Updates in Molecular Breast Imaging

Abstract

Molecular breast imaging (MBI) is a nuclear medicine study performed with dedicated gamma camera systems optimized to image the uptake of Tc-99m sestamibi in the breast. MBI provides a relatively low-cost and simple functional breast imaging method that can identify breast cancers obscured by dense fibroglandular tissue on mammography. Recent studies have also found that background levels of uptake in benign dense tissue may provide breast cancer risk information. This article discusses the latest updates in MBI technology, recent evidence supporting its clinical use, and work in progress that may aid in wider adoption of MBI.

Introduction

Modalities classified as “molecular imaging” are capable of probing and characterizing the functional aspects of tissues, which reflect the status of the underlying chemical and biological processes at the cellular level. Molecular imaging can be an important complement to anatomic methods, such as x-ray-based modalities, that provide structural information. Thus, nuclear medicine methods for imaging the breast have adopted the term “molecular breast imaging” (MBI) as they depict the preferential uptake of radiopharmaceuticals that reflect aspects such as increased blood flow, mitotic activity and cellular proliferation and may improve detection and characterization of cancers beyond what is seen with x-ray mammography.

MBI technologies initially comprised conventional gamma cameras and single photon emission tomography (SPECT) systems designed for whole body imaging; this technique was originally called “scintimammography” because of the scintillating NaI detectors. Today’s commercial MBI systems are smaller cameras designed for dedicated breast imaging. The most recent commercial systems employ semiconductor-based cadmium zinc telluride (CZT) detectors capable of higher resolution and imaging at reduced radiation doses relative to that with previous conventional gamma camera systems. It should be noted that there are also dedicated positron emission mammography (PEM) systems designed to image positron-emitting isotopes (i.e., F-18). In keeping with recent classifications by the American College of Radiology (ACR), Society of Nuclear Medicine and Molecular Imaging (SNMMI) and European Association of Nuclear Medicine (EANM), this article defines and discusses MBI as the technique that uses a dedicated gamma camera for planar imaging of Tc-99m sestamibi uptake in the breast.

Tc-99m sestamibi uptake on MBI, which reflects blood flow and mitotic activity of breast tissues, is known to detect breast cancers and more recently found to also identify benign but proliferative tissue that may be at increased risk of breast cancer. The primary clinical advantage of MBI is its ability to identify cancers that are obscured on mammography by dense fibroglandular tissue or post-surgical changes (Figure 1). MBI has also shown utility in monitoring response to neoadjuvant therapies. However, after decades of development, the emergence of commercial MBI units, and numerous reports of promising clinical results, MBI is yet routinely used only in a limited number of centers. This article discusses the status of MBI technology and work in progress that may overcome barriers to more widespread implementation of MBI and enable future advancements in its contribution to breast cancer care.

Figure 1.

Breast cancer surveillance imaging performed in 53-year-old woman with history of invasive breast cancer removed by lumpectomy three years prior. The diagnostic digital breast tomosynthesis examination (panel A, left mediolateral oblique synthesize 2D view) was interpreted as negative, noting postoperative changes in the left upper outer breast but no masses or calcifications were identified. Because of the patient’s cancer history and heterogeneously dense tissue on mammography, MBI was recommended. MBI performed 2 weeks after the tomosynthesis, with 307 MBq (8.3 mCi) Tc-99m sestamibi identified a 1.2 cm area of focal uptake anterior to the lumpectomy site. Biopsied revealed a 2.3 cm, grade 1 invasive ductal carcinoma that was node negative.

Guidance for MBI in Practice

Several documents provide guidance for best practices in MBI technique and clinical indications, including a 2017 ACR Practice Parameter for MBI and newly released joint SNMMI Procedure Standard and EANM Practice Guideline for MBI.^1,2 Other publications provide detailed guidance tailored to radiologist’s interpretation of MBI, technologists performing MBI, and quality control personnel^3–5.

MBI Radiopharmaceuticals

During the 1990s, it was discovered that radiopharmaceuticals used in nuclear medicine myocardial perfusion imaging – Tc-99m sestamibi and Tc-99m tetrofosmin – are also taken up in breast lesions, leading to several studies evaluating their use in breast cancer imaging.^6,7 In current practice, sestamibi is most used for MBI, although some centers in Europe also use tetrofosmin. Tc-99m sestamibi is FDA-approved as a second line diagnostic drug after mammography to assist in evaluation of breast lesions in patients with an abnormal mammogram or a palpable breast mass; and EMA-approved for detection of suspected breast cancer when mammography is equivocal, inadequate, or indeterminate. These radiopharmaceuticals can be used for other indications as well, including supplemental screening (described in detail in the subsequent section on “clinical Indications”). Today MBI examinations are routinely performed with an activity of approximately 300 MBq Tc-99m sestamibi or lower, which is substantially less than stated in the original pharmaceutical package inserts for Tc-99m sestamibi (740–1110 MBq per FDA and 700–1000 MBq per EMA). This higher activity is no longer necessary due to improved count sensitivity of dedicated gamma cameras⁸.

Tc-99m is a single-photon emitter, producing gamma rays with principal photon energy of 140 keV. Its physical half-life is 6 hours. Following intravenous injection, Tc-99m sestamibi is largely taken up by first-pass extraction and clears from the bloodstream within 2 to 3 min. Tc-99m sestamibi uptake in breast tissue has minimal washout over a typical examination time (<1 h), therefore MBI acquisition may begin within minutes after injection; minor delays between injection and imaging are not problematic⁴. The exact mechanism of sestamibi uptake in breast cancer is not entirely clear, but prior studies have established that sestamibi is sequestered in the cellular mitochondria of tumors and its retention is related to perfusion and cell viability⁹.

Administration of 300 MBq (8 mCi) Tc-99m sestamibi for MBI delivers a dose to the breast of 1.1 mGy and effective dose to female patients is estimated as 2.1 mSv in the most updated nuclear medicine dosimetry models.¹⁰ The only contraindications to Tc-99m sestamibi are pregnancy and known history of allergic reaction to sestamibi.² Adverse events after sestamibi injection are rare (1 to 6 events per 100,000; < 0.006%) and can include allergic reaction but are typically mild in severity (e.g., flushing, rash, injection site inflammation, or brief metallic taste).^11,12

MBI Equipment

Small field-of-view gamma camera systems for dedicated breast imaging have the primary advantage of minimal “dead space” or unusable imaging area along the edge of the detector, as is the case with conventional gamma cameras. Elimination of this dead space allows the breast to be positioned directly on the detector in a configuration similar to mammography. As spatial resolution of gamma cameras degrades with distance from the detector, minimizing the distance between breast lesions and the camera leads to substantial improvements in spatial resolution over conventional gamma cameras. Spatial resolution is further improved with application of mild compression to minimize movement and bring the distant breast tissue closer to the detector.

Although several types of MBI detectors and configurations have been explored in the research and development settings, currently there are three types of MBI technology commercially available. The first commercial dedicated system was the Dilon 6800, originally sold by Dilon Technologies and now sold by SmartBreast as the Eve Clear Scan e680 system, which comprises a single detector head with pixelated NaI elements and position-sensitive photomultiplier tubes. An advantage of this system is that it is mounted on moveable cart. Biopsy capability is also available¹³.

The two most recent commercial MBI systems comprise dual-head pixelated CZT detectors with matched collimation designed to maintain high count sensitivity and spatial resolution necessary to detect small breast tumors (approximately 3 to 5 mm and larger). One CZT-based unit, the Discovery NM 750b was initially manufactured by GE Healthcare and is now sold as the Eve Clear Scan e680 system. The other CZT-based unit is the LumaGem manufactured by CMR Naviscan. Direct biopsy capability is currently available for the e680¹⁴ and in development for the LumaGem.

MBI Technique

MBI examinations are often performed by nuclear medicine technologists with additional specialty training in mammographic positioning techniques. Depending on local regulations, it may be possible for patients to receive the radiopharmaceutical injection from nuclear medicine staff and have imaging performed by mammography technologists.

Although it is not required, a 3 hr fast (no calorie intake) prior to the MBI injection may improve Tc-99m sestamibi uptake in breast tissue, as was suggested by O’Connor et al.¹⁵ This study also showed that applying a warming blanket around the patient’s shoulders for about 5 min prior to injection could increase peripheral blood flow and increase uptake of Tc-99m sestamibi in the breast.¹⁵ Before Tc-99m sestamibi injection, the technologist should confirm the patient is not pregnant and has no contraindications such as previous allergic reaction to Tc-99m sestamibi.

At the time of the MBI examination, patients should change into a gown, removing all clothing from the waist up. Tc-99m sestamibi is administered to the patient via an indwelling venous catheter or butterfly needle in an upper extremity vein. Approximately 300 MBq (8 mCi) is commonly used with modern CZT-based MBI systems. Imaging may begin immediately (within 5 min of injection); specific timing of the acquisition with injection is not necessary. The patient is seated at the MBI system with one breast at a time placed directly on the detector, with either a second detector (for dual-head systems) or compression paddle applied to provide gentle stabilization during the acquisition. Typically, craniocaudal and mediolateral oblique views similar to mammographic projections are acquired, but other special mammographic positions may also be acquired as needed. Typical image acquisition time is between 7 to 10 min per view.

As imaging times for MBI are relatively long compared to mammography, a supportive chair like those specifically designed for mammography and additional pillows should be placed to support the patient’s back.⁴ During the exam, patients may breathe normally and may read or watch videos if the breast position is maintained. In general, MBI is well tolerated by patients.

Clinical Indications

MBI has been evaluated for a variety of clinical indications, including supplemental screening, problem solving for indeterminate imaging or clinical findings, breast cancer staging, monitoring response to neoadjuvant therapy, and surveillance for breast cancer recurrence.^1,2 Because MBI’s ability to detect breast cancer is not limited by dense fibroglandular tissue like mammography is, MBI has been shown to be most useful in settings where conventional imaging such as mammography, including tomosynthesis, and ultrasound are insufficient, such as in women with dense breast tissue or post-surgical changes. MBI provides functional imaging with rapid radiologist learning curve and relatively low cost; therefore, it may be particularly useful when breast magnetic resonance imaging (MRI) would be warranted but is contraindicated, unavailable, or not pursued due to patient’s cost concerns.

Several studies have evaluated the use of MBI as a supplemental screening technique in women with mammographically dense breasts, increased risk for breast cancer, or both.¹⁶ A single-center prospective trial of 1585 women with dense breasts found that addition of MBI to 2D mammography provided an incremental cancer detection rate (additional cancers beyond mammography per 1000 women screened) of 6.9 for invasive cancers and 8.8 for all cancers.¹⁷ Addition of MBI to 2D mammography increased sensitivity to 90% (19/21) relative to 24% (5/21) with mammography alone (p<0.001). Specificity was decreased from 89% for mammography alone to 83% for the combination of mammography and MBI (p<0.001). The interval cancer rate was 1.3 cancers per 1000 women screened. Similar results were reported from a retrospective review of 1696 women undergoing supplemental screening MBI in clinical practice: after negative 2D full field digital mammography (FFDM), MBI provided an incremental cancer detection rate of 6.5 for invasive cancers and 7.7 for all cancer.¹⁸ Across four studies reporting screening MBI performance, a total of 41 cancers were detected only by supplemental MBI; of these, 31 (76%) were invasive and 18 (44%) were ≥ 1 cm.¹⁶

In patients recently diagnosed with breast cancer, MBI has shown utility in evaluating disease extent and in detecting additional sites of ipsilateral and contralateral disease. A recent study comparing performance of MBI with contrast-enhanced mammography (CEM) and MRI for breast cancer staging showed all three methods to provide similar detection of 110 index lesions with sensitivities of 92% for MBI, 91% for MRI, and 93% for CEM.¹⁹ For non-index lesions, MBI provided a positive predictive value of 44%, compared to 52% for CEM and 28% for MRI.¹⁹ MBI can overestimate disease extent compared to pathologic size; in the study by Sumkin et al MBI overestimated tumor extent by 1.5 cm in 15% of cases compared to overestimation by MRI in 24%. Another study evaluating disease extent prior to and after neoadjuvant chemotherapy showed MBI and MRI to provide similar assessment prior to therapy; neither modality provided sufficient accuracy in disease detection after therapy to obviate tissue sampling for diagnosis of residual disease.²⁰

In addition to detecting breast cancer recent analyses have shown that the background parenchymal uptake (BPU), which refers to the level of uptake in breast fibroglandular tissue relative to that in fat, may provide important information about a patient’s breast cancer risk. Among 2992 women who underwent MBI and were followed for subsequent breast cancer diagnoses for a median 7.3 years, elevated BPU (mild, moderate, or marked) was associated with greater breast cancer risk (hazard ratio 2.4), with the highest association among postmenopausal women (hazard ratio 3.5).²¹ The 5-year absolute risk of breast cancer was 4.3% (95% CI, 2.9–5.7%) for women with elevated BPU versus 2.5% (95% CI, 1.8–3.1%) for those with low BPU.²¹ These data suggest that among women with dense breasts, those with elevated BPU on MBI may be at highest risk and more likely to benefit from supplemental screening or preventive options.

Density MATTERS Trial

The Density MATTERS trial, currently underway, will provide the first prospective, multicenter evaluation of MBI screening in women with dense breasts, relative to mammography performed with digital breast tomosynthesis. Inclusion of two annual screening rounds will provide currently lacking data on MBI’s impact on reducing advanced breast cancers and interval cancers. Preliminary results indicate that MBI will have a similar incremental cancer detection rate relative to tomosynthesis as that previously reported relative to 2D mammography.²²

An additional outcome of the Density MATTERS trial will be evaluation of the cost-effectiveness of supplemental MBI screening. A prior analysis of the costs of screening and downstream workup in women with dense breasts previously showed MBI screening to be cost-effective.²³ The addition of MBI to 2D mammography increased the cost-per-patient screened from $176 for mammography alone to $571 for the combination. But, adding MBI to mammography detected ~4 times as many cancers as mammography alone (19 vs. 5), resulting in a lower cost-per-cancer detected for the combination ($47,597) relative to mammography alone ($55,851). Updated cost-effectiveness analysis in the setting of digital breast tomosynthesis, which may have increased cost but lower recall rate, will be performed in Density MATTERS.

MBI Radiation Dose

The current effective radiation dose of MBI using 8 mCi Tc-99m sestamibi (2.1 mSv) is below annual background radiation levels (average 3 mSv; range 2 to 10 mSv) and two orders of magnitude lower than the threshold at which radiation has been associated with risk of harmful effects (100 mSv).²⁴ Therefore, it is the opinion of this author that MBI as currently performed can be considered safe for routine use, even in screening.²⁵ However, MBI does deliver a higher dose compared to 2D mammography and digital breast tomosynthesis (approximately 0.5 mSv each); concerns about this higher dose have inhibited wider adoption and endorsement of MBI. Because the ACR considers tests with effective doses less than 1 mSv, including mammography, to be very low risk and appropriate for screening, achieving this effective dose with MBI is desirable. Work is underway to validate new denoising image processing algorithms that will allow further reductions in MBI’s administered activity, acquisition time, or both.²⁶

Conclusion

MBI is a functional breast imaging technique shown to provide complementary information to 2D mammography and tomosynthesis, including a high rate of incremental cancer detection in women with dense breasts. MBI offers a low-cost, low-complexity, and safe functional imaging option for patients who have challenging or indeterminate conventional imaging or patients in whom breast MRI is warranted but cannot be performed. Ongoing work to evaluate MBI screening in a multicenter trial and to further reduce MBI’s radiation dose will be important to aid more widespread clinical use.