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Cairo University National Cancer Institute
The Correlation Between Hormone
Receptors, HER 2 and Topoisomerase II and Response to Neoadjuvant Chemotherapy in
Locally Advanced Breast Cancer Thesis Thesis Thesis Thesis
submitted in partial fulfillment for the MD degree in Medical Oncology
ByByByBy Dalia Hamouda ElDalia Hamouda ElDalia Hamouda ElDalia Hamouda El----Sadek ElSadek ElSadek ElSadek El----SaidSaidSaidSaid Assistant lecturer of internal medicine
Faculty of Medicine – Zagazig University
Under supervision of
Prof. Dr. Nasr M. Ali EL-Lahloby
Professor of Medical Oncology National Cancer Institute
Cairo University
Prof. Dr. Magda Mourad El-Sayed
Professor and head of Pathology department
National Cancer Institute Cairo University
Prof. Dr
Fouad Mohamed Abou-Taleb Professor of Medical Oncology
Faculty of Medicine Zagazig University
Prof. Dr. Osman Mohamed Mansour Professor of Medical Oncology
National Cancer Institute Cairo University
2012
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ACKNOWLEDGEMENT
First and above all, my greatest thanks to mighty ALLAH, the
most merciful, the most gracious for helping us all to complete this
work.
I would like to express my sincere gratitude to the supervisors of this
work Prof. Dr. Nasr M. Ali EL-Lahloby, Professor of Medical
Oncology, NCI, Cairo University for his precious time that he
dedicated for our study and his invaluable guidance.
I wish to express my gratitude and appreciation to Prof. Dr. Magda
Mourad El-Sayed, Professor and head of Pathology department, NCI,
Cairo University, for her kind meticulous supervision, unlimited help
and for the time and effort she gave to me. She did her best to help
me.
Thanks to Prof. Dr. Fouad M. Abu-Taleb, Professor of Medical
Oncology, Faculty of Medicine, Zagazig University, for his
continuous encouragement and invaluable guidance throughout the
work.
I am particularly grateful to Prof. Dr. Osman Mohamed
Mansour, Professor of Medical Oncology, NCI, Cairo University, for
his precious time that he dedicated for our study.
Their knowledge and perception had a significant impact on the
structure and relevance of the completed research. They provided a
sense of purpose and direction to the entire research project.
AIM OF THE WORK
Page 5
AIM OF THE WORK
Primary end point:
- Association between overexpression of Topo II-α, HER2-neu, and
hormone receptors and response to primary anthracyclin-based
chemotherapy in locally advanced breast cancer.
Secondary end point:
- Toxicity of anthracyclin-based chemotherapy regimen.
- Two years Relapse Free Survival.
REVIEW OF LITERATURE
Page 6
Epidemiology of Breast Cancer
Globally, breast cancer is the most frequently diagnosed cancer, and
the leading cause of cancer death in females. Breast cancer incidence rates
are highest in North America, Australia/New Zealand, and in western and
northern Europe and lowest in Asia and sub-Saharan Africa. Despite the
decreases in incidence rates in North America, breast cancer incidence has
been increasing in other parts of the world, such as Asia and Africa (Jemal,
et al., 2011) .These international differences are thought to be related to
societal changes occurring during industrialization (e.g., changes in fat
intake, body weight, age at menarche, and/or lactation, and reproductive
patterns such as fewer pregnancies and later age at first birth) (Costanza, et
al., 2011).
Breast cancer is the most common malignancy in women, accounting
for 27% of all female cancers, it account for <1% of all cancer cases in
men. Breast cancer also is responsible for 15% of cancer deaths in women,
making it number two cause of cancer death (Jardines, et al., 2011).
Breast cancer represents a major health problem, with more than
1,000,000 new cases and 370.000 deaths yearly worldwide (Jemal et al.,
2011). In the last decade, inspite of an increasing incidence, breast cancer
mortality has been declining in the majority of developed countries .This is
the combined result of better education, widespread screening programs
and more efficacious adjuvant treatments (Kohler, et al., 2011).
Approximately 210,000 new cases of invasive breast cancer are
expected to be diagnosed in the United States in 2010, and 40,000 die from
the disease. The lifetime probability of developing breast cancer is one in
six overall (one in eight for invasive disease) (Jemal, et al, 2010).
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In Egypt it ranks the second highest frequency among the Arab
world. Female Breast cancer in Egypt ranks as the first malignancy-
affecting females (37.5% in NCI Egypt), it affects 1 in 14 women during
their life time (Omar, et al., 2010).
Risk Factors
Many risk factors have been associated with breast cancer:
• Age and gender
• Race and ethnicity
• Benign breast disease
• Personal history of breast cancer
• Lifestyle and dietary factors
• Reproductive and hormonal factors
• Family history and genetic factors
• Exposure to ionizing radiation
• Environment factors
I-Age/Gender
Age and gender are among the strongest risk factors for breast
cancer. Breast cancer occurs 100 times more frequently in women than in
men. In the US in 2010, there will be an estimated 207,000 invasive breast
cancers diagnosed among women versus 2000 in men (Jemal, et al., 2010).
Incidence rates rise sharply with age until about the age of 45 to 50
when the rise is less steep (SEER, 2011). The change in slope probably
reflects the impact of hormonal change (menopause), although alternative
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hypotheses have been proposed. At age 75 to 80, the curve flattens and
decreases only slightly thereafter (Peto and Mack, 2010).
II-Race/Ethnicity
In the US, breast cancer is the most common cancer among women
of every major ethnic group, although there are inter racial differences as,
in data from the American Cancer Society, the highest rates occur in whites
(124 cases per 100,000 women) The rates are lower in blacks (113 per
100,000), Asian Americans/Pacific Islanders (82 per 100,000),
Hispanic/Latina women (90 per 100,000), and American Indians/Alaska
natives (92 per 100,000) ( Kohler ,et al 2011).
Much of these ethnic differences are attributable to factors associated
with lifestyle and socioeconomic status (e.g., access to diagnosis and
treatment), which also appear to explain at least some of the disparities in
survival that are often attributed solely to race. Genetic and/or biologic
factors also may contribute (Palmer, et al., 2003).
The following observations have been noted in black women: black
women have an earlier age peak than Caucasian women (Costanza, et al.,
2011). Despite the lower incidence overall, black women have higher
mortality rates from breast cancer than do white women. This is due to both
more advanced stage at diagnosis and higher stage-specific mortality. At
least some data suggest that black women have more aggressive cancers
(e.g., hormone receptor-negative) that are associated with a higher
mortality rate (Carey, et al., 2006).
III-Benign Breast Disease
Benign breast conditions include a wide spectrum of pathologic
entities. Single nonproliferative lesions (fibrocystic change, solitary
REVIEW OF LITERATURE
Page 9
papilloma, simple fibroadenoma) are not associated with an increased risk
for breast cancer. The presence of multiple nonproliferative lesions may
increase the risk for breast cancer modestly (RR 1.8 at 10 years in one
cohort study (Worsham, et al., 2007).
The more important precursors of noninvasive or invasive breast
cancer are proliferative lesions, particularly those with cytologic atypia.
The risk of invasive breast cancer is slightly increased (relative risk 1.3 to
2) for a proliferative lesion without atypia (complex fibroadenoma,
moderate or florid hyperplasia, sclerosing adenosis, intraductal
papillomas). It is higher (relative risk 4 to 6) for a proliferative lesion with
atypia (atypical lobular hyperplasia, atypical ductal hyperplasia) and higher
still (10-fold) when the atypia is multifocal (Degnim, et al., 2007).
IV-Personal History of Breast Cancer
A personal history of invasive or in situ breast cancer increases the
risk of developing an invasive breast cancer in the contralateral breast.
With in situ lesions, the 10-year risk of developing a contralateral invasive
breast cancer is 5 percent. In women with invasive breast cancer, the risk of
developing contralateral breast cancer is 1 and 0.5 percent per year for
premenopausal and postmenopausal women, respectively (Costanza, et al.,
2011).
V-Lifestyle and Dietary Factors
1-Socioeconomic status:
Women of higher socioeconomic status are at greater risk for breast
cancer, with as much as a twofold increase in incidence from lowest to the
highest strata. However, it does not appear that socioeconomic status is an
independent risk factor. Instead, the influence of socioeconomic status
REVIEW OF LITERATURE
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(educational, occupational, and economic level) is thought to reflect
differing reproductive patterns with respect to parity, age at first birth, age
at menarche, smoking, and utilization of screening mammography
(Chlebowski, et al., 2009).
2-Geographic residence:
There are marked variations in breast cancer incidence and mortality
among countries. In addition, incidence and mortality rates vary within a
country (Vieira, et al., 2005). Most likely, these clusters are due to
differences in known breast cancer risk factors such as reproductive
hormonal factors including age at first birth or menarche and breastfeeding
(Costanza, et al., 2011).
3-Body mass index:
A-Weight
Weight and body mass index have opposite influences on
postmenopausal as compared to premenopausal breast cancer. in
postmenopausal women higher weight/BMI and postmenopausal weight
gain have been associated with a higher risk of breast cancer in multiple
studies (Ahn, et al., 2007). The influence of weight is the strongest in
women who do not use HRT. In premenopausal women the majority of
prospective cohort studies have found an inverse association between
obesity and premenopausal breast cancer. In the previously described
pooled analysis of seven prospective cohort studies, premenopausal women
with a BMI ≥31 kg/m2 were 46 percent less likely to develop breast cancer
than those with a BMI <21 kg/m2 (Michels, et al., 2008).
The biologic mechanisms underlying this association are unclear.
High BMI can be associated with irregular or long menstrual cycles or with
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polycystic ovary syndrome, and it has been suggested that anovulation,
which is associated with these characteristics and with decreased levels of
estradiol and progesterone, may explain the lower risk of breast cancer
(Ahn, et al., 2007).
However, the data are conflicting Although anovulatory fertility was
associated with a decreased risk of breast cancer in the Nurses' Health
Study adjustment for menstrual patterns and ovulatory infertility in the
statistical models did not significantly influence the inverse association
between premenopausal BMI and breast cancer Thus, it is likely that other
mechanisms besides ovulation underlie the BMI/breast cancer relationship
in premenopausal women (Michels, et al., 2008).
B-Height:
In the majority of studies, increased height has been associated with
a higher risk of both premenopausal and postmenopausal breast cancer This
was illustrated in the previously described pooled analysis of seven
prospective cohort studies: women who were at least 175 cm (69 inches)
tall were 20 percent more likely to develop breast cancer than those less
than 160 cm (63 inches) tall. The exact mechanism underlying this
association is not known but may include prenatal as well as childhood
exposures, such as birth weight and diet/energy balance, or the components
of the insulin-like growth factor (IGF) axis (Morimoto, et al., 2009).
4-Physical activity:
Regular physical exercise appears to provide modest protection
against breast cancer but the relationship is complex, particularly in
premenopausal women. Some studies have shown a decreased risk of
premenopausal breast cancer in women who exercise more, particularly
REVIEW OF LITERATURE
Page 12
during adolescence (Maruti, et al., 2008), but others have shown no
difference These discrepant findings may reflect counterbalancing effects
on risk factors. In premenopausal women, even moderate physical activity
can be associated with anovulatory cycles, which are associated with
decreased risk. On the other hand, thinner premenopausal women have a
higher risk of breast cancer than do heavier women (Monninkhof, et al.,
2009).
5-Smoking:
Accumulating evidence supports an association between active and
passive tobacco smoking and increased breast cancer risk, particularly in
premenopausal women. The relationship between cigarette smoking and
breast cancer has been complicated by the interaction of smoking with
alcohol and endogenous hormonal influences (Costanza, et al., 2011).
Although results have varied widely, many cohort studies and meta-
analyses show a modestly increased risk, and several authoritative reviews
and expert panels, including the Canadian Expert Panel on Tobacco Smoke
and Breast Cancer Risk and the United States Surgeon General, have
concluded that the evidence is suggestive of a causal relationship Increased
risks are most consistent in studies for early initiation, longer duration
and/or higher pack-years of smoking, N-acetyltransferase-2 slow
acetylators, and in genetically susceptible subgroups (Johnson, et al.,
2011).
6-Alcohol:
Alcohol intake is the dietary factor with the strongest evidence of an
association with breast cancer incidence (Costanza, et al., 2011).
REVIEW OF LITERATURE
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Alcohol intake is associated with an increased risk of hormone
receptor-positive breast cancer, and the effect appears to be additive with
hormone therapy. Several mechanisms have been postulated to explain this
effect (Hamajima, et al., 2008).
7-Fat intake:
Animal and ecologic studies have shown a positive correlation
between fat consumption and increased breast cancer risk. However, the
results of case-control and prospective cohort studies have been mixed,
possibly because of the limited range of dietary fat in the typical American
diet and an interaction between reproductive variables, menopausal status,
and fat intake (Sieri, et al., 2008).
8-Red meat:
An association between intake of red meat and ER/PgR-positive
premenopausal breast cancer was also observed in the Nurses' Health Study
II and in the UK women's cohort study (Taylor, et al., 2007).
9-Calcium/vitamin D:
Several studies suggest that intake of low-fat dairy products may
protect against breast cancer, mainly in premenopausal women (Lin, et al.,
2007). In the largest prospective cohort study of over 88,000 women in the
Nurses' Health Study, there was an inverse association between breast
cancer risk and the intake of low-fat dairy products, calcium (mainly dairy
intake), and vitamin D (mainly non-dairy intake) in premenopausal but not
postmenopausal women (Costanza, et al., 2011).
10-Antioxidants:
There is no strong evidence for an effect of intake of vitamin E, or C
or beta-carotene on breast cancer risk, the data are conflicting on vitamin A
REVIEW OF LITERATURE
Page 14
and breast cancer (Nagel, et al., 2010). Some studies on selenium suggest
that the lowest levels may be associated with an increased risk, but higher
levels are not protective. Others have suggested that alterations in selenium
concentration are a consequence rather than a cause of cancer (Lin, et al.,
2009).
11-Caffeine:
A number of studies have failed to show any association between
caffeine intake and breast cancer risk (Ishitani, et al., 2008).
VI-Reproductive/Hormonal Risk Factors
Prolonged exposure and higher concentrations of endogenous
estrogen increases the risk of breast cancer. The production of estrogen
subtypes (estradiol, estriol, and estrone) is modulated by ovarian function:
menarche, pregnancy, and menopause. After menopause, the main source
of estrogen is DHEA, which is produced in the adrenal gland and
metabolized in peripheral fat tissue to estradiol and estrone (Clemons and
Goss, 2001).
The key reproductive factors that influence breast cancer risk are age
at menarche, age at first live birth, age at menopause, and possibly parity
and breast feeding (Parkin, et al., 2005).
1-Age at menarche and menopause:
Younger age at menarche is associated with a higher risk of breast cancer.
In one study, for every two-year delay in the onset of menarche, there was
a 10 percent reduction in cancer risk (Hsieh, et al., 1999).
Age at menarche may influence the biology of breast cancer, with
one case control study of disease-concordant monozygotic twin pairs
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observing that the twin with earlier onset of menses was five times more
likely to be diagnosed with breast cancer before the other (Hamilton and
Mack, 2008).
In contrast, other hormonal factors (i.e., later first pregnancy, lower
parity, later menopause) did not predict an earlier diagnosis when both
twins were affected. Cumulative lifetime estrogen exposure may explain
the association between age of menarche and breast cancer; later
menopause increases breast cancer risk. The relative risk increases by 1.03
percent for each year older at menopause, which is comparable to the
increase with HT use. Bilateral oophorectomy before the age of 40 reduces
lifetime risk by 50 percent; yet, this risk reduction is eliminated if
replacement estrogens are given (Brinton, et al., 1998).
2-Pregnancy-related factors:
A-Parity:
Nulliparous women are at increased risk for breast cancer compared
with parous women; the relative risk ranges from 1.2 to 1.7. The protective
effect of pregnancy is not seen until after 10 years following delivery.,
breast cancer risk increases transiently after a full-term pregnancy. Whether
multiparity confers protection against breast cancer has been a matter of
controversy; the majority of studies suggest a decreased risk with
increasing number of pregnancies (Colditz and Rosner, 2007).
B-Age at first birth:
The younger a woman is at her first full-term pregnancy, the lower
her breast cancer risk, but a later age at first full-term birth can be
associated with an increased risk. In data from the Nurses' Health Study,
the cumulative incidence of breast cancer up to age 70 for parous versus
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nulliparous women was 20 percent lower if the first birth was at age 20, 10
percent lower for first birth at age 25, and 5 percent higher if the first birth
was at age 35.the risk for a nulliparous woman is similar to that of a
woman with a first full term birth at age 30 (Prentice, et al., 2006).
The explanation for the effect of early first live birth is that full
cellular differentiation, which occurs in the gland during and after
pregnancy, protects the breast from breast cancer development. A later age
at first birth is hypothesized to confer a greater risk than nulliparity because
of the additional proliferative stimulation placed on breast cells that have
already become initiated and are at a later stage in development and
perhaps more prone to cell damage (Rosner, et al., 2004).
C-Abortion:
Since abortion disrupts the maturation process of the breast, it has
been hypothesized to increase breast cancer risk. Research in this area has
been difficult to perform because of concerns about under reporting of
abortions, particularly in the United States. As a result, the best data come
from registry studies from Europe, where abortions are performed through
the National Health Service. Both a large pooled analysis and population-
based cohort studies do not support an association between abortion and
breast cancer risk. The National Cancer Institute convened a workshop
evaluating the link between early reproductive events and breast cancer,
which concluded that induced abortion is not associated with an increase in
breast cancer risk (Reeves, et al., 2009).
D-Breast feeding:
A protective effect of breastfeeding has been shown in multiple case-
control and cohort studies, the magnitude of which may be dependent on
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Page 17
the duration of breastfeeding, and on the confounding factor of parity. The
protective effect of breastfeeding may be stronger for the development of
breast cancer during the premenopausal years and in women with a first-
degree relative with breast cancer (Stuebe, et al., 2009).
A large pooled analysis that included individual data from 47
epidemiologic studies including 50,302 women with invasive breast cancer
and 96,973 controls estimated that the relative risk of breast cancer was
reduced by 4.3 percent for every 12 months of breastfeeding, in addition to
a decrease of 7 percent for each birth (Collaborative Group on Hormonal
Factors in Breast Cancer, 2002).
3-Endogenous hormone levels:
A-Estrogen level:
Obese postmenopausal women have higher estrogen levels than non-
obese postmenopausal women, due to the conversion of adrenal androgens
to estrogens in fatty tissue. Obese postmenopausal women also have a
higher risk of breast cancer. Furthermore, reducing estrogen levels (by
suppressing ovarian function in premenopausal women or use of drugs
such as aromatase inhibitors in postmenopausal women) lowers breast
cancer risk. These observations suggest that serum estrogen levels are
linked to the risk of breast cancer (Lahmann, et al., 2008).
Because bone contains estrogen receptors and is highly sensitive to
circulating estrogen levels, bone mineral density may be a surrogate marker
for long-term exposure to endogenous estrogen. In multiple studies, women
with higher bone density had a higher breast cancer risk. In one study, for
example, incidence rates of breast cancer per 1000 person-years increased
from 2.0 among women in the lowest age-specific quartile for metacarpal
REVIEW OF LITERATURE
Page 18
bone mass, to 2.6, 2.7, and 7.0 among those in the second, third, and
highest quartiles, respectively (Chen, et al., 2008).
B-Androgen level:
Both androgens and estrogens are considered sex steroids and their
relative ratios differ through the course of the menstrual cycles and also
through a woman's lifetime. The strongest data exist for testosterone levels,
which have been associated with an increased risk of postmenopausal
breast cancer in most but not all studies (Cummings, et al., 2009). Most of
these studies have focused only on hormone receptor-positive breast
cancer, however. At least one case-control study suggests that higher
testosterone levels are associated with a significantly lower risk of hormone
receptor-negative breast cancer (Farhat, et al., 2011). This finding is
supported by preclinical data that suggest that testosterone has dual effects
on breast tumorigenesis, with a proliferative effect mediated by the ER and
an antiproliferative effect mediated by the androgen receptor (Brettes and
Mathelin, 2008).
C-Exogenous hormone factors:
The use of oral contraceptive agents, especially by women with a
positive family history of breast cancer, appears to increase breast cancer
risk, although use of oral contraceptive agents has been shown to reduce
ovarian cancer risk (Garbrick, et al., 2000).
Worldwide data reanalyzed by the Collaborative Group on Hormonal
Factors in Breast Cancer have shown that, among current and recent users
of hormonal therapy, the risk of breast cancer increases with increasing
duration of use and this excess diminishes after cessation of use
(Collaborative Group on Hormonal Factors in Breast Cancer, 1997).
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D-Other hormones
• Prolactin: Only a few studies have evaluated prolactin, but there
may be a modest association with premenopausal breast cancer
(Tworoger, et al., 2006).
• Insulin pathway and related hormones: A large pooled analysis
drawing from 17 prospective studies showed that IGF-1 was
associated with breast cancer risk in both premenopausal and
postmenopausal women (Endogenous Hormones and Breast
Cancer Collaborative Group, 2010).
VII-Family History and Genetic Risk Factors:
1-Family history:
The overall risk of breast cancer in a woman with a positive family
history in a first-degree relative (mother, daughter, or sister) is 1.7,
premenopausal onset of the disease in a first-degree relative is, associated
with a threefold increase in breast cancer risk, whereas postmenopausal
diagnosis increases the risk by only 1.5, when the first-degree relative has
bilateral disease, there is a fivefold increase in risk. The risk for a woman
whose first-degree relative developed bilateral breast cancer prior to
menopause is nearly 9 (Collaborative Group on Hormonal Factors in
Breast Cancer, 2001).
2- Genetic factors:
Hereditary forms of breast cancer constitute only 5% to 10% of
breast cancer cases overall. However, the magnitude of the probability that
a woman will develop cancer if she inherits a highly penetrate cancer gene
mutation justifies the intense interest in predictive testing. Several genes
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(BRCA1, BRCA2, tumor protein p53 gene [TP53]) associated with a high
risk of breast cancer development (Lichtenstein, et al., 2009).
Elevated risk of breast cancer is also associated with mutations in the
PTEN gene in Cowden's syndrome, In addition, a modest increased risk
(relative risk [RR] of 3.9 to 6.4) may be seen in women who are
heterozygous for a mutation in the ataxia telangiectasia mutated gene
(ATM gene), which is associated with the recessive disease ataxia-
telangiectasia in the homozygous state. A moderately increased risk of
breast cancer (2-fold for women and 10-fold for men) has also been
associated with a variant (1100 delC) in the cell-cycle checkpoint kinase
gene, CHEK2 (Deng, 2006).
The BRCA1 gene is located on chromosome 17. This gene is
extremely large and complex, and there are more than 1,000 different
possible mutations. BRCA1 mutations are inherited in an autosomal-
dominant. Fashion and are associated with an increased risk of breast,
ovarian, and, to a lesser degree, prostate cancers. A BRCA1 mutation
carrier has a 56% to 85% lifetime risk of developing breast cancer and a
15% to 45% lifetime risk of developing ovarian cancer (Walsh and King,
2007).
The BRCA2 gene was localized to chromosome 13. BRCA2 is
approximately twice as large as BRCA1 and is similarly complex.
Alterations in BRCA2 have been associated with an increased incidence of
breast cancer in both women and men (6% lifetime risk). BRCA2
mutations are also associated with an increased risk of ovarian cancer,
pancreatic cancer, prostate cancer, and melanoma. Together, mutations of
BRCA1 and BRCA2 have been linked to most hereditary breast and