Table Of ContentMOLECULAR
DIAGNOSTICS
The Key Driver in Personalized Cancer Medicine
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Copyright © 2010 by Pan Stanford Publishing Pte. Ltd.
The Key Driver in
Personalized Cancer
Medicine
MOLECULAR
DIAGNOSTICS
Editors
Jan Trøst Jørgensen
Dx-Rx Institute, Denmark
Henrik Winther
Dako, Denmark
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Copyright © 2010 by Pan Stanford Publishing Pte. Ltd.
Published by
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INTRODUCTION
It is now 10 years ago since Robert Langreth and Michael Waldholz
announced the “New Era of Personalized Medicine” in the Wall Street
Journal. This article introduced the concept of personalized medicine to a
broader audience, but in fact, the first step towards a more individualized
drug therapy was taken already several decades before this manifesto.
With the discovery of the estrogen receptor in the 1960’s and the
introduction of the anti-estrogen tamoxifen in the 1970’s the road was
prepared for a more individualized treatment of cancer patients – in this
case patients with breast cancer. The assay for estrogen receptor (ER)
status became an important stratification factor for anti-estrogen
treatment. In the 1990’s another targeted drug was introduced which was
also aimed at a selected group of cancer patients: women whose breast
cancer tumors over-expressed the human epidermal growth factor
receptor 2 (HER2). The drug was the monoclonal antibody trastuzumab
®
(Herceptin , Genentech, CA, USA), which was specifically targeted
towards the HER2 protein of the tumor cells. Also, for trastuzumab a
pharmacodiagnostic test played an important role in relation to treatment
stratification. This was the immunohistochemical assay for the HER2
™
protein (HercepTest , Dako, Glostrup, Denmark).
Since the turn of the century other targeted cancer drugs have been
introduced which are guided by a pharmacodiagnostic test or companion
diagnostics in order to identify the patients who are most likely to
respond to treatment. The development of pharmacodiagnostic tests are,
however, not restricted to new drugs only. As our knowledge about the
cancer pathophysiology at the molecular level increases and the
mechanisms of action of the drugs are explained, it has also become
possible to develop pharmacodiagnostic tests for drugs that are already
used in the clinic. One recent example is the predictive fluorescence
v
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vi J. T. Jørgensen & H. Winther
in situ hybridization (FISH) assay for anthracycline treatment of patients
™
with primary breast cancer (TOP2A FISH pharmDx , Dako Glostrup,
Denmark). In fact, the cover of this book is embellished with a picture of
breast cancer cells showing amplification of the TOP2A gene assessed by
this assay.
The advancement within molecular diagnostics, especially genomics,
is a very important driver of this development. In a recent report from the
US; “Priorities for Personalized Medicine”, published by the President’s
Council of Advisors on Science and Technology (PCAST), it is stated
that molecular diagnostics is identified as a key drivers of personalized
medicine. In this respect pharmacodiagnostics or companion diagnostics
are not only important tools used in the development of new targeted
anticancer drugs, but they are just as important with respect to
improvement of the quality of patient care. The PCAST report points at
the potential of personalized medicine in relation to two important
trends - the increasing costs of healthcare and the decreasing rate of new
medical products being developed. For the quality of patient care the use
of diagnostics will enable the treating physician to distinguish in advance
those patients who will benefit from a given treatment and those who are
likely to suffer the adverse effects only. The use of pharmacodiagnostics
or companion diagnostics will lead to a more rational treatment of cancer
that could also result in cost savings for the healthcare system. Moreover,
with respect to drug development, diagnostics can be used to stratify
patients according to their likelihood of response to the drug under
development. Such approach could result in reduced size, duration, and
costs of clinical trials, thus facilitating the development of more new
drugs.
Drug-diagnostic co-development will be the future development
model in stratified and personalized cancer medicine. We will see more
and more drugs and diagnostics being developed in parallel in order to
increase the effectiveness and safety of new anticancer drugs, and it is
our hope that this book will contribute to this development and be an
inspiration to those who are engaged in this important work.
Copyright © 2010 by Pan Stanford Publishing Pte. Ltd.
Introduction vii
Working with this book has been a pleasure and has convinced us
even more that molecular diagnostics will be a decisive factor with
respect to further improvement of cancer treatment.
We would like to express our gratitude to all the authors who have
contributed so positively to this book.
Jan Trøst Jørgensen and Henrik Winther
Copenhagen, November 2009
Copyright © 2010 by Pan Stanford Publishing Pte. Ltd.
CONTENTS
Introduction v
Jan Trøst Jørgensen and Henrik Winther
Developing Molecular Diagnostics in Cancer 1
Henrik Winther and Jan Trøst Jørgensen
The Estrogen and Progesterone Receptors — Setting the Scene for
Pharmacodiagnostics 21
Kwok-Leung Cheung
The Development of the HercepTest™ — From Bench to Bedside 43
Jan Trøst Jørgensen and Henrik Winther
Predictive Biomarkers and Translational Cancer Medicine 61
Anne-Sofie Schrohl, Pernille Bræmer Hertel,
Maj-Britt Jensen and Nils Brünner
Pharmacodiagnostic Testing — Immunohistology 87
Anthony S.-Y. Leong and Trishe Y.-M. Leong
In Situ Hybridisation for Pharmacodiagnostic Testing 119
John M.S. Bartlett and Fiona M. Campbell
®
MammaPrint Translating Research into a Diagnostic Test 139
Annuska M. Glas, Leonie Delahaye and Oscar Krijgsman
DNA Biomarkers in the Diagnosis and Management of Cancer 165
Reza Rafiolsadat Serizawa and Per Guldberg
Validating the Analytical Power and Parameters of an
Immunohistochemical Test 185
Søren Nielsen
ix
.iex
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x Contents
Drug and Pharmacodiagnostic Co-Development: Statistical
Considerations 207
Richard Simon
Clinical Validation of Biomarkers in Cancer 227
Sumithra J. Mandrekar and Daniel J. Sargent
Pharmacogenomic Markers for Cancer Therapy 251
Sharon Marsh
Safety and Effective Biomakers in Oncology — A Regulatory Drug
and Device Perspective 275
Atiqur Rahman and Francis Kalush
Personalizing Treatment Selection for Breast Cancer 297
Lajos Pusztai and Chit Cheng Yeoh
Pharmacodiagnostics and Personalized Medicine in Cancer 325
Jan Trøst Jørgensen
Copyright © 2010 by Pan Stanford Publishing Pte. Ltd.
CHAPTER 1
DEVELOPING MOLECULAR DIAGNOSTICS IN CANCER
Henrik Winther
ImmunoHistology R&D Business Area, Dako A/S
Produktionsvej 42, DK-2600 Glostrup, Denmark
E-mail:
2 H. Winther & J. T. Jørgensen
housekeeping proteins (internal tissue controls) will indeed increase the
standardisation and robustness levels and thereby optimise the IHC
assay quality and patient care.
1. Introduction
When discussing the development of molecular diagnostics, the obvious
starting point would be a clear definition of biomarkers and their
indicator classification – e.g. classification into diagnostics, prognostics
and predictive biomarkers.
A biomarker is to be considered a substance used as an indicator of a
biologic state. It is a characteristic that is objectively measured and
evaluated as an indicator of normal biologic processes, pathogenic
1
processes, or pharmacologic responses to a therapeutic intervention .
Within this chapter, the biomarker substances will be dealt with as
antibodies.
In literature, there is a confusion of terms with regard to the indicator
classification of biomarkers and hence we will briefly take you through
our definition of a diagnostic-, prognostic- and predictive biomarker
(Figure 1).
A diagnostic biomarker will be considered to be an antibody that is
presently used in a routine setting in routine diagnostic pathology
laboratories. The antibody is used as a confirmatory test and is therefore
an add-on to the pathologist in confirming the diagnosis initially based
on the patient clinical history and tissue biopsy morphological
(macroscopic and microscopic) observations. Classification and sub-
typing of tumours, e.g. lymphomas, is typically performed by using a
2
diagnostic biomarker . The majority of diagnostic biomarkers are
classified as IVD class I products when considered from a regulatory
point of view. IVD class I products can be defined as “confirmatory
products”.
A prognostic biomarker will be characterised as an antibody being
able to provide additional information to the pathologist – e.g. it is not
just a confirmatory test, but a test that will guide the pathologist towards
a therapeutic rational. In its strict sense a prognostic biomarker could be
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