Aromatase Inhibition and Breast Cancer - W. Miller, R. Santeen (Marcel Dekker, 2001) WW

328 Pages·2001·1.97 MB·English

Aromatase Inhibition
and Breast Cancer

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Aromatase Inhibition
and Breast Cancer

edited by

William R. Miller
Western General Hospital
Edinburgh, Scotland

Richard J. Santen
University of Virginia
Charlottesville, Virginia

Cover: Mammograms of the same breast before therapy (left) and after 3 months’
therapy (right) with Femara®. Clear resolution of the cancer in the upper quadrant
can be seen with therapy.

ISBN: 0-8247-0412-6

This book is printed on acid-free paper.

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Preface

Estrogens are key regulators of the normal development and growth of many tis-
sues within the body, most notably the female reproductive system and secondary
sexual organs. Given this central role, it is not surprising that excessive exposure
to or inappropriate stimulation by estrogens may result in aberrant development
and growth. In many instances, corrective procedures that reduce the production
of estrogen may produce therapeutic benefits. Among such strategies is the use
of drugs that inhibit the production of estrogen. In this respect, it is important to
note that estrogens lie at the end of a biosynthetic sequence and that the blockade
of any step in the pathway potentially inhibits estrogen production. However, the
most specific method of blocking biosynthesis is to inhibit the final step in the
sequence—the conversion of androgens to estrogens by the aromatase enzyme.
Drugs that have the potential to inhibit aromatase have been available for some 30
years. In that time, the inhibitors have been used clinically to treat estrogen-de-
pendent disease, most notably breast cancer, without making a major impact. Thus,
even patients with breast cancer, which was suspected to be endocrine-sensitive,
were unlikely to be given aromatase inhibitors as first-line hormone therapy, and
then only after antiestrogens and progestins.
Given this background, a meeting entitled “Aromatase Inhibitors into the Mil-
lennium” would not have been imagined until a few years ago. What makes the
concept highly attractive now is the development of new, third-generation drugs
that can inhibit the aromatase enzyme with extraordinary potency and specificity.
The testimony to this is that milligram doses of the inhibitors given orally and
daily to postmenopausal women are capable of reducing circulating estrogens to
undetectable levels without having apparent effects on any other class of steroid
hormones.
iii

iv
Preface

The objectives of this volume are to (1) provide evidence of the endocrine
effects of these novel aromatase inhibitors; (2) demonstrate how these effects
translate into clinical benefits, using breast cancers as a primary example; (3)
explore the other clinical indications for which aromatase inhibitors may be use-
fully employed; and (4) highlight recent research directed toward development of
reagents, technologies, and models by which to optimize the use of aromatase
inhibitors.
The scene is set by Mitch Dowsett and Harold Harvey, respectively, who re-
view the drug development of aromatase inhibitors and the current management
of advanced breast cancers (to date the major clinical setting in which inhibitors
have been used). Steve Johnston and Ian Smith then go on to identify the place of
aromatase inhibitors within the context of endocrine treatment of advanced breast
cancers. They present evidence that new inhibitors such as letrozole, anastrozole,
and exemestane all have proven efficacy when used as second-line therapy (after
antiestrogens) and, indeed, in certain studies may produce benefits in terms of
antitumor effects and less toxicity beyond older aromatase inhibitors or progestins.
As a consequence, randomized trials are underway comparing the drugs with
antiestrogens as first-line therapy and the question that is now seriously being
asked is: “Can aromatase inhibitors replace antiestrogens as first-choice endo-
crine therapy?” Further and more direct evidence of powerful antitumor effects
and clinical response can be elicited from studies in which aromatase inhibitors
are given neoadjuvantly and the volume of the cancer within the breast is moni-
tored. Mike Dixon presents the experience of the Edinburgh Breast Group.
These highly promising results have led to the use of aromatase inhibitors in
earlier stages of the disease as an adjuvant to surgery. Henning Mouridsen re-
views the major adjuvant trials that have been established to determine if the drugs
may be used to treat micrometastatic disease and delay recurrence. However, it is
clear that even in selected populations of patients, not all women will derive ben-
efits from adjuvant treatment and there is a pressing need to identify accurately
tumors that will respond to treatment. Manfred Wischnewsky explains how ma-
chine learning techniques may be used to address this issue. In terms of predict-
ing and monitoring response, the ability to measure aromatase activity and ex-
pression may be important. Because levels of aromatase are low in peripheral
tissues in postmenopausal women (in whom aromatase inhibitors are largely used),
there is an immediate need to develop new reagents, technologies, and appropri-
ate model systems. Hironobu Sasano and Urs Eppenberger provide state-of-the-
art accounts of immunohistological assessments of aromatase protein and RT-
PCR measurements at the level of mRNA.
While these reagents and technologies will be applied to relevant clinical ma-
terial, there are limitations to patient-based studies, and these must be supple-
mented by experiments in appropriate model systems. The contributions by Bill
Miller and Angela Brodie illustrate how model systems based on human material

Preface
v

may be used to optimize the use of aromatase inhibitors in terms of differences
between individual inhibitors and their combination with other forms of endo-
crine manipulations.
The adjuvant long-term use by breast cancer patients who are ostensibly dis-
ease-free will provide detailed information on the toxicity profiles of the new
aromatase inhibitors and their long-term acceptability. This knowledge will be
invaluable if the drugs are to be used in a preventative setting. Paul Goss is confi-
dent that aromatase inhibitors will be used to prevent breast cancer. If this occurs
as a consequence of delaying the clinical appearance of occult disease, the
antipromotional effects of aromatase inhibitors may be no greater than those of
other forms of endocrine deprivation—for example, antiestrogens. On the other
hand, if the estrogen molecules are carcinogenic initiators, the ability of aromatase
inhibitors to reduce estrogen to exceptionally low levels (whereas antiestrogens
such as tamoxifen do not) may provide a degree of protection beyond other hor-
monal agents.
The powerful endocrine properties of the new generation of aromatase inhibi-
tors contraindicate widespread use in women without disease at this stage, and it
is likely that they will be restricted to high-risk groups who will require careful
monitoring to determine if effects at nontarget sites are associated with toxicity.
Thus there is a need to appreciate health–economic issues in terms not only of
the cost of side effects to the patient but also of financial constraints. This topic
is reviewed by Suzanne Wait. Such considerations are particularly relevant if
aromatase inhibitors are to be administered on a broader basis, for diseases in
which the drugs are not classically indicated. The case for using aromatase inhibi-
tors as therapy for pubertal gynecomastia is presented by Paul Kaplowitz, for
prostate cancer by Matthew Smith, and for treatment of benign and malignant en-
dometrial conditions by Serdar Bulun. The effective and optimal control of these
and other hormone-dependent diseases still depends on the answers to basic ques-
tions, such as which inhibitor to use, at what dose, for how long, in what sequence,
and for which patients? The next decade in the new millennium should provide
many of the answers. The turn of the century is truly an exciting time for endocri-
nologists and oncologists interested in the enzyme called “aromatase.”

William R. Miller
Richard J. Santen

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Contents

Preface
iii
Contributors
xi

PART I PLENARY LECTURE

1.
Aromatase Inhibition: The Outcome of 20 Years of Drug
Development
3
Mitch Dowsett

PART II ADVANCED BREAST CANCER

2.
Role of Hormonal Therapy and Chemotherapy in Advanced
Breast Cancer: An Overview
19
Harold A. Harvey and Kush Sachdeva

3.
Place of Aromatase Inhibitors in the Endocrine Therapy of
Breast Cancer
29
Stephen R. D. Johnston, Ian E. Smith, and Mitch Dowsett

vii