Screening for Breast Cancer with MRI

Breast cancer remains the second leading cause of cancer death in women. Mammography is the single large-scale method currently employed in screening for breast cancer in asymptomatic women. Although the effect of mammography in decreasing mortality is debated, multiple studies have shown its efficacy, particularly in patients aged 50 to 69 years. But mammographic imaging has limitations, including patient exposure to ionizing radiation and low sensitivity, especially in women with dense breasts. Between 10% and 15% of cancers may not be detected on mammography because of density of the breast tissue. Additionally, diffuse cancers and lobular carcinomas are often difficult to differentiate from normal glandular tissue on mammography. For this reason, contrast-enhanced magnetic resonance imaging (MRI), which is more sensitive than mammography, has been increasingly employed for screening purposes, in particular in populations with a relatively high lifetime risk of malignancy.

However, MRI is more logistically complex than mammography: screening MRI demands the use of intravenous contrast agent and requires exclusion of patients with magnetic resonance (MR)-incompatible hardware in their bodies. Additionally, for optimal imaging, scans should be timed for days 7 to 14 of the patient’s menstrual cycle to decrease confounding background parenchymal enhancement. Most crucially, MRI is more costly than mammography and may also lead to larger numbers of false-positive determinations and unnecessary biopsies.

In this chapter, we discuss the available literature evaluating MRI breast screening, review current guidelines for MRI breast screening, and consider controversies regarding which populations are considered appropriate candidates for screening.

Search Criteria

In evaluating the literature, we performed a search of the PubMed database using the Medical Subject Heading (MeSH) terms “early detection of cancer,” and/or “breast neoplasms/diagnosis,” and/or “breast,” and/or “magnetic resonance imaging,” and “sensitivity and specificity”; this resulted in 1564 results. After we removed duplicate entries, unrelated articles, case studies, and articles not published in English, a total of 132 articles remained.

High-Risk Groups

At present, the 2007 American Cancer Society (ACS) guidelines recommend annual MRI breast cancer screening for those with a BRCA1 or BRCA2 mutation or those with a first-degree relative with a BRCA mutation. MRI screening is also recommended for people who have a clinical history of radiation to the chest between 10 and 30 years of age and those with specific genetic mutations known to increase the risk of breast cancer such as Li-Fraumeni syndrome ( TP53 gene mutations) and Cowden and Bannayan-Riley-Ruvalcaba syndromes ( PTEN gene mutations), or their first-degree relatives ( Table 4.1 ).

Table 4.1

American Cancer Society 2007 Guidelines for MRI Breast Cancer Screening

Saslow D, Boetes C, Burke W, et al.: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57:75-89, 2007.

Risk	Recommendation
High risk ≥20%-25% lifetime risk of developing breast cancer BRCA1 , BRCA2 or untested first-degree relatives of BRCA mutation carriers Lifetime risk of 20%-25% or more using a breast cancer risk model History of radiation to chest between age 10 and 30 years Presence of genes known to cause Li-Fraumeni, Cowden, Bannayan-Riley-Ruvalcaba, or first-degree relatives of such carriers	Annual MRI breast cancer screening
Moderate risk 15%-20% lifetime risk of developing breast cancer	Insufficient evidence for or against annual MRI
Low risk <15% lifetime risk of developing breast cancer	No screening

Although these known genetic mutations are associated with a lifetime risk of cancer estimated at 50% to 80%, the majority of women with a family history of breast cancer do not have an identified genetic mutation. The ACS recommends annual screening for those with a 20% to 25% or greater lifetime risk of breast cancer, a risk usually assessed by applying models that evaluate family history. Commonly used risk-prediction models include the Gail model, Claus model, and Tyrer-Cuzick model. However, a recent meta-analysis of breast cancer risk-prediction models of 18 prediction models and 7 validating studies found only consistently poor to fair discriminatory accuracy in internal and external validation. Although those models are imperfect, they remain the standard means of assessing risk for the majority of the high-risk population.

The bulk of the large prospective studies evaluating MRI sensitivity and specificity in the literature have been performed on this high-risk population ( Table 4.2 ). Table 4.3 shows that in these studies, MRI specificity (81.0% to 97.2% across studies) is consistently lower than for mammography (93.0% to 99.8%). However, MRI sensitivity (77% to 91% across studies) has consistently been shown to be greater than that of mammography (32.6% to 50.0%). As Table 4.4 shows, the yield for cancer detected on MRI alone in the compared studies ranges from 1.2% to 3.6%.

Table 4.2

Prospective Studies Evaluating MRI Breast Screening: Patient Demographics

Study	Year	Number of Patients	Risk	Mutation Carriers	Number of Patients with a Personal History of Cancer	Modalities
Sardanelli et al.	2011	501	≥25%	330	218 breast and/or ovary	Annual MRI, mammography, ultrasound, CBE x at least 2 rounds ^∗
Hagen et al.	2007	491	BRCA	All	None	Annual mammography, MRI
Lehman et al.	2007	195	BRCA or ≥20% chance of carrying BRCA mutation	80	47	Annual mammography, MRI, ultrasound
Kuhl et al.	2005	529	BRCA or suspected BRCA	43	139	Annual mammography, MRI, 6-month CBE, ultrasound
Leach et al.	2005	649	≥25%	120	None	Annual mammography, MRI
Kriege et al.	2004	1909	≥15%	358	None	Annual mammography, MRI, 6-month CBE
Warner et al.	2004	236	BRCA1 and BRCA2	All	Breast 70 Ovary 22	Annual mammography, MRI, ultrasound, 6-month CBE

CBE, Clinical breast examination.

∗ Clinical breast examination for at least two rounds of screening.

Table 4.3

Prospective Studies Evaluating Sensitivity, Specificity, and Positive Predictive Value of Breast Cancer Screening Modes

Study	Year	MRI: Sensitivity Specificity PPV (%)	Mammography: Sensitivity Specificity PPV (%)	Clinical Breast Exam: Sensitivity Specificity PPV (%)	Ultrasound: Sensitivity Specificity PPV (%)
Sardanelli et al.	2011	91.0 96.7 56.0	50.0 99.0 71.4	17.6 99.3 56.3	52.0 99.0 71.4
Hagen et al.	2007	86.0 NR NR	50.0 NR NR	—	—
Kuhl et al.	2005	91.0 97.2 50.0	32.6 96.8 23.7	—	39.5 90.5 11.3
Leach et al.	2005	77.0 81.0 NR	40.0 93.0 NR	—	—
Kriege et al.	2004	79.5 89.8 60.0 ^∗	33.3 95.0 100 ^∗	17.9 98.1 50.0 ^∗	—
Warner et al.	2004	77.0 95.4 42.0 ^†	36.0 99.8 83.0 ^†	9.1 99.3 NR	33.0 96.0 23.0 ^†

NR, not reported; PPV, positive predictive value.

∗ PPV was analyzed per American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) categories or level of suspicion. Numbers are taken from the BI-RADS 5 or suspicious clinical breast examination category.

† PPV was analyzed per screening year. Percentages are given for year 1.

Table 4.4

Magnetic Resonance Imaging Cancer Detection and Cancer Yield

Study	Year	Cancers		Interval Cancers	Cancers Found		Cancer Yield for MRI Alone (%)
Study	Year	Total	Invasive Breast	Interval Cancers	With MRI	With Mammography	Cancer Yield for MRI Alone (%)
Sardanelli et al.	2011	52	44	3	48	25 ^∗	16/501 (3.2)
Hagen et al.	2007	25	21	5	18	10	8/491 (1.6)
Lehman et al.	2007	6	6	NA (No FUP)	6	2	4/171 (2.3)
Kuhl et al.	2005	43	34	1	39	14 ^†	19/529 (3.6)
Leach et al.	2005	35	29	2	19	6	19/649 (2.9)
Kriege et al.	2004	51 ^‡	44	4	32	18	22/1909 (1.2)
Warner et al.	2004	22	16	1	17	8	7/236 (3.0)

FUP, follow-up; N/A, not applicable.

∗ Seventeen cancers were found with film screen mammography and eight with digital mammography.

† Fourteen cancers were identified by mammography alone, and an additional 21 were identified with combined mammography and ultrasound.

‡ One of the 51 cancers detected was non-Hodgkin lymphoma. Five cancers were excluded from analysis of the modalities.

BRCA1 and BRCA2 Mutation Carriers

Molecular genetic testing is available to determine mutations in germline BRCA1 and BRCA2 in women with a family history of or relatives with known BRCA mutations, although it is important to realize that not all identified mutations have the same clinical presentation. BRCA1 tumors are frequently estrogen receptor (ER) and progesterone receptor (PR) negative as well as HER2/neu receptor negative and are often high grade. Cancers in this group have been shown to grow rapidly and to be larger at diagnosis in an annual screening setting than tumors in other high-risk cases ( Figure 4.1 ). BRCA2 tumors are more likely to be ER and PR positive and to be similar to sporadic cancers ( Figure 4.2 ). If the patient desires treatment rather than surveillance, prophylactic mastectomy, and/or oophorectomy may be pursued. Chemopreventive treatment with tamoxifen has been shown to reduce the risk of receptor-positive tumors for women who are known BRCA1 or BRCA2 mutation carriers.

FIGURE 4.1, This 26-year-old BRCA1 carrier presented with a palpable mass. The parenchyma is extremely dense, and the lesion is occult on mediolateral oblique ( A ) and craniocaudal ( B ) mammographic images. C, Post-contrast T1-weighted subtraction image demonstrates an oval enhancing mass ( circle ). D, The mass is hyperintense on the T2-weighted image ( arrow ). E, Targeted ultrasound shows an oval hypoechoic mass with circumscribed margins and posterior acoustic enhancement ( double arrows ). Final pathology was triple negative invasive ductal carcinoma.

FIGURE 4.2, This 61-year-old BRCA2 mutation carrier presented on screening MRI with a new 6 mm mass seen in the left breast at 5 o’clock ( arrow ) on this T1-weighted postcontrast sagittal image. The mass demonstrated a type II (plateau) kinetic curve. MR-guided biopsy was performed, indicating invasive ductal carcinoma.

Of the seven studies we compare in Table 4.2 , five were performed on BRCA1 and BRCA2 mutation carriers in women with a high-risk family history and two were on BRCA1 and BRCA2 mutation carriers alone. The number of mutation carriers in the studies ranges from 43/529 (8%) to 100% of the total. Some screening trials have shown that when these BRCA1 and/or BRCA2 mutation carriers are analyzed as a subset distinct from other women at high risk of developing cancer, there may be an even greater relative increase in sensitivity of MRI compared with the sensitivity of mammography. For example, Kuhl and colleagues showed that sensitivity for cancer detection was 91% in all women with MRI versus 33% with mammography, but in the cohort of women who were mutation carriers, 100% sensitivity was noted with MRI versus 25% sensitivity with mammography. Of note, however, there were only 8 patients in this subgroup. Kriege and colleagues, who divided their cohort into mutation carriers (50% to 85% lifetime risk), women at high risk of developing breast cancer (20% to 29% lifetime risk), and women at moderate risk (15% to 20% lifetime risk) found the highest cancer detection rate (26.5/1000) to be in women with known genetic mutations ( BRCA1 , BRCA2 , PTEN , and TP53 ) as opposed to women in the non–mutation-carrier high-risk group (5.4/1000) or moderate-risk group (15% to 20% risk; 7.8/1000). Leach and colleagues found that contrast-enhanced MRI was particularly sensitive for BRCA1 cancers relative to mammography (77% for MRI vs. 40% for mammography for all patients and 92% vs. 23% for BRCA1 carriers (13 cancers), probably because of the lower sensitivity of mammography for BRCA1 cancers, as described previously.

Chest Irradiation

Fewer studies have been dedicated to evaluating MRI sensitivity in the subset of women with a history of chest irradiation. Sung and colleagues performed a retrospective review of 247 screening examinations in 91 women who had a history of chest irradiation. Ten cancers were identified in the study period, four on MRI alone (invasive carcinomas) and three with mammography alone (ductal carcinoma in situ [DCIS] and DCIS with microinvasion). The sensitivity of MRI and mammography was identical (66.7%), and the authors conclude that MR imaging is a useful adjunct to mammography ( Figure 4.3 ).

Estimated Size of High-risk Population

How many women fit the aforementioned high-risk criteria for MRI screening in the United States? Using data from the 2000 and 2005 National Health Interview Survey and the National Cancer Institute Breast Cancer Risk Assessment Tool (Gail model 2), Graubard and colleagues calculated that 1.09% of women aged 30 to 84 years have a lifetime absolute breast cancer risk of 20% or more, which at the time of the study entailed 880,063 U.S. women eligible for MRI screening.

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