Benign and Malignant Breast

disorders
Dr. Manisha, Dr. Pawlak, Dr. Gupta, Dr. Prasad
 Learning objectives
At the end of the class, the student should be able to:
• Describe the anatomy and histology of the breast.
• Understand Relationship of fibrocystic changes in the breast to Breast
carcinoma
• Describe the causes and risk factors for breast cancer
• Describe the morphological patterns of benign and malignant breast
tumors
• Describe the mechanism of action and adverse effects of drugs used
in treatment of Breast cancer
Anatomy of Breast
Breast
• The mammary glands (modified
sweat glands) in the breasts are
accessory to reproduction in women
• Present in the subcutaneous tissue
overlying the pectoralis and major
and minor muscles
• The amount of fat surrounding the
glandular tissue determines the size
of non-lactating breasts
• At the greatest prominence of the
breast is the nipple surrounded by a
circular pigmented area of skin, the
areola
• Body of the breast rests on a bed which extends transversely from the lateral
border of the sternum to the midaxillary line and vertically from the second
through sixth ribs
• Between the breast and the pectoral fascia is a loose connective tissue plane or
potential space – the retromammary space (bursa)
• A small part of the mammary gland extends along the inferolateral edge of the
pectoralis major toward the axillary fossa (armpit) forming an axillary process-
Tail of Spence
• The mammary gland is firmly attached to the dermis of the overlying skin,
especially by substantial skin ligaments ( of Cooper)
• These condensations of fibrous connective tissue, particularly well developed
in the superior part of the gland, help support the mammary gland lobules
• The lactiferous ducts give rise to buds which form 15-20 lobules of glandular
tissue which constitute the parenchyma of the mammary gland
• Each lobule is drained by a lactiferous duct
• Deep to each areola, each duct has a dilated portion , the lactiferous sinus
• The areola contains numerous sebaceous glands
• The nipples are conical or cylindrical prominences in the centres of the areola-
no fat, hair or sweat glands
• The tips of the nipples are fissured
• The alveoli are arranged in grape like clusters
Sagittal section of breast and anterior thoracic wall
Quadrants of the breast
Arterial Supply

• Medial mammary branches of

perforating branches
• Lateral thoracic and
thoracoacromial arteries
• Posterior intercostal arteries
Venous Drainage

• Axillary vein
• Internal thoracic vein
Transverse section of thorax
Lymphatic Drainage
• Role in the metastasis of cancer
cells
• Subareolar lymphatic plexus
• Most lymph (75%), especially from
the lateral breast quadrants, drain to
the axillary lymph nodes, initially to
the anterior or pectoral nodes for the
most part
• Some may drain directly to other
axillary nodes or even to
interpectoral, deltopectoral,
supraclavicular or inferior deep
cervical nodes
Lymphatic Drainage
• Most of the remaining (medial
breast quadrants) drain to the
parasternal lymph nodes or to the
opposite whereas lymph from the
inferior quadrants may pass deeply
to abdominal lymph nodes
(subdiaphragmatic inferior phrenic
lymph nodes)
• Lymph from the skin of the breast,
except the nipples and the areola,
drains into the ipsilateral axillary,
inferior deep cervical and
infraclavicular lymph nodes and
also into the parasternal lymph
nodes of both the sides
Lymphatic Drainage
• Subclavian lymphatic trunk
• Bronchomediastinal lymphatic trunk
• Jugular lymphatic trunk
• VENOUS ANGLE
Innervation of breast
• 4th-6th intercostal nerves
• Pass through the deep fascia
covering the pectoralis major to
reach the skin including the breast in
the subcutaneous tissue overlying
the muscle
• Sensory fibres-skin of the breast
• Sympathetic fibres- blood vessels
and smooth muscle in the overlying
skin and nipple
A normal mammogram
Breast Histology
 Breast – Non pregnant and pregnant states
• Mammary
• Mammary glands become
glands are active
inactive
• Duct system
• Small ducts grows rapidly
and few
lobules • Secretory units
larger and
• Not well extensively
developed branched
secretory
alveoli
The mammary glands of adult, non-pregnant women are inactive,
Non-Pregnant Pregnant
with small ducts and few lobules (L)
 Breast - Lactation
Structure During lactation, the lobules
are greatly enlarged and the
Development lumens of both the numerous
glandular alveoli (A) and the
Pregnancy
excretory ducts (D) are filled
with milk.
&
The protein content of milk
Lactation
makes it eosinophilic in
histological sections.
Post-lactational At this time the intralobular
regression
connective tissue is more
sparse and difficult to see,
except for small septa (arrows).
All X60, H&E.
Structure

Development

Pregnancy
&
Lactation

Post-lactational
regression
a) Micrograph shows alveoli (A) develop as spherical structures composed of cuboidal epithelial
cells surrounded by the contractile processes of myoepithelial cells (M). A small amount of milk is
beginning to accumulate in the lumen of the duct (arrow). X400. H&E b) Secretory cells of the
lactating gland are more columnar and contain variously sized lipid droplets, which are also visible
in the milk (LD)
 Breast
Near the opening of nipple,
Structure
the lactiferous ducts dilate to
form lactiferous sinuses lined
Development
by stratified squamous
epithelium at their external
Pregnancy openings that changes to
& stratified columnar or

Lactation cuboidal proximally.

Lining of lobular ducts and

Post-lactational terminal ducts is formed of
regression simple cuboidal epithelium
with closely packed
myoepithelial cells.
 Breast
Connective tissue surrounding alveoli contains
Structure many lymphocytes and plasma cells (increase at
end of pregnancy – secrete IgA)

Development
Nipple – externally covered by keratinized
stratified squamous epithelium
Pregnancy
Abundant sensory nerve endings
&
Lactation
Areola – skin around
the nipple –
Post-lactational darkens during
regression
pregnancy

What is this image?

 Pregnancy and Lactation
Structure Pregnancy

1. Undergo intense growth under

Development influence of estrogen,
progesterone, and prolactin
Pregnancy 2. Proliferation of alveoli at the
& ends of terminal ducts
Lactation
3. Fat droplets and secretory
vacuoles (containing milk
Post-lactational protein) seen in cytoplasm of
regression
alveolar cells

4. Stellate myoepithelial cells

found
Pregnancy and Lactation
Lactation
Structure 1. Milk is produced by epithelial
cells of alveoli

Development 2. Accumulate in their lumen

and ducts

Pregnancy 3. Secretory cells become low

& cuboidal

Lactation 4. Cytoplasm contains spherical

triglyceride droplets

Post-lactational 5. Large number of membrane-

regression bound vacuoles containing
milk proteins (casein, α-
lactalbumin, IgA)
 Post-Lactational Regression
Structure Weaning (cessation of breast-feeding)

Development
Alveoli undergo degeneration through apoptosis
Pregnancy
&
Lactation Sloughing of whole cells

Autophagy of cellular components

Post-lactational
regression

Dead cells and debris removed by macrophages

Inflammatory disorders of
breast
Clinical situations

• Lumps/nodules

• Nipple discharge

• Inflammation

• Abnormality in mammographic screening

Specimen Processing
• Needle core biopsies: 14-18 gauge needle for localized breast lesions
(replaced FNAC)
• Excision biopsies
• Mastectomies: simple skin sparing (only removes areola-nipple
complex)
• Radical: including pectoralis mj muscles
• Modified radical: includes axillary LNs
• Subcutaneous mastectomies (without skin; performed on men)
• Prophylactic mastectomies
• Therapeutic mastectomies
Clinical case 1
A 32 year-old female presents with a lump in her breast. She is worried
that it could be cancer. What would be the diagnostic possibilities?

• Abnormal physiologic response to hormones

• Retained secretions

• Inflammation

• Benign tumor

• Malignant tumor

• How can they be distinguished?

Galactocele

• Cystic dilatation of obstructed duct (during lactation)

• Painful lump

• May get infected - persistent induration.

Clinical case

• A 28 year old female nursing her baby in the postpartum

period, notices sudden enlargement and pain in her left breast.
It became reddish and the nipple was cracked.

• Suggests infection.

• When did it occur, which bugs?

• What other inflammations in breast? – duct ectasia, fat

necrosis, implant reactions
Inflammations
• Clinical: pain and tenderness

• Types: Acute mastitis (abscess), mammary duct ectasia (dilation),

traumatic fat necrosis, reaction to implants

• Acute Mastitis: usually in lactating state

• Inspissated secretions,

• Fissures in nipples attract bacteria

Staph: small, localized under nipple, may leave residual indurated

scar

Strep: whole breast, marked swelling and tenderness heals

without scar.
Acute Mastitis
Etiology
• In early weeks of nursing, breast is
vulnerable to bacterial infection
• Cracks and fissures in nipples---
Staphylococcus aureus or Microscopy
Streptococci, invade breast
substance. Diffuse infiltration by
acute inflammatory cells

Gross Destroy ducts, lobules, and

surrounding stroma
• Breast is swollen, erythematous,
and painful
 Sequele
• Extensive necrosis → destroyed breast substance is replaced by
fibrous scar.

• Scarring → localized area of increased consistency + skin/nipple

retraction ~ neoplasm
Chronic Mastitis

Granulomatous inflammation
• Secondary to a systemic disease
• TB or sarcoidosis
Peri-ductal Mastitis
Painful erythematous sub-areolar mass

• fistula tract tunnels under smooth muscle of

Recurrent cases nipple -- opens onto skin at edge of areola

Inverted nipple • secondary to fibrosis and scarring

> 90% of women • epithelium of lactiferous sinuses altered

are smokers

Not associated • Lactation, specific reproductive history, age

with
Duct Ectasia

Occurs when a milk duct

beneath the nipple becomes
dilated and inflammed

Age
• In post-menopausal women

Clinically
• Can be misdiagnosed as carcinoma
Dilatation of collecting ducts in sub-areolar region

Peri-ductal fibrosis

Chronic inflammatory cells (+ plasma cells)

Lumina of ducts- Inspissated amorphous material

Chronic inflammation and
fibrosis surround an
ectatic duct filled with
inspissated debris.
 Fat Necrosis

• Unusual lesion produced by injury or trauma to breast

• Produces tumoral masses that clinically ~ carcinomas

• Microscopy:
• Adipose tissue- Inflammation and necrosis (fat necrosis)

• Areas of saponification and calcification

• Chronic inflammatory cells

• Lipid-filled macrophages
Fat Necrosis
Implants

• Cosmetic – paraffin, silicone

• May lead to abscess

• Foreign body granuloma

• Fistulae.
Clinical case
• A 32 year old female presents with a lump in her breast. She is
worried that it could be cancer. What could be the diagnostic
possibilities?

• Physical exam: vague nodularity, bilateral, tendency to increase

before menses, skin normal, no axillary LN.

• Suggests abnormal response to hormones

• FCC
Fibrocystic Changes of Breast
Single most
common Changes in fibrocystic
Location
disorder of disease include:
breast (40%)
Sclerosing
adenosis

Fibrosis
Upper outer
quadrant Ductal epithelial
proliferation

Apocrine
metaplasia
Epidemiology
• Age: 20-40 years
• Peaks at or just before menopause
• Rarely develops after menopause

Incidence of FBD

60%
50%
40%
30%
50%
20%
10% 20%
10%
0%
Under 21 Years Menstrual years Pre-menopausal
 Pathophysiology
Hormonal basis Methyl-xanthiones

• Oestrogen & Progesterone • Increased intake of coffee,

• Estrogen predominance tea, cold drinks and
over progesterone is chocolate is associated
considered causative with development of
• Prolactin levels are Fibrocystic Disease of the
increased Breast
• Estrogen dominance of
pituitary
• Thyroid
• Sub-optimal levels
sensitize mammary
epithelium to Prolactin
stimulation
 Estrogen & Progesterone
• Pre Menstrual tension syndrome
• more likely to develop

• Anovulatory women
• Excess of estrogens or
• Deficiency of progesterone

• Oral contraceptive use decreases risk

• Balanced source of progesterone and estrogen
 Predominantly afflicted are

• Women with menstrual abnormalities

• Nulli-parous women
• H/O spontaneous abortions
• Non-users of oral contraceptives
• Women with early menarche and late menopause
• Rare in
• Ovulating women
• Multiparous women
• Women using oral contraceptives
Symptoms and Signs
Breast pain (mastodynia)

Tenderness

In 40-60% patients, associated with

• Irregular menses
• Dysmenorrhea
• Menometrorrhagia
• Ovarian cysts
 Fine fibro-fatty tissue with
Gross cystic spaces

• filled with fluid

Cysts • may appear blue when seen through
cyst wall (Blue-domed cysts)
Microscopy Microcysts
• Cysts not visible to naked eye

Ductal epithelial proliferation

• may form a lace-like pattern filling
ducts
Apocrine metaplasia
• Normal cuboidal epithelium →
columnar epithelium with
abundant eosinophilic cytoplasm

Adenosis
• Elongated compressed proliferation
of acini/ducts in lobular pattern
Fibrosis
Risk of Cancer
Non-proliferative forms

• Fibrosis and cyst formation

• No increased risk of breast
cancers

Epithelial hyperplasia (with

atypia) or sclerosing
adenosis,complex
sclerosing
• Slightly increased risk of cancer
• Risk of cancer definite when
hyperplastic epithelium
demonstrates atypia
Benign tumors of breast
 Small Duct Papillomas
Occur deep in breast

Usually clinically silent

• Large duct papillomas
• bloody nipple discharge
Microscopy
• Fibrovascular cores extend
into small duct lumens
• Lined by normal 2-cell
layer
A central fibrovascular core extends from the wall of a duct.
Papillae arborize within the lumen and are lined by
myoepithelial and luminal cells
Fibro-adenoma

New growth composed

Most common benign
of both fibrous and
tumor of female breast
glandular tissue

Etio-pathogenesis
• 50% women receiving cyclosporin A after renal
transplantation develop fibroadenomas
• drug-related growth stimulation
• Frequently multiple and bilateral
Pathology
• Location- Upper quadrant of
breast

• Size
• <1 cm to 10-15cm in diameter
(giant fibroadenoma)

• Gross
• Well-circumscribed, rubbery,
grayish white nodules
• Bulge above surrounding tissue
• Slit like spaces
Microscopy

Tumor consists of
two components

• Proliferation of
connective tissue stroma
• Atypical multiplication
of ducts and acini

Both components
are histologically
benign
Proliferation of intra-
lobular stroma
surrounding and often
pushing and distorting
the associated
epithelium.
Clinical features
Young women -
Age Older women
Palpable mass
• <30 years • Spherical • Mammographic
• Any age in nodule; sharply density
reproductive circumscribed
life • Freely
mobile(Mouse
of the breast)
• ↑es in size &
tenderness in
pregnancy
 Mammogram- Well- A rubbery, white, well-circumscribed mass is
circumscribed mass. clearly demarcated from surrounding yellow
Fibroadenoma does not adipose tissue
contain adipose tissue and
thus appears denser than
surrounding normal tissue
on mammogram
Phyllodes Tumor
Arise from intra-lobular stroma

Age
• Any age; usually in 6th decade
• 10-20 years later than fibro-adenoma

Clinical course
• Low grade tumors (85% are benign)
• Recur locally but rarely metastasize
• Cystosarcoma Phyllodes
• High grade lesions behave aggressively
• Local recurrences common
• Distant hematogenous metastases, LN metastases are rare
Pathology

Histology ~
fibroadenoma
• Stroma is more
cellular
• Pleomorphism with
atypia of ductal or
stromal elements
may be present

These tumors can

be quite large
Phyllodes tumor
Increased stromal
cellularity, cytologic
atypia, and stromal
overgrowth →
typical leaf-like
architecture
 Gynecomastia

Proliferation of branching,
intermediate-sized ducts

Ductal epithelium – Hyperplastic

Increase in surrounding fibrous

tissue ----palpable mass
Gynecomastia

Enlargement of adult male breast

Bilateral
• Intake of exogenous estrogens or
estrogen-like agents (e.g., digitalis,
opiates)
Causes • Hormone-seceting Adrenal/testicular
Hormones & tumors
Certain • Paraneoplastic production of
gonadotropins by cancers of liver, lung
medications • Metabolic disorders - Liver disease,
hyperthyroidism ---- ↑ed conversion of
androstenedione into estrogen
Malignant breast tumors
Carcinoma of Breast
2nd most common malignancy of women

Incidence is higher in postmenopausal women

Location

• Upper outer quadrant of breast

• Often unilateral

Metastasis

• Axillary lymph nodes, lung ,liver and bone

• Demonstrates estrogen and progesterone
receptors in some tumor cells
• Presence is correlated with a better prognosis

• Is not predisposed by current regimens of oral

contraceptive therapy.
Risk Factors
Age

• Incidence ↑es with age

Early Menarche and Late menopause

• ↑ed duration of reproductive life and associated

hormonal activity

First Live Birth

• Women with 1st full-term pregnancy at <20 yrs of

age or women > 35 yrs at their 1st birth
First-Degree Relatives with Breast Cancer:

• Risk ↑es with no. of affected 1st-degree relatives

(mother, sister, or daughter)
• Inherited mutation in p53, BRCA1 or BRCA2

Breast Biopsies:

• ↑ed risk associated with prior breast biopsies showing

atypical hyperplasia

Race:

• Incidence- lower in women of African-American

ancestry- ↑ed mortality rate compared with white
women
Additional Risk Factors
1. Estrogen Exposure
2. Radiation Exposure
3. Carcinoma of the Contralateral Breast or
Endometrium
4. Geographic Influence
5. Diet
6. Obesity
7. Exercise
8. Breast-Feeding
9. Tobacco
Etiology and pathogenesis
• Hormonal exposure • Family history or
• Age at menarche and germ-line mutations
menopause,
reproductive history, • Mutated BRCA1 -
breast-feeding, and Increases risk of
exogenous estrogens ovarian carcinoma
• Postmenopausal
women and over- • BRCA2 - Small risk for
express ER ovarian carcinoma ,
• Estrogen metabolites more frequent with
→ mutations or male breast cancer
generate DNA-
damaging free radicals
→ proliferation of pre-
malignant lesions

Sporadic cases Hereditary cases

 Classification of breast carcinoma

• Almost all breast malignancies are adenocarcinomas

• Several histological subtypes

• Most frequent- Invasive Ductal Carcinoma (Scirrhous Carcinoma)
Carcinomas
Divided into in situ carcinomas and
invasive carcinomas

• Neoplastic population of cells limited to

Carcinoma in ducts and lobules by BM
situ • Does not invade into lymphatics and
blood vessels and cannot metastasize

Paget • Cells can extend to overlying skin

without crossing BM
disease
Histological Variants

Pre-invasive lesions:
• Ductal Carcinoma in Situ, DCIS
• Lobular Carcinoma in Situ, LCIS
• Paget's disease of nipple

Invasive ductal carcinoma (Infiltrating)

• Most common (80%)

Invasive lobular carcinoma (Infiltrating)

• 5-10 % of cases
Histological Variants

• Mucinous (colloid) carcinoma

• Medullary carcinoma

• Tubular carcinoma

• Inflammatory carcinoma
 Invasive Carcinoma
• Infiltrating carcinoma
• Invades beyond BM into stroma

• Cells invade into vasculature and reach regional LN and distant sites

• Even the smallest invasive breast carcinomas have some capacity to

metastasize
 Ductal Carcinoma in Situ (DCIS)

• No invasion

• Solid sheets of malignant cells, with central necrosis and calcification

• Malignant cells spread throughout a ductal system and produce

extensive lesions involving an entire sector of a breast.
DCIS- Architectural
subtypes

• Comedo
carcinoma

• Solid

• Cribriform

• Papillary

• Micropapillary
 • Solid sheets of pleomorphic cells with
Comedo high-grade nuclei and central necrosis
• Necrotic cell membranes
Carcinoma • commonly calcify
• detected on mammography as clusters of
linear and branching micro-calcifications
Comedo DCIS
• Mammogram - Multiple clusters of small, irregular
calcifications in a segmental distribution
Comedo DCIS fills several
adjacent ducts; large
central zones of necrosis
with calcified debris
Lobular Carcinoma in
In ≥ one terminal
Situ (LCIS) ducts or ductules
(acini)
• Monomorphic population
of cells having oval or
round nuclei with small
nucleoli
• Rarely distorts underlying
architecture, and involved
lobules remain
recognizable
• Rarely associated with
calcifications and never
forms a mass
Invasive Ductal Carcinoma
(Scirrhous Carcinoma)

On palpation

70-80% of carcinomas • Infiltrative

attachment to
surrounding
structures
Scirrhous Carcinoma • Fixation to
underlying chest
• Marked increase in dense, wall
fibrous tissue stroma
• Tumor develops a hard • Dimpling of skin
consistency • Retraction of nipple
Carcinoma of breast

Peau d' orange

• Dimpling of skin ---

appearance of an orange
• due to obstruction of
subcutaneous lymphatics
--- localized lymphedema.
Gross
• Fairly sharply delimited nodules of stony-
hard consistency

An irregular dense white mass

within yellow adipose tissue
Microscopy

Malignant cells
• In cords, nests, tubules,
anastomosing masses --
invading into stroma

Desmoplasia
characterizes
invasive ductal
carcinoma
Invasive Ductal Carcinoma
• Mammogram - Density with an irregular border with a
small, superimposed, incidental calcification
 Invasive Lobular Carcinoma

• 5-10% of breast carcinomas

• Bilateral and multi-centric within the same breast

• Better prognosis than that for invasive ductal carcinoma.

Microscopy
Parallel arrays of small, regular cells with
• Strands of infiltrating tumor cells scant cytoplasm infiltrate singly in linear
• Often only one cell in width arrays or as small clusters of cells
• In the form of a single file(Indian file
pattern)
“Indian-file appearance”
Medullary Carcinoma
1-5% of all mammary carcinomas

In younger women; carrying the BRCA1 gene

Gross
• Soft, fleshy consistency; well circumscribed

Microscopy
• No striking desmoplasia of the usual carcinomas
• Lymphatic or vascular invasion is never seen
Slightly better prognosis
Microscopy

Sheets of tumor cells

Pushing margins

Lymphoid infiltrate at
periphery
 Colloid (Mucinous) Carcinoma

• Unusual variant (1-6% of all carcinomas)

• Occurs in older women
• Grows slowly during the course of many years

• Gross
• Extremely soft
• Consistency and appearance of pale gray blue gelatin
• Usually well circumscribed
• May mimic benign lesions on physical examination and on mammography.
Tumor cells as small clusters within large
pools of mucin. Borders are typically well
circumscribed; ~ benign masses
Tubular Carcinoma

2% of all breast carcinomas

C/F
• Detected as irregular mammographic densities
• Presenting age- Late forties
• Multi-focal within one breast

> 95% carcinomas express hormone receptors

Excellent prognosis
 All are well differentiated
Microscopy
• Exclusively well-formed tubules

Myo-epithelial cell layer is absent

• Tumor cells are in direct contact with stroma
 Inflammatory Carcinoma

• Lymphatic involvement of skin by underlying carcinoma → Red, hot

skin ~ inflammatory process

• Peau d’orange skin ~ an orange peel

• Poor prognosis.
Paget's Disease Form of DCIS
of Nipple
Extent
• from DCIS within
ductal system into
nipple skin without
crossing the
basement
membrane.
• Large cells at the
dermal-epidermal
junction that stain
positively for mucin
Skin of nipple and areola involved
• Frequently fissured, ulcerated, Eczematous & oozing
• Surrounding inflammatory hyperemia and edema
• Occasional total nipple ulceration
Epidermis involved by malignant cells (Paget cells)
• Large; abundant clear/lightly staining cytoplasm
• nuclei with prominent nucleoli

Cells over-express (Her2/Neu)

• may play a role in pathogenesis of this disease
 Prognosis

• Determined by pathologic examination

• Primary carcinoma

• Axillary lymph nodes

• Few women (<10%) with distant metastases at presentation or with

inflammatory carcinoma
Major Prognostic Factors
• Invasive carcinoma or in situ disease

• Distant metastases

• Lymph node metastases

• Axillary lymph node status is the most important prognostic factor for
invasive carcinoma in the absence of distant metastases

• Tumor size
• Second most important prognostic factor and is independent from
lymph node status

• Locally advanced disease

• Inflammatory carcinoma
 Minor Prognostic Factors

• Histological subtypes
• Tumor grade
• Estrogen receptors
• Progesterone receptors
• Hyper-expression of c-erbB2 (HER2/neu) Associated with poor
prognosis
• Lymphovascular invasion
• Proliferative rates
• DNA content
Self examination
• Periodic regular self examination can pick up
very early lesions.

• Training required for self examination.

• Next best is periodic examination by a

physician.
Pharmacological therapy of
Breast Carcinoma
List of Chemotherapy drugs used in treatment
of breast carcinoma
• Adriamycin (doxorubicin), Epirubicin
• Cyclophosphamide
• 5-fluorouracil
• Methotrexate
• Taxane (docetaxel or paclitaxel)
• Trastuzumab
 Tamoxifen
• First-line therapy in the treatment of estrogen receptor–
positive breast cancer.
• Mechanism of action: Tamoxifen binds to estrogen receptors in
the breast tissue, and prevents translocation into the nucleus
for its action
• Used for treatment of both early & advanced breast cancer;
reduces the risk of developing contralateral breast cancer
and approved for primary prevention in high risk pts.
• Adverse effects:
• Hot flashes (Anti estrogenic), vaginal bleeding and discharge
(estrogenic), thromboembolism
• Tamoxifen has the potential to cause endometrial cancer.
Selective estrogen receptor modulators (SERMs)
Raloxifene:

Estrogen receptor agonist on bone and antagonist on breast and uterus. Used in
treatment of osteoporosis.
Tamoxifene: ER antagonist on breast and agonist on others
Raloxifene: ER antagonist on breast and uterus; agonist on others

Estrogen Effects

Estrogen acts Estrogen acts as

Estrogen acts as as agonist on Estrogen acts
agonist and
agonist on bone to Uterus to as agonist on
increases risk of
prevent cause breast to
thromboembolic
osteoporosis endometrial cause breast
disorder
carcinoma carcinoma
Fulvestrant
• Estrogen receptor antagonist given to patients with
hormone receptor– positive metastatic breast cancer
• Causes estrogen receptor down-regulation on tumors
• Side effects are seen due to estrogen deficiency; hot
flashes, osteoporosis, menopausal symptoms
 Aromatase inhibitors
• Anastrozole and letrozole:
• Peripheral aromatization is an important source of
estrogen in postmenopausal women. Aromatase
inhibitors decrease the production of estrogen
• No risk of endometrial cancer
• Used for breast cancer in postmenopausal women
• Effective in women whose breast tumors have
become resistant to tamoxifen and with advanced
breast cancer
Important:

• Aromatase inhibitors and Estrogen receptor antagonists flare up the

symptoms of menopause
• Vasomotor symptoms: Hot flashes
• Osteoporosis
 What are HER2/neu receptors?

• HER2/neu receptors are tyrosine-

protein kinase receptors expressed on
aggressive type of breast cancers

• Trastuzumab blocks HER2/neu

receptors, blocks the signals of cell
activation and activates the signals for
apoptosis

• Trastuzumab is associated with cardiac

failure