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Breast Cancer

Mammography is currently the gold standard for the detection of early, clinically occult breast cancer (1, 2). One feature of particular diagnostic significance is the presence of micro-calcifications on the mammogram (1). Frequently these calcifications are the only mammographic feature that indicates the presence of a tumoral lesion. Two major types of micro-calcifications are found in breast tissue. Calcium oxalate dihydrate crystals are seen most frequently in benign ductal cysts and are rarely found in foci of carcinoma, whereas calcium phosphate deposits (in the form of hydroxyapatite) are most often seen in proliferative lesions, including carcinomas (3). While mammography is widely used as a screening tool, it has its limitations, particularly for screening younger women. These limitations include an inability to visualize cancers in women with dense breasts and the increase lifetime risk of cancer caused by exposure to ionizing radiation. There is increasing adoption of Magnetic Resonance Imaging (MRI) of the breast both as a screening examination for younger women who are at high risk for developing breast cancer (4-6) or as a problem solving tool following mammography and/or ultrasound imaging (7-11).

The visualization and characterization of breast lesions on MRI is based on a combination of the morphological features of the lesion seen on pre-contrast injection images as well as the patterns of dynamic contrast enhancement seen on images acquired post-injection of gadolinium based contrast agents. Women with a strong family history of breast cancer are more likely to develop the disease at a younger age when breast density is higher, limiting the effectiveness of screening mammography in this population. Also recent multi-center MRI studies of high-risk subjects have shown that there are significant numbers of so-called “interval cancers” that are detected using annual examinations, suggesting that more frequent screening examinations are necessary in this population. The goal of this project is the development of MR and PET contrast agent that can selectively determine the presence of hydroxyapatite that has up to now been invisible on MRI. The ability to selectively visualize hydroxyapatite in breast cancers on MRI should improve both its sensitivity and specificity for the detection of breast lesions without exposure to any ionizing radiation. These new imaging capabilities would have direct benefits in the diagnosis of breast cancer.

We have previously reported on the preparation and NIR imaging of Pam78, a near infra-red (NIR) fluorescent adduct that binds specifically to hydroxyapatite in vivo (12). We have also demonstrated in a small pilot study that this compound can be used to image hydroxyapatite in animal model systems for breast cancer (13). We have extended this work to prepare and evaluate analogous PET and MRI agents based on pamidronate (14)). See Figure 1 for the synthesis of the PET agent.

 

LL_BC_fig1

Figure 1. The synthetic scheme for preparing the PET agent that specifically binds to hydroxyapaptite.

 

This project will complete the development and evaluation of the pamidronate based PET agent that we have found in pilot studies to be specific for imaging hydroxyapatite. It is likely that for regulatory reasons, the PET agent will be ready for first-in-human trials before the MRI agent.

Over the past decade, positron emission tomography (PET) has evolved to become one of the most promising molecular imaging techniques for oncology, and the indications for its use in breast cancer have grown (15). The power of PET lies in its high sensitivity and relatively high resolution. To be compatible with PET scanners, disease-targeted diagnostic agents must produce positrons, which in turn interact with tissue to produce the anti-parallel, 511-keV photons that are used to reconstruct a 3-D image.

18F-fluoro-2-deoxyglucose (18F-FDG) is the only currently FDA-approved 18F, positron-emitting radiopharmaceutical for routine clinical use in cancer patients in the United States. Although the justification for using 18F-FDG is that in most forms of cancer, glucose transporter upregulation and high glycolytic activity of malignant cells contribute to elevated uptake of 18F-FDG, it is far from a perfect imaging agent for breast cancer. For this reason, there are a number of novel agents being developed either in-house, or in the community, which have the potential for clinical use. For example, 18FLT (fluoro-l-thymidine), an agent thought to be an indicator of DNA turnover is being evaluated in oncology. ApoSense, an 18F agent developed by the Israeli company Aposense (http://www.Aposense.co.il/technology/overview.htm), targets cells that are undergoing programmed cell death (apoptosis). The specificity for this cellular process makes ApoSense particularly attractive for assessing the response of breast cancer to neo-adjuvant therapies. Our laboratory is developing (see Project 2A) a variety of breast cancer-specific 18F diagnostic agents, including 18F-Pam, which is specific for the hydroxyapatite micro-calcifications found in malignant primary breast cancers.

A major problem in the field is that conventional whole-body PET scanners are not optimized for high-resolution, high-sensitivity imaging of the human breast. Also, while the number of whole-body scanners is increasing rapidly, access to this modality when compared with conventional mammography, for example, is still limited. Recently, dedicated breast PET imaging units have been developed for the diagnosis of breast cancer (16, 17). These dedicated PET mammography units have several important benefits over whole-body PET imaging, including high sensitivity for the emitted radiation, improved in-plane spatial resolution (1-2 mm), substantially reduced tissue attenuation, and lower cost. Because these dedicated units are also much more compact than conventional whole body PET units, they can be easily sited in a breast imaging facility. A recent multi-center trial on the FDA approved Naviscan PEM scanner (http://www.naviscanpet.com/pemflex.htm) showed a sensitivity of 0.91, specificity of 0.93, positive predictive value of 0.95, and negative predictive value of 0.88 in characterizing breast lesions (18). We believe that the development of targeted, breast cancer-specific PET agents will further improve diagnostic accuracy. The short-term benefits to UTSW patient population and the larger community are immediate improvements the diagnosis and treatment of breast cancer, and the ability to market the device to referring physicians. The longer-term benefits will be the acceleration in the development and clinical evaluation of novel targeted PET agents for breast cancer.

 

References

  1. Bassett LW. Mammographic Analysis of Calcifications. Radiol Clin N Am. 1992;30(1):93-105.
  2. Bassett LW. Digital and Computer-Aided Mammography. Breast J. 2000;6(5):291-3.
  3. Frappart L, Boudeulle M, Boumendil J, Lin HC, Martinon I, Palayer C, Mallet-Guy Y, Raudrant D, Bremond A, Rochet Y, et al. Structure and composition of microcalcifications in benign and malignant lesions of the breast: study by light microscopy, transmission and scanning electron microscopy, microprobe analysis, and X-ray diffraction. Hum Pathol. 1984;15(9):880-9.
  4. Liberman L. Breast cancer screening with MRI–what are the data for patients at high risk? N Engl J Med. 2004;351(5):497-500.
  5. Lord SJ, Lei W, Craft P, Cawson JN, Morris I, Walleser S, Griffiths A, Parker S, Houssami N. A systematic review of the effectiveness of magnetic resonance imaging (MRI) as an addition to mammography and ultrasound in screening young women at high risk of breast cancer. European Journal of Cancer. 2007;43(13):1905-17.
  6. Warner E, Messersmith H, Causer P, Eisen A, Shumak R, Plewes D. Systematic review: Using magnetic resonance imaging to screen women at high risk for breast cancer. Annals of Internal Medicine. 2008;148(9):671-9.
  7. Bleicher RJ, Morrow M. MRI and breast cancer: Role in detection, diagnosis, and staging. Oncology-New York. 2007;21(12):1521-+.
  8. Kuhl C. The current status of breast MR imaging – Part I. Choice of technique, image interpretation, diagnostic accuracy, and transfer to clinical practice. Radiology. 2007;244(2):356-78.
  9. Morris EA. Diagnostic breast MR imaging: Current status and future directions. Radiol Clin N Am. 2007;45(5):863-+.
  10. Saslow D. American cancer society guidelines for breast screening with MRI as an adjunct to mammography (vol 57, pg 75, 2007). Ca-a Cancer Journal for Clinicians. 2007;57(3):185-.
  11. Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, Morris E, Pisano E, Schnall M, Sener S, Smith RA, Warner E, Yaffe M, Andrews KS, Russell CA. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. Ca-a Cancer Journal for Clinicians. 2007;57(2):75-89.
  12. Zaheer A, Lenkinski RE, Mahmood A, Jones AG, Cantley LC, Frangioni JV. In vivo near-infrared fluorescence imaging of osteoblastic activity. Nat Biotechnol. 2001;19(12):1148-54.
  13. Lenkinski RE, Ahmed M, Zaheer A, Frangioni JV, Goldberg SN. Near-infrared fluorescence imaging of microcalcification in an animal model of breast cancer. Academic Radiology. 2003;10(10):1159-64.
  14. Bhushan KR, Misra P, Liu F, Mathur S, Lenkinski RE, Frangioni JV. Detection of Breast Cancer Microcalcifications Using a Dual-modality SPECT/NIR Fluorescent Probe. Journal of the American Chemical Society. 2008;130(52):17648-+.
  15. Franc BL, Hawkins RA. Positron emission tomography, positron emission tomography-computed tomography, and molecular imaging of the breast cancer patient. Seminars in Roentgenology. 2007;42(4):265-79.
  16. Abreu MC, Almeida P, Balau F, Ferreira NC, Fetal S, Fraga F, Martins M, Matela N, Moura R, Ortigao C, Peralta L, Rato P, Ribeiro R, Rodrigues P, Santos AI, Trindade A, Varela J. Clear-PEM: A dedicated pet camera for improved breast cancer detection. Radiation Protection Dosimetry. 2005;116(1-4):208-10.
  17. Rosen EL, Turkington TG, Soo MS, Baker JA, Coleman RE. Detection of primary breast carcinoma with a dedicated, large-field-of-view FDG PET mammography device: Initial experience. Radiology. 2005;234(2):527-34.
  18. Berg WA, Weinberg IN, Narayanan D, Lobrano ME, Ross E, Amodei L, Tafra L, Adler LP, Uddo J, Stein W, Levine EA, Positron Emission Mammography W. High-resolution fluorodeoxyglucose positron emission tomography with compression (“positron emission mammography”) is highly accurate in depicting primary breast cancer. Breast Journal. 2006;12(4):309-23.

Breast Publications

  1. Lenkinski RE, Ahmed M, Zaheer A, Frangioni JV, Goldberg SN. Near-infrared fluorescence imaging of microcalcification in an animal model of breast cancer. Academic Radiology. 2003;10(10):1159-64.
  2. Maril N, Collins CM, Greenman RL, Lenkinski RE. Strategies for shimming the breast. Magnetic Resonance in Medicine. 2005;54(5):1139-45.
  3. Maril N, Lenkinski RE. An automated algorithm for combining multivoxel MRS data acquired with phased-array coils. Journal of Magnetic Resonance Imaging. 2005;21(3):317-22.
  4. Bhushan KR, Misra P, Liu F, Mathur S, Lenkinski RE, Frangioni JV. Detection of breast cancer microcalcifications using a dual-modality SPECT/ NIR fluorescent probe. Journal of the American Chemical Society. 2008;130(52):17648-9.
  5. Liu F, Bloch N, Bhushan KR, De Grand AM, Tanaka E, Solazzo S, Mertyna PM, Goldberg N, Frangioni JV, Lenkinski RE. Humoral bone morphogenetic protein 2 is sufficient for inducing breast cancer microcalcification. Molecular Imaging. 2008;7(4):175-86.
  6. Lenkinski RE, Wang X, Elian M, Goldberg SN. Interaction of gadolinium-based MR contrast agents with choline: Implications for MR spectroscopy (MRS) of the breast. Magnetic Resonance in Medicine. 2009;61(6):1286-92.
  7. Liu F, Misra P, Lunsford EP, Vannah JT, Liu Y, Lenkinski RE, Frangioni JV. A dose- and time-controllable syngeneic animal model of breast cancer microcalcification. Breast Cancer Research and Treatment. 2010;122(1):87-94.
  8. Inoue K, Liu F, Hoppin J, Lunsford EP, Lackas C, Hesterman J, Lenkinski RE, Fujii H, Frangioni JV. High-resolution computed tomography of single breast cancer microcalcifications in vivo. Molecular Imaging. 2011;10(4):295-304.
  9. Hancu I, Govenkar A, Lenkinski RE, Lee SK. On shimming approaches in 3T breast MRI. Magnetic Resonance in Medicine. 2012.
  10. Lenkinski RE. Hyperpolarized C-13 studies of cancer metabolism in animal models. Hype or real? European Journal of Radiology. 2012;81(SUPPL1):S85-S6.
  11. Seiler S, Lenkinski RE. Dedicated PET device for breast PET and MRI/PET correlations. European Journal of Radiology. 2012;81(SUPPL1):S149-S50.
  12. Hancu I, Govenkar A, Lenkinski RE, Lee SK. On shimming approaches in 3T breast MRI. Magnetic Resonance in Medicine. 2013;69(3):862-7.