the correlation between hormone receptors, her 2 … university national cancer institute the...

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

>5;:9 ا567ه3ة

اCD:E7 اA;B67 7@ورام

٢ا"4(23 1 0 و/&د '-,+*(ت ا"!�'&ن وا"! �واBس,@>21 "?4(ج ا"< =>وى آ4(ج ٢وا",&1&ای7و' �از

او"B<G HI Hت س�F>ن ا"DEى ا"=,+Dم

0' J'D+' Kدآ,&را J"<رس

داليا حموده الصادق السيد/ الطبيبه

امعة الزقازيقج -مدرس مساعد باطنه اورام

وطئه للحصول على درجة الدكتوراه فى طب االورام

تPQ إN�اف

اTس,>ذ ا"Dآ,&رH?U D=Q' �VW H1&?!?"ا

أس,>ذ XF اBورام />'J4 ا"+>ه�ة- ا"=D!4 ا"+&'Z" Hورام

اTس,>ذ ا"Dآ,&ر D -"اد ا�ة 'D/<'

ا"*>ث&"&/H ور` _ 3-^ أس,>ذ />'J4 ا"+>ه�ة- ا"=D!4 ا"+&'H "(ورام

اTس,>ذ ا"Dآ,&رX"<F &1أ D=Q' ادbI

أس,>ذ XF اTورام Xc"ا J ?آ- dا"37>زی J4'</

اTس,>ذ ا"Dآ,&ر D=Q' ن<=EUر&Ve'

أس,>ذ XF اTورام />'J4 ا"+>ه�ة- ا"=D!4 ا"+&'Z" Hورام

٢٠١٢

بسم اهللا الرحمن الرحيم

�� إ� �� "� ��ا �� إ�� أ�� ا�� ا�� "

٣٢سورة البقرة اآلية

صدق اهللا العظيم

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

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

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).


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


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


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


(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


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


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).


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


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


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


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


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


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).


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


(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

the correlation between hormone receptors, her 2 … university national cancer institute the...

Documents