A positive family history is one of the most important risk factors for breast cancer
. Women with a family history of breast cancer are not only at greater risk of developing breast cancer, but their risk also increases at a younger age than in the general population
. In over 75% of the families that display clear clustering of breast cancer no causative gene mutation like BRCA1 or BRCA2 can be detected
. Tumour stage at detection is of key influence on survival
. Aiming at early detection and ultimately to reduce mortality risk, women, with a positive family history for breast cancer, are often offered annual screening with mammography before age 50
[5–7]. However, screening also causes false-positive test results.
In the last decade several screening trials in high-risk women have been completed and Magnetic Resonance Imaging (MRI) had a significantly higher sensitivity for invasive breast cancer than mammography in all studies
[8–12]. However, MRI was expensive and was associated with significantly more false-positive results in most studies. Furthermore, mammography had better sensitivity for the pre-invasive stage of breast cancer: ductal carcinoma in situ (DCIS)
. Therefore, mammography should perhaps not be omitted completely when MRI screening is offered.
Despite the higher costs of MRI and the false-positive results, screening with yearly MRI in addition to mammography is considered cost-effective for female BRCA1 and BRCA2 gene mutation carriers aged 30–60 years or women who have a 50% chance of carrying such a mutation
[14–16]. For women with a familial risk, from families without a proven genetic predisposition, results are inconclusive
[17, 18]. Since previous screening studies have performed MRI and mammography simultaneously the difference in stage of the tumours when detected by mammography alone is not known. A randomized controlled trial is therefore needed.
Apart from a positive family history and age, high breast tissue density is a well documented risk factor for breast cancer. Breast density increases breast cancer incidence significantly
[19, 20]. At the same time, high mammographic density impairs the sensitivity of mammography
[19–22], but far less the sensitivity of MRI
. The lower sensitivity of mammography in dense breasts is most likely caused by a masking effect, rather than by a higher tumour growth rate in denser tissue
[21, 24]. Breast density is high or very-high in about 50-74% of women between 40 to 49 years of age, whereas only 20-44% of women in their 60s have dense or extremely dense breast tissue
[25, 26]. This dual effect of breast density on cancer incidence and sensitivity of mammography results in women with the highest risk being screened with a tool with limited effectiveness: mammography.
To the best of our knowledge, no study has been published assessing the cost-effectiveness of MRI specifically in women with a familial risk for breast cancer, without a known genetic predisposition. Therefore, guidelines for breast cancer screening for women with a familial risk vary widely internationally and are weakly underpinned. The 2008 American Cancer Society and 2010 American College of Radiologists guidelines advise MRI screening for women with a familial cumulative lifetime risk (CLTR) > 20%
, while the Dutch guidelines advise screening with mammography only
Robust cost-effectiveness analyses cannot be based on the published studies, as all had a paired design (i.e. all participants received both mammography and MRI). These studies cannot examine the improvement in tumour stage at diagnosis, as one cannot know in what stage the tumour would have been diagnosed by either test alone. A randomized controlled trial is needed for a valid answer to these questions.
Furthermore, cost-effectiveness of either imaging technique may vary across categories of mammographic density. Breast density has not yet been evaluated as a parameter to identify sub-groups of women with a familial risk, for whom MRI is cost-effective. A prospective randomized trial in women with increased breast cancer risk, taking breast density into account, will give robust evidence on which screening tool, MRI or mammography, is best suited for a particular woman. These issues are addressed in the Familial MRI Screening study (FaMRIsc).