ABUS systems are designed to overcome limitations of hand-held ultrasound such as operator dependency by standardizing the acquisition protocol and to overcome the inability of hand-held ultrasound to compare examinations with relevant priors by enabling storage and retrieval of large (standardized) 3D imaging volumes. Operators of ABUS need only little training compared with hand-held ultrasound which requires highly trained sonographists and therefore ABUS might be less costly. In this thesis we have focused on cancer detection and differentiation of findings in a screening setting, mainly because ABUS systems are designed for mass screening. Nevertheless, other indications have been proposed for ABUS such as a role in staging, second-look ultrasound after breast MRI and monitoring treatment response during and after neoadjuvant chemotherapy.
Vendors of these ABUS systems have also been marketing the preoperative capabilities, by specifically promoting the coronal reconstruction as the more comprehensive “surgical view” because of the supine position of the women during both the scanning process and surgery. It is unclear what the effect of 3D ABUS is on the outcome of breast surgery.
The large size of the three-dimensional imaging volumes may allow for a more accurate tumor size measurement than conventional hand-held ultrasound and may also result in better estimations of the tumor extent than DBT(230,231). In Chapter 2 we describe multiple frequently found artefacts that may impair tumor extent measurements using ABUS such as incorrect placement of the transducer, air contact artefacts, posterior nipple shadowing, edge shadowing and breathing artefacts. As a results of these artefacts the ABUS scans need to be repeated or, alternatively, other additional imaging modalities are required. Breast MRI outperforms ABUS, hand-held ultrasound and mammography during the staging process in terms of visualizing different types of breast cancer (e.g. that includes invasive lobular carcinomas and non-calcifying ductal carcinoma in situ which can be very challenging to detect with other modalities such as ultrasound), assessing tumor extent and detecting additional disease (230,231). Breast MRI has already been established as the most accurate modality for staging and is even more accurate than ultrasound, mammography and clinical examination combined (127). Therefore, the role of ABUS in a preoperative stage is very limited when breast MRI is available. Furthermore, ABUS systems are not able to visualize the axillas, therefore lymfnode assessment as part of the staging process is not feasible with ABUS only. Although the evidence of using ABUS during (a part of) the staging process is little, it may be considered when breast MRI is not available. In our opinion large studies are needed to investigate the cost-effectiveness of implementing ABUS during staging when breast MRI is not available.
Current previously described ABUS systems do not allow real-time evaluation of the images during the scanning process and current systems do not allow US-guided biopsies of breast lesions. Consequently, breast radiologists will have to resort to hand-held ultrasound guided biopsy procedures when an abnormality is seen on ABUS. ABUS does have the advantage of re-assessment of already stored images including correlation with breast MRI. Theoretically this
Summary and general discussion Chapter 9
9
9
might result in a decrease of false-positive recalls and unnecessary anxiety among women when used as a second-look modality after breast abnormality detection using breast MRI. Although ABUS has been proposed as a non-inferior second look modality after MRI instead of hand-held ultrasound (232,233), it is unclear whether the actual cost-effectiveness ratio is positive using ABUS instead of hand-held ultrasound as a second-look modality.
Temporal comparison of 3D imaging volumes is also relevant in monitoring the response of breast cancer to neoadjuvant chemotherapy. The current standard practice in response monitoring of neoadjuvant chemotherapy is breast MRI. Breast MRI outperforms ABUS, mammography and DBT, however early reports have shown that ABUS has good correlation to histological evaluation and MRI response monitoring (234–236). Therefore, ABUS might be a practical alternative in neoadjuvant response monitoring when breast MRI is not available. As discussed earlier, ABUS has potential to help identify imaging biomarkers that may assist in predicting (neo)adjuvant chemotherapy outcome (chapter 4). Nevertheless, in chapter 2 we describe sonographically inconspicuous cancers and cancers that are prone to underestimation of tumor size using ultrasound (such as invasive lobular carcinoma and ductal carcinoma in situ), which should be kept in mind when considering ABUS in neoadjuvant treatment response monitoring. Most breast imaging facilities today offer mammography, digital breast tomosynthesis, ultrasound and magnetic resonance imaging. For each screening indication, one or more modalities are preferred and described in the international guidelines (4,126,237,238). However, most current guidelines do not recommend bilateral whole breast ultrasound in asymptomatic women. A recent meta-analysis has shown that adding ultrasound to mammography in women with dense breasts consistently increases the detection of mammography-occult small but invasive breast cancers, but the authors conclude that due to the increase in use of resources supplemental breast ultrasound will probably be more feasible in asymptomatic women at high risk than those in the average risk population (239). ABUS is considered more efficient than screening with hand-held ultrasound because the acquisition is standardized and does not require highly trained personnel, however there is currently no evidence that supports the idea of a better cost-effectiveness ratio compared with screening with hand-held devices performed by highly trained sonographists.
According to the guidelines current standard practice is to offer combined annual breast MR imaging and mammography to asymptomatic women at high risk (a lifetime risk (LTR) of more than 20%) for the development of breast cancer. Recent publications have shown inconsistent
does not help to detect additional cancers and does not lead to earlier detection of breast cancer, likely because of the overall superiority of breast MR imaging in detection of cancers in an early stage. Nevertheless, in two women who carry the BRCA1 mutation (2 out of 10 BRCA1 carriers with breast cancer in our study), cancers were detected earlier with the interval ABUS exam, but classified as a BI-RADS 2 (benign) lesion. One of these cancers evolved rapidly into a T2 interval cancer that could have been treated in an earlier stage if it was recognized as a cancer instead of a benign lesion. This underlines the difficulty of detecting breast cancers in BRCA1 carriers with ultrasound because in these women a high prevalence of high grade triple-negative invasive ductal cancers occurs that may mimic benign breast lesions (63). The positive predictive value of ABUS in our study was very low at approximately 10% both in the first round and in subsequent screening rounds. Based on our study and the results published by Sardanelli et al (203), Kuhl et al (56) and Riedl et al (15) we neither recommend to implement ABUS nor handheld ultrasound to a screening protocol that includes breast MR.
International guidelines recommend to add MR imaging to mammography in women at a LTR >20%. But many local guidelines deviate by reserving MR imaging only for the highest risk categories due to limited availability of MR equipment and the high costs. Supplemental ABUS could help to detect mammography-negative breast cancer in women with dense breasts who are at higher risk, but do not participate in a breast MR screening program. Kim et al (240) and Cho et al (241) reported higher cancer detection of mammography and ultrasound combined compared with mammography alone in women with dense breasts who were treated for breast cancer. An unpublished interim analysis of supplemental ABUS in 656 women at high risk with a Volpara Density Grade 3 or 4 screened at the Radboud University Medical Center (Nijmegen, NL) between July 2014 and September 2015 resulted in an additional cancer detection rate of 3.1 per 1000 screens (242). All cancers were detected in women who underwent annual follow-up after treatment for breast cancer. Therefore, ultrasound (thus also ABUS) remains an alternative for women at high risk who do not undergo routine surveillance with MR imaging.
Rebojl et al (239) state in the conclusion of their meta-analysis that supplemental ultrasound might be more feasible in women with the highest breast density because the financial strain of organizing supplemental ultrasound screening is likely outweighed by the high prevalence of cancers in these women. Modern mammography systems are equipped with digital breast tomosynthesis (DBT). DBT also detects mammography negative cancers in women with dense breasts (9,11,12). The addition of DBT to routine mammography might negate the need for supplemental whole breast ultrasound. However early comparative reports between whole
Summary and general discussion Chapter 9
176 177