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 Leyland-Jones
Oncology
Translational Medicine Series 7
about the book…
Pharmacogenetics is becoming increasingly relevant in the diagnosis, treatment,
and recovery of cancer patients. A major problem facing oncologists is the out-
standing varied efficacy of treatment. Promising advances in pharmacogenetics
have allowed the development of effective agents which will enable personalized

Pharmacogenetics of Breast Cancer

cancer chemotherapy to become routine for the clinical practice.

Pharmacogenetics
Written by experts in the field and combining information that is unable to be
found in a single source volume, Pharmocogenetics of Breast Cancer:
• combines a complete overview of pharmacogenetics and how it relates to
breast oncology for diagnosis, treatment, and the recovery of patients using
an individualized therapy model

of Breast Cancer
• is the first single source reference demonstrating the application of
pharmacogenetics in the care of breast cancer patients
• enables physicians a coherent interpretation of the emerging science of
pharmacogenetics, aiding them to incorporate individual therapies in their
own practice
• gives practical guidance on various forms of specimen collection, tissue
selection, and handling procedures

Towards the
about the editor...
Individualization of Therapy
BRIAN LEYLAND-JONES is Associate Vice President and Director, Emory Winship
Cancer Institute, Emory University, Atlanta, Georgia. Dr. Leyland-Jones’ main

Individualization of Therapy
Towards the
research interests are pharmacodynamics, pharmacokinetics, and pharmacogen-
etics in oncological clinical trials; translation of preclinical models into the clinic;
biomarker endpoints in Phase I/II clinical trials; and screening and mechanistic
studies of novel targeted and chemotherapeutic anti-cancer agents. He has
authored more than 125 peer-reviewed articles and book contributions, 150
abstracts, and 29 patents.
Printed in the United States of America Edited by
Brian Leyland-Jones
H8637
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[gajendra][][D:/informa_Publishing/H5293_Leyland_Jones_112035/z_production/
z_3B2_3D_files/978-1-4200-5293-0_CH0000_Series_pageO.3d] [3/4/08/10:56:5]
[1–2]

TRANSLATIONAL MEDICINE SERIES

1. Prostate Cancer: Translational and Emerging Therapies, edited by

Nancy A. Dawson and W. Kevin Kelly
2. Breast Cancer: Translational Therapeutic Strategies, edited by Gary
Lyman and Harold Burstein
3. Lung Cancer: Translational and Emerging Therapies, edited by
Kishan J. Pandya, Julie R. Brahmer, and Manuel Hidalgo
4. Multiple Myeloma: Translational and Emerging Therapies, edited by
Kenneth C. Anderson and Irene Ghobrial
5. Cancer Supportive Care: Advances in Therapeutic Strategies,
edited by Gary H. Lyman and Jeffrey Crawford
6. Cancer Vaccines: Challenges and Opportunities in Translation,
edited by Adrian Bot and Mihail Obrocea
7. Pharmacogenetics of Breast Cancer: Towards the Individualization
of Therapy, edited by Brian Leyland-Jones
[gajendra][D:/Informa_Projects/H5293_Leyland_Jones_112035/z_production/z_3B2_3D_files/978-
1-4200-5293-0_CH0000_O.3d] [11/4/08/16:0:41] [1–16]
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1-4200-5293-0_CH0000_O.3d] [15/4/08/16:2:55] [1–16]

Informa Healthcare USA, Inc.

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Informa Healthcare is an Informa business

No claim to original U.S. Government works

Printed in the United States of America on acid-free paper
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International Standard Book Number-13: 978-1-4200-5293-0 (Hardcover)

This book contains information obtained from authentic and highly regarded sources. Reprinted material is
quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable
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Library of Congress Cataloging-in-Publication Data

Pharmacogenetics of breast cancer : towards the individualization of therapy / edited by

Brian Leyland-Jones.
p. ; cm. — (Translational medicine series ; 7)
Includes bibliographical references and index.
ISBN-13: 978-1-4200-5293-0 (hardcover : alk. paper)
ISBN-10: 1-4200-5293-4 (hardcover : alk. paper)
1. Breast—Cancer—Genetic aspects. 2. Breast—Cancer—Chemotherapy.
3. Pharmacogenetics. I. Leyland-Jones, Brian. II. Series.
[DNLM: 1. Breast Neoplasms—genetics. 2. Breast Neoplasms—drug therapy.
WP 870 P536 2008]
RC280.B8P43 2008
616.990 449—dc22
2008001013

For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department,
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Preface

I write this preface on Christmas Day, 2007, in Costa Rica. Christmas is always a
special time for me, since my parents were married on Christmas Day sixty
nine years ago. It is almost unimaginable to think how far we have progressed
since 1938. My parents were married in the year before the Second World
War. The nitrogen mustards, from which arose the first chemotherapies, were
developed during the war. I was fortunate during my training at Sloan-Kettering
to work in the laboratories of Fred Phillips, Joe Burchenal, and Jack Fox, which
conducted some of the pivotal work on these compounds. Indeed, the first task
force for childhood leukemia was set up in Washington in the year of my birth.
However, we all have to remember how slowly treatments are disseminated to
the community; I can remember, as a child, my next-door neighbor having a leg
amputated for metastatic lung cancer since no other treatments were accessible
locally!
The rest is history, but again it is difficult to believe that the Nobel Prize
for the discovery of the cellular origin of retroviral oncogenes was awarded to
Bishop and Varmus only in 1989.
Now we face the challenge of too few patients eligible for clinical trials to
adequately test the myriad of targeted therapies available as well as the avail-
ability of high-quality starting material with associated clinical and phenotypic
data. Various platforms are available for the identification of biomarkers: early
technologies have focused on reverse transcriptase polymerase chain reaction
and expression arrays. Now single nucleotide polymorphisms, array comparative
genomic hybridization, methylation signatures, microRNAs, and proteomics are
increasingly included in biomarker profiling; nanotechnology, molecular imag-
ing, and the use of circulating tumor cells are advancing at a tremendous pace.
By the time this book is released, the specimen collection guidelines for breast
cancer, representing a joint effort between the North American cooperative

iii
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iv Preface

groups and those comprising the Breast International Group (BIG), will have
been published and be available for open Web access. We have attempted to
cover the breadth of these diverse areas in this book.
I am especially proud of three aspects of the book. The first is the timeliness,
as so many new approaches to individualization of therapy have emerged, and
when two very large randomized trials are aggressively accruing on the basis of
Oncotype and mammoprint. Second, the diversity of the topics covered, ranging
from pathology, tissue handling, DNA-, expression-, and epigenetic-based
approaches, nanotechnology, stem cells, circulating tumor cells, endocrine, and
chemotherapeutic through to pharmacologic aspects and the key pivotal trials.
Third, I am proud that so many of my most distinguished friends and colleagues
from around the world have been so generous with their time and devotion to
make this book outstanding.
Finally, in writing this preface from one of the most beautiful places on
earth, I am deeply reminded of the disparities in access to healthcare. We are all
immensely grateful that my friends and colleagues John Seffrin and Otis
Brawley at the American Cancer Society have been leaders in bringing this
critical issue to the forefront of public consciousness, but we must never fail to
remember that severe disparities in access to care remain, not only in the United
States but globally. Individualized therapy is not only meant to direct therapy to
those who will benefit most but also intended to reduce waste and improve cure
rates dramatically, so that this therapy is available to all who suffer. Let us, the
privileged, never move our focus from the most disadvantaged in our world and
aim at using individualized therapy as a means to make our most sophisticated
treatment available and affordable to all.
Brian Leyland-Jones, M.D., Ph.D.
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Acknowledgments

Many thanks are owed on a personal level, especially to all my friends and
coauthors who have been immensely generous in dedicating their nonexistent
spare moments to contributing the various chapters. I am deeply grateful to the
publisher, Informa Healthcare, who not only had the insight to partner with
me on this book but also had the patience to wait for the “nonexistent spare
moments” of the contributing authors to materialize. I must also profoundly
apologize to several colleagues who were approached early on to contribute
chapters but who were unable to because of the original time lines and now must
be frustrated because the time lines were forced to be extended considerably.
Most especially, I must thank my dear, dear colleague, Dr. Brian R. Smith, who
was relentless in organization, follow-up, and advice, a man whose wisdom I
rely upon at so many critical moments and to whose structured approach I aspire.
I am deeply, deeply grateful to Charles Bronfman, whose chair in the memory of
his dear sister, Minda, sustained me over the past 17 years and who now has
inspirationally established his own Institute of Personalized Cancer Therapy in
New York. I am grateful also to the Flanders family who have shown me a depth
of kindness, support, and friendship that is without equal. Finally, I am humbled
by my research and clinical colleagues who instruct and guide me constantly,
and especially by each and every patient who inspires us and teaches, in each and
every encounter, just how personalized breast cancer therapy really is.

v
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Contents

Preface .......... iii

Acknowledgments .... v
Contributors . . . . . . . . xi

1. Pharmacogenetics of Breast Cancer: Toward the Individualization

of Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1
Jenny C. Chang, Susan G. Hilsenbeck, and Suzanne A. W. Fuqua

2. Pharmacology, Pharmacogenetics, and Pharmacoepidemiology:

Three P’s of Individualized Therapy .................... 11
Shaheenah Dawood

3. Role of Genetic Variability in Breast Cancer Treatment

Outcomes ........................................ 25
Kandace L. Amend, Ji-Yeob Choi, and Christine B. Ambrosone

4. The Role of Epigenetics in Breast Cancer: Implications for

Diagnosis, Prognosis, and Treatment .................... 45
Amy M. Dworkin, Tim H.-M. Huang, and Amanda E. Toland

5. Comparative Genomic Hybridization and Copy Number

Abnormalities in Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . 61
Nicholas Wang and Joe Gray

vii
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viii Contents

6. Gene Expression Profiling as an Emerging Diagnostic Tool

to Personalize Chemotherapy Selection for Early Stage
Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Cornelia Liedtke and Lajos Pusztai

7. Gene Expression–Based Predictors of Prognosis and Response

to Chemotherapy in Breast Cancer ..................... 97
Soonmyung Paik

8. Utilization of Genomic Signatures for Personalized

Treatment of Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 107
P. Kelly Marcom, Carey K. Anders, Geoffrey S. Ginsburg,
Joseph R. Nevins, and Anil Potti

9. Personalized Medicine by the Use of Microarray Gene

Expression Profiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Stella Mook, Laura J. van ’t Veer, and Fatima Cardoso

10. Predictive Markers for Targeted Breast Cancer Treatment ... 135
Hans Christian B. Pedersen and John M. S. Bartlett

11. Circulating Tumor Cells in Individualizing Breast Cancer

Therapy ........................................ 151
James M. Reuben and Massimo Cristofanilli

12. Individualization of Endocrine Therapy in Breast Cancer .... 167

Amelia B. Zelnak, Ruth M. O’Regan, and Clodia Osipo

13. TAILORx: Rationale for the Study Design ............... 185

Joseph A. Sparano

14. Taking Prognostic Signatures to the Clinic ............... 197

Michail Ignatiadis and Christos Sotiriou

15. Tissue is the Issue ................................. 213

Adekunle Raji

16. Acquisition and Preservation of Tissue for Microarray

Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Brian R. Untch and John A. Olson
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Contents ix

17. Tapping into the Formalin-Fixed Paraffin-Embedded (FFPE)

Tissue Gold Mine for Individualization of Breast
Cancer Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Mark Abramovitz and Brian Leyland-Jones

18. Breast Cancer Stem Cells and Their Niche: Lethal Seeds in
Lethal Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Danuta Balicki, Brian Leyland-Jones, and Max S. Wicha

19. Molecular Imaging in Individualized Cancer Management ... 291

David M. Schuster and Diego R. Martin

20. Cancer Nanotechnology for Molecular Profiling and

Individualized Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
May Dongmei Wang, Jonathan W. Simons, and Shuming Nie

Index . . . . . . . 323
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Contributors

Mark Abramovitz VM Institute of Research, Montreal, Québec, Canada

Christine B. Ambrosone Department of Cancer Prevention and Control,

Roswell Park Cancer Institute, Buffalo, New York, U.S.A.

Kandace L. Amend Department of Oncological Sciences, Mount Sinai School

of Medicine, New York, New York, U.S.A.

Carey K. Anders Duke Institute for Genome Sciences & Policy, Department
of Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.

Danuta Balicki Department of Medicine and Research Centre, Centre

Hospitalier de l’Université de Montréal; Department of Medicine, Université de
Montréal; and Breast Cancer Prevention and Genetics and Breast Cancer Risk
Assessment Clinic, Ville Marie Multidisciplinary Breast Cancer Centre,
Montréal, Québec, Canada

John M. S. Bartlett Endocrine Cancer Group, Cancer Research Centre,

Western General Hospital, Edinburgh, United Kingdom

Fatima Cardoso Department of Medical Oncology, Institute Jules Bordet,

Brussels, Belgium

Jenny C. Chang Breast Center, Dan L. Duncan Cancer Center, Baylor College
of Medicine, Houston, Texas, U.S.A.

Ji-Yeob Choi Department of Cancer Prevention and Control, Roswell Park

Cancer Institute, Buffalo, New York, U.S.A.

xi
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xii Contributors

Massimo Cristofanilli Department of Breast Medical Oncology, The

University of Texas M. D. Anderson Cancer Center, Houston, Texas, U.S.A.

Shaheenah Dawood Department of Medical Oncology, Dubai Hospital,

Dubai, United Arab Emirates

Amy M. Dworkin Human Cancer Genetics Program, Department of

Molecular Virology, Immunology, and Medical Genetics, The Ohio State
University, Columbus, Ohio, U.S.A.

Suzanne A. W. Fuqua Breast Center, Dan L. Duncan Cancer Center, Baylor

College of Medicine, Houston, Texas, U.S.A.

Geoffrey S. Ginsburg Duke Institute for Genome Sciences & Policy,

Department of Medicine, Duke University Medical Center, Durham,
North Carolina, U.S.A.

Joe Gray Life Sciences Division, Lawrence Berkeley National Laboratory,

Berkeley, California, U.S.A.

Susan G. Hilsenbeck Breast Center, Dan L. Duncan Cancer Center, Baylor

College of Medicine, Houston, Texas, U.S.A.

Tim H.-M. Huang Human Cancer Genetics Program, Department of

Molecular Virology, Immunology, and Medical Genetics, The Ohio State
University, Columbus, Ohio, U.S.A.

Michail Ignatiadis Department of Medical Oncology, Translational Research

Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

Brian Leyland-Jones Winship Cancer Institute, Emory University School of

Medicine, Atlanta, Georgia, U.S.A.

Cornelia Liedtke Department of Breast Medical Oncology, The University of

Texas, Anderson Cancer Center, Houston, Texas, U.S.A.

P. Kelly Marcom Duke Institute for Genome Sciences & Policy, Department
of Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.

Diego R. Martin Department of Radiology, Emory University, Atlanta,

Georgia, U.S.A.
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Contributors xiii

Stella Mook Department of Pathology, The Netherlands Cancer Institute,

Amsterdam, The Netherlands

Joseph R. Nevins Duke Institute for Genome Sciences & Policy, Department
of Molecular Genetics and Microbiology, Duke University Medical Center,
Durham, North Carolina, U.S.A.

Shuming Nie Departments of Biomedical Engineering and Chemistry and

the Winship Cancer Institute, Emory University and Georgia Institute of
Technology, Atlanta, Georgia, U.S.A.

Ruth M. O’Regan Emory Winship Cancer Institute, Atlanta, Georgia, U.S.A.

John A. Olson Institute for Genome Sciences and Policy and the Department
of Surgery, Duke University Medical Center, Durham, North Carolina, U.S.A.

Clodia Osipo Loyola University, Maywood, Illinois, U.S.A.

Soonmyung Paik Division of Pathology, NSABP Foundation, Pittsburgh,

Pennsylvania, U.S.A.

Hans Christian B. Pedersen Endocrine Cancer Group, Cancer Research

Centre, Western General Hospital, Edinburgh, United Kingdom

Anil Potti Duke Institute for Genome Sciences & Policy, Department of
Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.

Lajos Pusztai Department of Breast Medical Oncology, The University of

Texas, Anderson Cancer Center, Houston, Texas, U.S.A.

Adekunle Raji Eastern Cooperative Oncology Group Pathology Coordinating

Office, Northwestern University, Evanston, Illinois, U.S.A.

James M. Reuben Department of Hematopathology, The University of Texas

M. D. Anderson Cancer Center, Houston, Texas, U.S.A.

David M. Schuster Division of Nuclear Medicine and Molecular Imaging,

Department of Radiology, Emory University, Atlanta, Georgia, U.S.A.

Jonathan W. Simons The Prostate Cancer Foundation, Santa Monica,

California, U.S.A.
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xiv Contributors

Christos Sotiriou Department of Medical Oncology, Translational Research

Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

Joseph A. Sparano Albert Einstein College of Medicine, Montefiore Medical

Center, Bronx, New York, U.S.A.

Amanda E. Toland Human Cancer Genetics Program, Department of

Molecular Virology, Immunology, and Medical Genetics, The Ohio State
University, Columbus, Ohio, U.S.A.

Brian R. Untch Institute for Genome Sciences and Policy and the Department
of Surgery, Duke University Medical Center, Durham, North Carolina, U.S.A.

Laura J. van ’t Veer Department of Pathology, The Netherlands Cancer

Institute, Amsterdam, The Netherlands

May Dongmei Wang Departments of Biomedical Engineering and Electrical

and Computer Engineering, Georgia Institute of Technology and Emory
University, Atlanta, Georgia, U.S.A.

Nicholas Wang Life Sciences Division, Lawrence Berkeley National

Laboratory, Berkeley, California, U.S.A.

Max S. Wicha Comprehensive Cancer Centre, Department of Internal

Medicine, Division of Hematology-Oncology, University of Michigan, Ann
Arbor, Michigan, U.S.A.

Amelia B. Zelnak Emory Winship Cancer Institute, Atlanta, Georgia, U.S.A.

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15:4:48] [1–10]

1
Pharmacogenetics of Breast Cancer:
Toward the Individualization of Therapy

Jenny C. Chang, Susan G. Hilsenbeck, and Suzanne A. W. Fuqua

Breast Center, Dan L. Duncan Cancer Center,
Baylor College of Medicine, Houston, Texas, U.S.A.

INTRODUCTION
Mortality from breast cancer results from the ability of some tumors to meta-
stasize to distant sites. Selecting patients with micrometastases at diagnosis is
crucial for clinicians in deciding who should, and who should not, receive toxic
and expensive adjuvant chemotherapy to eradicate these metastatic cells.
Although many individual biomarkers were originally attractive, over the years
most have failed to become clinically useful. In addition, the management of
breast cancer has changed, with the majority of node-negative patients now
undergoing systemic adjuvant therapy because we cannot precisely determine an
individual’s risk of recurrence. A majority of node-negative patients are being
unnecessarily overtreated because if left systemically untreated, only about 25%
of node-negative patients would ever develop recurrence. There is therefore a
critical need to identify patients with sufficiently low risk of breast cancer
recurrence so as to avoid further treatment. In addition, in patients at risk of
recurrence and in need of therapy, optimal therapeutic selection is an increas-
ingly important objective. Recent developments in applying microarray tech-
nologies to breast tumor samples suggest that these new techniques may provide
for the transition of molecular biological discoveries to clinical application and

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2 Chang et al.

will generate clinically useful genomic profiles that more accurately predict the
long-term outcome of individual breast cancer patients.

BACKGROUND
Until recently, evaluations of prognostic and predictive factors have considered
one factor at a time or have used small panels of markers. However, with the
advent of new genomic technologies such as microarrays, capable of simulta-
neously measuring thousands of genes or gene products, we are beginning to
construct molecular fingerprints of individual tumors so that accurate prognostic
and predictive assessments of each cancer may be made. Clinicians may one day
base clinical management on each woman’s personal prognosis and predict the
best individual therapies according to the genetic fingerprint of each individual
cancer.
Breast cancer is characterized by a very heterogeneous clinical course. A
major goal of recent studies is to determine whether RNA microarray expression
profiling or DNA array gene amplification or gene loss patterns can accurately
predict an individual’s long-term potential for recurrence of breast cancer, so that
appropriate treatment decisions can be made. Microarrays can be used to mea-
sure the mRNA expression of thousands of genes at one time or survey genomic
alterations that may distinguish molecular phenotypes associated with long-term,
recurrence-free survival or clinical response to treatment. These new tech-
nologies have been successfully applied to primary breast cancers and may
eventually outperform currently used clinical parameters in predicting disease
outcome.
Since RNA expression microarray technology provided a method for
monitoring the RNA expression of many thousands of human genes at a time,
there was considerable anticipation that it would quickly and easily revolutionize
our approaches to cancer diagnosis, prognosis, and treatment. The reality
remains extremely promising but is also complex. A potential complication in
the application of microarray technology to primary human breast tumor samples
is the presence of variable numbers of normal cells, such as stroma, blood
vessels, and lymphocytes, in the tumor. Indeed, it has been demonstrated using
gross analysis of human breast cancer specimens compared with breast cancer
cell lines that the tumors expressed sets of genes in common not only with these
cell lines but also with cells of hematopoietic lineage and stromal origin (1,2).
Laser capture microdissection has also been successfully used to isolate pure-cell
populations from primary breast cancers for array profiling (3). Sgroi et al. (3)
utilized laser capture microdissection to isolate morphologically “normal” breast
epithelial cells, invasive breast cancer cells, and metastatic lymph node cancer
cells from one patient and were able to demonstrate the feasibility of using
microdissected samples for array profiling as well as following potential pro-
gression of cancer in this patient. However, with the emerging data supporting
important roles for the surrounding stroma in breast cancer progression and the
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15:4:48] [1–10]

Pharmacogenetics of Breast Cancer 3

labor-intensive and technically challenging nature of laser capture technology

with subsequent amplification of RNA for quantitation, most published inves-
tigations to date have evaluated total gene expression to identify prognostic
profiles, as will be described in the next section.

MOLECULAR CLASSIFICATION OF BREAST CANCER

A study of sporadic breast tumor samples by Perou et al. (2) was the first to show
that breast tumors could be classified into subtypes distinguished by differences
in their expression profiles. Using 40 breast tumors and 20 matched pairs
of samples before and after doxorubicin treatment, an “intrinsic gene set” of
476 genes was selected that was more variably expressed between the 40 sporadic
tumors than between the paired samples. This intrinsic gene set was then used to
cluster and segregate the tumors into four major subgroups: a “luminal cell-like”
group expressing the estrogen receptor (ER); a “basal cell-like” group express-
ing keratins 5 and 17, integrinb4, and laminin, but lacking ER expression; an
“Erb-B2-positive” group; and a “normal” epithelial group (Fig. 1).
In a subsequent study with 38 additional cancers, the investigators found
the same subgroups as before (4), except that the luminal, ER-positive group was
further subdivided into subsets with distinctive gene expression profiles. In
univariate survival analysis, performed on the 49 patients diagnosed with locally
advanced disease but without evidence of distant metastasis, ER positivity was
not a significant prognostic factor on its own, but the luminal-type group enjoyed
a more favorable survival compared with the other groups. Conversely, the
basal-like group had a significantly poorer prognosis. Although small and
exploratory, this study suggests that important differences in outcome can be
ascertained from microarray expression profiling.
An interesting study was reported by Gruvberger et al. (5), who profiled 58
grossly dissected primary invasive breast tumors and used artificial neural network
analysis to predict the ER status of the tumors on the basis of their gene expression
patterns. They then determined which specific genes were the most important for ER
classification. By comparing to Serial Analysis of Gene Expression (SAGE) data
from estradiol-stimulated breast cancer cells, they determined that only a few genes
of the many genes that were associated with ER expression in tumors were indeed
estrogen responsive in cell culture. This observation lent further support to the
hypothesis developed by Perou et al. (1) that basic cell lineages, such as the luminal
ER-positive cell type, can be partly explained by observed genomic gene expression
patterns rather than downstream effectors of only one pathway, such as the ER.

PROGNOSTIC IMPLICATIONS
Microarrays have also been used to predict lymph node status and very short-
term relapse-free survival in two groups (n ¼ 37 and 52, respectively) of het-
erogeneously treated patients (6). Although prediction of nodal status is of
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