Table Of ContentBreast
Cancer
Translational
Therapeutic Strategies
Edited by
Gary H. Lyman
University of Rochester School of Medicine and Dentistry
and James P. Wilmot Cancer Center
University of Rochester Medical Center–
Strong Memorial Hospital
Rochester, New York, U.S.A.
Harold J. Burstein
Dana-Farber Cancer Institute
Harvard Medical School
Boston, Massachusetts, U.S.A.
New York London
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Library of Congress Cataloging‑in‑Publication Data
Breast cancer : translational therapeutic strategies / edited by Gary H. Lyman, Harold
J. Burstein.
p. ; cm. ‑‑ (Translational medicine ; 2)
Includes bibliographical references and index.
ISBN‑13: 978‑0‑8493‑7416‑6 (hardcover : alk. paper)
ISBN‑10: 0‑8493‑7416‑2 (hardcover : alk. paper)
1. Breast‑‑Cancer‑‑Treatment‑‑Technological innovations. I. Lyman, Gary H. II.
Burstein, Harold J. III. Series.
[DNLM: 1. Breast Neoplasms‑‑therapy. WP 870 D82425 2007]
RC280.B8B6893 2007
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To my wife, Nicole, and my sons, Stephen and Christopher.
—G. H. L.
To Mary.
—H. J. B.
B Foreword
The past 30 years have seen considerable progress in the detection, diagnosis, treat-
ment and prevention of breast cancer. Such progress followed developments on two
parallel tracks: empirical observations and, increasingly, translational research.
Empirical observations have been at the heart of medical progress for millennia
and, until the middle of the 19th century, were largely responsible for all progress
in medicine. The emerging fields of biology and genetics have achieved increasing
importance, and over the past 30 years the explosion of knowledge about the
process of malignant transformation has been dramatic. We now understand that
all cancers, including all breast cancers, are ultimately the result of one or more
molecular genetic anomalies that result in the loss of customary control processes
for cell growth and communal organization. These molecular genetic anomalies
can result from a variety of inherited conditions, or external or internal influences.
Certainly exposure to environmental carcinogens is one obvious mechanism, but
dysregulation of physiologic processes is another common pathway. Research in
this area has revealed the central importance of steroid hormone physiology and,
in its diseased state, pathophysiology in the development of premalignant and
malignant changes of breast tissue. Further research has identified other critical
growth hormone and receptor systems, including the type I tyrosine kinase receptor
family. Other growth hormone families and the intricate network of intracellular
signaling steps that govern cellular behavior and survival have acquired more
prominent roles in our global understanding of breast cancer. All these pieces of
the puzzle also serve to open opportunities for identifying therapeutic targets
and lead to the development of molecularly targeted therapies. The past few
years have witnessed the coming together of these various discoveries and led to
a substantive paradigm change in our approach to breast cancer. Tamoxifen, as a
targeted approach to the estrogen receptor signaling network, and trastuzumab,
as a molecular modulator of HER2 signaling, became the prototypes of what
many of us hope will be an increasing stream of smart drugs that will approach
breast cancer treatment by identifying specific molecular targets that are critical
to the survival of the malignant cell and cutting that lifeline.
Recent years have also witnessed our increased understanding of the critical
importance of stroma in the development and prospering of cancer cell colonies,
whether primary or metastatic. Stromal cells mediate the progression from in situ
to invasive breast cancer; normal vascular cells are the precursors of tumor neovas-
cularity in an incestuous relationship with malignant cells. Stromal cells signal to
malignant cells and provide the complement of growth factors and cytokines
needed for tissue homing, invasion, and metastasis. Such developments opened
avenues for entirely novel therapeutic strategies already shown to be clinically
effective and relevant.
It is important to understand that this process of discovery to clinical appli-
cation is delicate, frail, and can be derailed by a variety of external influences.
v
Our understanding of basic biology, while markedly expanded compared to a few
decades ago, is still woefully incomplete. The path from discovery of a potentially
active compound in an in vitro system to a drug candidate depends on a series of
economically motivated, and sometimes politically charged, influences within
pharmaceutical companies, and on the uncertainties of peer-reviewed research
support and the vagaries of health care reimbursement in academic centers.
Strong credentials and sometimes luck are helpful for new drugs to succeed. A
persistent champion that pushed the candidate drug through the existing system
is often largely responsible for success or failure.
The process of translating laboratory-based discoveries into practical clinical
tools is convoluted and full of obstacles. Basic scientists are ill equipped to travel
this road, and most clinical investigators are unskilled to initiate the process.
The necessary bridge to make this process succeed is that rare breed of physician
scientists labeled “translational investigators.” Few centers are equipped to train
such individuals, and even fewer provide the support and career opportunities
to ensure their success. Clinicians look at translational investigators as incomplete
physicians, while basic scientists might consider them intruders with inadequate
credentials. They compete, on a part-time basis, with full-time scientists of clinical
investigators, and they are expected to not only succeed, but also to drag their skep-
tical colleagues to follow their lead. And yet, if we don’t foster the development of
well-trained, biologically oriented translational investigators, basic science discov-
eries, as critical as they might be, will languish in someone’s desk drawer for lack of
an effective “translator.”
This volume brings together scientists and clinicians, laboratory investigators
and clinical trialists. Ably led by the two editors, accomplished translational inves-
tigators themselves, it brings to light the accomplishments and challenges of the
paradigm shift mentioned previously. While our accomplishments to date are
solidly anchored on the increased acceptance and use of the randomized clinical
trial, it is clear that many of our new therapeutics will need novel clinical trial
approaches for optimal effectiveness and to minimize the possibility of discarding
new drugs with biological effects different from traditionally understood cytotox-
icity. The development of high-throughput analytical methods have enhanced
manifold our ability to analyze the genome, proteome, and metabolome, but also
led to new challenges in the interpretation and analysis of massive amounts of
data, often obtained from limited numbers of samples. Minimizing the probability
of false discovery has become a major task of our statisticians, and maintaining
a balance between discovery-led investigations and hypothesis-based research
has become an important objective in itself. Technological advances now permit
testing not only for overt molecular genetic abnormalities, but also for genetic poly-
morphisms that are considered to be normal variants. This field will expand
substantially in years to come, since it might explain the substantial variability in
pharmacokinetics and, more importantly, pharmacodynamics of most drugs, and
especially those that require metabolic activation or catabolism. This might lead
to improved dosification of all our therapeutics, and perhaps a marked increase
in the therapeutic ration of potentially toxic drugs. Clinical and biochemical
markers of prognosis have emerged over the past few decades. Most provide
reasonably accurate prognostic information for groups of patients but are seldom
useful for prognostication of individuals. New molecular markers might provide
individually accurate markers of prognosis or predictors of response or resistance
to therapy. It is also possible that combinations of multiple markers, as in gene
vi
Foreword
expression profiles, might provide the best prognostic models. The volume also
summarizes evolving knowledge about multiple molecularly targeted therapeutic
strategies and points out directions for future research.
These are exciting times to be involved in oncology. The pace of discovery, the
opportunities to improve our care for patients with breast cancer, and the increasing
possibility of developing effective and nontoxic prevention strategies make this an
invigorating and intellectually challenging field. How rapidly conceptual advances
translate into applicable clinical tools will depend on the process of translation and
the dedication and skills of our translational investigators, as well as the increasing
involvement of the oncology community at large to effect the clinical validation
of novel scientific concepts. I invite you to enjoy this excellent primer and hope it
will provide useful, practical information and further provoke your intellectual
curiosity.
Gabriel N. Hortobagyi, MD, FACP
Professor and Chair, Department of Breast Medical Oncology, and
Nellie B. Connally Chair in Breast Cancer,
The University of Texas M. D. Anderson Cancer Center
Houston, Texas, U.S.A.
Foreword
vii
B Preface
Full fathom five thy father lies;
Of his bones are coral made;
Those are pearls that were his eyes:
Nothing of him that doth fade
But doth suffer a sea-change
Into something rich and strange.
—William Shakespeare, The Tempest
We are living amidst a sea-change in our treatment of breast cancer. As Shakespeare
imagined the sailor under the sea, so this medical transformation is both rich and
strange. It was this richness, and a desire to make it less strange, that prompted
this book, Breast Cancer: Translational Therapeutic Strategies.
While the processes of the ocean are timeless, it is worth asking why the sea-
change in breast cancer medicine is happening now. There are several major contri-
butors to this transformation. The first has been the recent availability of novel
targeted drugs. Breast cancer medicine had for decades depended on two systemic
treatment options—chemotherapy and endocrine therapy; the latter representing
the earliest successful effort to target therapies based on an improved under-
standing of tumor biology and biomarker testing. The emergence of anti-HER2
targeted therapy with the humanized monoclonal antibody trastuzumab in the
1990s heralded a major new class of therapeutic modalities. Laboratory and clinical
evidence indicated that trastuzumab would be effective only in tumors that were
markedly HER2 overexpressing. This created a pressing need for diagnostic tests
for HER2 overexpression so that tumors, and thus patients, could be appropriately
selected for therapy. The impact of trastuzumab on HER2-positive metastatic breast
cancer revised treatment algorithms such that therapy depended entirely on tumor
HER2 status. In 2005, reports from several major adjuvant trials of trastuzumab
demonstrated that this therapeutic impact extended into early stage breast cancer
management as well.
In addition to the apparent clinical benefits of targeted therapy, the focus on
HER2 testing and targeted treatment fueled research into the second major trans-
forming event in breast cancer medicine—the characterization of clinical subsets
of breast cancer. It became obvious that not all breast cancers were the same.
Indeed, several major clinical types of breast cancer could be characterized by
marker analysis: estrogen receptor and/or progesterone receptor positive, HER2
positive, and “triple negative” (lacking estrogen receptor and/or progesterone
receptor and HER2 expression) subsets. These subsets had immediate practical
clinical implications in terms of selecting therapy for both early- and late-stage
breast cancers.
ix
