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Wednesday, May 31, 2017

Molecular Imaging Agents for Breast Cancer

Author: Amy M. Fowler, MD, PhD

Molecular imaging is a promising approach for achieving precision medicine. It can provide important functional information for improved diagnosis, treatment planning, prognostic and predictive information and evaluation of treatment response for cancer patients. The purpose of this article is to review the current status of molecular imaging agents applicable to breast cancer.

1.  FDA Approved Molecular Imaging Agents

Molecular imaging agents are defined as “the probes used to visualize, characterize, and quantify biological processes at the molecular and cellular levels in humans and other living systems” (1).  Similar to therapeutic drugs, exogenously administered molecular imaging agents are required to undergo approval by the U.S. Food and Drug Administration (FDA) prior to clinical use in patients outside of a research study.  This is an arduous and expensive process which explains why there are hundreds of molecular imaging agents being studied for breast cancer but only a few with FDA approval.

1.1  2-Deoxy-2-18F-fluoroglucose (FDG)

FDG is the most commonly used molecular imaging agent for oncology.  FDG is an analog of glucose that accumulates within tissues with high glucose metabolism, such as the brain and myocardium, infections or inflammatory processes and, of course, cancer.  FDG enters cells via glucose transport proteins then becomes phosphorylated by hexokinase.  Since FDG-6-phosphate cannot continue through glycolysis and also cannot exit the cell, it becomes trapped intracellularly.  FDG is a positron-emitting radiopharmaceutical with a half-life of 109.8 minutes.  The positron emitted during the decay process collides with a nearby electron and produces two 511-keV photons oriented 180° from each other.  These annihilation photons are detected in vivo using positron emission tomography (PET) and reconstructed to form a three-dimensional image visualizing the location of the site of FDG accumulation.

            Forty years of data regarding FDG PET imaging in humans have been obtained thus far.  In August 1976, FDG was synthesized at the Brookhaven National Laboratory and flown to the University of Pennsylvania for brain and whole body imaging of two normal volunteers (2).  In 1991, the initial clinical evaluation of FDG PET imaging of primary and metastatic breast cancer patients was published which demonstrated its feasibility for detecting breast cancer (3).   Figure 1 illustrates a case of invasive ductal carcinoma of the breast with axillary nodal disease demonstrating increased FDG uptake using whole-body FDG PET/CT imaging.  In 1994, FDG was approved by the FDA.  Subsequently, the Centers for Medicare and Medicaid Services (CMS) approved coverage for reimbursement of FDG PET in 2002 as an adjunct to standard imaging modalities for (i) staging for distant metastases, (ii) restaging patients with suspected recurrence or metastasis, and (iii) monitoring treatment response for patients with locally advanced and metastatic breast cancer to determine if therapy should be altered (4).  There is insufficient evidence for clinical utility of FDG PET imaging in the initial diagnosis of breast cancer and initial staging of axillary lymph nodes as indications for coverage.  In 2010, evidence-based clinical indications for the use of FDG PET imaging first became incorporated in the National Comprehensive Cancer Network (NCCN) guidelines.  For clinical stage III, including locally advanced and inflammatory breast cancer, and recurrent disease or suspected metastases, FDG PET imaging is considered optional and may be most helpful in situations where standard staging studies (CT or MRI with bone scan) are equivocal or in identifying unsuspected regional nodal disease or distant metastases (5).    

            Further discussion of the clinical use of FDG PET/CT imaging for staging and treatment monitoring for breast cancer patients is provided in another article in this series (“Breast Cancer Staging. Physiology Trumps Anatomy” by Maxine Jochelson, MD).  The use of FDG in conjunction with dedicated breast imaging devices such as positron emission mammography (PEM) is also highlighted in a separate article in this series (“Current Status of Dedicated Nuclear Breast Imaging” by Wendie Berg, MD, PhD) and has been reviewed previously (6).

1.2  Sodium 18F-fluoride (NaF)

            Bone is the most common metastatic site for breast cancer which can present as lytic, sclerotic, or mixed lytic and sclerotic lesions (7).  NaF is a molecular bone-imaging agent that accumulates at sites of bone turnover and can detect both osteolytic and osteoblastic metastases from breast cancer (8, 9)18F incorporates on the surface of new bone formation by substituting for hydroxyl groups in hydroxyapatite.  Compared with conventional bone scintigraphy with 99mTc-methylene diphosphonate (MDP), NaF PET/CT imaging offers higher sensitivity and specificity in detecting bone metastases with shorter uptake and patient scan times (8).

            It is important to note that NaF does not image carcinoma cells directly, only the osteoblastic response to local bone destruction incited by the tumor.  Thus, false negative exams can occur with early, small osteolytic metastases (8).  Likewise, false positive uptake can be seen in benign processes with increased bone turnover such as arthritis, trauma, fibrous dysplasia, and Paget disease (8).  Combined NaF PET/CT imaging improves specificity in these instances by allowing correlation of PET lesions with their characteristic benign imaging features on the corresponding CT.

            NaF was the first radiopharmaceutical approved by the FDA in 1972.  Despite its early FDA approval, widespread clinical implementation and reimbursement has lagged behind.  Reimbursement of NaF PET imaging for the detection of bone metastases for cancer patients began in 2011 but only through the Coverage with Evidence Development/National Oncologic PET Registry (NOPR) program (10).  This program requires data submission to a clinical registry to determine whether PET imaging changes the referring physician’s intended management plan for the patient.  However, this coverage method may change by the end of 2017.  CMS recently determined that the evidence collected through NOPR indicates that use of NaF PET imaging for detection of bony metastases is “not reasonable and necessary” to justify coverage under § 1862(a)(1)(A) of the Social Security Act.

            NaF PET/CT is currently included in the NCCN guidelines as an optional alternative to conventional bone scan for patients with clinical stage III, locally advanced and inflammatory breast cancer, and recurrent/metastatic breast cancer (5).  However if a patient already has FDG PET/CT imaging which clearly demonstrates bone metastases on both the PET and CT components, then conventional bone scan and/or NaF PET/CT are not indicated (5)Figure 2 demonstrates the imaging appearance of sclerotic and lytic lesions on NaF and FDG PET imaging in two patients with bone-dominant metastatic breast cancer (11).

1.3 Anti-1-amino-3-18F-fluorocyclobutane-1-carboxcylic acid (18F-fluciclovine, FACBC)

            Upregulated amino acid transport is a hallmark of cancer and is necessary to support the increased protein synthesis and proliferation of malignant cells.  A radiolabeled synthetic analog of the amino acid leucine, FACBC, was approved by the FDA in 2016.  While it received approval for localization of biochemically-recurrent prostate cancer, it may have “off-label” utility for breast cancer imaging.  FACBC is commercially available (AxuminTM, Blue Earth Diagnostics) and has received Transitional Pass-Through Status from CMS in 2017 for Medicare billing in the hospital outpatient setting.

Molecular imaging is a promising approach for achieving precision medicine.  It can provide important functional information for improved diagnosis, treatment planning, prognostic and predictive information and evaluation of treatment response for cancer patients.  The purpose of this article is to review the current status of molecular imaging agents applicable to breast cancer.

1.  FDA Approved Molecular Imaging Agents

            Molecular imaging agents are defined as “the probes used to visualize, characterize, and quantify biological processes at the molecular and cellular levels in humans and other living systems” (1).  Similar to therapeutic drugs, exogenously administered molecular imaging agents are required to undergo approval by the U.S. Food and Drug Administration (FDA) prior to clinical use in patients outside of a research study.  This is an arduous and expensive process which explains why there are hundreds of molecular imaging agents being studied for breast cancer but only a few with FDA approval.

1.1  2-Deoxy-2-18F-fluoroglucose (FDG)

            FDG is the most commonly used molecular imaging agent for oncology.  FDG is an analog of glucose that accumulates within tissues with high glucose metabolism, such as the brain and myocardium, infections or inflammatory processes and, of course, cancer.  FDG enters cells via glucose transport proteins then becomes phosphorylated by hexokinase.  Since FDG-6-phosphate cannot continue through glycolysis and also cannot exit the cell, it becomes trapped intracellularly.  FDG is a positron-emitting radiopharmaceutical with a half-life of 109.8 minutes.  The positron emitted during the decay process collides with a nearby electron and produces two 511-keV photons oriented 180° from each other.  These annihilation photons are detected in vivo using positron emission tomography (PET) and reconstructed to form a three-dimensional image visualizing the location of the site of FDG accumulation.

            Forty years of data regarding FDG PET imaging in humans have been obtained thus far.  In August 1976, FDG was synthesized at the Brookhaven National Laboratory and flown to the University of Pennsylvania for brain and whole body imaging of two normal volunteers (2).  In 1991, the initial clinical evaluation of FDG PET imaging of primary and metastatic breast cancer patients was published which demonstrated its feasibility for detecting breast cancer (3).   Figure 1 illustrates a case of invasive ductal carcinoma of the breast with axillary nodal disease demonstrating increased FDG uptake using whole-body FDG PET/CT imaging.  In 1994, FDG was approved by the FDA.  Subsequently, the Centers for Medicare and Medicaid Services (CMS) approved coverage for reimbursement of FDG PET in 2002 as an adjunct to standard imaging modalities for (i) staging for distant metastases, (ii) restaging patients with suspected recurrence or metastasis, and (iii) monitoring treatment response for patients with locally advanced and metastatic breast cancer to determine if therapy should be altered (4).  There is insufficient evidence for clinical utility of FDG PET imaging in the initial diagnosis of breast cancer and initial staging of axillary lymph nodes as indications for coverage.  In 2010, evidence-based clinical indications for the use of FDG PET imaging first became incorporated in the National Comprehensive Cancer Network (NCCN) guidelines.  For clinical stage III, including locally advanced and inflammatory breast cancer, and recurrent disease or suspected metastases, FDG PET imaging is considered optional and may be most helpful in situations where standard staging studies (CT or MRI with bone scan) are equivocal or in identifying unsuspected regional nodal disease or distant metastases (5).    

            Further discussion of the clinical use of FDG PET/CT imaging for staging and treatment monitoring for breast cancer patients is provided in another article in this series (“Breast Cancer Staging. Physiology Trumps Anatomy” by Maxine Jochelson, MD).  The use of FDG in conjunction with dedicated breast imaging devices such as positron emission mammography (PEM) is also highlighted in a separate article in this series (“Current Status of Dedicated Nuclear Breast Imaging” by Wendie Berg, MD, PhD) and has been reviewed previously (6).

1.2  Sodium 18F-fluoride (NaF)

            Bone is the most common metastatic site for breast cancer which can present as lytic, sclerotic, or mixed lytic and sclerotic lesions (7).  NaF is a molecular bone-imaging agent that accumulates at sites of bone turnover and can detect both osteolytic and osteoblastic metastases from breast cancer (8, 9)18F incorporates on the surface of new bone formation by substituting for hydroxyl groups in hydroxyapatite.  Compared with conventional bone scintigraphy with 99mTc-methylene diphosphonate (MDP), NaF PET/CT imaging offers higher sensitivity and specificity in detecting bone metastases with shorter uptake and patient scan times (8).

            It is important to note that NaF does not image carcinoma cells directly, only the osteoblastic response to local bone destruction incited by the tumor.  Thus, false negative exams can occur with early, small osteolytic metastases (8).  Likewise, false positive uptake can be seen in benign processes with increased bone turnover such as arthritis, trauma, fibrous dysplasia, and Paget disease (8).  Combined NaF PET/CT imaging improves specificity in these instances by allowing correlation of PET lesions with their characteristic benign imaging features on the corresponding CT.

            NaF was the first radiopharmaceutical approved by the FDA in 1972.  Despite its early FDA approval, widespread clinical implementation and reimbursement has lagged behind.  Reimbursement of NaF PET imaging for the detection of bone metastases for cancer patients began in 2011 but only through the Coverage with Evidence Development/National Oncologic PET Registry (NOPR) program (10).  This program requires data submission to a clinical registry to determine whether PET imaging changes the referring physician’s intended management plan for the patient.  However, this coverage method may change by the end of 2017.  CMS recently determined that the evidence collected through NOPR indicates that use of NaF PET imaging for detection of bony metastases is “not reasonable and necessary” to justify coverage under § 1862(a)(1)(A) of the Social Security Act.

            NaF PET/CT is currently included in the NCCN guidelines as an optional alternative to conventional bone scan for patients with clinical stage III, locally advanced and inflammatory breast cancer, and recurrent/metastatic breast cancer (5).  However if a patient already has FDG PET/CT imaging which clearly demonstrates bone metastases on both the PET and CT components, then conventional bone scan and/or NaF PET/CT are not indicated (5)Figure 2 demonstrates the imaging appearance of sclerotic and lytic lesions on NaF and FDG PET imaging in two patients with bone-dominant metastatic breast cancer (11).

1.3 Anti-1-amino-3-18F-fluorocyclobutane-1-carboxcylic acid (18F-fluciclovine, FACBC)

            Upregulated amino acid transport is a hallmark of cancer and is necessary to support the increased protein synthesis and proliferation of malignant cells.  A radiolabeled synthetic analog of the amino acid leucine, FACBC, was approved by the FDA in 2016.  While it received approval for localization of biochemically-recurrent prostate cancer, it may have “off-label” utility for breast cancer imaging.  FACBC is commercially available (AxuminTM, Blue Earth Diagnostics) and has received Transitional Pass-Through Status from CMS in 2017 for Medicare billing in the hospital outpatient setting.

Uptake of FACBC by cancer cells occurs predominately via sodium-dependent amino acid transporters which are overexpressed in breast cancer (12).  Tumoral uptake of FACBC has been demonstrated in patients with primary and metastatic breast cancer with values greater than normal breast tissue and benign breast lesions (Figure 3) in small published studies with a combined total of 39 patients (13, 14).  The highest uptake was observed in triple negative and grade 3 subtypes (13).  Interestingly, invasive lobular carcinomas displayed higher uptake of FACBC than FDG (13, 14).  FACBC PET/CT imaging may also have a role in evaluating response to neoadjuvant chemotherapy (15)

            Other amino-acid based imaging agents, such as 11C-methionine and L-[1-11C]tyrosine, are also under investigation but are not yet approved by the FDA (16, 17).  Unlike 11C-based radiopharmaceuticals, FACBC cannot be further metabolized and incorporated via protein synthesis pathways after entering cells which is a desired feature of PET imaging agents (18).  Furthermore the longer half-life of 18F compared with 11C (110 versus 20 minutes), allows for greater distribution to end-user sites that may not have a cyclotron for local radiopharmaceutical production.

1.4  99mTc-methoxyisobutylisonitrile (99mTc-sestamibi)

                99mTc-sestamibi is a single-photon emitting radiopharmaceutical that was approved by the FDA in 1990.  While 99mTc-sestamibi is mainly used for cardiac perfusion imaging and parathyroid scintigraphy, it also accumulates within breast malignancies.  Sestamibi, a positively charged lipophilic cation molecule, localizes and concentrates within mitochondria.  99mTc-sestamibi has a 6 hour half-life and emits a single 140 keV photon during the decay process that can be detected via planar gamma camera imaging (“scintimammography”), single photon emission computed tomography with computed tomography (SPECT/CT), or dedicated breast specific gamma imaging (BSGI)/molecular breast imaging (MBI).

            NCCN guidelines and the American College of Radiology (ACR) Appropriateness Criteria for breast cancer screening currently do not support the routine use of breast scintigraphy with 99mTc-sestamibi for screening due to the increased radiation exposure compared with mammography (5, 19-21); further, unlike mammography, the radiation exposure with scintigraphy is to the whole body.  Efforts are being made to reduce administered radiation dose for use in supplemental screening of women with mammographically dense breasts (22, 23).  Further discussion of the screening and diagnostic clinical uses of 99mTc-sestamibi for dedicated breast imaging is provided in another article in this series (“Current Status of Dedicated Nuclear Breast Imaging” by Wendie Berg, MD, PhD) and has been reviewed previously (6)

2.  Non-FDA Approved Molecular Imaging Agents

            As of April 2015, there were more than 160 ongoing clinical trials of at least 30 different investigational PET radiopharmaceuticals for breast cancer (24).  These agents target important hallmark pathways of cancer including proliferation, apoptosis, angiogenesis, hypoxia, and growth factor and steroid hormone receptor signaling.  Given their investigational status, administration of research radiopharmaceuticals to subjects in clinical trials requires regulatory approval such as an FDA investigational new drug (IND) application or local Radioactive Drug Research Committee (RDRC) approval (25).  To foster multi-center clinical trials using these agents, the Cancer Imaging Program of the National Cancer Institute has created several INDs that are available to the research community.  The remainder of this article will focus on investigational molecular imaging agents closest to FDA approval and clinical practice.

2.1  3'-deoxy-3'-18F-fluorothymidine (FLT)

            A drawback of FDG PET/CT in oncologic imaging is that FDG can also accumulate at sites of infection, inflammation, or recent surgery.  This has fueled interest in imaging tumor cell proliferation as opposed to glucose metabolism to improve specificity.  FLT is the most widely investigated radiopharmaceutical for imaging proliferation (26).  After entering cells via nucleoside transporters, the enzyme thymidine kinase-1 phosphorylates FLT as part of the thymidine salvage pathway of DNA synthesis.  However, phosphorylated FLT cannot be incorporated further into DNA and becomes trapped intracellularly. 

            Uptake of FLT has been demonstrated in tumor sites in patients with primary and metastatic breast cancer with widely variable results (27, 28).  Standardized uptake values (SUV) measured on FLT PET imaging correlate with the clinical immunohistochemical marker of proliferation, Ki-67, with a correlation coefficient of 0.65 as shown by a small meta-analysis (N=33 total sample size) (29).  Despite its correlation with Ki67, the lower signal intensity of FLT uptake compared with FDG raises concern for the possibility of false-negative results, which limits its utility for staging evaluation.  Thus, further studies have shifted focus to its potential role for predicting and monitoring therapy response.

            Results from the American College of Radiology Imaging Network (ACRIN) Trial 6688 of FLT PET imaging were recently published (30).  This study was a multi-institutional phase II clinical trial that aimed to correlate FLT uptake with pathologic response to neoadjuvant chemotherapy in 51 patients with locally advanced breast cancer (30)Figure 4 illustrates a case from the trial in which a primary breast cancer and axillary lymph node metastasis show substantial reductions in FLT uptake after the first cycle of neoadjuvant chemotherapy, resolution of FLT uptake after completion of therapy, and pathologic complete response confirmed at surgery (30).  The investigators found that decreases in FLT uptake after the first cycle of chemotherapy only weakly correlated with pathologic complete response.  Limitations of the study were the heterogeneous patient population and variable chemotherapy regimens included in the protocol.  Additional studies are needed to better define the clinical efficacy of FLT PET/CT imaging for assessing early therapeutic response.

2.2  16α-18F-fluoro-17β-estradiol (FES)

            The majority of breast malignancies (~70%) express estrogen receptor alpha (ERα), which is responsible for estrogen signaling and tumor cell proliferation.  FES, a radiolabeled estrogen analog, accumulates in ER+ breast cancer cells by diffusing into cells then binding directly to the receptor in the nucleus.  Figure 5 illustrates intense FES uptake in a patient with primary ER+ breast cancer and an axillary lymph node metastasis (31)FES PET imaging has been studied in more than 1,000 patients with primary and metastatic breast cancer through clinical trials (32).   These studies have demonstrated strong correlation of FES SUV uptake with ERα protein expression (33, 34).  A recent meta-analysis (nine studies of 238 patients with primary and metastatic lesions, tumor size not reported) yielded pooled sensitivity and specificity values of 82% (95% CI: 74-88%) and 95% (95% CI: 86-99%), respectively, of FES PET imaging for detecting ER+ breast cancer (33, 35-43).  Thus, FES PET/CT imaging potentially offers an alternative method for determining hormone receptor status for metastatic lesions that are not accessible to biopsy.  Of note, due to lower FDG uptake demonstrated by ER+ luminal subtypes of breast cancer, these lesions may be falsely negative on FDG PET imaging (44).  

            Endocrine therapies that inhibit ERα function generally have initial therapeutic success; however, many patients eventually develop drug resistance and disease recurrence (45).  Predicting and identifying endocrine resistance early allows for initiation of alternative therapies, such as chemotherapy or other molecularly targeted therapies, in a timely manner.  The utility of FES PET imaging has also been investigated as an imaging biomarker for predicting clinical benefit from endocrine therapy in several small, single-institutional studies (32, 46).  Combining results of these studies demonstrated that, by using a SUV cutoff value of ≤ 1.5, a negative pre-treatment FES PET exam predicted lack of clinical benefit from endocrine therapy at 6 months in 37/42 patients (NPV 88%) (32).  A positive FES PET exam (i.e. SUV>1.5) predicted clinical benefit in 62/96 patients (PPV 65%) (32).  These results suggest that patients with metastatic lesions with FES SUV values of 1.5 or less should receive treatment regimens other than endocrine therapy, such as chemotherapy or other molecularly targeted therapy.  A multi-institutional phase II clinical trial (ACRIN EAI142; NCT02398773) is currently underway to validate the threshold SUV and predictive value of FES PET/CT imaging in newly diagnosed metastatic ER+ breast cancer patients. 

2.3  21-18F-fluoro-16α,17α-[(R)-(1’-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione (FFNP)

            A classic ERα target gene is progesterone receptor (PR), which is upregulated in the presence of estrogen.  Breast cancer PR expression is determined clinically along with ERα expression using immunohistochemistry of tissue biopsy samples and is a predictive biomarker of long-term benefit from adjuvant treatment with tamoxifen for ER+ breast cancer patients (47).  Downstream biomarkers in the ERα signaling pathway, such as PR, can be monitored as a functional measure of response to endocrine therapy (48)

            FFNP is a radiolabeled progestin which binds directly to PR protein and accumulates in PR+ breast cancer cells.  FFNP PET/CT imaging has been demonstrated to be safe and capable of visualizing PR+ breast cancers in patients (49).  FFNP uptake, as measured by tumor-to-normal breast tissue ratios, was greater in PR+ cancers (2.6±0.9; n=16) compared to PR- cancers (1.5±0.3; n=6; p=0.001) (49)Figure 6 illustrates increased FFNP uptake in a patient with primary PR+ breast cancer (50).  Research investigating the clinical utility of FFNP PET imaging as a pharmacodynamic biomarker of functional ERα activity is ongoing (NCT02455453).

Summary

            Research advances in molecular oncology continue to generate new targeted therapies contributing to the achievement of precision medicine.  Targeted radiopharmaceuticals and molecular/functional imaging are important tools that can be used to predict and monitor treatment response.  Continued clinical validation of these agents is necessary to fully achieve translation from initial preclinical status to FDA approval, reimbursement, and widespread clinical implementation with the ultimate goal of improving outcomes for breast cancer patients.

 

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