were negative.
B, Mediolateral oblique view (A) and corresponding magnification view (B) from digital mammography show small new cluster of suspicious pleomorphic calcifications (circle) in left breast. Subsequent stereotactically guided biopsy of calcifications showed in situ ductal carcinoma, with invasive lobular carcinoma found on histopathology of excised sample.
Fig. 4C —35-year-old woman with BRCA2 mutation. Screening MRI findings were negative.
C, Sagittal subtraction maximum-intensity-projection breast MR image obtained from first dynamic series shows no suspicious enhancement in region of calcifications on mammogram.
The mean size of the invasive cancers was 0.9 cm (range, 0.3–1.6 cm). Only one patient had documented lymph node metastases. In patient 2, the initial MRI examination was categorized as BI-RADS 3 and a 6-month follow-up MRI was recommended. At this follow-up MRI, a new rapidly enhancing 0.6-cm mass with delayed washout was found, which proved on pathology to be an invasive cancer. This was therefore scored as an MRI-detected cancer but considered a false-negative screening result (interval cancer) for the purposes of statistical analysis because the initial MRI assessment was BI-RADS 3 (considered “negative” in our study). Patient 10 had a complicated history of both ovarian and breast cancer. The initial screening MRI showed a suspicious area of enhancement in the ipsilateral breast and abnormal enhancement in the ipsilateral chest wall. An MRI-guided biopsy was recommended for the breast lesion (which was negative), and correlation with chest CT, along with possible CT-guided biopsy, was suggested for the chest wall enhancement. This was not initially performed, but the patient returned for a follow-up MRI in 6 months, at which time the chest wall enhancement had progressed and CT-guided biopsy was again recommended. This was subsequently performed, and histopathology revealed metastatic adenocarcinoma with features most supportive of a primary breast cancer; however, no definitive breast primary tumor was detected on follow-up imaging within 1 year. This was considered a true-positive MRI-detected malignancy because the initial screening MRI correctly characterized the chest wall enhancement as suspicious. For patient 11, initial MRI-guided biopsy showed atypical ductal hyperplasia only; however, subsequent lumpectomy specimen revealed a focus of DCIS. This was therefore scored as an MRI-detected malignancy.
Discussion
Our retrospective study of 650 women who underwent 806 MRI and mammography screening rounds has shown the sensitivity of MRI (92.0%) to be statistically higher than the sensitivity of mammography (30.8%); however, this was at the cost of decreased specificity (85.9% for MRI vs 96.8% for mammography). The addition of MRI resulted in an incremental cancer yield of 10 cancers per 1000 women screened as compared with mammography.
Our findings are in accordance with multiple other studies that have investigated the use of MRI screening in women at high risk for breast cancer. In 2008, Warner et al. [29] published a meta-analysis of 11 such prospective, nonrandomized studies. The sensitivity of MRI was higher than mammography in all studies, ranging from 64% to 100%, whereas the sensitivity of mammography ranged from 32% to 40%. In all but one study, by Kuhl et al. [20], the specificity of MRI was lower than that of mammography.
We considered only BI-RADS category 4 and 5 assessments to be positive findings. However, some studies have also considered BI-RADS category 3 assessments to be positive findings [17, 21, 23].
Although limited by its retrospective design, our study is notably different from most of the aforementioned major studies in that it reflects the results of high-risk screening in an everyday clinical setting, rather than within the confines of a clinical trial, where factors such as patient recruitment and selection of test interpreters are carefully manipulated and optimized. All of the radiologists in our breast imaging division participated in image interpretation, some of whom were only in their 1st year of practice; this is in contrast to the usual practice of employing only experienced readers in clinical trials [19, 30, 31].
Because this study was part of a provincially funded population-based program, no payer restraints limited access to the offered screening. Furthermore, because Canada has a universal health care system, no financial barriers existed to receiving appropriate diagnostic investigation or treatment as a result of the screening.
The prevalence of pure DCIS among the 12 primary cancers in our study was only 17% (25% if the case with microinvasion is included), similar to other studies, where its prevalence ranged from 8% to 28% [29]. This may in part be due to the inherently low prevalence of DCIS in BRCA1 mutations carriers, where invasion is thought to occur at an early stage of cancer development [35, 36]. Regardless, MRI proved to be much better than mammography at detecting in situ disease in our study, given that all three of the noninvasive cancers (DCISs) were detected by MRI alone. Of the eight invasive cancers detected by MRI, 75% were 1 cm in size or smaller (mean, 0.8 cm [range, 0.3–1.6 cm]), and only one (12.5%) was node positive. This is comparable to the data reported in the meta-analysis by Warner et al. [29], where more than 50% of the cancers detected on MRI were in situ or no larger than 1 cm, and 12–21% were node positive. In contrast, 50% of the invasive cancers detected by mammography in our study were larger than 1 cm, with an average size of 1.2 cm (range, 0.6–1.6 cm). Prior studies examining conventional mammography-based screening in high-risk women with BRCA mutations showed similarly disappointing results, with very few cases of DCIS detected, 40–78% of the invasive tumors being greater than 1 cm in size, and 20–56% being node positive [9, 10, 27, 37, 38]. The relatively poor performance of mammography has been attributed to the younger age of these high-risk women and the inherent biology of BRCA mutation–positive tumors. Younger age is associated with higher average breast density and faster tumor doubling time, whereas BRCA mutation–positive tumors exhibit a faster growth rate and may have round and pushing margins that may lead to their being misread as benign [11–15, 27]. Although there is no proof that the addition of breast MRI screening improves the survival rate of high-risk women, the assumption is that earlier detection of in situ disease and smaller tumors will likely allow better outcomes. However, long-term follow-up studies tracking distant disease-free survival in high-risk women are needed to corroborate this assumption.
The majority of the breast cancers in our study were detected in women with BRCA mutations. This was not surprising, given that they are at the highest risk, with a reported lifetime cumulative risk of breast cancer as high as 84% in some patients [8].
The majority of MRI-detected cancers in our study were seen as small enhancing masses, with an average size of 0.9 cm. About half of these could be correlated with a finding on a targeted ultrasound and consequently could be biopsied with ultrasound guidance—a much faster and cheaper procedure, as well as more comfortable for the patient. However, about half the cases necessitated MRI-guided biopsy; therefore, the capability to perform MRI-guided biopsies is essential for any center that offers MRI breast cancer screening. Nonmass enhancement was seen less commonly and was associated with DCIS. As expected, these lesions could not be detected on ultrasound.
In addition to women with BRCA mutations and elevated risk owing to various family history factors, our study included a subgroup of women not well studied previously—those who had received chest radiation when younger than 30 years old. The most recent (2007) revision of the American Cancer Society guidelines [39] includes breast MRI in the annual screening of high-risk women; nevertheless, the recommendation for MRI screening in this subgroup is based on expert consensus only, because the data on the results of breast MRI screening in these women are insufficient. In our study, 51 such patients were included, and one of the 13 cancers detected was in a 46-year-old woman who had received chest radiation when 29 years old for treatment of Hodgkin lymphoma. However, the cancer was detected concurrently on both MRI and mammography, which in this case does not inform as to the potential efficacy of one modality over the other. A recent retrospective review by Freitas et al. [16] reported on 98 women with a history of chest radiation who were screened with MRI and mammography and found that the sensitivity of MRI was 92% and the sensitivity of mammography was 69%, but this difference was not statistically significant. Further studies are therefore needed to clarify the utility of breast MRI screening in this subgroup.
Apart from its higher cost, the main drawback of MRI screening is the reduced specificity, which results in a much higher proportion of callbacks for additional imaging or follow-up, as well as a higher rate of benign biopsies. However, as was evident in our study, the callback rate significantly decreases if there is a previous MRI available for comparison. Logically, this is because any finding that was suspicious on a prior scan and determined to be benign would no longer be considered suspicious on the subsequent study. Similar findings were observed in other studies where the rate of callbacks from MRI decreased after the first round of screening [19, 29, 30].
The main limitation of our study is its retrospective design. This resulted in irregular time intervals between the MRI and mammography examinations performed in the same screening round and led to the exclusion of some cases from analysis. Furthermore, we were limited by our sample number and length of follow-up, with an average of only 1.24 rounds of screening per patient. The rates of prevalent versus incident cancers therefore could not be evaluated. Limited 1-year follow-up for negative studies led to the exclusion of a significant number of cases from statistical analysis. Furthermore, unlike a clinical trial, the radiologists interpreted the MRI and mammography studies in a clinical setting and thus were not blinded to the results of any prior investigations—including the screening mammogram if it was performed before MRI, and vice versa. It could therefore be argued that for the three cases in which a cancer was detected on both studies, the MRI was not truly a “screening” examination because the radiologist was already looking for an abnormality on the basis of the mammographic findings. However, there could not have been any bias for the other nine cancers diagnosed on MRI alone (because the mammographic findings were reported as normal) or for the lone cancer that was diagnosed on mammography alone (because the MRI findings were reported as normal).
Finally, there was some heterogeneity in the interpretation of screening studies, given that some patients had a prior MRI for comparison (performed either in the years before initiation of screening or during the first round of screening and available for comparison in the second round) whereas others did not. As expected, callback rates for additional investigations were significantly lower for studies that had a previous MRI for comparison than for those that did not. This may have also influenced the overall calculated sensitivity of MRI in our study; however, the sensitivity of 92.0% is in a range that was also seen in other clinical trials [29].
In addition to the aforementioned uncertainties, the most important of which is the yet-unknown impact of MRI screening on breast cancer mortality, further research will be needed to evaluate the utility of MRI in other high-risk groups (e.g., women with a history of a high-risk lesion on biopsy, those with very dense breasts, or those with breast cancer at a young age), as well as to determine the optimal age at which to begin and end screening and the optimal screening interval. These factors may vary for various high-risk subgroups—on the basis of their estimated cumulative risk, age, and breast density—and have yet to be determined.
In conclusion, despite the limitations mentioned, our study supports the addition of breast MRI to mammography in a population-based screening program for high-risk women. Its use has resulted in a significantly higher rate of cancer detection, although at the cost of more imaging and biopsies for lesions that ultimately proved to be benign.
Acknowledgment
For his help with statistical analysis, we thank George Tomlinson (Dalla Lana School of Public Health and Department of Medical Imaging, University of Toronto).
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Submitted: November 17, 2013
Accepted: July 15, 2014
First published: March 20, 2015
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