Supplemental MRI screening in women with very dense breasts reduces interval cancer rate but may cause overdiagnosis (DENSE)

Reference

Bakker MF, de Lange SV, Pijnappel RM, et al, for the DENSE Trial Study Group. Supplemental MRI screening for women with extremely dense breast tissue. N Engl J Med 2019;381(22):2091-2102.

Synopsis

Almost all guidelines recommend mammography every 2 years, typically in women aged 50 to 69 or 75 years. (The sole exception is the US American College of Radiology, which continues to recommend annual screening. Go figure.) In this Dutch study, women undergoing routine digital mammography who were identified as having very dense breast tissue (grade 4/4) and who had a normal digital mammogram result were randomized in a 1:4 ratio to receive supplemental MRI screening or usual care. After randomization, the women in the MRI group were notified and invited to participate. Obtaining consent after randomization is known as a Zelen design, and is thought to reduce protocol violations and anxiety in the women not randomized to MRI. Women with a Breast Imaging Reporting and Data System (BI-RADS) MRI score of 4 or 5 were recalled for further evaluation including biopsy. Women with a BI-RADS score of 3 had a second reading of the MRI and if the second reading was also 3, they had a follow-up MRI in 6 months. The primary outcome was the likelihood of interval cancer, defined as all cancers detected in the 24 months following a negative index digital or MRI mammogram and before the next scheduled mammogram (or within 24 months if aging out of the cohort). A total of 8061 women were randomized to receive supplemental MRI screening; 4783 (59%) agreed to the screening. The comparison group had 32,312 women. Of the 4783 women who underwent supplemental MRI screening, 79 (1.65%) had breast cancer detected on MRI. In the intention-to-screen analysis that included all 8061 women randomized to MRI, the rate of interval cancers was lower than in the usual care group (2.5 vs 5.0 per 1000 women). This is the appropriate comparison, since in other mammography trials women who ignore the invitation to screen had worse health outcomes than those who chose to volunteer. Among women randomized to MRI, the rate of interval cancers was 0.8 per 1000 women in those who volunteered and 5.0 per 1000 women (nearly identical to the control group rate of 4.9/1000) in those who did not. With regard to harms, for women undergoing supplemental MRI screening, 9.5% were recalled and 6.3% of all women had a biopsy. The false positive rate was 8.0% among women undergoing supplemental MRI. Of the 79 cancers detected in MRI group, approximately 80% were invasive and the remainder were ductal carcinoma in-situ. The characteristics of the interval cancers did not differ significantly between groups. At the second round of screening, the rate of invasive cancers was lower in the MRI group than in the digital mammography–only group (2.0 vs 7.0 per 1000) and they were more likely to be stage 0 or 1 cancers, suggesting that MRI advanced the time of detection. The study was not powered to detect a reduction in mortality.