Review Article | Open Access
Molecular Imaging-Guided Interventional Hyperthermia in Treatment of Breast Cancer
Breast cancer is the most frequent malignancy in women worldwide. Although it is commonly treated via chemotherapy, responses vary among its subtypes, some of which are relatively insensitive to chemotherapeutic drugs. Recent studies have shown that hyperthermia can enhance the effects of chemotherapy in patients with refractory breast cancer or without surgical indications. Recent advances in molecular imaging may not only improve early diagnosis but may also facilitate the development and response assessment of targeted therapies. Combining advanced techniques such as molecular imaging and hyperthermia-integrated chemotherapy should open new avenues for effective management of breast cancer.
Breast cancer is the most common malignancy in women worldwide. Although chemotherapy has improved the survival of breast cancer patients, some breast cancer subtypes are relatively insensitive to chemotherapy drugs. Breast cancers are highly heterogeneous, comprising different histologic tissues as well as gene expression and mutation patterns . In patients with refractory breast cancer or without surgical indication, hyperthermia (mild heat at approximately 42°C) may augment chemotherapy. Although thermal ablation (temperatures above 60°C) can directly destroy cancer tissue [2, 3], it has shown limited success in tumors located adjacent to normal structures, such as blood vessels, which are prone to thermal injury . Incomplete ablation also frequently occurs at treated tumor margins owing to heat dissipation by neighboring blood flow or incomplete coverage of large, irregularly shaped tumors by the ablation field. Because of these drawbacks, thermal ablation often results in tumor recurrence.
Radiofrequency- (RF-) mediated, nonablative local hyperthermia with body-tolerable temperatures of 40–44°C can significantly enhance the antitumor effects of different drugs in a variety of malignancies [5–9]. It may do so by heating fractured tissue or increasing cellular metabolism, the permeability of cytoplasmic membranes, or the activity of heat shock proteins [10, 11]. All of these mechanisms facilitate the entrance of therapeutics into the targeted tumor cells for effective destruction of tumor tissue. Motivated by the success of RF-mediated, nonablative hyperthermia, an innovative interventional oncologic technique termed “percutaneous intratumoral RF hyperthermia-enhanced chemotherapy of cancers” has been introduced [5–7]. This technique combines hyperthermia and chemotherapy and has increased survival in several randomized clinical trials [12–15]. For example, the 10-year disease-free survival rate was 53–72% in bladder cancer patients receiving a combination of hyperthermia and chemotherapy compared with 15% in those receiving chemotherapy alone [16, 17].
Molecular imaging is one of the frontiers in modern medical imaging . It can detect biological events occurring at the cellular and molecular levels in vivo and has demonstrated great potential in the early diagnosis and effective treatment of a number of life-threatening diseases including breast cancer. Molecular imaging can be potentially used to screen patients, stage tumors, guide therapy, and assess responses to therapy . Furthermore, recent development of a molecular imaging-guided, RF hyperthermia-enhanced interventional oncology technique has facilitated the efficient management of breast cancer by combining molecular imaging and hyperthermia technology-integrated chemotherapy . In this paper, we review the current status of molecular imaging-guided hyperthermia in breast cancer treatment.
2. Molecular Subtypes and Targeted Therapies in Breast Cancer
To date, breast cancer has four main subtypes: luminal A, luminal B, basal-like, and human epidermal growth factor 2- (HER2-) enriched . This classification is based on information gathered from different molecular assays including DNA methylation assays, exome sequencing, microRNA sequencing, and DNA copy number, mRNA, and reverse-phase protein arrays (Table 1) [21, 22]. The different subtypes have different molecular characteristics and different sensitivities to chemotherapy. The luminal A subtype has the best prognosis after chemotherapy, followed by the luminal B subtype, while the basal-like and HER2-enriched subtypes have the worst prognosis . The luminal A and B subtypes are amenable to hormone therapy, and the HER2-enriched subtype is a potential candidate for trastuzumab therapy .
|IHC: immunohistochemistry; ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; PR: progesterone receptor; +: positive; −: negative; TNBCs: triple-negative breast cancers; pCR: pathological complete response after neoadjuvant chemotherapy.|
The primary goal of targeted therapy—killing tumor cells while sparing surrounding healthy cells—is the basis of personalized medicine. Personalized medicine in breast cancer has two primary components: targeted diagnosis and targeted treatment. The goal of targeted diagnosis is to accurately differentiate the subtypes of breast cancer according to the patient’s molecular profile to ensure that the most effective treatments are selected. The goal of targeted treatment is to produce therapeutic-carrying probes that specifically target molecules uniquely expressed or overexpressed in tumors, as identified via molecular profiling, and thereby effectively treat the targeted lesions without damaging surrounding healthy tissues. Manufacturing probes with imaging-visible materials, such as metals for X-ray imaging, nucleoids for nuclear imaging, and heavy metals for magnetic resonance (MR) imaging (MRI), also achieves targeted imaging [25, 26]. Even with the current technologies, the specific targeting of systemically administered imaging and therapeutic probes is still limited because the molecular targets overexpressed in lesions may also be expressed at certain levels in healthy tissues.
Interventional radiology, which uses images to guide minimally invasive interventions, can help deliver targeted probes directly to targeted lesions, thus avoiding systemic toxicity of the probes in vital normal organs . It can also expand the capabilities of currently available molecular imaging techniques to (i) reach deep-seated targets, (ii) enable a close look at small targets, (iii) precisely guide delivery of nontargeted imaging tracers or therapeutics, and (iv) selectively enhance the effectiveness of targeted imaging and treatment [28, 29].
3. Molecular Imaging in Breast Cancer
Molecular imaging is one of the hottest topics in modern medical imaging. Molecular imaging modalities can assess biologic processes at the molecular and cellular level, which is useful for early detection of cancer and complements traditional anatomic imaging methods . Molecular imaging can be potentially used for breast cancer screening, staging, and guiding and assessing responses to therapy . Techniques for molecular imaging of breast cancers include MRI, optical imaging, radionuclide imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT), and contrast-enhanced ultrasound imaging .
For molecular imaging of breast cancer, proteins (e.g., receptors) overexpressed in breast tumors are starting points for the development of tumor-specific tracers (Figure 1) . Hormone receptors are expressed in most breast tumor cells, and many receptors (e.g., HER2, epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor, and platelet-derived growth factor β receptor) are present in the plasma membranes of tumor cells, which facilitates targeting because the probes do not need to enter cells. Receptor ligands, such as vascular endothelial growth factor (VEGF) and transforming growth factor β, are secreted by tumor cells into the tumor microenvironment, which allows regional molecular imaging of tumors. In addition, proteins (e.g., VEGF receptors, EGFRs, -integrin, fibronectin, and endostatin) and conditions (e.g., hypoxia) involved in angiogenesis play important roles in breast tumor growth and thus are reasonable targets for molecular imaging of breast tumors . Tumor cells have a higher metabolism and proliferation rate than do normal cells.
3.1. Molecular MRI
Conventional dynamic contrast-enhanced (DCE) or contrast-enhanced MRI of the breasts involves an intravenous injection of a low molecular weight T1-shortening paramagnetic contrast agent or dye. The rate of contrast agent uptake into breast lesions is nonlinear and differs between malignant and benign lesions. How a tumor responds to treatment is indicated by changes in the parameters of DCE-MRI. Diffusion-weighted- (DW-) MRI is based on the movement of water over distances of 0 to 30 μm in 50 to 100 ms . Differentiation between malignant and benign breast tumors via DW-MRI has been reported, with the mean apparent diffusion coefficient of malignant lesions being significantly lower than that of benign lesions or normal breast tissue [32, 33]. Breast tumors are less hypoxic than normal breast tissue . Blood oxygen level-dependent or intrinsic susceptibility-weighted MRI relies on the paramagnetic property of deoxyhemoglobin .
In contrast to conventional DCE-MRI, molecular MRI depends on the specificity and amplified action of both contrast agents and targeted molecular probes to improve its sensitivity and can assess molecular events in both normal and tumor cells in vivo. Proteins associated with the physiopathology and biology of breast cancer, such as estrogen, p53, HER2, Ki-67, VEGF, progesterone, and EGFRs, represent specific molecular targets for molecular MRI of breast cancers (Figure 2) [36–38].
3.2. PET, SPECT, PET/MRI, and Computed Tomography (CT)
For current molecular imaging of tumor receptors, PET and SPECT appear to be more feasible than MRI because they use nuclide tracers with high specific activity . PET requires positron-emitting radionuclides, such as 18F, 11C, 13N, , 120/124I, 110In, 66/68Ga, and 61/64Cu, while SPECT uses nuclear imaging γ emitters, such as , 123/131I, 67Ga, and 111In . As a whole imaging modality, 18F-fluorodeoxyglucose-PET, a highly investigated and clinically used whole-body imaging modality, provides accurate diagnostic information in patients with breast cancer . Hybrid PET/MRI imaging systems are being developed and promise to improve the diagnostic work-ups of patients with recurrent breast cancer. PET/MRI potentially provides high diagnostic accuracy, soft tissue resolution (via MRI), and specificity (owing to the metabolic information obtained from PET). It may increase diagnostic accuracy after gamma knife (GK) surgery (Figure 3) [25, 40].
Multimodality imaging, which combines the advantages of different imaging techniques, provides more information on early diagnosis than other systems and allows dynamic monitoring of the responses of the breast cancer to drugs. Figure 4 presents a typical case in which PET/CT was used. In this case, a 35-year-old woman with an infiltrating breast ductal carcinoma responded to therapy quantified by using a standardized uptake value assessment (SUV) (Figure 4) .
3.3. Targeted Ultrasound Imaging
Ultrasound imaging discriminates between fluid-filled and solid tissue structures. However, it is not suitable for detailed evaluation of physiopathological changes such as angiogenesis and breast inflammation. A solution to this deficiency is the use of ultrasound contrast agents (UCAs) . Current clinically approved UCAs basically consist of gas microbubbles encapsulated in protein or liposomal carriers [43, 44]. Attempts have been made to produce targeted UCAs. Antibodies, peptides, and other targeting moieties can be bound to microbubbles to target molecules to breast cancer cells that promote angiogenesis and inflammation. One study demonstrated that UCAs targeting HER2, which is dysregulated or overexpressed up to 100-fold in certain subtypes of breast cancer, could generate high-quality ultrasound images of the breast cancer with sufficient mean pixel intensity .
3.4. Molecular Optical Imaging
Molecular optical imaging offers the possibility of noninvasive, inexpensive, and highly sensitive imaging of breast cancers. Most optical imaging approaches are based on the intrinsic contrast of major tissue chromophores such as hemoglobin, water, and lipids. The main challenges of optical imaging are depth penetration and signal quantification, as well as the development, validation, and approval of relevant optical imaging agents for human use. Light penetration in tissue is limited. However, with the application of near-infrared light, along with the development of more sensitive detection equipment, light penetration in human tissue is now up to 15 centimeters.
Another exciting application of optical technology is the combination of optical imaging with other imaging modalities. Recent efforts have been made to equip hybrid optical imaging with acoustic ultrasound, which may improve the sensitivity and specificity of molecular optical imaging in breast cancer .
4. Basic Concept of Thermal Ablation and Hyperthermia in Breast Cancer
Thermal ablation enables treatment of localized small breast tumors (2 to 3 cm) [46, 47]. The typical thermal ablation approach is radiofrequency ablation (RFA), which is produced by frictional heating; RF-connected electrode tips placed in the lesion initiate ionic agitation, which generates heat and ultimately destroys cells [48, 49]. RFA was initially used to treat metastatic cancer in the liver and subsequently to treat breast cancer . It is a promising nonsurgical treatment for breast cancer, with reported technical success rates ranging from 76% to 100% [46, 47, 51].
Although there are no standard guidelines for selecting patients for RFA based on tumor size, studies report consistent complete destruction of breast cancers up to 2 cm in diameter; tumors larger than 5 cm usually should be excluded [52, 53]. Patients diagnosed with a single small biopsy-confirmed invasive breast carcinoma are ideal candidates, while extensive diseases including invasive lobular carcinoma and multifocal or multicentric breast lesions are contraindications for curative RFA .
Hyperthermia or mild heat at body-tolerable temperatures of 40–44°C has become an effective means of enhancing the efficacy of radiotherapy or chemotherapy in various tumor types [55, 56]. The benefits of hyperthermia combined with radiotherapy or chemotherapy have been documented by several studies of primary and recurrent breast malignancies [57–60]. Hyperthermia can be performed using antennas or applicators that generate heat or photothermal conversion nanoparticles, which are also chemotherapeutic carriers [61, 62].
5. Molecular Imaging-Guided Hyperthermia in Breast Cancer
Technologic advances over the last decade have made it possible to cure primary breast malignancies using percutaneous minimally invasive therapeutic approaches . Despite achievements in hyperthermia-based treatments, applying local hyperthermia to deep-seated tumors remains challenging. For example, in pancreatobiliary malignancies, percutaneous RFA or laser ablation has a high risk of damaging adjacent normal structures such as blood vessels, while high-intensity focused ultrasound (HIFU) cannot be used for deep-seated targets owing to inhibition of HIFU energy transfer by adjacent air-containing structures such as the intestine. Application of intrabiliary RF heating by use of antennas or microthermal generators may solve these problems.
Molecular imaging may be useful in this regard. Recent interest in this technique among both diagnostic radiologists and interventionists has led to the establishment of a new concept, namely, “interventional molecular imaging” . This concept aims to fully combine the advantages of two advanced imaging fields, interventional radiology and molecular imaging, with two primary goals. The first goal is local delivery of molecular imaging probes to targets using image-guided interventional techniques, which should prevent renal and hepatic clearance of the probes, as what occurs with systemically administered probes. The second goal is precise image-guided placement of miniature molecular imagers, such as endoluminal optical imagers, in deep-seated targets. This will allow molecular optical imaging not otherwise achieved via percutaneous approaches because of light loss due to tissue scattering and reflection. Molecular imaging can precisely guide probes and assess the responses of their tumor targets to interventional therapies, which is extremely helpful in advanced treatments such as gene therapy and stem cell therapy.
As a step toward molecular imaging-guided hyperthermia in breast cancer, different imaging techniques have been applied. These include HIFU, nanomagnetic particle-based thermotherapy, and real-time thermal mapping (termed MR thermometry) for monitoring breast tumors treated via RFA.
5.1. Molecular Imaging-Guided Thermal Ablation and Hyperthermia
5.1.1. MRI-Guided RFA
Compared with other imaging techniques, MRI (i) offers more accurate preoperative assessment of the size and extent of the breast cancer, (ii) detects multifocal breast lesions as small as 3 mm , (iii) precisely guides the placement of interventional instruments in targeted breast lesions [65, 66], and (iv) allows MR thermometry at controlled ablative temperatures in lesions (Figure 5) . It has been reported that MRI-guided RFA results in complete tumor ablation .
5.1.2. MRI Guided Laser-Induced Interstitial Thermotherapy of Breast Cancer
MR-guided, laser-induced interstitial thermotherapy (LITT) can be used to treat primary breast cancer and breast cancer metastases. This technique showed excellent long-term survival results in clinical trials [67, 68] and is a minimally invasive option for treatment of primary breast cancer and especially metastatic tumors.
5.1.3. MRI-Guided HIFU
HIFU is an advanced noninvasive therapeutic technique. Clinical trials consisting of more than 20,000 patients with liver, kidney, or pancreatic cancer, are currently underway in Europe and Asia [69–72]. Because it allows three-dimensional treatment planning and continuous temperature mapping for real-time monitoring of thermal damage in the target zone, MRI-guided HIFU is a valid noninvasive treatment for breast cancer . The current technique requires targets in immobilized organs (e.g., breast and uterus), in which mechanical waves are not attenuated or dispersed by other organs.
Magnetic nanoparticles have been used to assess tumor response and to provide evidence of ablation after treatment. Recent studies support the possibility of generating mild hyperthermia via MRI-guided HIFU for treatment of fibrosarcoma and, in combination with magnetic nanoparticles, treatment of breast cancer [74, 75].
5.1.4. Molecular Image-Guided Radiofrequency-Enhanced Gene Therapy
One of the current limitations of gene therapy is its low capacity to sufficiently transfect/transduce genes/vectors into targets. RF can enhance gene transfer and gene expression by creating local heat. Molecular image-guided RF can also be used to monitor the delivery of nontargeted imaging tracers or therapeutic agents to their specific targets. Yang et al., for example, used intravascular high-spatial resolution MRI to monitor gene delivery to vascular walls . To be visible in MR images, gene vectors are first mixed with an MR contrast agent, and the mixture is locally infused into the vessel wall of the targeted tumor through a balloon catheter. The distribution of contrast agent (and thus of the gene) within the vessel wall is precisely monitored via intravascular high-spatial-resolution MRI .
5.2. Molecular Imaging in Thermorelated Nanoparticles for Diagnosis and Treatment of Breast Cancers
Nanoparticles are an interdisciplinary topic of interest for research pertaining to the diagnosis and treatment of breast cancer. Nanomaterials can be engineered to serve as targeted molecular imaging contrast agents and antitumor drug delivery vehicles . Specific targeting of nanoparticles allows controlled drug release and enhances drug permeability and retention despite the leaky vasculature of cancerous tissues. The identification of specific molecular and biological pathways in breast cancer has spurred the development of novel nanoscale approaches for diagnosis and treatment of breast cancer .
Coencapsulating chemotherapeutic drugs and MRI-visible agents in one carrier provide a valid tool for image-guided, temperature-induced drug release. Hyperthermia-induced release of capsule contents can be monitored indirectly by corelease of an MRI contrast agent once the nanoparticles arrive at the target. Within the nanoparticles, some MRI contrast agents cannot be visualized because of limited water exchange across the lipid bilayer of the cell membrane. However, when the temperature of the phase transition of the cell membrane rises, water exchange increases and/or contrast agent is released from the nanoparticles, which thereby shortens the 1H MR relaxation time of the surrounding tissues for generating MR signals.
Magnetic nanoparticles provide a good signal in soft tissue and thus morphological/anatomical information, while MR thermometry evaluates alterations in hyperthermia at different dimensions within the heated tissues [78, 79]. Some investigators coencapsulated doxorubicin and manganese (a T1 MRI contrast agent) in one nanocarrier for molecular MRI-guided drug delivery and, by doing so, created the concept of “dose painting,” which was demonstrated via MRI [80, 81]. A milestone in molecular imaging-guided hyperthermia was the conjugation of magnetic nanoparticles to HER2 monoclonal antibodies to allow specific binding of the nanoparticles to HER2, which is present in approximately 17% of breast cancers. HER2-specific magnetic nanoparticles can carry and release coloaded chemotherapeutic drugs both in vitro and in vivo  and have been successfully used to inhibit the proliferation of breast cancer cells [82–84] and in primary systemic therapy prior to surgical intervention . Magnetic hyperthermia and magnetic nanoparticles in alternating magnetic fields could partially or completely destroy small occult lesions, which would limit the extent of or need for surgical intervention [85, 86].
PET and SPECT imaging are often used to visualize nanoparticles delivered to certain types of tumors. Nanoparticles can also be labeled with radionuclides such as , 111In, 201TI, 18F, 123I, 131I, and 6Ga [87–90]. By the use of these radioactive nanoparticles, molecular imaging-guided interventions have become feasible.
Molecular imaging is an excellent technique for early detection and guided targeted therapy of breast cancer. Molecular imaging-guided intervention in combination with hyperthermia can further improve the treatment of this common, worldwide life-threatening malignancy in women. The combination of advanced multidisciplinary technologies such as molecular imaging-integrated hyperthermia and interventional radiology, as well as gene therapy and chemotherapy, provides new options for effective management of breast cancer.
Conflict of Interests
The authors have no conflict of interests.
This study was supported by the National Basic Research Program of China (973 Program, 2014CB744505), a National Institutes of Health Grant (R01EB012467), and the Program for National Science and Technology Major Project of China (2013ZX10002004-001-005).
- M. Ignatiadis and C. Sotiriou, “Luminal breast cancer: from biology to treatment,” Nature Reviews Clinical Oncology, vol. 10, no. 9, pp. 494–506, 2013.
- M. van den Bosch, B. Daniel, V. Rieke, K. Butts-Pauly, E. Kermit, and S. Jeffrey, “MRI-guided radiofrequency ablation of breast cancer: preliminary clinical experience,” Journal of Magnetic Resonance Imaging, vol. 27, no. 1, pp. 204–208, 2008.
- J. Palussière, C. Henriques, L. Mauriac et al., “Radiofrequency ablation as a substitute for surgery in elderly patients with nonresected breast cancer: pilot study with long-term outcomes,” Radiology, vol. 264, no. 2, pp. 597–605, 2012.
- B. M. Künzli, P. Abitabile, and C. A. Maurer, “Radiofrequency ablation of liver tumors: actual limitations and potential solutions in the future,” World Journal of Hepatology, vol. 3, no. 1, pp. 8–14, 2011.
- T. Zhang, F. Zhang, Y. Meng et al., “Diffusion-weighted MRI monitoring of pancreatic cancer response to radiofrequency heat-enhanced intratumor chemotherapy,” NMR in Biomedicine, vol. 26, no. 12, pp. 1762–1767, 2013.
- F. Zhang, T. Le, X. Wu et al., “Intrabiliary RF heat-enhanced local chemotherapy of a cholangiocarcinoma cell line: monitoring with dual-modality imaging-preclinical study,” Radiology, vol. 270, no. 2, pp. 400–408, 2014.
- X. Yang, E. Atalar, D. Li et al., “Magnetic resonance imaging permits in vivo monitoring of catheter-based vascular gene delivery,” Circulation, vol. 104, no. 14, pp. 1588–1590, 2001.
- X. Yang, “Imaging of vascular gene therapy,” Radiology, vol. 228, no. 1, pp. 36–49, 2003.
- X. Du, B. Qiu, X. Zhan et al., “Radiofrequency-enhanced vascular gene transduction and expression for intravascular MR imaging-guided therapy: feasibility study in pigs,” Radiology, vol. 236, no. 3, pp. 939–944, 2005.
- D. P. Madio, P. van Gelderen, D. DesPres et al., “On the feasibility of MRI-guided focused ultrasound for local induction of gene expression,” Journal of Magnetic Resonance Imaging, vol. 8, no. 1, pp. 101–104, 1998.
- A. G. Doukas and T. J. Flotte, “Physical characteristics and biological effects of laser-induced stress waves,” Ultrasound in Medicine and Biology, vol. 22, no. 2, pp. 151–164, 1996.
- M. Franckena, R. Canters, F. Termorshuizen, J. Van Der Zee, and G. Van Rhoon, “Clinical implementation of hyperthermia treatment planning guided steering: a cross over trial to assess its current contribution to treatment quality,” International Journal of Hyperthermia, vol. 26, no. 2, pp. 145–157, 2010.
- M. R. Horsman and J. Overgaard, “Hyperthermia: a potent enhancer of radiotherapy,” Clinical Oncology, vol. 19, no. 6, pp. 418–426, 2007.
- J. van der Zee, D. González González, G. C. van Rhoon, J. D. P. van Dijk, W. L. J. van Putten, and A. A. M. Hart, “Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial,” The Lancet, vol. 355, no. 9210, pp. 1119–1125, 2000.
- J. Van der Zee and G. C. Van Rhoon, “Cervical cancer: radiotherapy and hyperthermia,” International Journal of Hyperthermia, vol. 22, no. 3, pp. 229–234, 2006.
- R. Colombo, A. Salonia, Z. Leib, M. Pavone-Macaluso, and D. Engelstein, “Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC),” BJU International, vol. 107, no. 6, pp. 912–918, 2011.
- R. Wessalowski, D. T. Schneider, O. Mils et al., “Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study,” The Lancet Oncology, vol. 14, no. 9, pp. 843–852, 2013.
- R. Weissleder and U. Mahmood, “Molecular imaging,” Radiology, vol. 219, no. 2, pp. 316–333, 2001.
- T. H. O. Munnink, W. B. Nagengast, A. H. Brouwers et al., “Molecular imaging of breast cancer,” Breast, vol. 18, supplement 3, pp. S66–S73, 2009.
- Y. Zhou, G. Han, Y. Wang et al., “Radiofrequency heat-enhanced chemotherapy for breast cancer: towards interventional molecular image-guided chemotherapy,” Theranostics, vol. 4, no. 11, pp. 1145–1152, 2014.
- D. C. Koboldt, R. S. Fulton, M. D. McLellan et al., “Comprehensive molecular portraits of human breast tumours,” Nature, vol. 490, no. 7418, pp. 61–70, 2012.
- J. S. Reis-Filho and L. Pusztai, “Gene expression profiling in breast cancer: classification, prognostication, and prediction,” The Lancet, vol. 378, no. 9805, pp. 1812–1823, 2011.
- K. M. Cornejo, D. Kandil, A. Khan, and E. F. Cosar, “Theranostic and molecular classification of breast cancer,” Archives of Pathology & Laboratory Medicine, vol. 138, no. 1, pp. 44–56, 2014.
- R. Rouzier, C. M. Perou, W. F. Symmans et al., “Breast cancer molecular subtypes respond differently to preoperative chemotherapy,” Clinical Cancer Research, vol. 11, no. 16, pp. 5678–5685, 2005.
- C. M. Gaeta, J. L. Vercher-Conejero, A. C. Sher, A. Kohan, C. Rubbert, and N. Avril, “Recurrent and metastatic breast cancer PET, PET/CT, PET/MRI: FDG and new biomarkers,” Quarterly Journal of Nuclear Medicine and Molecular Imaging, vol. 57, no. 4, pp. 352–366, 2013.
- M. A. Oghabian, M. Jeddi-Tehrani, A. Zolfaghari, F. Shamsipour, S. Khoei, and S. Amanpour, “Detectability of Her2 positive tumors using monoclonal antibody conjugated iron oxide nanoparticles in MRI,” Journal of Nanoscience and Nanotechnology, vol. 11, no. 6, pp. 5340–5344, 2011.
- R. D. Baird and C. Caldas, “Genetic heterogeneity in breast cancer: the road to personalized medicine?” BMC Medicine, vol. 11, article 151, 2013.
- X. Yang, “Interventional molecular imaging,” Radiology, vol. 254, no. 3, pp. 651–654, 2010.
- N. Abi-Jaoudeh, A. G. Duffy, T. F. Greten, E. C. Kohn, T. W. I. Clark, and B. J. Wood, “Personalized oncology in interventional radiology,” Journal of Vascular and Interventional Radiology, vol. 24, no. 8, pp. 1083–1092, 2013.
- J. M. Specht and D. A. Mankoff, “Advances in molecular imaging for breast cancer detection and characterization,” Breast Cancer Research, vol. 14, no. 2, article 206, 2012.
- D. G. Norris, “The effects of microscopic tissue parameters on the diffusion weighted magnetic resonance imaging experiment,” NMR in Biomedicine, vol. 14, no. 2, pp. 77–93, 2001.
- R. Woodhams, K. Matsunaga, S. Kan et al., “ADC mapping of benign and malignant breast tumors,” Magnetic Resonance in Medical Sciences, vol. 4, no. 1, pp. 35–42, 2005.
- S. C. Partridge, W. B. DeMartini, B. F. Kurland, P. R. Eby, S. W. White, and C. D. Lehman, “Differential diagnosis of mammographically and clinically occult breast lesions on diffusion-weighted MRI,” Journal of Magnetic Resonance Imaging, vol. 31, no. 3, pp. 562–570, 2010.
- S. P. Li, N. J. Taylor, A. Makris et al., “Primary human breast adenocarcinoma: imaging and histologic correlates of intrinsic susceptibility-weighted MR imaging before and during chemotherapy,” Radiology, vol. 257, no. 3, pp. 643–652, 2010.
- E. A. M. O'Flynn and N. M. deSouza, “Functional magnetic resonance: biomarkers of response in breast cancer,” Breast Cancer Research, vol. 13, article 405, 2011.
- D. Artemov, N. Mori, R. Ravi, and Z. M. Bhujwalla, “Magnetic resonance molecular imaging of the HER-2/neu receptor,” Cancer Research, vol. 63, no. 11, pp. 2723–2727, 2003.
- O. Fernández-Guinea, A. Andicoechea, L. O. González et al., “Relationship between morphological features and kinetic patterns of enhancement of the dynamic breast magnetic resonance imaging and clinico-pathological and biological factors in invasive breast cancer,” BMC Cancer, vol. 10, article 8, 2010.
- J. Qiao, S. Xue, F. Pu et al., “Molecular imaging of EGFR/HER2 cancer biomarkers by protein MRI contrast agents,” Journal of Biological Inorganic Chemistry, vol. 19, no. 2, pp. 259–270, 2014.
- S. Cunha, L. Gano, G. Ribeiro Morais, T. Thiemann, and M. C. Oliveira, “Progesterone receptor targeting with radiolabelled steroids: an approach in predicting breast cancer response to therapy,” Journal of Steroid Biochemistry and Molecular Biology, vol. 137, pp. 223–241, 2013.
- T. Momose, T. Nariai, T. Kawabe et al., “Clinical benefit of 11C methionine pet imaging as a planning modality for radiosurgery of previously irradiated recurrent brain metastases,” Clinical Nuclear Medicine, vol. 39, no. 11, pp. 939–943, 2014.
- M. A. Jacobs, R. Ouwerkerk, A. C. Wolff et al., “Monitoring of neoadjuvant chemotherapy using multiparametric, 23Na sodium MR, and multimodality (PET/CT/MRI) imaging in locally advanced breast cancer,” Breast Cancer Research and Treatment, vol. 128, no. 1, pp. 119–126, 2011.
- A. Milgroom, M. Intrator, K. Madhavan et al., “Mesoporous silica nanoparticles as a breast-cancer targeting ultrasound contrast agent,” Colloids and Surfaces B: Biointerfaces, vol. 116, pp. 652–657, 2014.
- A. A. Doinikov, L. Aired, and A. Bouakaz, “Acoustic scattering from a contrast agent microbubble near an elastic wall of finite thickness,” Physics in Medicine and Biology, vol. 56, no. 21, pp. 6951–6967, 2011.
- S. R. Sirsi and M. A. Borden, “Microbubble compositions, properties and biomedical applications,” Bubble Science, Engineering and Technology, vol. 1, no. 1-2, pp. 3–17, 2009.
- S. A. Ermilov, M. P. Fronheiser, V. Nadvoretsky et al., “Real-time optoacoustic imaging of breast cancer using an interleaved two-laser imaging system coregistered with ultrasound,” in Photons Plus Ultrasound: Imaging and Sensing, vol. 7564 of Proceedings of SPIE, San Francisco, Calif, USA, February 2010.
- F. Izzo, R. Thomas, P. Delrio et al., “Radiofrequency ablation in patients with primary breast carcinoma—a pilot study in 26 patients,” Cancer, vol. 92, no. 8, pp. 2036–2044, 2001.
- M. Noguchi, “Radiofrequency ablation treatment for breast cancer to meet the next challenge: how to treat primary breast tumor without surgery,” Breast Cancer, vol. 10, no. 1, pp. 1–3, 2003.
- W. E. Burak Jr., D. M. Agnese, S. P. Povoski et al., “Radiofrequency ablation of invasive breast carcinoma followed by delayed surgical excision,” Cancer, vol. 98, no. 7, pp. 1369–1376, 2003.
- A. N. Mirza, B. D. Fornage, N. Sneige et al., “Radiofrequency ablation of solid tumors,” Cancer Journal, vol. 7, no. 2, pp. 95–102, 2001.
- S. S. Jeffrey, R. L. Birdwell, D. M. Ikeda et al., “Radiofrequency ablation of breast cancer—first report of an emerging technology,” Archives of Surgery, vol. 134, no. 10, pp. 1064–1068, 1999.
- S. E. Singletary, “Radiofrequency ablation of breast cancer,” American Surgeon, vol. 69, no. 1, pp. 37–40, 2003.
- B. D. Fornage, N. Sneige, M. I. Ross et al., “Small (-cm) breast cancer treated with US-guided radiofrequency ablation: feasibility study,” Radiology, vol. 231, no. 1, pp. 215–224, 2004.
- I. M. C. van der Ploeg, S. van Esser, M. A. A. J. van den Bosch et al., “Radiofrequency ablation for breast cancer: a review of the literature,” European Journal of Surgical Oncology, vol. 33, no. 6, pp. 673–677, 2007.
- A. H. Hayashi, S. F. Silver, N. G. van der Westhuizen et al., “Treatment of invasive breast carcinoma with ultrasound-guided radiofrequency ablation,” The American Journal of Surgery, vol. 185, no. 5, pp. 429–435, 2003.
- C. W. Song, A. Shakil, R. J. Griffin, and K. Okajima, “Improvement of tumor oxygenation status by mild temperature hyperthermia alone or in combination with carbogen,” Seminars in Oncology, vol. 24, no. 6, pp. 626–632, 1997.
- B. M. Dicheva and G. A. Koning, “Targeted thermosensitive liposomes: an attractive novel approach for increased drug delivery to solid tumors,” Expert Opinion on Drug Delivery, vol. 11, no. 1, pp. 83–100, 2014.
- C. C. Vernon, J. W. Hand, S. B. Field et al., “Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials,” International Journal of Radiation Oncology Biology Physics, vol. 35, no. 4, pp. 731–744, 1996.
- C. Nistico, A. De Matteis, E. Rossi et al., “Primary chemotherapy with epirubicin and vinorelbine in women with locally advanced breast cancer,” Anticancer Research, vol. 25, no. 2, pp. 1343–1348, 2005.
- D. Yamamoto, T. Inui, Y. Tsubota et al., “The utility of hyperthermia for local recurrence of breast cancer,” World Journal of Surgical Oncology, vol. 10, article 201, 2012.
- T. Feyerabend, G. J. Wiedemann, B. Jäger, H. Vesely, B. Mahlmann, and E. Richter, “Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease,” International Journal of Radiation Oncology, Biology, Physics, vol. 49, no. 5, pp. 1317–1325, 2001.
- D. Needham, G. Anyarambhatla, G. Kong, and M. W. Dewhirst, “A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model,” Cancer Research, vol. 60, no. 5, pp. 1197–1201, 2000.
- C. Ayala-Orozco, C. Urban, M. W. Knight et al., “Au nanomatryoshkas as efficient near-infrared photothermal transducers for cancer treatment: benchmarking against nanoshells,” ACS Nano, vol. 8, no. 6, pp. 6372–6381, 2014.
- D. F. Kacher and F. A. Jolesz, “MR imaging—guided breast ablative therapy,” Radiologic Clinics of North America, vol. 42, no. 5, pp. 947–962, 2004.
- D. R. Fischer, S. Wurdinger, J. Boettcher, A. Malich, and W. A. Kaiser, “Further signs in the evaluation of magnetic resonance mammography: a retrospective study,” Investigative Radiology, vol. 40, no. 7, pp. 430–435, 2005.
- M. Saeed and M. Wilson, “Value of MR contrast media in image-guided body interventions,” World Journal of Radiology, vol. 4, no. 1, pp. 1–12, 2012.
- G. Manenti, A. L. Scarano, C. A. Pistolese et al., “Subclinical breast cancer: minimally invasive approaches. our experience with percutaneous radiofrequency ablation vs. cryotherapy,” Breast Care, vol. 8, no. 5, pp. 356–360, 2013.
- T. J. Vogl, V. Freier, N.-E. A. Nour-Eldin, K. Eichler, S. Zangos, and N. N. N. Naguib, “Magnetic resonance-guided laser-induced interstitial thermotherapy of breast cancer liver metastases and other noncolorectal cancer liver metastases: an analysis of prognostic factors for long-term survival and progression-free survival,” Investigative Radiology, vol. 48, no. 6, pp. 406–412, 2013.
- A. Carpentier, R. J. McNichols, R. J. Stafford et al., “Laser thermal therapy: real-time MRI-guided and computer-controlled procedures for metastatic brain tumors,” Lasers in Surgery and Medicine, vol. 43, no. 10, pp. 943–950, 2011.
- H. Y. Sung, S. E. Jung, S. H. Cho et al., “Long-term outcome of high-intensity focused ultrasound in advanced pancreatic cancer,” Pancreas, vol. 40, no. 7, pp. 1080–1086, 2011.
- T. H. Yu and J. Luo, “Adverse events of extracorporeal ultrasound-guided high intensity focused ultrasound therapy,” PLoS ONE, vol. 6, no. 12, Article ID e26110, 2011.
- F. A. Jolesz and K. Hynynen, “Magnetic resonance image-guided focused ultrasound surgery,” Cancer Journal, vol. 8, supplement 1, pp. S100–S112, 2002.
- R. O. Illing, J. E. Kennedy, F. Wu et al., “The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population,” British Journal of Cancer, vol. 93, no. 8, pp. 890–895, 2005.
- A. Payne, R. Merrill, E. Minalga et al., “Design and characterization of a laterally mounted phased-array transducer breast-specific MRgHIFU device with integrated 11-channel receiver array,” Medical Physics, vol. 39, no. 3, pp. 1552–1560, 2012.
- M. Peller, A. Schwerdt, M. Hossann et al., “MR characterization of mild hyperthermia-induced gadodiamide release from thermosensitive liposomes in solid tumors,” Investigative Radiology, vol. 43, no. 12, pp. 877–892, 2008.
- T. Tagami, W. D. Foltz, M. J. Ernsting et al., “MRI monitoring of intratumoral drug delivery and prediction of the therapeutic effect with a multifunctional thermosensitive liposome,” Biomaterials, vol. 32, no. 27, pp. 6570–6578, 2011.
- M. A. Hahn, A. K. Singh, P. Sharma, S. C. Brown, and B. M. Moudgil, “Nanoparticles as contrast agents for in-vivo bioimaging: current status and future perspectives,” Analytical and Bioanalytical Chemistry, vol. 399, no. 1, pp. 3–27, 2011.
- R. Dhankhar, S. P. Vyas, A. K. Jain, S. Arora, G. Rath, and A. K. Goyal, “Advances in novel drug delivery strategies for breast cancer therapy,” Artificial Cells, Blood Substitutes, and Biotechnology, vol. 38, no. 5, pp. 230–249, 2010.
- M. L. Matteucci, G. Anyarambhatla, G. Rosner et al., “Hyperthermia increases accumulation of technetium-99m-labeled liposomes in feline sarcomas,” Clinical Cancer Research, vol. 6, no. 9, pp. 3748–3755, 2000.
- M. de Smet, E. Heijman, S. Langereis, N. M. Hijnen, and H. Grüll, “Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study,” Journal of Controlled Release, vol. 150, no. 1, pp. 102–110, 2011.
- B. L. Viglianti, A. M. Ponce, C. R. Michelich et al., “Chemodosimetry of in vivo tumor liposomal drug concentration using MRI,” Magnetic Resonance in Medicine, vol. 56, no. 5, pp. 1011–1018, 2006.
- A. M. Ponce, B. L. Viglianti, D. Yu et al., “Magnetic resonance imaging of temperature- sensitive liposome release: drug dose painting and antitumor effects,” Journal of the National Cancer Institute, vol. 99, no. 1, pp. 53–63, 2007.
- T. K. Jain, M. A. Morales, S. K. Sahoo, D. L. Leslie-Pelecky, and V. Labhasetwar, “Iron oxide nanoparticles for sustained delivery of anticancer agents,” Molecular Pharmaceutics, vol. 2, no. 3, pp. 194–205, 2005.
- E. Munnier, S. Cohen-Jonathan, C. Linassier et al., “Novel method of doxorubicin-SPION reversible association for magnetic drug targeting,” International Journal of Pharmaceutics, vol. 363, no. 1-2, pp. 170–176, 2008.
- M. M. Yallapu, S. P. Foy, T. K. Jain, and V. Labhasetwar, “PEG-functionalized magnetic nanoparticles for drug delivery and magnetic resonance imaging applications,” Pharmaceutical Research, vol. 27, no. 11, pp. 2283–2295, 2010.
- M. Ahmed and M. Douek, “The role of magnetic nanoparticles in the localization and treatment of breast cancer,” BioMed Research International, vol. 2013, Article ID 281230, 11 pages, 2013.
- E. Alphandéry, “Perspectives of breast cancer thermotherapies,” Journal of Cancer, vol. 5, no. 6, pp. 472–479, 2014.
- G. A. Koning and G. C. Krijger, “Targeted multifunctional lipid-based nanocarriers for image-guided drug delivery,” Anti-Cancer Agents in Medicinal Chemistry, vol. 7, no. 4, pp. 425–440, 2007.
- K. J. Harrington, S. Mohammadtaghi, P. S. Uster et al., “Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes,” Clinical Cancer Research, vol. 7, no. 2, pp. 243–254, 2001.
- M. R. Dreher, W. G. Liu, C. R. Michelich, M. W. Dewhirst, and A. Chilkoti, “Thermal cycling enhances the accumulation of a temperature-sensitive biopolymer in solid tumors,” Cancer Research, vol. 67, no. 9, pp. 4418–4424, 2007.
- M. L. Matteucci, G. Anyarambhatla, G. Rosner et al., “Hyperthermia increases accumulation of technetium-99 m-labeled liposomes in feline sarcomas,” Clinical Cancer Research, vol. 6, no. 9, pp. 3748–3755, 2000.
Copyright © 2015 Yurong Zhou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.