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Summary

Molecular Breast Imaging (MBI) refers to a medical examination requiring intravenous (IV) injection of a radiopharmaceutical, typically 99mTc-sestamibi, whose preferential uptake in breast cancer cells are detected using dedicated imaging systems [1,2]. In October 2017, the American College of Radiology released practice parameter guidelines for the performance of an MBI examination using a dedicated system, Res 38-2017. [3]. These include use-cases for problem-solving when conventional breast imaging tools are indeterminate, detection of recurrence of breast cancer, breast cancer screening for women contra-indicated for breast MRI, evaluation of response to neoadjuvant chemotherapy, and preoperative staging for extent of disease. MBI is one of the options for supplemental screening for dense breasts in the 2016 Society of Breast Imaging white paper [4].

History

The field of MBI began with medical serendipity – In the 1990’s, radiologists realized that the recently developed myocardial perfusion tracer, 99mTc-sestamibi, would detect breast cancer in some women undergoing a cardiac stress test [5]. The general purpose SPECT systems they used did not have the spatial resolution or the sensitivity for this discovery to be clinically useful. Dedicated systems were then developed using a single gamma cameras that imaged the breast in planar view analogous to that of breast mammography. The procedure was then known as Breast Specific Gamma Imaging (BSGI) and the gamma cameras utilized scintillator based indirect conversion technology [6]. In 2011, in collaboration with the Mayo Clinic, GE and GammaMedica-Ideas both released the first-generation FDA cleared MBI devices, Discovery NM750b and LumaGEM respectively, consisting of dual planar cameras in opposing geometry that hold the breast in mild compression between them. The gamma cameras for MBI utilized CdZnTe (CZT) semiconductor detectors that directly convert the gamma rays to an electric pulse, which leads to higher spatial resolution and sensitivity than scintillator based gamma cameras [7]. Further refinements to the collimator design by the Mayo Clinic and adjustments of operating parameters have led to current generation MBI systems that have demonstrated high sensitivity and specificity to detect breast cancer at very low radiation dose [8].

Radiotracer

First introduced in 1991 as a myocardial perfusion tracer, 99mTc-sestamibi has a long history of safe use, with few contraindications other than prior allergic reaction to sestamibi and pregnancy [9]. Because 99mTc-sestamibi is a lipophilic cation, it is driven into the mitochondria by the electron gradient between plasma and mitochondrial membrane potentials [10]. Consequently, its strong preferential uptake in cancer cells has been found in in vitro studies [11]. Adverse reactions to 99mTc-sestamibi are rare (1–6 events per 100,000 injections) and are mild in severity (e.g., flushing, rash, metallic taste) [12].

Concerns with Patient Exposure to Radiation

A persistent barrier to MBI acceptance is concern about its radiation risks from the injected radiopharmaceutical [13,14,15]. Because ionizing radiation can cause carcinogenic effects in humans, it is prudent to strive for ways to minimize radiation exposure and follow the ALARA (as low as reasonably achievable) principle. The lowest levels of radiation in our environment are from background radiation, which range from 2 mSv to more than 10 mSv per year in the United States [16]. Between the range of 10–100 mSv, there is a lack of statistically reliable data to support either a hormesis effect or a carcinogenic effect, even in the largest epidemiologic studies [17,18]. The American Association of Physicists in Medicine [19] offers the guidance that “doses below 50 mSv for single procedures or 100 mSv for multiple procedures over short time periods are too low to be detectable and may be nonexistent.” The Health Physics Society has issued similar guidance [20]. The effective dose (which takes into account relative sensitivities of all irradiated organs in the body) from MBI performed with 8 mCi of 99mTc-sestamibi is approximately 2.4 mSv [28], whereas the effective dose of mammography and tomosynthesis is typically between 0.5 and 1.2 mSv. Although the dose of MBI is technically a factor of two to fivefold that of the dose from mammography, the doses from both examinations are at least an order of magnitude smaller than doses at which consideration of risks from radiation are warranted (above 50–100 mSv). Attempts to calculate radiation risk from mammography and MBI have shown that than the anticipated benefit is much greater than the hypothetical risk [21,22]

Commercial Vendors

Dilon Technolgies offers the biopsy guidance capable Dilon 6800 with a single gamma camera system utilizing s a scintillating sodium iodide (NaI) detector an array of pixelated crystals coupled to specialized position-sensitive photomultiplier tubes [23]. GE Healthcare offers the biopsy guidance capable Discovery NM 750b utilizing dual-camera CZT detector technology [24]. With the Oct 2017 acquisition of the assets from GammaMedica, CMR-Naviscan now offers the LumGEM MBI system with dual-camera CZT detector technology [25].

Clinical Data

A number of prospective and retrospective peer-reviewed papers have been published demonstrating the clinical efficacy of MBI. Please refer to review articles by Hruska [2] and Breg [26]. A description of patient workflow in clinical setting is given by Shermis [1]. Below are the summaries of a MBI studies conducted on asymptomatic women. A prospective clinical trial conducted by the Mayo Clinic, a total of 1651 asymptomatic women with mammographically dense breasts on prior mammography underwent screening mammography and adjunct MBI performed with 300-MBq 99mTc-sestamibi and dual-camera CZT MBI systems. In 1585 participants with a complete reference standard, 21 were diagnosed with cancer: two detected by mammography only, 14 by MBI only, three by both modalities. Of 14 participants with cancers detected only by MBI, 11 had invasive disease (median size, 0.9 cm; range, 0.5–4.1 cm). With the addition of MBI to mammography, the overall cancer detection rate (per 1000 screened) increased from 3.2 to 12.0 (p < 0.001) (supplemental yield 8.8). [27]

In a retrospective study at the ProMedica Hospital, Toledo, OH, women with dense breasts and negative mammography results who subsequently underwent screening with 300 MBq (8 mCi) 99mTc-sestamibi molecular breast imaging were analyzed []. Screening of 1696 women in this study resulted in the detection of 13 mammographically occult malignancies, of which 11 were invasive, one was node positive, and one had unknown node positivity. The lesion size ranged from 0.6 to 2.4 cm, with a mean of 1.1 cm. The incremental cancer detection rate was 7.7‰ (95% CI, 4.5– 13.1‰), the recall rate was 8.4% (95% CI, 7.2–9.8%), and the biopsy rate was 3.7% (95% CI, 2.9%–4.7%). The PPV for recall (PPV 1) was 9.1% (95% CI, 5.4–15.0%), and the PPV for biopsy (PPV 3) was 19.4% (95% CI, 11.4–30.9%). [28]

Researchers at George Washington University, led by Dr. Rachel Brem, have published a retrospective analysis of 849 patients using single gamma camera Dilon system with injected dose ranging from 7 to 30 mCi. In this study patients with a recent negative mammogram and at least one breast cancer risk factor were selected. The addition of BSGI to the annual breast screen of asymptomatic women at increased risk for breast cancer yielded 16.5 cancers per 1,000 women screened. When high-risk lesions and cancers were combined, BSGI detected 33.0 high-risk lesions and cancers per 1,000 women screened were discovered [29].

A 2011 prospective study lead by the Mayo clinic using previous generation dual-camera MBI systems with non-optimized collimators used 20 mCi of 99mTc-sestamibi to study 1007 asymptomatic women with dense breast and an additional risk factor. Of 936 participants, 11 had cancer (one with mammography only, seven with gamma imaging only, two with both combined, and one with neither). Diagnostic yield was 3.2 per 1000 (95% confi dence interval [CI]: 1.1, 9.3) f,or mammography, 9.6 per 1000 (95% CI: 5.1, 18.2) for gamma imaging, and 10.7 per 1000 (95% CI: 5.8, 19.6) for both ( P = .016 vs mammography alone) [30]

Key words Molecular Breast Imaging (MBI), Breast Specific Gamma Imaging (BSGI), CdZnTe (CZT) detectors, CMR-Naviscan, Dilon, LumaGEM, QuadraSquare, 99mTc-sestamibi, sestamibi (MIBI)

References 1] RB Shermis, RE Redfern, J Burns, H Kudrolli, “Molecular breast imaging in breast cancer screening and problem solving” RadioGraphics, 2017, 37:1309–1327, https://doi.org/10.1148/rg.2017160204 2] Hruska CB, “Molecular breast imaging for screening in dense breasts: state of the art and future directions” American Journal of Roentgenology. 2017;208: 275-283. 10.2214/AJR.16.17131 3] ACR Practice Parameter for the Performance of Molecular Breast Imaging (MBI) Using a Dedicated Gamma Camara Res. 38 – 2017 https://www.acr.org/Quality-Safety/Standards-Guidelines/Practice-Guidelines-by-Modality/Nuclear-Medicine 4] https://www.sbionline.org/Portals/0/White%20Papers/Breast%20Density%20and%20Supplemental%20Screening_Sept%202016.pdf 5] Khalkhali I, Cutrone JA, Mena IG, et al. Scintimammography: the complementary role of Tc-99m sestamibi prone breast imaging for the diagnosis of breast carcinoma. Radiology 1995; 196:421–426 6] Brem RF, Floerke AC, Rapelyea JA, Teal C, Kelly T, Mathur V. Breast-specific gamma imaging as an adjunct imaging modality for the diagnosis of breast cancer. Radiology 2008; 247:651–657 7] https://www.accessdata.fda.gov/cdrh_docs/pdf11/K111791.pdf 8] Rhodes DJ, Hruska CB, Conners AL, et al. Journal club: molecular breast imaging at reduced radiation dose for supplemental screening in mammographically dense breasts. AJR 2015; 204:241–251 9] Nyakale N, Lockhat Z, Sathekge MM. Nuclear medicine-induced allergic reactions. Curr Allergy Clin Immunol 2015; 28:10–17 10] Cordobes MD, Starzec A, Delmon-Moingeon L, et al. Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cells: correlation with mdr gene expression. J Nucl Med 1996; 37:286–289 11] Delmon-Moingeon LI, Piwnica-Worms D, Van den Abbeele AD, Holman BL, Davison A, Jones AG, et al. Uptake of the cation hexakis(2- methoxyisobutylisonitrile)-technetium-99m by human carcinoma cell lines in vitro. Cancer Res 1990; 50:2198–2202 12] Silberstein EB, Ryan J. Prevalence of adverse reactions in nuclear medicine. J Nucl Med 1996; 37:185–192 13] Hendrick RE, Pisano ED, Averbukh A, et al. Comparison of acquisition parameters and breast dose in digital mammography and screen-film mammography in the American College of Radiology Imaging Network digital mammographic imaging screening trial. AJR 2010; 194:362–369 14] O’Connor M, Li H, Rhodes D, Hruska C, Vetter R. Comparison of radiation exposure and associated radiation-induced cancer risks from mammography and molecular imaging of the breast. J Nucl Med 2010; 37:6187–6198 15] Hendrick RE, Tredennick T. Benefit to radiation risk of breast-specific gamma imaging compared with mammography in screening asymptomatic women with dense breasts. Radiology 2016 16] Environmental Protection Agency website. Calculate your radiation dose. www.epa.gov/radiation/calculate-your-radiation-dose. Updated May 12,2016. 17] Tubiana M, Feinendegen LE, Yang C, Kaminski JM. The linear no-threshold relationship is inconsistent with radiation biologic and experimental data. Radiology 2009; 251:13–22 18] Shore RE. Low-dose radiation epidemiology studies: status and issues. Health Phys 2009; 97:481–486 19] American Association of Physicists in Medicine website. AAPM position statement on radiation risks from medical imaging procedures. www.aapm.org/org/policies/details.asp?id=318&type=PP 20] Health Physics Society website. Radiation risk in perspective: position statement of the Health Physics Society. hps.org/documents/radiationrisk.pdf 21] Yaffe MJ, Mainprize JG. Risk of radiation-induced breast cancer from mammographic screening. Radiology 2011; 258:98–105 22] Hendrick RE, Tredennick T. Benefit to radiation risk of breast-specific gamma imaging compared with mammography in screening asymptomatic women with dense breasts.Radiology 2016 23] http://www.dilon.com/ 24] https://www.accessdata.fda.gov/cdrh_docs/pdf16/K160933.pdf 25] http://www.cmr-naviscan.com/ 26] Berg WA, Nuclear Breast Imaging: Clinical Results and Future Directions, J Nucl Med. 2016 Feb;57 Suppl 1:46S-52S. doi: 10.2967/jnumed.115.157891. 27] Rhodes DJ, Hruska CB, Conners AL, et al. Journal club: molecular breast imaging at reduced radiation dose for supplemental screening in mammographically dense breasts. AJR 2015; 204:241–251 28] Shermis RB, Wilson KD, Doyle MT, et al. Supplemental breast cancer screening with molecular breast imaging for women with dense breast tissue. AJR 2016; 207:450–457 29] Brem RF, Ruda RC, Yang JL, Coffey CM, Rapelyea JA. Breast-specific γ-imaging for the detection of mammographically occult breast cancer in women at increased risk. J Nucl Med 2016; 57:678–684 30] Rhodes DJ, Hruska CB, Phillips SW, Whaley DH, O’Connor MK. Dedicated dual-head gamma imaging for breast cancer screening in women with mammographically dense breasts. Radiology 2011; 258:106–118