Endocrine Therapy of Breast Cancer: Current Developments and New Methodologies

69 Pages·1987·4.646 MB·English

by  F. Cavalli (auth.), Franco Cavalli (eds.)

Monographs
Series Editor: U.Veronesi
R Cavalli (Ed.)
Endocrine Therapy
of Breast Cancer II
Current Developments and
New Methodologies
Springer-Verlag Berlin Heidelberg New York
London Paris Tokyo
Franco Cavalli
Division of Oncology, Ospedale San Giovanni,
6500 Bellinzona, Switzerland
The European School of Oncology gratefully acknowledges sponsorship for the Task Force
received from lei Pharmaceuticals Division, originators and manufacturers of Nolvadex (Trademark).
ISBN-13: 978-3-642-72985-0 e-ISBN-13: 978-3-642-72983-6
DOl: 10.1 007/978-3-642-72983-6
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© Springer-Verlag Berlin Heidelberg 1987
Softcover reprint of the hardcover I st edition 1987
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Foreword
Starting in 1986, the European School of Oncology has expanded its activities in
postgraduate teaching, which consisted mainly of traditional disease-orientated
courses, by promoting new educational initiatives. One of these is the cloister
seminars, short meetings intended for highly qualified oncologists and dealing with
specific, controversial aspects of clinical practice and research. Another is the
institution of permanent study groups, also called task forces, where a limited
number of leading experts are invited to meet once a year with the aim of defining
the state of the art and possibly reaching a consensus on developments and
treatment in specific fields of oncology.
This series of ESO Monographs was designed with the specific purpose of
disseminating the results of the most interesting of the seminars and study groups,
and providing concise and updated reviews of the subjects discussed.
It was decided to keep the layout very simple in order to keep costs to a minimum
and make the monographs available in the shortest possible time, thus overcoming a
common problem in medical literature: that of the material being outdated even
before publication.
Umberto Veronesi
Chairman, Scientific Committee
European School of Oncology
Table of Contents
Introduction
F. CAVALLI . 1
Preliminary Assessment of New Methodologies in the Determination of
Hormonal Receptors
S. SAEZ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Adjuvant Chemotherapy in Premenopausal Patients: A More Complicated
Form of Oophorectomy?
A. GOLDHIRSCH, R. D. GELBER, and H. T. MOURIDSEN .......... 11
Evaluating the Benefits of Therapies for Breast Cancer
R.D. GELBERandA. GOLDHIRSCH .......... . 21
Clinical Trials in Advanced Breast Cancer: Are the Right Questions Asked?
F. CAVALLI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Values and Limitations of Current Criteria for Objective Response in
Advanced Breast Cancer
H. T. MOURIDSEN and C. ROSE . . . . . . . . . . . . . . . . . . . 41
Evaluation Criteria in Comparative Clinical Trials in Advanced Breast
Cancer: A Proposal for Improvement
K. W. BRUNNER. . . . . . . . . . . . . . . . . . . . . . . . . . 47
Target Site Specificity of Tamoxifen: A Balance of Estrogenic and
Antiestrogenic Properties
V. C. JORDAN . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Antiestrogenes Old and New: The Search for a Non-Toxic Agent with No
Estrogenic Properties
V. C. JORDAN • . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59
Introduction
F. Cavalli
Division of Oncology, Ospedale San Giovanni, 6500 Bellinzona, Switzerland
In my introductory remarks to the Monograph on Endocrine Therapy of Breast Cancer,
Vol. I, one year ago, I expressed some skepticism regarding the possible success of
the book, considering the vast amount of literature already existing on the topic of
breast cancer. And this in spite of the fact that I was convinced that our Monograph
contained a wealth of provocative thoughts and many attractive chapters. My
skepticism was not justified: we have received many positive comments following the
appearance of the first volume which, prompted us to a rapid publication of the results
of our second meeting, held in spring 1987 in Venice, on the new premises of the
European School of Oncology. I think that the quality of this second volume is even
better and I am therefore confident of its success.
This year we devoted only a limited part of our time to basic aspects. Dr. Saez has
given a preliminary assessment of new methodologies in the determination of
hormonal receptors, while Dr. Jordan once more emphasized the need to search for
antiestrogens without estrogenic properties. The major part of the discussions was
focused on important methodological problems, such as: Are our current methods of
measuring tumor response in breast cancer really adequate? Or should we rather look
for a more appropriate methodology in the objective assessment of clinical trials?
Goldhirsch has taken a new and rather refreshing look at the real merit of adjuvant
chemotherapy in premenopausal patients, while Gelber has investigated the question
of what experience from trials in the adjuvant setting can be applied in order to
improve the methodology of trials in advanced breast cancer. This is a unique and
very provocative approach since, in general, we are used to applying the experience
obtained from the advanced situation to adjuvant trials. The two central chapters of the
Monograph address key questions in this area. What is the real merit of our
methodology in the evaluation of what we call "objective response" in advanced
breast cancer? Is the design of most trials adequate in order to obtain, in metastatic
breast cancer, the answers ,sought for? The views expressed by the authors of this
Monograph are rather pessimistic. Nevertheless, and considering the current plateau
of results in the treatment of advanced breast cancer, we feel it is worthwhile to
discuss opinions which some readers might consider to be excessively negative. Dr.
Brunner even proposes a new methodology to be used for the assessment of the
results of trials in this area: a most provocative chapter which should be read by all
those interested in the subject.
Our next meeting is planned for spring 1988, when we shall proceed with our efforts
towards a critical review of important matters in this controversial field. In the
meantime, we hope to receive some useful and interesting feed-back from our
readers.
Preliminary Assessment of New Methodologies in the
Determination of Hormonal Receptors
S. Saez
Centre Leon Berard, Lyon, France
Hormone receptors in human breast cancer have been the matter of widespread
biochemical and clinical investigations during the last 15 years. A large number of
laboratories and oncology departments have published data demonstrating the
advantage of these measurements in the selection ofthe most appropriate treatments.
These studies were restricted to estrogen receptors (ER) during a first period. At a later
stage progesterone receptors (PGR) were studied as well. They were shown to
provide the initially expected as estimated, i.e., they represent the right parameters for
evaluating hormone dependency. Furthermore, they were found to be related to
another characteristic of the tumor, namely its aggressiveness. The great advantage of
the knowledge of these 2 parameters led to the rapid development of the methods of
measurement in a large number of laboratories, in order to make the information
available for clinicians. However, this new biological approach benefits mainly those
patients with hormone-dependent tumors who usually experience the best prognosis.
Basis of Steroid Hormone Measurements
The rationale governing the interest in these studies was based on the early
experiments of Glascock and Jensen [1,2]. These authors found at first that breast
tumor tissue retained labeled estradiol injected in vivo for a longer time and to a
greater extent than the normal surrounding tissue of the gland [3]. They subsequently
described a similar phenomenon in endometrium [4] and put forward the hypothesis of
a general mechanism of steroid action on target tissue and its mediation by
intracellular receptors.
It was established that the existence of specific receptors is the first requirement to
define target cells, and also that these Feceptors are the obligatory mediators for
hormonal activity. They are present -in very tiny amounts and are effective solely on
account of their extremely high affinity and specificity for the hormone [5]. As a
consequence, they cannot be quantitated as being protein in any purified extract. The
only reliable methods were those using their properties of binding the specific
hormone with a high affinity and specificity. Even on this basis, the methods were still
dependent on the availability of pure hormone labeled with a high specific activity.
Another condition was the availability of a steroid compound demonstrating the same
specificity as the physiological substance and giving stable findings in in vitro assays.
Steroid receptors were defined as cell protein binding labeled hormone with the
required affinity, specificity and saturability. They were effectively quantitated as the
4
amount of hormone they were able to bind in these condit10ns, and the number of sites
was expressed in terms of weight of hormone bound and normalized either per
protein, DNA, or wet tissue weight (usually fmol per mg protein) [6-8]. The
demonstration of a biological effect consecutive to hormone binding was also required
to fulfill the definition of receptor.
These procedures allowed the analysis of the general mechanism of action of steroids
on their target organs, their ontogenesis and their regulation in physiological and
experimental conditions.
The binding criteria were applied as the best parameters of quality control for
"receptor" measurements in a variety of pathological conditions and the most fruitful
applications were found in tumor tissue analysis. They provided the best hypothesis
ever put forward to explain why some breast tumors were very sensitive to endocrine
ablation and others were not. This was confirmed very early by clinical studies. It was
found also that hormone dependency defined by the presence of receptors
corresponded to the selection of a population of tumors growing less aggressively, as
previously observed only with clinical criteria [9-11]. The great majority of the data
published until recently have been obtained with these methods.
General Results of ER and PGR Measurements by the Standard Methods
According to most authors, 60% to 80% of breast tumors contain ER. Positivity is
defined as a binding. capacity superior to 5 or 10 fmoles per mg protein. Positivity of
PGR content is similarly defined by values superior to 10 fmoles and both ER and PGR
are found present in 30% to 40% of the total cases. PGR positivity in the absence of
ER is a rare exception [10].
We found that the incidence of positivity does not vary significantly in relation to age or
menopausal status, except for the category characterized as ER+ PGR- which is less
numerous after the menopause [1'0-13]. Neither does it differ with the size of the tumor,
or the presence of invaded nodes.
Early studies suggested that receptor-positive tumors become less frequent when the
disease is more advanced. But futher analysis indicated that biopsies from strict stage
IV tumors which have not been treated previously, present the same percentage of
positive cases regardless of the site where the biopsy was taken.
Later, it was shown that tumors which have been submitted to cytotoxic or hormonal
treatment may have changed their structure and their biological properties, including
the receptor content [14-16]. This example indicates that receptor data must be
interpreted in relation to parameters which can introduce variability in quantitative and
qualitative results. These parameters include the tissue biopsy itself, the physiological
environment, and treatments.
The conditions in which the biopsy is taken have to be carefully registered, including
its origin in the body and its macroscopical aspect. In the case of a small biopsy
containing a minimal amount of epithelial tissue, the exact content may be
underestimated or even remain under the threshold of detectability. This risk of error is
encountered in very small primary tumors and in cutaneous recurrences in which it is
sometimes difficult to discard the totality of the dermal tissue. In such cases, the
numeric result which is obtained would merit additional comments.
5
The exact number of sites may also vary from one area to another in the same mass
[17] but the status is usually not different.
Apparently the receptor content is submitted to up and down regulation related to the
variation of endogenous hormones.
ER content increases in relation to age by an unknown mechanism. It rises after
ovariectomy and is more elevated in menopausal than in premenopausal patients of
the same age [12]. PGR increases under stimulation by follicular estrogens during the
first part of the menstrual cycle. Afterwards, its level decreases during the luteal phase
and may even become undetectable if the progesterone production is high as
compared to that of estrogens. Therefore, the absence of PGR in premenopausal
patients should be interpreted with caution [18].
In normal and in tumor target tissue, the antiestrogen tamoxifen stimulates the
synthesis of PGR [19,20] while treatment with high doses of progestin reduces PGR, as
does endogenous progesterone during the menstrual cycle [21 ,22].
Thus, the general pattern of hormone receptor status, as assessed in numerous
populations of patients and in studies from various other laboratories, is almost
homogeneous. ER and PGR follow variations consistent with those observed - or
expected - in normal counterparts in human tissue or experimental animal material.
Nevertheless, individual aspects of receptor properties, behavior during the course of
the natural history of the disease, or changes observed after treatments, point to
differences between normal and pathological tissues [23-25]. Firstly, the binding
capacity, even normalized for the epithelial cellularity of the tissue, is more elevated
than the mean values described in benign material [26,27]. Also, a linear relationship
has been observed between the amounts of ER and PGR [10]. But on analyzing
individual data, it is found that PGR does not coexist in all cases where ER is elevated
and the coexistence of ER and PGR is the most reliable criterion.
Analysis of successive biopsies during the course of the disease provided interesting
data. Independently of intercurrent treatment, discordance between 2 consecutive
biopsies coincides with aggressiveness of the tumor [28]. Tumors which remain PGR+
after antiestrogen therapy have a better prognosis than those which become negative.
Under cytotoxic treatment, as after X-ray therapy, the disappearance of both receptors
may be consistent with the decreased cellularity of the tissue, or it may be that only
PGR disappears, demonstrating that it is more labile than ER- [29,30]. It is striking also
that late recurrence some time after any treatment very often reproduced the same
pattern of receptor status as the initial tumor.
To summarize the above data, it can be assumed that the ER and PGR content of
breast carcinoma is basically determined by specific properties of the cells. This
content is rather rich as compared to its paucity in benign tumors. It remains sensitive
to the mechanisms of endocrine regulation, but to a limited extent. This sensitivity is
also the basis of the hormone dependency of these tumors and of their response to
endocrine treatments. ER escapes from these regulatory processes more often than
PGR: examples of this are its incapacity to induce PGR under antiestrogens and its
persistence under cytotoxic treatments.
Other steroid receptors have been investigated in breast tumors: glucocorticoids and
androgen receptors. Their presence in significant amounts coincides with that of ER
and PGR, but it has not been demonstrated whether they contribute to delineating a
population with a different outcome. The biological significance of androgen receptors
6
in breast tumors is not known since there are no available data on normal adult
human tissue of the same origin.
It can be speculated that the presence and characteristics of the steroid binding
capacity found in tumors might be, at the same time, related to the target nature of the
tissue of origin and to the transformation processes. The receptor activities may
coincide with some or almost all the properties of the target tissue, or even mimic the
normality. This variability is consistent with the diversity of behavior between individual
tumors.
Other Methodologies for Steroid Receptor Measurement
Recently, monoclonal antibodies raised against the steroid receptors themselves
offered a new tool for investigating hormone dependency [31]. They have been used
for the development of 2 different approaches for the detection of receptors: an
enzyme immunoassay applied to tissue extracts (EIA), and an
immunoenzymohistochemical technique applicable to cell smears or slices on
microscope slides.
While the previous methods were based on radioligand binding, these are based on
an immunoperoxidase technique using antibodies directed against the steroid
receptor. Monoclonal antibodies against ER were available first, followed by others
against PGR, both being reactive with human tissues [30-35]. An important point is that
they are able to r,ecognize the receptor independently of its occupancy by
endogenous hormone.
At present, two kinds of anti-ER products are commercially available for laboratory
use.
1. The 05 antibody is an IgG1. It is specific for the human species and recognizes a
29KO protein which is not ER itself. It does not bind the hormone, but it is related to ER
as assessed by immunoprecipitation studies [31,32]. It can be used in an
immunoradiometric method for determination of cytosol reactivity [33]. It can be used
also for immunohistochemical studies. It has been shown that in both cases it
recognizes a component which is locali~ed in the cytoplasm. The pattern is consistent
with that reported in other studies indicating that.it is distinct from the estrogen binding
moiety of the receptor. This antibody does not detect antigen in ER-negative cytosol
evaluated with the radioligand assay. In the future, parallel assays using both methods
and their comparison with corresponding clinical data may provide new information on
receptors in tumor tissues.
2. Green and Jensen developed a series of monoclonal and polyclonal antibodies
against ER [31,32]. Among the monoclonals 11 are IgG, 2 are IgM and 12 recognize
different antigenic determinants on the estrogen receptor molecule. Interestingly,
those determinants which are conserved across species appear to be localized close
either to the steroid binding domain, or to the ONA binding domain of the molecule.
One of each class of antibodies has been selected for the development of the
analytical immunoradiometric assay (IRMA) and the commercially available
colorimetric assay (EIA, Abbott).