Contrast-enhanced mammography for the assessment of screening recalls: a two-centre study

While the benefits of mammographic screening outweigh its harms [1‐4], various issues of the whole screening process are still unresolved [3]. Alongside a strong drive towards personalisation of screening strategies [5], research efforts are targeting a major drawback of mammographic screening, i.e. false positive recalls [3]. Indeed, even the current multi-layered imaging assessment still implies that women undergoing screening mammography have an estimated cumulative risk of undergoing a biopsy with a final benign outcome ranging between 2 and 6% [3, 6]. This figure is mirrored by the constantly high proportion of benign lesions (between 44 and 73%) reported in large-scale biopsy series [7‐10].

Currently, the most employed assessment modalities—such as additional mammographic views, digital breast tomosynthesis, and ultrasound—rely exclusively on a morphologic appraisal of suspicious findings. Conversely, imaging techniques able to provide morphologic and functional information may foster a decrease in biopsy rates, i.e. an increase in the positive predictive value (PPV) of work-up examinations. This notion rests on the biological bases of functional assessment through contrast-enhanced examinations: tumour neoangiogenesis, resulting in leaky vessels that allow the entry of contrast agents into the interstitium, is a predominant feature of invasive cancers and more aggressive lesions [11, 12].

Among morpho-functional breast imaging techniques, contrast-enhanced mammography (CEM) could be better suited [13‐15] than contrast-enhanced breast magnetic resonance imaging (CE-MRI) [16] for the work-up of screen-detected suspicious findings, as the latter has considerable contraindications, cost-related pitfalls, and may be suboptimal in assessing calcifications [17]. The potential of CEM has been highlighted also by a recent meta-analysis [18], where CEM had a 92% sensitivity and an 84% specificity when applied on mammography-detected suspicious findings.

CEM consists in a pair of mammograms (one low-energy, one high-energy) sequentially acquired after contrast agent administration and then recombined to minimize the appearance of unenhancing breast tissue, making enhanced areas recognizable [19]. Moreover, save from contrast administration, CEM is similar in workflow and time to a standard 4-view mammography or tomosynthesis [20], thus being much more tolerated, affordable, and available than CE-MRI [21‐24].

The aim of this study was therefore to assess the potential of CEM for curtailing the biopsy rate in a prospectively enrolled population of women recalled for assessment of suspicious findings at screening mammography.

Between January 25, 2019, and July 29, 2021, 220 women were enrolled in this study, 122 at Centre 1 and 98 at Centre 2. CEM proved unfeasible in 3 of these 220 women (1.4%) because of contrast extravasation, while 10 other women were excluded from analysis after enrolment due to screening failure of exclusion criteria. The remaining 207 women who underwent both SA and CEM were included in the analysis: they had a median age of 56.6 years (IQR 50.1–65.3 years), 140/207 (67.6%) had already entered menopause, and 26/207 (12.6%) reported a family history of breast or ovarian cancer, no woman declaring to be a carrier of a genetic mutation increasing breast cancer risk. Out of 207 patients, 3 (1.4%) developed mild self-limiting adverse reactions to iodinated contrast agents, without the need of any medical intervention. The median CEM examination time was 4 min and 46 s (286 s, IQR 262–318 s).

The SA was prompted by a single suspicious finding in 191/207 women (92.3%), while in the remaining 16/207 women (7.7%) SA detected 2 suspicious findings (ipsilateral in 12 women, contralateral in 4 women). Of these 223 suspicious findings, 214 (95.9%) were already detectable on baseline mammography, 3/223 (1.4%) were suspicious axillary lymph nodes detected by ultrasonography, and the remaining 6/223 (2.7%) were inconclusive mammographic findings that were confirmed as suspicious by ultrasonography. Moreover, in 2 women (1.0%) rCEM identified an additional suspicious finding (both of them in the breast contralateral to the suspicious finding that prompted the recall).

As detailed in the study flowchart (Fig. 1), 225 suspicious findings were ultimately analysed for the assessment of the primary endpoint (Tables E1–E4): 131/225 were referred to biopsy by SA, for a SA biopsy rate of 58.2% (95% CI 51.7–64.5%), while 94/225 were referred to biopsy by rCEM, for a rCEM biopsy rate of 41.8% (95% CI 35.5–48.3%). Therefore, information from rCEM images would have engendered a 16.4% reduction in the biopsy rate, from 58.2 to 41.8% (p < 0.001). More specifically, SA and rCEM agreed on referring to biopsy 90/225 (40.0%) suspicious findings and agreed on sending to follow-up 90/225 (40.0%) suspicious findings. Conversely, rCEM would have spared the biopsy prompted by SA in 41/225 cases (18.2%) and effectively recommended biopsy for 4 findings (1.8%): 2 would have been sent to follow-up according to the SA, and 2 were rCEM-only detected findings. Thus, a biopsy was recommended either by SA or by rCEM for 135 suspicious findings. For 3 of them the procedure proved unfeasible, 2 other women elected to perform the recommended biopsy in other centres and were lost at follow-up, and 2 women—for whom CEM recommended a biopsy in contrast to the follow-up referral recommended by SA—refused to undergo the procedure.

Ultimately, 128 biopsies were performed at the two study centres, 75/128 (58.6%) under ultrasound guidance and 53/128 (41.4%) under stereotactic guidance. Overall, all 53 stereotactic-guided biopsies and 2 of the ultrasound-guided biopsies were performed as vacuum-assisted biopsies, while among the 73 remaining ultrasound-guided biopsies 68 (93.1%) were core-needle biopsies and 5 (6.9%) were fine-needle sampling. As detailed in Table 1, 42/128 biopsies had a benign result (32.8%) and 79/128 resulted in a diagnosis of malignancy (61.7%): DCIS accounted for 31.6% of malignancies (25/79). The remaining 7/128 biopsies (5.5%) had a B3 result: 4 cases were sent to imaging follow-up and were excluded from secondary endpoint analyses, while the other 3 were referred for surgery, 2 being downgraded to B2 lesions at surgical histopathology and one upgraded to a B5b lesion.

Thus, 124 lesions (44 benign and 80 malignant, 25 of which DCIS) had an available final histopathology report and were considered for the evaluation of the secondary endpoints related to diagnostic performance. Among the 122/124 lesions sent to biopsy by SA, 44 (36.1%) proved benign at histopathology, while the remaining 78 (63.9%) were classified as malignant, 24 of them being DCIS. The 2/124 suspicious findings that were not detected by SA but had a biopsy prompted by rCEM also resulted to be B5 lesions (one grade 2 DCIS and one invasive carcinoma of no special type). The sensitivity of SA (Table 2) was therefore 97.5% (95% CI 91.3–99.3%), with a PPV of 63.9% (95% CI 55.1–71.9%). Among the 90 suspicious findings sent to biopsy according to the information coming from rCEM images, 75/90 (83.3%, 20/90 DCIS) were malignant lesions (true positives, Fig. 2 and Fig. E2), while the remaining 15/90 (16.7%) were benign lesions (false positives, Fig. 3) Conversely, among the 34 biopsies with final reports that would have been spared by the evaluation of rCEM images (Table 3), histopathology revealed 29 benign (true negatives, Figs. 4 and 5) and 5 malignant lesions (false negatives, Fig. 6). Of note, all 5 were pure DCIS, i.e. without microinvasion (3 grade 2 and 2 grade 3): while none of them exhibited suspicious contrast enhancement on rCEM images, all were detectable on low-energy CEM images due to the presence of suspicious calcifications. Thus, while rCEM sensitivity (Table 4) was 93.8% (95% CI 86.2–97.3%), with a 65.9% specificity (95% CI 51.1–78.1%) and an 83.3% PPV (95% CI 74.3–89.6%), a combined reporting of rCEM images and low-energy images (focused on suspicious calcifications) to guide biopsy referral would have increased sensitivity to 100% (95% CI 95.4−100.0%).

Since the early days of CEM implementation, its use in the evaluation of abnormalities detected at screening mammography has been one of the most reported applications [14, 15]. Albeit with some caveats related to the contrast uptake of benign lesions [14, 15] and to equivocal enhancement conspicuity associated with calcifications clusters [29‐31], retrospective studies have highlighted the potential of CEM to increase the PPV of the work-up process without compromising cancer detection [31‐35]. We investigated this issue in a prospective setting, assessing the diagnostic gain granted by contrast-enhanced (rCEM) images, since low-energy CEM images—equivalent to standard mammograms [26, 27]—are also available in the SA process used as a comparator.

We observed a potential 16.4% net reduction of the biopsy rate that could be obtained by rCEM in the overall cohort of 225 suspicious findings, accompanied, in a subanalysis on 124 findings with final diagnosis, by a 19.4% PPV increase, in accordance with the multireader retrospective study by Zuley et al [35] on 60 BI-RADS 4 masses referred for biopsy. While their higher negative predictive value (98.3% versus our 85.3%) was likely prompted also by their exclusion of calcifications, we found similar, even though slightly higher, sensitivity (93.8% versus 90.3%) and specificity (65.9% versus 61.0%). Of note, we should consider that our specificity was negatively influenced by the exclusion of lesions referred for follow-up and will be recalculated after follow-up completion.

The biopsy increase solely attributable to CEM, i.e. the number of CEM-referred biopsies of suspicious findings that would have been sent to follow-up by SA plus the number of additional suspicious lesions detected by CEM but missed by screening mammography and SA, was 4/225 (1.8%). While the component of additional CEM-only findings (2/225, 0.9%) is of course lower than the 7.7% rate presented by Houben et al [34] in a study where screening mammography was the comparator instead of SA, we highlight that both cases in which the patient accepted to undergo the biopsy solely prompted by CEM were diagnosed as malignant lesions (one invasive carcinoma of no special type, one grade 2 DCIS), with a 100% PPV.

Importantly, DCIS presenting as calcifications clusters without associated contrast enhancement or with extremely faint enhancement were altogether responsible for the 6.2% drop in sensitivity of rCEM compared to the virtual 100% sensitivity of a combined reporting of low-energy images focused on suspicious calcifications and rCEM images, thus still supporting a direct biopsy referral of suspicious calcifications on the basis of their appearance on standard mammography or low-energy CEM images [31]. Without venturing in considerations about potential DCIS overdiagnosis [36], we however highlight that all were pure DCIS, without any microinvasion foci (3 intermediate grade, 2 high grade). As already reported [29‐31], the negative predictive value of rCEM images for suspicious calcifications remains to be ascertained and, in our opinion, only large-scale dedicated studies will allow to solve this issue, especially also addressing DCIS overdiagnosis. Options in this direction involve the identification of characteristic enhancement patterns for cancers of low biological relevance [37] and the application of artificial intelligence–driven radiomic analysis [38]. The latter could be particularly useful considering how interpretation thresholds are influenced by the more equivocal visual conspicuity of lesion enhancement in rCEM images than in CE-MRI, compared to standard background parenchymal enhancement. In addition, only 3/207 patients (1.4%) developed mild self-limiting adverse reactions to iodinated contrast agent, confirming the CEM safety profile already reported in a meta-analysis [20].

Limitations of this study include—first—the only potential nature of the biopsy reduction we described and the non-randomised design: these characteristics prevented a clinical comparison of the SA and CEM-based work-up, also including patients’ preferences and cost-effectiveness, as will be done by the RACER trial [39]. Second, as already discussed for suspicious calcifications resulting in rCEM false negatives, our study design also factually oriented the analysis towards an appraisal of the contribution of rCEM information rather than of the “whole” CEM examination (low-energy and rCEM images). Finally, the ongoing follow-up period prevented us from exploring secondary endpoints related to diagnostic performance in the whole cohort, such as the correlation of imaging features with histopathology.

In conclusion, our study showed how a rCEM-based assessment of women recalled at first-level screening mammography is able to potentially engender a 16.4% reduction in biopsy rates compared to SA, maintaining high sensitivity (93.8%) with false negatives represented only by DCIS clearly detectable on low-energy CEM images. Coupled with the absence of moderate and severe adverse reactions to contrast agent, these data further highlight the role of CEM for the assessment of suspicious findings detected at screening mammography, avoiding a sizable number of unnecessary biopsies.