The clinical impact of MRI screening for BRCA mutation carriers: the first report in Japan

The most significant finding of the current study is the difference in size between the lesions detected by MRI and the lesions detected by other modalities (5 mm vs 26 mm; P = 0.004). Of MRI-detected lesions, two cases were diagnosed by MRI-guided biopsy; one patient underwent both MRI screening exam and MRI-guided biopsy at her own expense because it was not covered by national health insurance yet at that time, as only since April 2018 has MRI-guided biopsy been covered by the national health insurance; the other lesion was the first case reported as having undergone MRI-guided biopsy for high-risk patients through coverage of the national health insurance. On the other hand, the third case was visible on second-look US and diagnosed by US-guided biopsy. A similar such case of HBOC surveillance was reported by Tozaki et al. [7]. These two cases will be part of a larger surveillance study, which is supported by the Health Labor Science Research Grant and is still ongoing. The MRI-detected lesions were all associated with BRCA1 mutation. These cases may not be unusual in countries outside of Japan where “quality-assured MRI screening” [8] is standard of care for high-risk patients. Guidelines for this screening modality are outlined in the ACS 2007 [4] and NCCN Guidelines Version 1. 2018 for Genetic/Familial High-Risk Assessment (http://​www.​nccn.​org). As part of high-quality breast MRI screening, ability to perform biopsy under MRI guidance is a required condition.

In Japan, however, the studies of MRI-guided biopsy were reported only by Tozaki et al. [9, 10] and this study is the first report about cases of MRI-guided biopsy performed for high-risk patients. Due to the lack of coverage by national health insurance, MRI-guided biopsy was not widely accessible before April 2018. Therefore, most of the facilities generally performed US-guided biopsy for MRI-detected lesions. As found by Sakamoto et al. [11], the false-negative rate of US-guided biopsy for MRI-detected lesions (26%; 8/31) was significantly higher than that for US-detected lesions (3.5%; 5/144) (P = 0.0002). They concluded that MRI-guided biopsy was required for MRI-detected lesions.

According to the most recent Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer released in 2018, CRRM is strongly recommended for patients who have developed breast cancer associated with HBOC. This guideline was not available before the initiation of national insurance coverage of MRI-guided biopsy. It is necessary to review the utility of MRI-guided biopsy from the viewpoint of cost-effectiveness in the current environment when it is covered by the national health insurance. In addition to the guidelines regarding CRRM, we further recommend MRI screening and MRI-guided biopsy, given that they improve early detection as evidenced by the fact that the three MRI-detected lesions in our series were very small, at an average size of 5 mm.

Our study included two prophylactic mastectomies with BRCA2 cancers, which were diagnosed as DCIS (4 mm and 8 mm in extent, respectively). They were both undetected by any modalities during pre-operative evaluation. Findings of previous studies showed that most of the lesions diagnosed by CRRM were DCIS [12]. It is important for high-risk women to obtain diagnosis by excision of tumors at an early stage such as DCIS. On the other hand, one of the three MRI-detected lesions was diagnosed as DCIS with the size of 3 mm in our study. Though this result does not prove that MRI screening surveillance is superior to CRRM, we may consider providing this option to patients as well as CRRM. Previous studies indeed suggested MRI surveillance might be more suitable for the detection of contralateral breast cancer compared with other modalities [13, 14].

These features have been discussed in the past, as breast cancer with BRCA1 mutation carriers has the tendency to develop rapidly growing triple-negative cancer with poor prognosis [2, 15]. Rijnsburger et al. [16] also showed that results in the BRCA1 group were worse compared to the BRCA2 for mammography sensitivity, tumor size at diagnosis, proportion of DCIS and interval cancers, and age at diagnosis. As the result of Japanese data by Nakamura et al. [17], the proportion of triple-negative cancer in BRCA-positive tumors was larger than that of BRCA2-positive tumors (BRCA1, 62.2% [23/37]; BRCA2, 14.3% [5/35]). The result of Vreeman et al. [18] demonstrated that MRI surveillance is insufficient for BRCA1 mutation carriers because the sensitivity of a combined annual MR examination with mammography breast cancer screening program in BRCA1 mutation carriers was the lowest (81.3%) compared with other groups (BRCA2, 92.0%; family history, 95.2%; personal history, 91.1%). The previous study by Kuchenbaecker et al. [19] on contralateral breast cancer showed a 20-year cumulative risk after breast cancer diagnosis in 40% of BRCA1 carriers and 26% of BRCA2 carriers (hazard ratio for comparing BRCA2 vs BRCA1, 0.62; 95% CI 0.47–0.82; P = 0.001). These results suggest the need for a tailored management plan based on the risk stratification of the high-risk groups in Japan. CRRM might be recommended for BRCA1 cancers, while BRCA2 cancers may avoid CRRM through the use of thorough MRI surveillance and improvements in the indication and the technical skills required in MRI-guided biopsy. The data gleaned from the three cases of MRI-detected lesions in BRCA1 mutation carriers discussed in our study would be valuable in developing such a surveillance plan in Japan.

BRCA1 tumors did not present as microcalcifications on mammography, but rather as masses on MRI. In addition, no DCIS was observed in BRCA1-positive cancers. As reported by Kuhl et al. [20], BRCA1 tumors tend to grow rapidly, and as a result, having imaging characteristics of a benign tumor, such as a fibroadenoma or cyst. It is, therefore, crucial for radiologists to be vigilant in the imaging diagnosis, as well as the management decisions regarding proper follow-up interval for surveillance. For BRCA2 mutation carriers, however, six lesions showed non-mass enhancement, and all these involved microcalcification with luminal subtype. Four of these cases were diagnosed as DCIS. Thus, the fact that while BRCA1- positive tumors have potentially aggressive characteristics to develop triple-negative cancers, BRCA2-positive tumors are more likely to present as luminal type or DCIS, which is reflected in the imaging features of these lesions for our study population, a finding that is consistent with the previous studies [2, 3].

Based on our results, the sensitivity of mammography was 84.7% (50/59). Such high sensitivity is also consistent with the results of previous studies [2, 3]. However, other studies reported lower mammography sensitivity [21, 22]. Ha et al. [2] reported that high detectability on mammography might be partly due to the stage of patients with breast cancer registered in the study. Relatively large size at the time of diagnosis on MRI was indeed common in the current study, as shown in Table 4. Another possible explanation for the observed high sensitivity of mammography may relate to diagnostic suspicion bias in these retrospective studies.

Mammography as surveillance for high-risk patients requires discussion about the age at which mammography surveillance is recommended and potential benefits. As shown in NCCN guidelines, the combination of MRI and mammography is recommended for high-risk patients older than 30 years, which is based on a study using a computer simulation modeling [23]. Mammography indeed makes a significant contribution through its ability to detect microcalcifications. Phi et al. [24] reported that mammography’s specific ability to detect microcalcifications is especially valuable in BRCA2 mutation carriers because the proportion of calcified DCIS in women who are BRCA2 mutation carriers was larger than that of women who are BRCA1 mutation carriers.

Two additional issues about the significance of mammography warrant further discussion. The first is the issue about breast density, and the second is about pathological grade. The strong tendency of high-risk groups to have dense breast tissue is known [25]. The rate of Japanese women with dense breasts is especially higher than Western people [26‐28]. In addition, it has been suggested that breast density is associated with the risk of breast cancer [29, 30]. Indeed, the rate of dense breasts in our study was relatively higher than the rate found in previous Western studies about imaging features of high-risk women [3, 20]. Sawada et al. [26] also reported that the false-negative rate for Japanese women with dense breasts was high. For our current study, in all the cases where mammography was unable to detect the lesions, the breast density was described as either heterogeneous or extreme density. Furthermore, our results did not include any breast cancer cases that were MR negative and mammography positive. Previous studies also demonstrated that the sensitivity of MRI is superior to that of mammography for follow-up in high-risk groups [8, 16, 21, 31‐34]. The result of the study by Kuhl et al. [35] showed that 83% of the cases of only mammography-positive DCIS were non-high grade although 60% of DCIS diagnosed by MRI alone were high grade. They also suggested that some of the cases of DCIS diagnosed by mammography were biologically benign and would never threaten a woman’s life. As the result of other studies [34, 36, 37], BRCA mutation carriers younger than 40 years may not benefit from mammography in addition to MRI, because they rarely develop MRI-occult breast cancers. We must also not forget the critical issue of the susceptibility to the mutagenic effects of radiation [38]. According to the EVA trial [8], which was a prospective multicenter observational cohort study looking at 687 women at elevated familial risk, women undergoing quality-assured MRI annually would not require mammography, ultrasound, or even clinical breast exam. MRI alone was sufficient for cancer detection, especially in the preinvasive stage. In the future, larger population-based studies evaluating the added value of mammography will be needed for the development of a surveillance system and risk models in Japan.

The current study demonstrated that lesions associated with BRCA mutation carriers tended to develop in the posterior portion of the breast (Table 4). This result is also consistent with the study by Schrading et al. [20] and Ha et al. [2]. Triple-negative breast cancers have a tendency toward a posterior portion [39]. We believe the results of these reports are related to the tendency of BRCA1 mutation carriers to develop triple-negative cancers as shown earlier. However, the mechanisms for the skewed localization was not completely provided in the articles published previously. We should remember the tendency of these lesions to be located along the posterior aspect of the breast, which makes it challenging for MRI-guided biopsy. As discussed by Perlet et al. [40], the medial and posterior areas are considered “dead space”, and such a location can be a potential contraindication to MRI-guided biopsy. MRI surveillance for BRCA mutation carriers is especially important for early detection of posteriorly located lesions, as these are difficult to detect on both self-breast exam and clinical breast exam.

Our study has several limitations. First, this study was retrospective. Second, this was a single institutional study. Third, the image database we used was not acquired by one designated image protocol, because it included radiographic data patients from other facilities. Therefore, we need a larger population-based study in the future to improve and develop our study and the surveillance screening examination systems in Japan.

In this study, MRI-detected lesions were significantly smaller at the time of diagnosis than lesions detected by mammography and US. We have reported the first two MRI-detected lesions in high-risk females in Japan which underwent MRI-guided biopsy. There were no cases of breast cancer that were MRI negative and mammography positive. The results of this study suggest that in the near future, MRI screening and MRI-guided biopsy are likely to play important roles in the HBOC surveillance system established in Japan for high-risk women who have not yet developed breast cancer, especially since MRI-guided biopsy is covered by Japan’s national health insurance as of this year.