Although annual MRI screening has improved early diagnosis of hereditary breast cancer, fast growth rates of BRCA1-associated cancers can still lead to interval cancers and/or node-positive disease. Using MRI with shorter screening intervals helps to effectively avoid both interval cancers and node-positive stages, whereas there is no role for mammography in these women.
See related article by Guindalini et al., p. 1786
In this issue of Clinical Cancer Research, Guindalini and colleagues demonstrate that half-yearly screening with MRI definitively ensures early diagnosis of familial breast cancers while they are small (mean size of 6 mm) and in a node-negative state, and that it effectively avoids development of interval cancers. Moreover, they provide consolidating evidence for the fact that in women undergoing MRI, mammographic screening does not contribute to early diagnosis and, thus, should be avoided (1).
Improved early diagnosis is not equivalent to improved survival. But it is a good starting point.
The stage of screen-detected cancers (tumor size, rate of positive lymph nodes) and the rate of interval cancers (rate of cancers detected clinically after a normal screening test) are appropriate surrogate endpoints to rate the efficacy of screening methods. Yet beyond the diagnostic accuracies of the respective methods used for screening, both outcome metrics will greatly depend on the composition of the screening cohort. The higher the prevalence of biologically aggressive (i.e., rapidly growing, early metastasizing) cancer in a given cohort, the more difficult will it be for a screening test to ensure diagnosis of cancers while they are small and node negative, and to avoid interval cancers. Screening intervals should therefore be tailored to the average growth rates of cancers to be expected in a given cohort, or the prevalence of such rapidly growing cancers. However, more frequent screening is only useful as long the screening test is at all able to reliably detect the target condition. If a screening test is insensitive for the cancers that are to be expected in a given population, then increasing the frequency of that screening test will not be useful to improve outcome. High-risk women in general, and women with pathogenic BRCA1-mutation in particular, tend to develop aggressive cancers with high or exceedingly high growth rates. Mammography has been shown to be insensitive specifically for the imaging phenotypes of biologically aggressive cancers (Fig. 1), and, as an independent problem, has been shown to be insensitive in women with higher amounts of fibroglandular breast tissue. This explains why, before the advent of breast MRI, surveillance of young women suspected or proven to be carriers of a breast cancer susceptibility gene was a sobering experience. At that time, women underwent annual mammography for screening, and yet over half of cancers that arose in screening participants were diagnosed clinically as interval cancers in between screening rounds, and over half of women with screen-detected or interval cancers had positive nodes at the time of diagnosis (2).
It is well established that in high-risk women, MRI is far superior to mammography (3–8). Accordingly, screening with annual MRI has become the current standard of care. Already with annual MRI screening, cancers detected are small (8–9 mm; refs. 3, 4); the rates of node-positive cancers range from 16 % in early (5, 6) down to 8% in more recent studies (3, 7), while rates of interval cancer ranged from 6 % (5, 6) down to zero %, for example, in the EVA trial (3). These outcome metrics demonstrate that even annual MRI screening of high-risk women is quite successful, in particular in view of the fast growth rates of cancers in these women compared with women at average risk. As a matter of fact, the outcome metrics of annual MRI screening of high-risk cohorts, and even of BRCA mutation carriers, are more favorable than the respective outcome metrics of mammographic screening of women at average risk, where a node-positive rate of 25%, and an interval cancer rate of about 30% is observed (8). One could thus argue that even annual MRI screening of women at high or very high risk of breast cancer leaves little room for improvement, whereas there is a greatly larger unmet need to improve screening of women at average risk.
This study finds that offering MRI more frequently is even more successful than annual MRI in terms of the abovementioned outcome metrics. Although the study design does not allow a direct comparison of semiannual versus annual MRI, the results of this screening program are unprecedented: Half-yearly breast MRI helped avoid lymph node metastases and interval cancers altogether, in each of the young women diagnosed with breast cancer. This was achieved in spite of the high rate of rapidly growing, aggressive breast cancers, corresponding to dedifferentiated, grade 3 disease in almost three-quarters (71%; 12/17) of cases.
What do we learn from this study? For one, the results provide further evidence for the fact that what is frequently referred to as the “high-risk cohort” is indeed a heterogeneous group. In agreement with previous results on the different tumor biologies as well as imaging phenotypes of BRCA1-associated versus other types of familial breast cancers (9), authors found that the cancer detection rates especially at half-yearly MRI were by far greatest for BRCA1 mutation carriers. This is in good agreement to recent observations of van Zelst and colleagues (10), who concluded: “Carriers of the BRCA1 germline mutation are at high risk of developing interval cancers despite intensified imaging surveillance.” Future screening guidelines should account for this and should recommend to use genomic characterization of individuals to distinguish between women with BRCA1 mutation, and other high-risk individuals, and recommend half-yearly MRI specifically for BRCA1 mutation carriers.
For another, the results demonstrate that MRI is now a mature technology. Earlier trials, conducted at a time when breast MRI was a new method, and radiologists had limited experience in interpreting the studies, screening with MRI was associated with a very low positive predictive value (PPV). This has led to reservations against breast MRI for screening, although most women would agree that avoiding false-negative results, especially of aggressive breast cancer, is far more important than avoiding false-positive diagnoses. This study demonstrates that with modern breast MRI, one can achieve both: high sensitivity, as well as high specificity and PPV. Over the past decade, reader expertise has improved, as have the standards of image acquisition and reporting, all leading to the fact that the specificity and predictive value of MRI is now equivalent to, or even higher than that of screening mammography, while preserving its unsurpassed sensitivity.
Furthermore, studies should investigate the cost efficacy of half-yearly MRI for surveillance of BRCA1 mutation carriers. Such studies will consider additional immediate direct and indirect costs due to additional MR imaging and MR-guided biopsy, as well as cost-saving opportunities, for example, by saving expenses for mammograms. Moreover, they will model the impact of possible downstream effects due to reduced need for systemic therapy or reduced numbers of productive life years lost. Costs of breast MR imaging vary greatly between countries; still, it is one of the most expensive imaging methods of contemporary clinical medicine. A possible strategy to improve access to such intensified, half-yearly MRI-screening programs could therefore be to use abbreviated MRI protocols. Abbreviated MRI yields comparable results to full-protocol MRI if used for screening women at intermediate risk of breast cancer, while improving patient tolerability and reducing costs due to reduced time in the magnet, and reduced radiologist reading time (Fig. 1; ref. 11;). In view of the frequently atypical imaging presentation of BRCA1-associated breast cancer, it may be prudent to stick to a full protocol MRI at least for the baseline, or possibly all annual screening MR examinations. However, all follow-up MRI studies, or at least all half-yearly MRI studies, could probably be done with greatly abbreviated protocols, thus substantially reducing the financial burden of this approach.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Conception and design: C.K. Kuhl
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S. Schrading
Writing, review, and/or revision of the manuscript: C.K. Kuhl
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Schrading