Early Diagnosis of Hereditary Breast Cancer by Magnetic Resonance Imaging: What Is Realistic?
Authors: Jan G.M. Klijn
Journal: Journal of Clinical Oncology (2010)

A family history of breast cancer is one of the major risk factors for breast cancer. It is estimated that hereditary factors play a causative role in more than 25% of patients. Currently, many genetic alterations associated with highly (4 to 10 ), moderately (2 to 4 ), and slightly (1 to 2 ) increased risk for developing breast cancer have been identified. However, in daily clinical practice, mutations in a few high-risk genes are mainly being determined (ie, BRCA1, BRCA2, TP53, and PTEN). Mutations in these genes are roughly associated with a cumulative life-time risk (CLTR) of 50% to 85% and are characterized by early onset of disease, starting from the age of 25. However, such highly dominant genetic alterations occur in only a small minority (approximately 5%) of patients with breast cancer. In women with a family history of breast cancer without a proven gene mutation, the CLTR of breast cancer varies between 15% and 50% depending on the pedigree and other risk factors. Women with a moderately to highly increased genetic risk of breast cancer have the option to reduce their risk by prophylactic surgery or chemoprevention. Prophylactic bilateral mastectomy reduces the risk of breast cancer by nearly 100% and prophylactic bilateral salpingo-oophorectomy by approximately 50%. Chemoprevention for 5 years reduces the risk by 40% to 50%, but is used by only a very small minority ( 10%) of high-risk women, mainly in North-America. A promising strategy to reduce the risk of breast cancer death in women with a genetic predisposition is early diagnosis by intensive surveillance, usually from the age of 25. In the 1990s, several retrospective and prospective studies were performed assessing the efficacy of yearly mammography screening, sometimes in combination with (semi-annual) clinical breast examination (CBE) and/or ultrasound. Indeed, it was possible to detect breast cancer in a significant number of asymptomatic women, but the sensitivity (40% to 60%) appeared to be low in comparison with the results of population-based mammographic screening in women between 50 and 75 years of age. Especially in carriers of BRCA1/2 gene mutations, interval cancers frequently occurred (ie, in approximately 40% to 60% of breast cancers). Since the late 1990s, a new approach has involved the addition of magnetic resonance imaging (MRI) to yearly mammographic screening. In the past 10 years, results of different pilot studies and large prospective clinical trials investigating this approach have been published—all nonrandomized because of practical and ethical reasons. The first results of five large prospective studies (with at least 20 breast cancers detected) have shown that MRI appears to be about twice as sensitive as mammography in detecting tumors in women with a genetic susceptibility to breast cancer (Table 1 ); in the pooled analysis of Sardanelli involving 3,571 women the sensitivity of MRI was 81% versus 40% similar to the review of Warner of 11 studies (77% v 39%). Subsequently, the application of MRI has been incorporated in national guidelines in various Western countries, but no consensus on the optimal screening protocol exists for all risk groups. Meanwhile, inconsistent results of the sensitivity of MRI in detecting ductal carcinoma in situ (DCIS) have been reported. Currently, in daily clinical practice, the combination of yearly MRI and mammography is being used in women with a genetic risk of breast cancer because mammography adds significantly to the diagnostic accuracy of MRI, especially in DCIS. In Journal of Clinical Oncology, Kuhl et al previously reported on the results of a large single center study performed at the University of Bonn, Germany. In the current issue of JCO, the results of a multicenter trial (the EVA EVAluation of imaging methods for secondary prevention of familial breast cancer trial) coordinated by Kuhl in four German centers are reported. The main objective of the EVA trial was to compare the respective efficacy in terms of cancer yield and stage at diagnosis of CBE, mammography, ultrasound, and quality-assured breast MRI, used alone and in different combinations, for screening of women at elevated risk for breast cancer quantified using the BRCAPRO model. A secondary objective was to investigate the cancer yield of additional half-yearly screening with ultrasound and CBE in a subgroup of 371 women. Six hundred eighty-seven asymptomatic women with a family history of breast cancer (CLTR 20%) were included. Median age was 44 years (range, 25 to 71) and median follow-up was 2.4 years (range, 1.1 to 3.3). In 65 women (9.5%), a BRCA1/2 mutation was documented, while 212 women (including 26 BRCA1/2 mutation carriers) had a personal history of breast cancer (31%). Twenty-seven women were diagnosed with breast cancer (11 of 27 had DCIS) resulting in an overall detection rate of 15.5 per 1,000 woman-years. Nine breast cancers occurred in women with a personal history of breast cancer and five breast cancers occurred in BRCA1/2 mutation carriers. No interval cancers occurred and most tumors were in an early stage. All women were diagnosed with the combination of MRI and mammography. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 28 NUMBER 9 MARCH 2