Development of Companion Diagnostics

https://doi.org/10.1053/j.semnuclmed.2015.09.002Get rights and content

The goal of individualized and targeted treatment and precision medicine requires the assessment of potential therapeutic targets to direct treatment selection. The biomarkers used to direct precision medicine, often termed companion diagnostics, for highly targeted drugs have thus far been almost entirely based on in vitro assay of biopsy material. Molecular imaging companion diagnostics offer a number of features complementary to those from in vitro assay, including the ability to measure the heterogeneity of each patient’s cancer across the entire disease burden and to measure early changes in response to treatment. We discuss the use of molecular imaging methods as companion diagnostics for cancer therapy with the goal of predicting response to targeted therapy and measuring early (pharmacodynamic) response as an indication of whether the treatment has “hit” the target. We also discuss considerations for probe development for molecular imaging companion diagnostics, including both small-molecule probes and larger molecules such as labeled antibodies and related constructs. We then describe two examples where both predictive and pharmacodynamic molecular imaging markers have been tested in humans: endocrine therapy for breast cancer and human epidermal growth factor receptor type 2−targeted therapy. The review closes with a summary of the items needed to move molecular imaging companion diagnostics from early studies into multicenter trials and into the clinic.

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)

  • L. Sundararajan et al.

    18F-fluoroestradiol

    Semin Nucl Med

    (2007)
  • C.J. Mathias et al.

    Characterization of the uptake of 16 alpha-([18F]fluoro)-17 beta-estradiol in DMBA-induced mammary tumors

    Int J Rad Appl Instrum B

    (1987)
  • D.A. Mankoff et al.

    Analysis of blood clearance and labeled metabolites for the estrogen receptor tracer [F-18]-16 alpha-fluoroestradiol (FES)

    Nucl Med Biol

    (1997)
  • T.J. Tewson et al.

    Interactions of 16alpha-[18F]-fluoroestradiol (FES) with sex steroid binding protein (SBP)

    Nucl Med Biol

    (1999)
  • M. van Kruchten et al.

    PET imaging of oestrogen receptors in patients with breast cancer

    Lancet Oncol

    (2013)
  • S.J. Potts et al.

    Evaluating tumor heterogeneity in immunohistochemistry-stained breast cancer tissue

    Lab Invest

    (2012)
  • H.M. Linden et al.

    Novel methods and tracers for breast cancer imaging

    Semin Nucl Med

    (2013)
  • L. Hartwell et al.

    Cancer biomarkers: A systems approach

    Nat Biotechnol

    (2006)
  • M.D. Farwell et al.

    How imaging biomarkers can inform clinical trials and clinical practice in the era of targeted cancer therapy

    JAMA Oncol

    (2015)
  • D.A. Mankoff

    Imaging studies in anticancer drug development

  • A.F. Shields et al.

    Carbon-11-thymidine and FDG to measure therapy response

    J Nucl Med

    (1998)
  • W.A. Weber

    Positron emission tomography as an imaging biomarker

    J Clin Oncol

    (2006)
  • D.A. Mankoff et al.

    Tumor receptor imaging

    J Nucl Med

    (2008)
  • D.A. Pryma et al.

    Radioiodine therapy for thyroid cancer in the era of risk stratification and alternative targeted therapies

    J Nucl Med

    (2014)
  • F. Dehdashti et al.

    Positron tomographic assessment of estrogen receptors in breast cancer: Comparison with FDG-PET and in vitro receptor assays

    J Nucl Med

    (1995)
  • S.M. Larson et al.

    Tumor localization of 16beta-18F-fluoro-5alpha-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer

    J Nucl Med

    (2004)
  • A.S. Clark et al.

    Using nuclear medicine imaging in clinical practice: Update on PET to guide treatment of patients with metastatic breast cancer

    Oncology (Williston Park)

    (2014)
  • M. van Essen et al.

    Neuroendocrine tumours: The role of imaging for diagnosis and therapy

    Nat Rev Endocrinol

    (2014)
  • A. Dimitrakopoulou-Strauss et al.

    Fluorine-18-fluorouracil to predict therapy response in liver metastases from colorectal carcinoma

    J Nucl Med

    (1998)
  • N.H. Hendrikse et al.

    A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier

    Cancer Res

    (1999)
  • D. Piwnica-Worms et al.

    Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex

    Cancer Res

    (1993)
  • L. Sasongko et al.

    Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography

    Clin Pharmacol Ther

    (2005)
  • D. Rischin et al.

    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

    (2006)
  • D.A. Mankoff et al.

    Molecular imaging biomarkers for oncology clinical trials

    J Nucl Med

    (2014)
  • S. Surti

    Update on time-of-flight PET imaging

    J Nucl Med

    (2015)
  • H.M. Linden et al.

    Fluoroestradiol positron emission tomography reveals differences in pharmacodynamics of aromatase inhibitors, tamoxifen, and fulvestrant in patients with metastatic breast cancer

    Clin Cancer Res

    (2011)
  • A.H. McGuire et al.

    Positron tomographic assessment of 16 alpha-[18F] fluoro-17 beta-estradiol uptake in metastatic breast carcinoma

    J Nucl Med

    (1991)
  • J.E. Mortimer et al.

    Metabolic flare: Indicator of hormone responsiveness in advanced breast cancer

    J Clin Oncol

    (2001)
  • M.D. Farwell et al.

    PET/CT imaging in cancer: Current applications and future directions

    Cancer

    (2014)
  • D.A. Mankoff et al.

    Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond

    Clin Cancer Res

    (2007)
  • W.A. Weber

    Assessing tumor response to therapy

    J Nucl Med

    (2009)
  • G.J. Kelloff et al.

    Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development

    Clin Cancer Res

    (2005)
  • R.K. Doot et al.

    Role of PET quantitation in the monitoring of cancer response to treatment: Review of approaches and human clinical trials

    Clin Transl Imaging

    (2014)
  • F. Dehdashti et al.

    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

    (2009)
  • B.F. Kurland et al.

    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

    (2012)
  • W.W. Ma et al.

    [18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy

    J Clin Oncol

    (2009)
  • J.R. Bading et al.

    Imaging of cell proliferation: Status and prospects

    J Nucl Med

    (2008)
  • M. Dowsett et al.

    Clinical studies of apoptosis and proliferation in breast cancer

    Endocr Relat Cancer

    (1999)
  • M. Dowsett et al.

    Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer

    Clin Cancer Res

    (2006)
  • K.A. Krohn et al.

    Imaging cellular proliferation as a measure of response to therapy

    J Clin Pharmacol

    (2001)
  • Cited by (40)

    • Imaging genomics: data fusion in uncovering disease heritability

      2023, Trends in Molecular Medicine
      Citation Excerpt :

      As the entire tumor can be imaged across multiple time points, imaging genomics enables tumor heterogeneity to be considered on a scale that is not possible with serial biopsies. Use of radiotracers in nuclear medicine targeted to key enzymes and proteins that become overexpressed in some cancers – for example, poly[ADP-ribose] polymerase 1 (PARP-1), estrogen receptor – provides direct insight into the regional expression of these important genes [25–27]. Although still a novel area of research, genetic variation can also be captured indirectly from anatomic imaging – for example by CT and MRI – using machine learning and other approaches to identify subtle changes in imaging features that are associated with particular genetic variants [28,29].

    • Medicinal products meet medical devices: Classification and nomenclature issues arising from their combined use

      2022, Drug Discovery Today
      Citation Excerpt :

      A companion diagnostic (CDx) is an in vitro diagnostic medical device (IVD) essential for the safe and effective use of a corresponding MP, the Summary of the Product’s Characteristics (SmPC) of which should include a reference to the specific biomarker.18 The purpose is the identification of patients who are most likely to benefit from the corresponding MP, in which case a reference to the specific biomarker should be included in section 4.1 (Therapeutic Indications) of the or patients likely to be at increased risk of serious adverse reactions.19,20 CDx are outside the scope of the MP + MD guideline and are addressed in the 2021 draft Guidance on the Procedural Aspects for the Consultation to the European Medicines Agency by a Notified Body on Companion Diagnostics issued by the EMA.21

    • Companion diagnostics and biomarker tests in the european medicines agency’s assessment of medicinal products

      2019, Companion and Complementary Diagnostics: From Biomarker Discovery to Clinical Implementation
    View all citing articles on Scopus

    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.

    View full text