Description and Pre-clinical Validation of Dynamic Molecular

Description and Pre-clinical Validation of Dynamic Molecular
Determinants of Sensitivity to Aromatase Inhibitors in Breast
Cancer.
PhD Thesis
Ander Urruticoechea Ribate
September 2007
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INDEX
Page
INTRODUCTION
Breast cancer ………………………... 4
Breast cancer origin and hormone dependence ………………………... 5
Oestrogen drives breast cancer biology through ER ……………………… 8
Gene regulation produced by ER activation ………………………... 11
The endocrine dependency: therapeutic target ………………………... 13
Resistance to endocrine treatment ………………………... 18
Endocrine treatment: research challenges ……………………….. 22
Breakthroughs in biomarkers in endocrine treatment ……………………….. 24
Objectives of the first study …………………………………………………………….. 33
First Study …………………………………………………………………….. 34
Molecular response to aromatase inhibitor treatment in primary breast
cancer
Objectives of the second study …………………………………………………... 66
Second study ……………………………………………………………….…… 67
Pre-Clinical Validation of Early Molecular Markers of Sensitivity to
Aromatase Inhibitors in a Mouse Model of Post-Menopausal Hormone-
Sensitive Breast Cancer.
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INTEGRATED DISCUSSION
Summary of individual discussions 89
New biomarkers description process ………………………….… 89
Three major differences between the 2 studies ……………………………. 92
Why the selection of candidate genes ………………………..... 95
Why two genes do not behave as expected ………………………..….. 96
Why Ki-67 was included in the panel ……………………..…..… 97
Potential applications of the markers …………………….……… 98
SUMMARY …………………………………………………………………… 103
CONCLUSIONS …………………………………………………………… 104
REFERENCES FOR INTRODUCTION AND DISCUSSION………….…………….. 105
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Breast Cancer
Cancer originating in the mammary gland is the most common type of cancer in
women. The lifetime risk of breast cancer for a woman in developed countries has
been calculated at around 1 in 7 to 1 in 10. When it comes to Catalonia, the latest
analyses report an accumulated lifetime risk of developing breast cancer of 1 in 11
with a 1 in 33 probability of death due to this disease[2]. This means that around 10%
of the female population will be diagnosed with breast cancer at some point of their life.
Out of these patients, around 30-40% will eventually die of this disease, mainly due to
the development of metastases, an incurable condition in most types of cancer.
This high incidence, the complexity and the economic costs of the treatment for this
disease make breast cancer one of the most relevant health problems in our society.
A neat decline in breast cancer specific mortality rate has been observed over the last
twenty years[3]. This increasing trend in patient survival rates can be attributed to both
early diagnosis and improved treatment efficacy. Widespread population-based
screening programmes implemented in Western countries over the last thirty years
have allowed the diagnosis of the disease at earlier stages with the consequent higher
rates of curability. On the other hand, better staging procedures and improvements in
surgery and radiotherapy have led to increased local control rates while minimizing
mutilation and the number of untoward effects related to treatment of the breast.
Considered as a systemic disease even from its earliest stages, improved systemic
treatments have resulted in an important breakthrough in patient outcome. To date,
systemic therapies used as a complement to local treatments in curative settings
include chemotherapy and targeted approaches such as hormonal manoeuvres and
anti-Her-2/neu treatments. Among these, hormone treatment has undoubtedly the best
established role in the adjuvant setting of most patients as well as the most favourable
toxicity/efficacy profile.
When cancer becomes incurable, mainly following its metastatic spread, local
treatments (surgery and radiotherapy) have a very limited role while systemic
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treatments have shown to be highly effective in prolonging life and providing improved
symptom control and better quality of life to the patients.
The availability of an increasing number of systemic therapies has urged the
development of research strategies to better define the sub-groups of patients most
likely to benefit from one therapy or another. This is relevant in both the adjuvant and
the metastatic settings. To this effect, tumour characteristics and the patients which
they identify as more or less likely to benefit from a certain treatment are known as
predictive factors and are of great importance. These factors are taken into account to
minimize long term side effects and economic costs in the adjuvant setting, in which
most patients may survive cancer. On the other hand, predictive factors are useful to
improve the quality of life of patients with incurable disease in whom therapeutic
approaches are aimed at following the “primum non nocere” rule to a maximum.
This thesis is focused on the utility of novel predictive markers in the use of hormonal
treatment in patients diagnosed with breast cancer.
The origin of breast cancer and hormone dependence
Virtually all breast adenocarcinomas (by far the most common type of breast cancer
and, herewith, referred to as breast cancer or breast carcinoma when the contrary is
not specified) appear to originate in normal breast glandular epithelium coating the
lumen of terminal duct lobular units (TDLUs). The sequence from normal TDLU to
invasive carcinoma follows a long evolution period in which epithelial cells can typically
be found in different stages of progression to cancer. Thus, when normal epithelium
has begun its malignant transformation it undergoes a first stage of excessive
proliferation known as hyperplasia followed by the appearance of cells showing
aberrant characteristics (atypical ductal or lobular hyperplasia). At a later stage, known
as carcinoma in situ, these cells acquire a full malignant phenotype,except the ability to
invade the surrounding parenchyma through the basal membrane. Nonetheless, in its
final phase the carcinoma cells break through the basal membrane and become an
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