Development of Companion Diagnostics☆
Introduction
The goal of individualized and targeted treatment—often termed precision medicine—requires the assessment of potential therapeutic targets to direct patients to those treatments most likely to be effective.1 A closely related need is the ability to measure the effect of the drug on the target and the underlying disease process to determine whether the selected therapy is likely to be effective. Both types of indicators can be broadly classified as disease biomarkers.1, 2 Biomarkers that are highly specific to a particular target or therapy are often called companion diagnostics and typically measure the therapeutic target itself or closely related partner molecules. Such markers fall under the general heading of predictive biomarkers.1, 3 Biomarkers that measure the effect of the treatment on the disease process are often termed as response biomarkers, and the class of these markers apropos to measuring early drug action on the target is often termed as pharmacodynamic (PD) markers.1, 3 PD markers measure downstream effects of the drug on the cancer cell and on the disease. In this review, we consider the application of molecular imaging to precision medicine—specifically to cancer treatment—as a companion diagnostic for selecting targeted cancer therapy. We provide an overview of molecular imaging as a companion diagnostic for targeted cancer therapy, discuss the approach to developing imaging probes for predictive and PD markers, and then highlight two examples of molecular imaging: endocrine therapy for breast cancer and human epidermal growth factor receptor type (HER2)-targeted treatments.
A model for using predictive and PD markers to guide targeted cancer therapy is illustrated in Figure 1. In this approach, individualized treatment selection is considered in two steps:
- 1)
What therapeutic targets are present?
- 2)
Does a selected treatment directed to one or more of the therapeutic targets have an effect on the cancer?
How can imaging aid this approach? For cancer, the identification of therapeutic targets is typically done by in vitro assay of biopsy material. Advances in methods to assess tumor genomics, gene expression, and protein expression provide an increasingly comprehensive characterization of each patient’s cancer and the identification of possible therapeutic targets for each patient.4 Imaging is unlikely to replace biopsy and in vitro assay in the initial assessment for treatment targets for newly diagnosed cancer as imaging measures only up to a few therapeutic targets, whereas assay of biopsy material can screen for many targets at the same time. However, imaging has a unique ability to measure the regional heterogeneity of target expression, especially in patients with advanced disease where target expression may vary from site to site. In this case, biopsy of a single site may not be representative of the entire burden of disease. Thus imaging can play a complementary role to biopsy in assessing target expression.
Molecular imaging can play an even more important role as a PD marker and has some significant advantages over other existing approaches.5 The noninvasive nature of imaging facilitates the repeat measurements needed to assess response. Imaging avoids the challenges (sampling error, patient comfort, and risk of complications) associated with serial biopsy to assess response. Molecular imaging also has significant advantages over other forms of largely anatomically based imaging in that it can quantify specific molecular processes likely to be affected early after the initiation of drug treatment—for example, tumor proliferation—long before anatomical changes can be detected.6, 7
Section snippets
Predictive Markers
Predictive markers designed to measure the expression of a therapeutic target require molecular imaging probes that are highly specific to the target. Traditionally these probes have been small molecules that target receptors, transporters, or enzymes with high affinity and selectivity, while at the same time having sufficiently rapid clearance from tissue not expressing the target to allow visualization of binding at the target by PET or SPECT.8 Perhaps, the earliest example of a radionuclide
Example 1: Molecular Imaging Companion Diagnostics of Endocrine Therapy for Breast Cancer
The physiology of sex steroids, in particular estrogens and progestins, is important for mammary gland development and function, and is also a key component of breast cancer pathogenesis and growth. Interruption of steroid hormone growth signal, often termed endocrine therapy, is one of the most important therapeutic strategies for treating breast cancer. Determination of the status of hormone receptors, both the estrogen receptor (ER) and progesterone receptor (PR), in patients with breast
Example 2: Molecular Imaging Companion Diagnostics for HER-2 Targeted therapy
HER2 is a member of the tyrosine kinase receptor family and has been recognized as a key driver of breast cancer growth in breast cancers that overexpress this protein, approximately 15%-25% of newly diagnosed invasive breast cancers.77 Besides conferring a more aggressive phenotype, studies have demonstrated that overexpression of HER2 results in impaired response to both hormonal therapy via crosstalk with the ER78, 79, 80, 81 as well as some forms of cytotoxic chemotherapy regimens.81, 82
Summary and Future Directions
Early experience with molecular imaging predictive and PD markers suggests considerable potential as companion diagnostics, complementary to diagnostics based on in vitro assay of biopsy material, for guiding targeted cancer therapy. Studies have demonstrated the potential for imaging agents to provide unique information as cancer biomarkers, including quantification of the heterogeneity of target expression, detection of changes in target expression with therapy, and facile measurement of
References (113)
- et al.
Cancer biomarkers
Mol Oncol
(2012) - et al.
Molecular imaging research in the outcomes era: Measuring outcomes for individualized cancer therapy
Acad Radiol
(2007) - et al.
A historical perspective on the specific activity of radiopharmaceuticals: What have we learned in the 35 years of the ISRC
Nucl Med Biol
(2013) - et al.
Antibody vectors for imaging
Semin Nucl Med
(2010) - et al.
18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec)
Eur J Cancer
(2003) - et al.
Hallmarks of cancer: The next generation
Cell
(2011) - et al.
Diffusion-weighted magnetic resonance imaging as a cancer biomarker: Consensus and recommendations
Neoplasia
(2009) - et al.
Hormonal therapy in breast cancer: A model disease for the personalization of cancer care
Mol Oncol
(2012) - et al.
Sequential estrogen receptor determinations from primary breast cancer and at relapse: Prognostic and therapeutic relevance. The International Breast Cancer Study Group (formerly Ludwig Group)
Ann Oncol
(1992) - et al.
Comparative breast tumor imaging and comparative in vitro metabolism of 16alpha-[18F]fluoroestradiol-17beta and 16beta-[18F]fluoromoxestrol in isolated hepatocytes
Nucl Med Biol
(1999)
18F-fluoroestradiol
Semin Nucl Med
Characterization of the uptake of 16 alpha-([18F]fluoro)-17 beta-estradiol in DMBA-induced mammary tumors
Int J Rad Appl Instrum B
Analysis of blood clearance and labeled metabolites for the estrogen receptor tracer [F-18]-16 alpha-fluoroestradiol (FES)
Nucl Med Biol
Interactions of 16alpha-[18F]-fluoroestradiol (FES) with sex steroid binding protein (SBP)
Nucl Med Biol
PET imaging of oestrogen receptors in patients with breast cancer
Lancet Oncol
Evaluating tumor heterogeneity in immunohistochemistry-stained breast cancer tissue
Lab Invest
Novel methods and tracers for breast cancer imaging
Semin Nucl Med
Cancer biomarkers: A systems approach
Nat Biotechnol
How imaging biomarkers can inform clinical trials and clinical practice in the era of targeted cancer therapy
JAMA Oncol
Imaging studies in anticancer drug development
Carbon-11-thymidine and FDG to measure therapy response
J Nucl Med
Positron emission tomography as an imaging biomarker
J Clin Oncol
Tumor receptor imaging
J Nucl Med
Radioiodine therapy for thyroid cancer in the era of risk stratification and alternative targeted therapies
J Nucl Med
Positron tomographic assessment of estrogen receptors in breast cancer: Comparison with FDG-PET and in vitro receptor assays
J Nucl Med
Tumor localization of 16beta-18F-fluoro-5alpha-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer
J Nucl Med
Using nuclear medicine imaging in clinical practice: Update on PET to guide treatment of patients with metastatic breast cancer
Oncology (Williston Park)
Neuroendocrine tumours: The role of imaging for diagnosis and therapy
Nat Rev Endocrinol
Fluorine-18-fluorouracil to predict therapy response in liver metastases from colorectal carcinoma
J Nucl Med
A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier
Cancer Res
Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex
Cancer Res
Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography
Clin Pharmacol Ther
Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: A substudy of Trans-Tasman Radiation Oncology Group Study 98.02
J Clin Oncol
Molecular imaging biomarkers for oncology clinical trials
J Nucl Med
Update on time-of-flight PET imaging
J Nucl Med
Fluoroestradiol positron emission tomography reveals differences in pharmacodynamics of aromatase inhibitors, tamoxifen, and fulvestrant in patients with metastatic breast cancer
Clin Cancer Res
Positron tomographic assessment of 16 alpha-[18F] fluoro-17 beta-estradiol uptake in metastatic breast carcinoma
J Nucl Med
Metabolic flare: Indicator of hormone responsiveness in advanced breast cancer
J Clin Oncol
PET/CT imaging in cancer: Current applications and future directions
Cancer
Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond
Clin Cancer Res
Assessing tumor response to therapy
J Nucl Med
Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development
Clin Cancer Res
Role of PET quantitation in the monitoring of cancer response to treatment: Review of approaches and human clinical trials
Clin Transl Imaging
PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer
Breast Cancer Res Treat
Feasibility study of FDG PET as an indicator of early response to aromatase inhibitors and trastuzumab in a heterogeneous group of breast cancer patients
EJNMMI Res
[18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy
J Clin Oncol
Imaging of cell proliferation: Status and prospects
J Nucl Med
Clinical studies of apoptosis and proliferation in breast cancer
Endocr Relat Cancer
Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer
Clin Cancer Res
Imaging cellular proliferation as a measure of response to therapy
J Clin Pharmacol
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This work was supported in part by Susan G. Komen Foundation Grant SAC140060, U.S. Department of Energy, United States Grant DE-SE0012476, U.S. Department of Defense, United States Grant W81XWH-13-1-0406, and National Institutes of Health, United States Grants U01CA148131 and P30CA016520.