Endocrine Therapy of Breast Cancer III

68 Pages·1989·4.098 MB·English

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

Monographs
Series Editor: U.Veronesi
F. Cavalli (Ed.)
Endocrine Therapy
of Breast Cancer III
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
~ Pharmaceuficam
ISBN-13:978-3-642-74506-5 e-ISBN-13:978-3-642-74504-1
001: 10.1007/978-3-642-74504-1
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2123/3145-543210
Foreword
The European School of Oncology came into existence to respond to a need for
information, education and training in the field of the diagnosis and treatment of
cancer. There are two main reasons why such an initiative was considered
necessary. Firstly, the teaching of oncology requires a rigorously multidiscipli
nary approach which is difficult for the Universities to put into practice since
their system is mainly disciplinary orientated. Secondly, the rate of technological
development that impinges on the diagnosis and treatment of cancer has been so
rapid that it is not an easy task for medical faculties to adapt their curricula
flexibly.
With its residential courses for organ pathologies and the seminars on new
techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the
principal therapeutic controversies (conservative or mutilating surgery, primary
or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of
the European School of Oncology to fill a cultural and scientific gap and,
thereby, create a bridge between the University and Industry and between these
two and daily medical practice.
One of the more recent initiatives of ESO has been 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 future developments in specific fields of on
cology.
The ESO Monograph series was designed with the specific purpose of dis
seminating the results of these study group meetings, and providing concise and
updated reviews of the topic discussed.
It was decided to keep the layout relatively simple, in order to restrict the costs
and make the monographs available in the shortest possible time, thus overcom
ing 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
Progression from Steroid Responsive to Unresponsive State in Breast Cancer
R. J. B. KING and P. D. DABRE . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3
Drug Resistance
S. SAEZ ..... . 17
Integration of Quality-of-Life Issues into Clinical Trials of Breast Cancer
R. D. GELBER, A. GOLDHIRSCH, R. J. SIMES, P. GLASZIOU and M. CASTIGLIONE . . . 27
Adjuvant Systemic Therapy for Breast Cancer Patients Without Lymph Node
Metastases (N-)
A. GOLDHIRSCH and R. D. GELBER . . . . . . . . . . . . . . . . . . . . . . . .. 37
New Developments in the Field of Aromatase Inhibitors
F. CAVALLI .......................... . 45
Resistance to Antioestrogen Therapy: a Challenge for the Future
V. C. JORDAN ............................. . 51
New Antioestrogens Without Oestrogenic Activity
A. E. WAKELING . . . . . . . . . . . . . . . . . . . . 61
Introduction
F. Cavalli
Division of Oncology, Ospedale San Giovanni, 6500 Bellinzona, Switzerland
This is the third issue of our Monograph on Endocrine Therapy of Breast Cancer. Even if
it still has to become a routine, we are no longer pioneers. The many positive comments
that we have received following the appearance of the first and second volumes should
help us to avoid the danger of starting to consider our endeavour a routine task which
has to be completed once a year. I am convinced that this third volume is of high quality
and that our undertaking continues to produce a wealth of provocative thoughts and
imaginative approaches.
This year we devoted our meeting to three main topics. The first is natural and acquired
resistance. This is currently a topic of paramount interest to clinicians and basic
researchers. Dr. King gives in his chapter a very provocative view concerning
progression from steroid-responsive to unresponsive states in breast cancer. Dr. Saez
looks at the same problem from a more pharmacological point of view, while Dr. Jordan
highlights once more the importance of understanding resistance to antioestrogen
therapy for the future comprehension of the biology of this disease.
The second topic is related to adjuvant treatment. The team Goldhirsch/Gelber this time
focuses on problems related to measuring quality of life, a key issue in the never-ending
discussion about adjuvant treatments. Considering the enormous excitement elicited
during ASCO 1988 by the statement of the NCI concerning treatment policy in node
negative patients, the reader will undoubtedly be keen to learn which is the position
taken by our group in this Monograph.
The third topic is related to new endocrine agents, with an introduction by myself on new
aromatase inhibitors.
Last but not least: a remark on our second volume. There we took an unorthodox and
provocative stand in relation to the results achieved in the treatment of metastatic breast
cancer. A few months later a similar attitude was presented in an editorial of the most
important American journal on oncology [1]: Europe is not always coming second!
Our next meeting is planned for Autumn 1989, where 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 feedback from our readers.
REFERENCE
Hayes OF, Henderson JC: CAF in metastatic breast cancer: Standard therapy or another effective regimen? J Clin
Oncol1987 (5):1497-1498
Progression from Steroid Responsive to Unresponsive State in Breast Cancer
R.J.B. King and P.O. Oabre
Hormone Biochemistry and Cellular Endocrinology Laboratories, Imperial Cancer Research Fund, Lincoln's Inn Fields,
London WC2A 3PX, United Kingdom
Introduction of the current status of multi-pathway evolu
tion of unresponsive tumours which will form
the basis of the present discussions. This
For over a century we have known that some chapter will deal with data derived from cUl
breast cancers respond to endocrine treat tured mammary tumour cell lines within the
ment whilst others are unresponsive and yet context of the role of steroids in the genesis of
we know little about differences or even the these pathways and the molecular events in
derivation of these two classes of breast can volved in this model. Transition from normal to
cer. The pioneering work of Foulds [1] pro neoplastic cells will not be discussed. The
duced the concept of progression from re chapter will conclude with clinical implications
sponsive to unresponsive state in which he of some of the points raised herein.
stressed that multiple pathways of progres
sion occurred. Unresponsive tumours could
be formed from responsive antecedents or Role of Steroids in Tumour Progres
directly without passing through a responsive sion
stage. His work with pregnancy-dependent
mouse mammary tumours fitted well with the
clinical picture in which both responsive and A widely held view is that unresponsive breast
unresponsive cancers can be identified at first cancers are formed from dependent cells by
presentation and endocrine-induced remis inheritable changes that confer advantage on
sion is almost invariably followed by relapse the former over the latter. A responsive state
[2]. Additional observations that progression also occurs that does not have an absolute
to the unresponsive state is a multistage pro requirement for hormone (Fig. 2). Support for
cess involving cell selection and different de these generalizations exists. Experimental
grees of hormone sensitivity [3-5] have been studies, mainly based on serial
helpful at the biological level but have not de transplantation of tumours in vivo, have
fined any of the underlying molecular events. demonstrated the transition from responsive
Figure 1 depicts a generally accepted version to unresponsive state [3-5]; clinically,
~
Fig. 1. Multippath HORMONE HORMONE HORMONE
way progression of NORMAL -----> DEPENDENT -----> RESPONSIVE -----> UNRESPONSIVE
normal to unrespon CANCER CANCER CANCER
sive cancer cells t t
4 R.J.B. King and P.O. Dabre
HORMONE TREATMENT HORMONE SENSITIVITY
o
..... ....... 0
DEPENDENT
----·0 o
RESPONSIVE
• UNRESPONSIVE
Fig. 2. Progression by cell selection.
Hormone treatment stops growth of de
pendent cells, slows growth of responsive
cells but has no effect on unresponsive
cells which therefore become the pre
dominant cell type. Adapted from refer
ence 4
CELLS/DISH
(X10-SM) +TESTOSTERONE
100 (3.5xl0-8M)
SUSPENSION
50 .. ..
-_
,.'
, CONTROL
I
I
I
10 I
5
MONOLAYER
CONTROL
• ____ -_e_---....
----
1
Fig. 3. Testosterone effects on S115
mouse mammary tumour cells in
monolayer and suspension culture. Cells
0.5 '--_---L_ _- L_ _- I were grown either in the presence (+
o 5 10 15 o 3 6 9 testosterone) or absence (control) of
androgen as monolayer (left-hand panel)
or suspension (right-hand panel) cultures
DAYS IN CULTURE
Progression from Steroid Responsive to Unresponsive State in Breast Cancer 5
hormone-induced remission followed by re androgens and inhibited by glucocorticoids
lapse has been ascribed to the same phe [11,15]. Importantly, unresponsiveness gen
nomenon. Furthermore, unresponsive tu erated by steroid deprivation can be pre
mours tend to be more active and grow faster vented by either androgen or glucocorticoid
than responsive ones [6-8]. Given the poor or alone. Thus, androgens prevent loss of
non-existent mutational effect ofoestrogens glucocorticoid sensitivity and glucocorticoids
[9,10], there have been no suggestions that maintain androgen response [16]. The impli
steroids could influence the initial, inheritable cation of this observation is that the presence
changes but endocrine therapy, by slowing or of any functional steroid receptor complex will
inhibiting growth of the responsive cells, could prevent progression. As loss of response in
facilitate growth of the unresponsive volves well-ordered, sequential changes in
population. several cell functions, all of which are
Cell biological studies on cultured breast tu susceptible to modulation [15,17,18], we
mour cells provide support for some, but not would hypothesise that multiple genes can be
all, of the pOints made above. With both switched on/off according to the steroid envi
mouse [11,12] and human [13,14] cells, ronment. In the mouse system, the early
steroid withdrawal leads to the formation of stages of steroid insensitivity can be reversed
unresponsive cells in an inherited manner. by readdition of steroid. However, the longer
Thus, progression can occur in culture and be the period of deprivation, the more truncated
mediated (prevented) by specific steroids, a the recovery until eventually a completely re
pOint that will be discussed later. In the mouse fractory state is generated [18].
S 115 mammary tumour system, the cells are The rate and extent of progression in these
initially androgen or glucocorticoid responsive culture models preclude selection of unre
in monolayer culture but dependent in sponsive cells resulting from classical muta
suspension culture (Fig. 3). Progression to tional events. The latter occur with a fre
androgen insensitivity occurs rapidly and in a quency of about 1 per 107 cell generations
large proportion of the population [11] (Fig. 4). [19] whereas early changes in androgen sen
With human breast cancer cell lines, oestro sitivity occur throughout the population of
gen deprivation can also generate popula mouse cells within 20 cell doublings. The fig
tions of cells that are unresponsive for oestro ures for oestrogen/human ZR-75 breast can
gen stimulated growth (Fig. 5). Detailed com cer cells are easier to define as the depen
parison of loss of response in the human dent cells do not proliferate in the absence of
[13,14] and mouse [11] systems have not yet oestradiol and the frequency of generation of
been made. Whether or not steroids other unresponsive clones is about 1 per 103 cells
than oestrogens are protective has not been plated [20]. Several other examples of high
established with the human cells. Proges rates of phenotypic modulation in breast [21]
terone receptor is oestrogen inducible and and other cancer [22,23] are known. Thus,
growth is inhibited by antioestrogens in the mechanisms exist other than by mutation for
growth-unresponsive human cells [14], which permanently changing cell function. The term
hints at differences to the murine cells. epigenetic of epimutation has been used to
A major feature common to both human (Fig. describe such processes [25].
5) and mouse (Fig. 4) models is that basal
growth in the absence of steroid increases
with no ultimate change in proliferation in the
presence of hormone. Thus, loss of response Molecular Changes Associated with
apparently reflects changes in steroid-inde Loss of Response
pendent events, a theme that will be devel
oped later.
In S 115 cells, proliferation is regulated both In the previous section, the importance of ele
by androgens and glucocorticoids paralleling vated steroid-independent growth was em
the presence of their respective receptors. phasised but this can also be accompanied
Most cell biological responses are similar with by functional changes in steroid-responsive
either class of steroid, the exception being genes. Thus, with S115 cells, induction of
that log-phase proliferation is stimulated by mouse mammary tumour virus (MMTV)
6 R.J.B. King and P.O. Dabre
RESPONSIVE UNRESPONSIVE
CELLS I PLATE (x10··)
100
-T
50 --~---~
+T
10 0·-0---0
_- - -T
- + - +
T T
DAYS IN CULTURE
Fig. 4. Effect of long-term androgen deprivation on androgen (T) sensitivity of proliferation and specific gene
expression in S115 mouse mammary tumour cells. Unresponsive cells were generated from responsive antecedents by
long-term androgen withdrawal (30 weeks) and the two populations tested for short-term (1 week) sensitivity to
testosterone (T). All growth responses are lost as is the regulation of a 16S mRNA transcribed from MMTV
o WEEKS 3 WEEKS 20 WEEKS
•••••• 0
........................
o.·· .. ···o.·····.D ·········. . D'···~···~···········o
........ Q· .. • ..
10·+---~~--__- -~--~~ 104+---~~r-~---r--~~ 1o · +---...---r--....,..---r---or--~
o 5 10 15 o 5 10 15 0 5 10 15
DA YS IN CULTURE
Fig. 5. Effect of long-term oestrogen deprivation on oestrogen sensitivity of proliferation in ZR-75 human breast cancer
cells. Cells were maintained as monolayer cultures in steroid-and phenol red-free media for the stated number of weeks
and then tested for oestradiol sensitivity in the presence (-. -) or absence (.. c .. ) of 10-8 M oestradiol