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A BRIEF HISTORY OF BREAST CANCER THERAPY
Smith Surgical Papyrus
-Earliest known document to refer to breast cancer
-“The cancer was in man, but the description encompassed
most of the common clinical features. In reference to this
cancer, the author concluded, there is no treatment.”
FIRST CENTURY
-In De Medicina: Celsus commented on the value of
operations for early breast cancer:
-“None of these may be removed but the cacoethes (early
cancer), the rest are irritated by every method of cure. The
more violent the operations are, the more angry they grow.”
SECOND CENTURY
Galen: Classical clinical observation
-“We have often seen in the breast a tumor exactly resembling
the animal, the crab. Just as the crab has legs on both sides of
his body, so in this disease the veins extending out from the
unnatural growth take the shape of a crab’s legs.”
Galenic System of Medicine:
-Ascribed cancers to an excess of black bile and concluded
that excision of a local bodily outbreak could not cure the
systemic imbalance
16th-17th CENTURY
-In 1652, Tulp introduced the idea that cancer was
contagious when he reported an elderly woman and her
housemaid who both developed breast cancer
-Majority of respected surgeons considered operative
intervention
-The Renaissance and the wars of the 16th and 17th centuries
brought developments in surgery No new theories espoused
in relation to cancer
Morgagni: surgical resections were more frequently
undertaken, including some early attempts at mastectomy and
axillary dissection.
17th century (Age of Enlightenment)
-Lasted until the 19th century
-Le Dran repudiated the abandonment of Galen’s humoral
pathology
-Virchow espoused the rise in cellular pathology
19th CENTURY
Moore (Middlesex Hospital, London-Emphasized complete
resection of the breast for cancer, and removal of palpable
axillary lymph nodes
Banks (1877)-Supported Moore’s concepts and advocated the
resection of axillary lymph nodes even when palpable
lymphadenopathy was not evident, recognizing that occult
involvement of axillary lymph nodes was frequently present
Halsted and Meyer (1894)-Reported their operations for
treatment of breast cancer by demonstrating superior logical-
regional control rates after radical resection, and established
RADICAL MASTECTOMY as state-of-the-art treatment for
that era
-Advocated complete dissection of axillary lymph node levels
I to III. Both routinely resected the long thoracic nerve and the
thoracodorsal neurovascular bundle with the axillary contents
1943
Haagensen and Stout described the Grave Signs of Breast
Cancer:
1. Edema of the skin of the breast
2. Skin ulceration
3. Chest wall fixation
4. An axillary lymph node >2.5cm in diameter
5. Fixed axillary lymph node
Women with two or more signs had a 42% local recurrence
rate and only a 2% five-year disease-free survival rate
Based on these findings, they declared that women with
grave signs were beyond cure by radical surgery
1948
Patey and Dyson (Middlesex Hospital, London)
-Advocated a MODIFIED RADICAL MASTECTOMY for
the management of advanced operable breast cancer
-Technique included removal of the breast and axillary
lymph nodes with preservation of the pectoralis major muscle
-Showed that removal of the pectoralis minor muscle
allowed access to and clearance of axillary lymph node
levels I to III
-There are 2types of modified radical mastectomy; the 1st type
is advocated by Patey and Dyson. They do not remove the
pectoralis major, but remove the pectoralis minor.
-Nowadays, we do not remove both pectoralis major and
minor. This was advocated by AUCHENCLOSS. We just do a
mastectomy with axillary lymph node dissection.
1970s
-Halsted Radical Mastectomy was changed by Modified
Radical Mastectomy as the surgical procedure most
frequently used by American surgeons to treat breast cancer
This transition acknowledged that:
-Fewer patients were presenting with advanced local disease
with or without the grave signs described by Haagensen
-Extirpation of the pectoralis major muscle was not essential
for local-regional control in stage I and II breast cancer
-Neither the modified radical mastectomy consistently
achieved local-regional control of stage III breast cancer
I. RADIATION THERAPY
-Incorporated into the management of advanced breast
cancer and demonstrated improvements in local regional
control
II. NATIONAL SURGICAL ADJUVANT BREAST AND
PROJECT (NSABP)
-Randomized trial in the early 1970s to determine the impact
of local and regional treatments on survival in operable breast
cancer. In the B-04 trial, 1,665 women were enrolled and
stratified by clinical assessment of the axillary lymph nodes
-The clinically node-negative women were randomized into 3
treatment groups:
a. Halsted radical mastectomy
b. Total mastectomy + radiation therapy
c. Total mastectomy alone
-The clinically node-positive women were randomized into
a. Halsted radical mastectomy
b. Total mastectomy + radiation therapy
-NO DIFFERENCES IN SURVIVAL between the 3 groups
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of node-negative women or between the 2 groups of node-
positive women.
These overall survival equivalence patterns have
persisted at 25 years of follow-up
III. DEVELOPMENT OF BREAST CONSERVING
SURGERY
 Breast conserving surgery and radium treatment was first
reported by Geoffrey Keynes of St. Bartholomew’s
Hospital, London in the British Medical Journal in 1937
 Several decades later, NSABP launched the B-06 trial, a
phase III study that randomized 1,851 patients into:
o Total mastectomy
o Lumpectomy alone
o Lumpectomy with breast irradiation
 Both NSABP B-04 and B-06 trials were taken to refute
the Halstedian concept that cancer spreads throughout
a region of the breast to lymphatics and then onto
distant sites
IV. ALTERNATIVE HYPOTHESIS
-Bernard Fisher proposed the “alternative hypothesis” that
breast cancer was a systemic disease at diagnosis
-Tumor cells had access to both the blood and lymphatic
systems and that regional lymph nodes were a marker of
systemic disease and not a barrier to the dissemination of
cancer cells
V. EARLY BREAST CANCER TRIALISTS’
COLLABORATIVE GROUP OVERVIEW
-Reported that “the avoidance of recurrence in a conserved
breast… avoids about one breast cancer death over the
next 15 years for every four such recurrences avoided.”
o Indicating that not all breast cancer is a systemic
disease at presentation
-During the 1970s, clinical trials were initiated to determine
the value of systemic therapy in the postoperative setting as
an adjuvant to surgery
-The Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG) was established in 1985 to coordinate the meta-
analysis of data from randomized clinical trials in order to
examine the impact of adjuvant treatments for breast cancer on
recurrence and mortality
 The EBCTCG Overview has demonstrated:
1. Anthracycline-containing regimens are superior to
CMF
2. That the addition of a taxane to an anthracycline-
based regimen reduces breast cancer mortality by
one-third
3. That tamoxifen is of benefit only in patients with
estrogen-receptor (ER) positive breast cancer
4. That tamoxifen may decrease mortality from breast
cancer by as much as 50%
5. That proportional reduction in risk was not
significantly affected by standard clinical and
pathologic factors such as tumor size, ER status, and
nodal status
-Underscores the importance of stratification of risk in
determining adjuvant therapy decisions in order to minimize
the toxicities of therapies.
1980s
-Many early randomized clinical trials viewed breast cancer as
more of a homogenous disease
-Breast cancer was defined by pathologic determinants using
conventional light microscopy and basic histologic
techniques
Immunohistochemistry
DNA  Labeling genes of interest and allowing
fluorescent dyes to quantify the abundance of a particular gene
and comparing a large number of genes simultaneously in a
single breast specimen
-Gene expression arrays have shown that breast cancers
cluster according to their intrinsic gene expression
patterns into at least five intrinsic subtypes and these
intrinsic subtypes correlate with breast cancer outcomes.
21st century
-Breast cancers are now classified by molecular subtypes
and these are being used for risk stratification and decision
making in terms of local-regional and systemic therapies
-Currently, 50% of American women will consult a surgeon
regarding breast disease, 25% will undergo breast biopsy for
diagnosis of an abnormality, and 12% will develop some
variant of breast cancer.
-Considerable progress has been made in the integration of
surgery, radiation therapy, and systemic therapy to control
local-regional disease, enhance survival, and improve the
quality of life of breast cancer survivors.
-Surgeons are traditionally the first physician consulted
for breast care and it is critical for them to be well trained in
all aspects of the breast from embryologic development, to
growth and development, and to benign and malignant disease
processes. This will allow the greatest opportunity to achieve
optimal outcomes for patients and their families.
EMBRYOLOGY OF THE BREAST
-At the 5th or 6th week of fetal development, two ventral
bands of thickened ectoderm (mammary ridges, milk lines)
are evident in the embryo.
-In most mammals, paired breasts develop along these ridges,
which extend from the base of the forelimb (future axilla) to
the region of the hindlimb (inguinal area)
-These ridges are not prominent in the human embryo and
disappear after a short time, except for small portions that may
persist in the pectoral region.
The mammary milk line. If
you see some discolorations
along that area, it may be
an accessory nipple.
-The breast remains undeveloped in the female until puberty,
when it enlarges in response to ovarian estrogen and
progesterone, which initiate proliferation of the epithelial
and connective tissue elements.
However, the breasts remain incompletely
developed until pregnancy occurs.
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ACCESSORY BREASTS (POLYMASTIA) or
ACCESSORY NIPPLES (POLYTHELIA)
-May occur along the milk line when normal regression fails
-Each breast develops when an ingrowth of ectoderm forms a
primary tissue bud in the mesenchyme.
-The primary bud initiates the development of 15-20
secondary buds
-Epithelial cords develop from the secondary buds and
extend into the surrounding mesenchyme
-Major (lactiferous) ducts develop, which open into a
shallow mammary pit
INVERTED NIPPLE
-During infancy, a proliferation of mesenchyme transforms the
mammary pit into a nipple. If there is failure of a pit to
elevate above skin level, an inverted nipple results.
- This congenital malformation occurs in 4% of infants.
WITCH’S MILK
-At birth, the breasts are identical in males and females
 Demonstrating only the presence of major ducts.
-Enlargement of the breast may be evident and a secretion,
historically referred to as witch’s milk, may be produced.
-These transitory events occur in response to maternal
hormones that cross the placenta.
AMASTIA
-Absence of breast
-Rare
-Results from an arrest in mammary ridge development that
occurs during 6th fetal week
POLAND’S SYNDROME
-Consists of hypoplasia or complete absence of the breast,
costal cartilage and rib defects, hypoplasia of the
subcutaneous tissues of the chest wall and brachysyndactyly
BREAST HYPOPLASIA
-May be iatrogenitically induced before puberty by trauma,
infection or radiation therapy
SYMMASTIA
-Rare anomaly recognized as webbing between the breasts
across the midline.
SUPERNUMERARY BREASTS (POLYMASTIA)
-May occur in any configuration along the mammary milk line
-Most frequently occur between the normal nipple location
and the symphysis pubis
Turner’s syndrome: Ovarian agenesis and dysgenesis
Fleischer’s syndrome
-Displacement of the nipple and bilateral renal hypoplasia
-May have polymastia as a component
-Accessory axillary breast tissue is uncommon and usually
bilateral
FUNCTIONAL ANATOMY OF THE BREAST
-Composed of 15-20 lobes each composed of several lobules
-Cooper’s suspensory ligaments which insert perpendicularly
into the dermis, and provide structural support
If this is affected by breast cancer, it may pull the nipple and
invert it. This also causes the dimpling of the skin
BOUNDARIES OF THE BREAST
Superiorly 2nd or 3rd rib
Inferiorly Infammamary fold at the 6th or 7th rib
Transversely Lateral border of the sternum to the anterior
axillary line
Deep or Rests on the fascia of the Pectoralis Major,
Posterior Serratus Anterior, and External Oblique
surface abdominal muscles and the upper extent
of the Rectus Sheath
Retromammary Bursa/Space
-Posterior aspect of the breast between the investing fascia of
the breast and the fascia of the Pectoralis Major muscle
-This is the area we usually dissect during modified radical
mastectomy together with the Pectoralis Major’s fascia.
AXILLARY TAIL OF SPENCE
-Extends laterally across the anterior axillary fold
-The upper outer quadrant of the breast contains a greater
volume of tissue than do the other quadrants
-That’s why breast tumors usually involve the upper outer
quadrant
-This is the most frequent site of breast tumors
THE BREAST
-Protuberant conical form
-Base of the cone is roughly circular, measuring 10 x 12 cm in
diameter
-Variations in the size, contour, and density of the breast are
evident among individuals
-Nulliparous breast has a hemispheric configuration with
distinct flattening above the nipple
-With the hormonal stimulation that accompanies
pregnancy and lactation, the breast becomes larger and
increases in volume and density
-During senescence, the breast is flattened, flaccid and has a
more pendulous configuration with decreased volume
NIPPLE-AREOLA COMPLEX
-Epidermis of the nipple-areola complex is pigmented and is
variably corrugated
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-During puberty, the pigment becomes darker and the
nipple assumes an elevated configuration
-Throughout pregnancy, the areola enlarges and
pigmentation is further enhanced

AREOLA
-Contains sebaceous glands, sweat glands, and accessory
glands

MONTGOMERY’S TUBERCLES
-Small elevations on the surface of the areola
SMOOTH MUSCLES BUNDLE FIBERS
-Which lie circumferentially in the dense connective tissue
-Responsible for the nipple erection that occurs with various
sensory stimuli
BATSON’S VERTEBRAL VENOUS PELXUS
-Route for breast cancer metastases to the vertebrae, skull,
pelvic bones and central nervous system
-Lymph vessels generally parallel the course blood vessels
-One of the common sites of metastasis

LYMPHATIC DRAINAGE OF THE BREAST

THE DERMAL PAPILLA
AXILLARY LYMPH NODES AT THREE LEVELS
-At the tip of the nipple
-Contains numerous sensory nerve endings and Meissner’s
Corpuscles.
-The rich sensory innervation is of functional importance,
because the sucking of the infant initiates a chain of
neurohormonal events in milk letdown.

ARTERIAL SUPPLY
Medial breast  Internal thoracic artery/Internal
mammary artery
 Medial Mammary Branch from the
Anterior Intercostal Artery
Lateral breast From the axillary artery: LEVELS OF AXILLARY LYMPH NODES
 Lateral Thoracic Artery Starts at the axilla going
 Thoracoacromial arteries Lateral to the medially
From the Posterior Intercostal Arteries Level I Pectoralis a. External Mammary LN
(derived from the aorta): Minor b. Axillary Vein LN
 Lateral mammary branches c. Scapular LN
 Supply the lateral aspect of the Deep/under the
breast in the 2nd, 3rd, & 4th a. Central LN
Level II Pectoralis
intercostal spaces b. Some Subclavian LN
Minor
Medial border
Level a. Subclavian/Apical
of the Pectoralis
III group of LN
Minor

THE PLEXUS OF LYMPH VESSELS IN THE

BREAST
-Arises in the interlobular connective tissue and in the walls
of the lactiferous ducts and communicates with the
Subareolar Plexus of Lymph Vessels
o The group of LN affected in Paget’s Disease
-Efferent lymph vessels from the breast pass around the
lateral edge of the Pectoralis Major muscle. They pierce the
Clavipectoral Fascia, ending in the External Mammary
The blood supply is mainly coming from the Subclavian
(anterior, pectoral) Group of Lymph Nodes.
Artery, Axillary Artery & Intercostal Arteries
-Some lymph vessels may travel directly to the Subscapular
(posterior, scapular) Group of Lymph Nodes
THE VEINS OF THE BREAST
-From the upper part of the breast, a few lymph vessels pass
 Correspond with the arteries draining into the Axillary
directly to the Subclavicular (Apical) Group of Lymph
and Internal Thoracic Veins/Internal Mammary Veins
Nodes

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AXILLARY LYMPH NODES
 Usually receive >75% of the lymph drainage from the
breast
 The rest is derived primarily from the medial aspect of the
breast perforating branches of the Internal Mammary
Artery, and enters the Parasternal (Internal Mammary)
Group of Lymph Nodes
NERVE SUPPLY
-Lateral cutaneous branches of the 3rd through the 6th
intercostal nerves provide sensory innervation of the breast
(Lateral Mammary Branches) and of the anterolateral chest
wall
-These branches exit the intercostal spaces between slips of
the Serratus Anterior muscle. Cutaneous branches that arise
from the Cervical Plexus, specifically the anterior branches of
the Supraclavicular Nerve, supply a limited area of the skin
over the upper portion of the breast.
-Intercostobrachial nerve
-The lateral cutaneous branch of the 2nd intercostal nerve and
may be visualized during surgical dissection of the axilla.
-Resection of the Intercostobrachial Nerve causes loss of
sensation over the medial aspect of the upper arm
SENSATION OF THE BREAST
1. Peripheral Nervous System innervation
 From (anterior) and side (lateral) cutaneous branches
of the 4th, 5th & 6th intercostal nerves
2. T4 nerve (Thoracic Spinal Nerve 4)
 Innervates the dermatomic area that supplies the
sensation to the nipple-areola complex
INACTIVE AND ACTIVE BREAST
THE INACTIVE BREAST
-The epithelium is sparse and consists primarily of ductal
epithelium
-In the early phase of the menstrual cycle, minor ducts are
cordlike with small lumina
-With estrogen stimulation at the time of ovulation, alveolar
epithelium increases in height, duct lumina become more
prominent, and some secretions accumulate.
-When the hormonal stimulation decreases, the alveolar
epithelium regresses
orifice (0.4-0.7 mm in diameter) into the ampulla of the
nipple
-Immediately below the nipple-areola complex, each major
duct has a dilated portion (lactiferous sinus)
-Major ducts: are lined by 2 layers of cuboidal cells
-Minor ducts: are lined by a single layer of columnar or
cuboidal cells
-Myoepithelial cells of ectodermal origin reside between the
epithelial cells in the basal lamina and contain myofibrils
The alveolar epithelium becomes conspicuous during the early
proliferative period.
WITH PREGNANCY
-Proliferative and developmental maturation
-As the breast enlarges in response to hormonal stimulation,
lymphocytes, plasma cells, and eosinophils accumulate within
the connective tissues
PHYSIOLOGY OF THE BREAST
BREAST DEVELOPMENT AND FUNCTION
-Initiated by a variety of hormonal stimuli, including estrogen,
progesterone, prolactin, oxytocin, thyroid hormone, cortisol
and growth hormone
ESTROGEN, PROGESTERONE AND PROLACTIN
Essential to normal breast development and function
a. ESTROGEN initiates ductal development
b. PROGESTERONE is responsible for the
differentiation of epithelium and for lobular
development
c. PROLACTIN
o Primary hormonal stimulus for lactogenesis in
late pregnancy and postpartum period
o Upregulated hormone receptors and stimulates
epithelial development

The epithelium that is primarily ductal, is now embedded

in loose connective tissue

THE ACTIVE BREAST

-Each lobe of the breast terminates in a major lactiferous
duct (2-4mm in diameter), which opens through a constricted

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-Secretion of NEUROTROPHIC HORMONES from the
hypothalamus, which is responsible for regulation of the
secretion of the hormones that affect the breast tissues
-Gonadotropins LUTEINIZING HORMONE (LH) and
FOLLICLE-STIMULATING HORMONE (FSH)
o Regulate the release of estrogen and progesterone
from the ovaries
o Release of LH and FSH from the basophilic cells of
the anterior pituitary is regulated by the secretion of
Gonadotropin-Releasing Hormone (GnRH) from
the hypothalamus
-Positive and negative feedback effects of circulating
ESTROGEN and PROGESTERONE regulate the secretion
of LH, FSH and GnRH
-During the 3rd trimester, fat droplets accumulate in the
alveolar epithelium and colostrum fills the alveolar and
ductal spaces.
-In the late pregnancy, prolactin stimulates the synthesis of
milk fats and proteins.
-After the delivery of the placenta-Circulating progesterone
and estrogen levels decrease, permitting full expression of
the lactogenic action of prolactin
Milk production and release-Are controlled by neural reflex
arcs that originate in nerve endings of the nipple-areola
complex
-Maintenance of lactation-Requires regular stimulation of
these neural reflexes, which results in prolactin secretion and
milk letdown
-Oxytocin release -Results from the auditory, visual, and
olfactory stimuli associated with nursing. Initiates
contraction of the myoepithelial cells, which results in
compression of alveoli and expulsion of milk into the
lactiferous sinuses
-After weaning of the infant-Prolactin and oxytocin release
decreases. Dormant milk causes increased pressures within the
ducts and alveoli, which results in atrophy of the epithelium
-Menopause-There is a decrease in the secretion of estrogen
and progesterone by the ovaries and involution of the ducts
and alveoli of the breast. The surrounding fibrous connective
tissue increases in density, and breast tissues are replaced by
adipose tissues.

IN THE FEMALE NEONATE

-Circulating estrogen and progesterone levels decrease after
birth and remain low throughout childhood because of the
sensitivity of the hypothalamic-pituitary axis to negative
feedback from these hormones

WITH THE ONSET OF PUBERTY

-There is a decrease in the sensitivity of the hypothalamic-
pituitary axis to negative feedback and an increase in its
sensitivity to positive feedback from estrogen
Initiate an increase in GnRH, FSH and LH secretion
Increase in estrogen and progesterone secretion by the
ovaries, leading to establishment of the menstrual cycle
-At the beginning of the menstrual cycle, there is an increase
in the size and density of the breast
-Engorgement of the breast tissues and epithelial proliferation
-With the onset of menstruation, breast engorgement subsides
and epithelial proliferation decreases

PREGNANCY, LACTATION, AND SENESCENCE
-A dramatic increase in circulating ovarian and placental
estrogen and progestins is evident during pregnancy, which
initiates striking alterations in the form and substance of
the breast
-The breast enlarges as the ductal and lobular epithelium
proliferates, the areolar skin darkens, and the accessory areolar
glands (Montgomery’s glands) become prominent
-In the 1st & 2nd trimesters, the minor ducts branch develop
The breast at different physiologic stages. The central column
contains 3D depictions of microscopic structures. (A)
Adolescence (B) Pregnancy (C)Lactation (D) Senescence
BREAST CANCER
RISK FOR BREAST CANCER
HORMONAL RISK FACTORS
-Increased exposure to estrogen  increased risk for
developing breast cancer

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-Reducing exposure  protective FROM THE BREAST CANCER DETECTION
-Factors that increase the number of menstrual cycles DEMONSTRATION PROJECT
o Early menarche, nulliparity, and late menopause, are  a mammography screening program conducted in the
associated with increased risk 1970s, Gail et al developed the model most frequently
-Moderate levels of exercise and a longer lactation period, used in the United States
factors that decrease the total number of menstrual cycles are  It incorporates:
protective 1. Age
-The terminal differentiation of breast epithelium associated 2. Age at menarche
with a full-term pregnancy is also protective 3. Age at first live birth
-Older age at first live birth  increased risk of breast 4. Number of breast biopsy specimens, any history of
cancer. Give birth before 30 years old. after that increase risk atypical hyperplasia.
already. 5. Number of first-degree relatives with breast cancer.
-There is an association between obesity and increased breast  It predicts the cumulative risk of breast cancer according
cancer risk. When you are obese you have more breast tissue, to decade of life.
the more risk you have for breast cancer.  To calculate breast cancer risk using the Gail model, a
Because the major source of estrogen in postmenopausal woman’s risk factors are translated into an overall risk
women is the conversion of androstenedione to estrone by score by multiplying her relative risks from several
adipose tissue categories
Obesity is associated with a long-term increase in
estrogen exposure.

NON-HORMONAL RISK FACTORS

A. RADIATION EXPOSURE
-Like your rad techs, who have high radiation exposure
-Young women who receive mantle radiation therapy for
Hodgkin’s lymphoma have a breast cancer risk that is 75x
greater than that of age-matched control subjects.
-Survivors of the atomic bomb blasts in Japan during
World War II have a very high incidence of breast cancer,
likely because of somatic mutations induced by the radiation
exposure.
-In both circumstances, radiation exposure during
adolescence, a period of active breast development, magnifies
the deleterious effect. Like the children who have cancer, they
have a higher risk for having breast cancer.

B. ALCOHOL
-Studies also suggest that the risk of breast cancer increases
as the amount of alcohol a woman consumes increases.
-Alcohol consumption is known to increase serum levels of
estradiol.

C. FOODS WITH A HIGH FAT CONTENT

-Long-term consumption of foods with a high fat content
contributes to an increased risk of breast cancer by
increasing serum estrogen levels.

RISK ASSESSMENT MODELS

-The average lifetime risk of breast cancer for newborn U.S.
females is 12%
-The longer a woman lives without cancer, the lower her
risk of developing breast cancer.
-A woman aged 50 years has an 11% lifetime risk of
developing breast cancer,
-A woman aged 70 years has a 7% lifetime risk of developing
breast cancer

RISK MANAGEMENT
-Several important medical decisions may be affected by a
woman’s underlying risk of developing breast cancer
-These decisions include:

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-When to use postmenopausal hormone replacement therapy -
Before giving your hormonal therapy you should tell them the
risks.
-Age to begin mammography screening or incorporate
magnetic resonance imaging (MRI) screening - nowadays we
have digital mammography
-When to use tamoxifen to prevent breast cancer
-When to perform prophylactic mastectomy to prevent breast
cancer
-Postmenopausal hormone replacement therapy was
widely prescribed in the 1980s and 1990s because of its
effectiveness in controlling the symptoms of estrogen
deficiency
-vasomotor symptoms such as hot flashes, night sweats and
their associated sleep deprivation, osteoporosis, and cognitive
changes.
-These hormone supplements were thought to reduce
coronary artery disease as well.
-Use of combined estrogen and progesterone became standard
for women who had not undergone hysterectomy, because
unopposed estrogen increases the risk of uterine cancer.
-Concerns of prolonging a woman’s lifetime exposure to
estrogen, coupled with conflicting data regarding the impact of
these hormones on cardiovascular health, motivated the
implementation of large-scale phase III clinical trials to
definitively evaluate the risks vs. benefits of postmenopausal
hormone replacement therapy.
-The Women’s Health Initiative was therefore designed by the
National Institutes of Health as a series of clinical trials to
study the effects of diet, nutritional supplements, and
hormones on the risk of cancer, cardiovascular disease, and
bone health in postmenopausal women.
-Breast cancer risk is 3-fold to 4-fold higher after >4 years of
use and there is no significant reduction in coronary artery or
cerebrovascular risks.
-The Collaborative Group on Hormonal Factors in Breast
Cancer combined and re-analyzed data from a number of
studies totaling 52,705 women with breast cancer and 108,411
women without breast cancer.
-They found an increased risk of breast cancer with every
use of estrogen replacement therapy. They also reported
increased risk among current users but not past users and
risk increased with increasing duration of use of hormone
replacement therapy.
-Cheblowski et al also reported from the WHI study that
estrogen + progesterone increased the incidence of breast
cancer.
-This was confirmed by the Million Women study which also
showed that the increased risk was substantially greater for
the combined estrogen + progesterone replacement therapy
than other types of hormone replacement therapy
BREAST CANCER SCREENING
-Routine use of screening mammography in women ≥50
years of age has been reported to reduce mortality from
breast cancer by 25%.
-As a result, the UK recently established an independent
expert panel to review the published literature and estimate the
benefits and harms associated with screening women >50
years in its national screening program.
-The expert panel estimated that an invitation to breast
screening delivers about a 20% reduction in breast cancer
mortality while at the same time the panel estimated that in
women invited to screening, about 11% of the cancers
diagnosed in their lifetime constitute over-diagnosis.
-Despite the over diagnosis, the panel concluded that breast
screening confers significant benefit and should continue.
-The use of screening mammography in women <50 years
of age is more controversial for several reasons:
a. breast density is greater and screening mammography
is less likely to detect early breast cancer (i.e.,
reduced sensitivity);
b. screening mammography results in more false-
positive test findings (i.e., reduced specificity), which
results in unnecessary biopsy specimens; and
c. younger women are less likely to have breast cancer
(i.e., lower incidence), so fewer young women will
benefit from screening.
-In the USA, on a population basis, however, the benefits of
screening mammography in women between the ages of 40
and 49 years is still felt to outweigh the risks; although
targeting mammography to women at higher risk of breast
cancer improves the balance of risks and benefits.
-In one study of women aged 40 to 49 years, an abnormal
mammography finding was 3x more likely to be cancer in a
woman with a family history of breast cancer than in a
woman without such a history.
-Mammographic breast density demonstrates an independent
correlation with breast cancer risk.
-Incorporation of breast density measurements into breast
cancer risk assessment models appears to be a promising
strategy for increasing the accuracy of these tools.
-Widespread application of these modified models is
hampered by inconsistencies in the reporting of
mammographic density.
-ULTRASONOGRAPHY can also be used for breast cancer
screening in women with dense breasts but there is no data
available that the additional cancers detected with this
modality reduce mortality from breast cancer. Nowadays, they
do sonomammogram.
-United States Preventive Services Task Force are that
women undergo biennial mammographic screening between
the ages of 50 and 74 years.
-The AMERICAN CANCER SOCIETY (ACS) continues to
recommend annual mammography for women beginning at
age 40 years to continue as long as she is in good health.
-A clinical breast examination by a health professional is
recommended annually.
-The use of MRI for breast cancer screening is
recommended by the ACS for women with a 20% to 25% or
greater lifetime risk using risk assessment tools based mainly
on:
a. Family history
b. BRCA mutation carriers
c. Those individuals who have a family member with a
BRCA mutation who have not been tested themselves
- effective to individuals with small sized cancers
through MRI guided core needle biopsy.
d. Individuals who received radiation to the chest
between the ages of 10 to 30 years
e. Individuals with a history of Li-Fraumeni
syndrome, Cowden syndrome, or Bannayan-
Riley-Ruvalcaba syndrome or those who have a
first-degree relative with one of these syndromes.
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-MRI is an extremely sensitive screening tool that is not
limited by the density of the breast tissue as mammography is,
however, its specificity is moderate leading to more false-
positive events and the increased need for biopsy. Aside
from being expensive, it might diagnose a fibrosis leading to a
false positive result.
CHEMOPREVENTION
-TAMOXIFEN, this is a hormonal drug, a selective estrogen
receptor modulator, was the FIRST DRUG shown to reduce
the incidence of breast cancer in healthy women.
-There have been 4 prospective studies published evaluating
tamoxifen vs. placebo for reducing the incidence of invasive
breast cancer for women at increased risk.
-Breast Cancer Prevention Trial (NSABP P-01) which
randomly assigned >13,000 women with a 5-year Gail relative
risk of breast cancer of 1.66% or higher or LCIS to receive
tamoxifen or placebo.
--After a mean follow-up period of 4 years, the incidence of
breast cancer was reduced by 49% in the group receiving
tamoxifen.
-The decrease was evident only in ER-positive breast cancers
with no significant change in ER-negative tumors.
TAMOXIFEN THERAPY currently is recommended only
for women who have a:
a. Gail relative risk of 1.66% or higher, who are aged
35 to 59.
b. Women over the age of 60
c. Women with a diagnosis of LCIS or atypical ductal
or lobular hyperplasia.
-The NSABP completed a second chemoprevention trial,
designed to compare tamoxifen and raloxifene for breast
cancer risk reduction in high-risk postmenopausal women.
-An updated analysis revealed that RALOXIFENE maintained
76% of the efficacy of tamoxifen in prevention of invasive
breast cancer with a more favorable side effect profile. The
risk of developing endometrial cancer was significantly higher
with tamoxifen use at longer follow-up.
-Aromatase inhibitors (AIs) have been shown to be more
effective than tamoxifen in reducing the incidence of
contralateral breast cancers in postmenopausal women
receiving AIs for adjuvant treatment of invasive breast
cancer.
-The American Society of Clinical Oncology recently updated
recommendations for chemoprevention in women at increased
risk of breast cancer as did the U.S. Preventive Services Task
Force.
-Both groups recommend offering tamoxifen to women at
increased risk for breast cancer or raloxifene to
postmenopausal women who are noted to be at increased
risk.
RISK-REDUCING SURGERY
-A retrospective study of women at high risk for breast cancer
found that prophylactic mastectomy reduced their risk by
>90%. Like what Angelina Jolie did.
-Effects of prophylactic mastectomy on the long-term quality
of life are poorly quantified. A study involving women who
were carriers of a breast cancer susceptibility gene (BRCA)
mutation found that the benefit of prophylactic mastectomy
differed substantially according to the breast cancer risk
conferred by the mutations.
-For women with an estimated lifetime risk of
o 40%, prophylactic mastectomy added almost 3 years
of life
o 85%, prophylactic mastectomy added >5 years of
life.
BRCA MUTATIONS
BRCA1
-Up to 5% of breast cancers are caused by inheritance of
germline mutations such as BRCA1 and BRCA2, which are
inherited in an autosomal dominant fashion with varying
degrees of penetrance.
-Both BRCA1 and BRCA2 function as tumor suppressor
genes, and for each gene, loss of both alleles is required for
the initiation of cancer.
BRCA2
-BRCA2 is located on chromosome arm 13q and spans a
genomic region of approximately 70 kb of DNA.
-Breast cancer susceptibility in BRCA2 families is an
autosomal dominant trait and has a high penetrance.
-Approximately 50% of children of carriers inherit the
trait.
IDENTIFICATION OF BRCA MUTATION CARRIERS
Identifying hereditary risk for breast cancer is a 4-STEP
process that includes:
1. Obtaining a complete, multigenerational family
history.
2. Assessing the appropriateness of genetic testing for a
particular patient.
3. Counseling the patient.
4. Interpreting the results of testing.
BRCA MUTATION TESTING
-Appropriate counselling for the individual being tested for
BRCA mutation is strongly recommended and
documentation of the informed consent is required.
-The test that is clinically available for analyzing BRCA
mutations is gene sequence analysis.
-A positive test result is one that discloses the presence of a
BRCA mutation that interferes with translation or function of
the BRCA protein.
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-A woman who carries a deleterious mutation has a breast
cancer risk of up to 85% (in some families) as well as a
greatly increased risk of ovarian cancer.
-Overall, the false-negative rate for BRCA mutation testing
is <5%. Some test results, especially when a single base-pair
change (missense mutation) is identified, may be difficult to
interpret.
CANCER PREVENTION FOR BRCA MUTATION
CARRIERS
Risk management strategies for BRCA1 and BRCA2 mutation
carriers include the following:
1. Risk-reducing mastectomy and reconstruction
2. Risk-reducing salpingo-oophorectomy
3. Intensive surveillance for breast and ovarian cancer
4. Chemoprevention
EPIDEMIOLOGY AND NATURAL HISTORY OF
BREAST CANCER
EPIDEMIOLOGY
-BREAST CANCER is the most common site-specific cancer
in women and is the leading cause of death from cancer for
women aged 20 to 59 years.
-It accounts for 29% of all newly diagnosed cancers in females
and is responsible for 14% of the cancer-related deaths in
women.
NATURAL HISTORY
-Bloom and colleagues described the natural history of breast
cancer based on the records of 250 women with untreated
breast cancers who were cared for on charity wards in the
Middlesex Hospital, London, between 1805 and 1933.
-The median survival of this population was 2.7 years after
initial diagnosis for these women were 18.0% and 3.6%,
respectively. Only 0.8% survived for 15 years or longer.
(Fig 17-13)
-Autopsy data confirmed that 95% of these women died of
breast cancer, whereas the remaining 5% died of other
causes.
-Almost 75% of the women developed ulceration of the
breast during the course of the disease.
-The longest surviving patient died in the 19th year after
diagnosis.
Survival of women with untreated breast cancer compared
with natural survival
PRIMARY BREAST CANCER
 More than 80% of breast cancers show productive
fibrosis that involves the epithelial and stromal tissues.
 With growth of the cancer and invasion of the
surrounding breast tissues, the accompanying
desmoplastic response entraps and shortens Cooper’s
suspensory ligaments to produce a characteristic skin
retraction.
 LOCALIZED EDEMA (PEAU D’ORANGE) develops
when drainage of lymph fluid from the skin is disrupted.
 With continued growth, cancer cells invade the skin,
and eventually ulceration occurs. As new areas of skin
are invaded, small satellite nodules appear near the
primary ulceration.
 The size of the primary breast cancer correlates with
disease-free and overall survival, but there is a close
association between cancer size and axillary lymph node
involvement.
 In general, up to 20% of breast cancer recurrences are
local regional, >60% are distant, and 20% are both local-
regional and distant.
AXILLARY LYMPH NODE METASTASES
 As the size of the primary breast cancer increases, some
cancer cells are shed into cellular spaces and transported
via the lymphatic network of the breast to the regional
lymph nodes, especially the axillary lymph nodes.
 Lymph nodes that contain metastatic cancer are at first
ill-defined and soft but become firm or hard with
continued growth of the metastatic cancer.
 Eventually the lymph nodes adhere to each other and
form a conglomerate mass. Cancer cells may grow
through the lymph node capsule and fix to contiguous
structures in the axilla, including the chest wall.
 Typically, axillary lymph nodes are involved sequentially
from the LOW (level I) to the CENTRAL (level II) to the
APICAL (level III) lymph node groups.
 Approximately 95% of the women who die of breast
cancer have distant metastases, and traditionally the most
important prognostic correlate of disease free and
overall survival was axillary lymph node status
 Women with node-negative disease had less than a 30%
risk of recurrence, compared with as much as a 75% risk
for women with node-positive disease.
DISTANT METASTASES
 At approximately the 20th cell doubling, breast cancers
acquire their own blood supply
(NEOVASCULARIZATION).
 Thereafter, cancer cells may be shed directly into the
systemic venous blood to seed the pulmonary circulation
via the axillary and intercostal veins or the vertebral
column via Batson’s plexus of veins, which courses the
length of the vertebral column.
 Successful implantation of metastatic foci from breast
cancer predictably occurs after the primary cancer
exceeds 0.5 cm in diameter, which corresponds to the
twenty-seventh cell doubling.
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 For 10 years after initial treatment, DISTANT
METASTASES are the most common cause of death in
breast cancer patients.
 Although 60% of the women who develop distant
metastases will do so within 60 months of treatment,
metastases may become evident as late as 20 to 30 years
after treatment of the primary cancer.
 Patients with estrogen receptor negative breast cancers
are proportionately more likely to develop recurrence in
the first 3 to 5 years, whereas those with estrogen
receptor positive tumors have a risk of developing
recurrence which drops off more slowly beyond 5 years
than is seen with ER negative tumors.
 Recently a report showed that TUMOR SIZE & NODAL
STATUS remain powerful predictors of late
recurrences compared to more recently developed tools
such as the immunohistochemical score (IHC4) and two B. Risk of metastases according to breast cancer volume and
gene expression profile tests (Recurrence Score and diameter.
PAM50).
 COMMON SITES of involvement, in order of
frequency, are BONE, LUNG, PLEURA, SOFT
TISSUES, AND LIVER.
 Brain metastases are less frequent overall although
with the advent of adjuvant systemic therapies it has
been reported that CNS disease may be seen earlier.
 There are also reports of factors which are associated with
the risk of developing brain metastases. For example,
they are more likely to be seen in patients with triple
receptor negative breast cancer (ER-negative, PR-
negative and HER2-negative) or patients with HER2-
positive breast cancer who have received chemotherapy
and HER2-directed therapies

A. Overall survival for women with breast cancer according to

axillary lymph node status. The time periods are years after
radical mastectomy.

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