An overview of breast cancer risk factors and diagnosis

AN OVERVIEW ON
BREAST CANCER
DR BASHIR BN YUNUS

OUTLINE
• INTRODUCTION
• RISK FACTORS
• PATHOLOGY
• DIAGNOSIS
• TREATMENT
• PREVENTION
• REFERENCES

INTRODUCTION
• Breast cancer is the most common malignancy in women and comprises
18% -25 % of all female cancers and 1% in males with a M:F 1:103
• In Nigeria, Commonest malignancy in Ibadan. In Ghana , it accounts for
16% of all malignancies.
• Life time risk for developing breast CA is about 12%, this higher in
Caucasians than in blacks.
• Incidence increases with age. Only 5% occur in women < 40yrs of age
• Account about 14% mortality, However, patients in developing countries
are more likely to die from the disease due to late presentation, lack of
adequate screening and diagnostic modalities and limitation in treatment
options.

RISK FACTORS
• Only 30% have well-established risk factors. 70% are idiopathic, with no well-
established risk factors (apart from gender +- age)
• Major
• Age
• Sex
• Genetic predisposition
• Previous breast cancer
• Intermediate
• Hormonal factors
• Irradiation
• Benign breast disease with severe atypia
• Diet
• alcohol
• Minor
• obesity
• Benign breast disease with mild to moderate atypia

AGE
• Risk increases with advancing age (especially after 50yrs).
• Rare before 20yrs (<2% cases)
• Incidence rises steadily between 30-80 years, until 80yrs when it becomes flat.
• However, young individuals (<45yrs) that develop breast CA tend to have more
aggressive disease and are more likely to be African.
SEX
• 99% of breast CA occurs in women, while men have 1%.
RACE
• Higher in Caucasians than blacks. In the US (1 in 8) and 1 in 14 among blacks.

GENETIC PREDISPOSITION
• (Hereditary): 5-10% of breast CA have a strong inherited risk due to some
genetic defects inherited from the parents. Such patients usually have a
positive family history
• Breast CA:
• Sporadic- 70-85%
• Inherited (15-30%):
• Familial- 10-20%;
• Genetic- 5-10%
• Hereditary breast CA is usually characterized by early age of onset, high
incidence of bilateral disease and associated with ovarian, colonic or prostate
(in men) cancer.

GENES
• BRCA
• BRCA 1 and 2 mutation (Breast related cancer antigen OR Breast
Cancer antigen):
• BRCA is a tumour suppressor gene.
• BRCA gene co-ordinates the repair of damaged DNA strands of PTEN. Cells with BRCA
mutation are not able to repair damaged PTEN. This allows the cells to continue unco-
ordinated growth and ultimately become malignant.
• Patients with BRCA mutation have 60-80% risk of developing breast CA in their lifetime
• 80% of hereditary breast CA cases have BRCA mutation.
• INHERITED AS AUTOSOMAL DOMINANT

• BRCA 1: located on 17q21
• 65-85% risk of breast CA.
• Predisposes to breast and prostate CA
• Invasive ductal breast CA which is usually triple negative-ER-, PR-, HER2/neu
Such tumours are thus high grade, more aggressive with poorer prognosis
• 50% risk of developing bilateral cancer
• BRCA 2: located on 13q12.
• 40-85% risk of breast CA (compared to 12% in the general population)
• Predisposes to Ovarian CA, Pancreatic CA, Prostate CA and Breast CA
• Breast CA: especially male breast CA & bilateral breast CA in both sexes. The
breast CA it causes are well differentiated and ER+ (compared to BRCA1
breast CA)

• TP53 (tumour protein 53):
• TP53 is an AD tumour suppressor gene located on 17p13.
• The 53 is due to its molecular mass- it run in a 53 kilodalton protein
• It regulates cell growth, thus described as ‘guardian of the genome. More
than 50% of human tumours have a mutation in TP53 gene
• It becomes mutated to P53, in Li-fraumeni syndrome
• The breast CA it causes is more of in younger women. 4% of women with
breast cancer under age 30 have a mutation in this gene

• PTEN
• PTEN is an AD tumour suppressor gene located on 10q23.
• It regulates cell growth.
• Germline PTEN mutation causes cowden syndrome
• ATM (Ataxia telangiectasia mutated gene): AR. 11q22
• ATM kinase phosphorylates some tumour suppressor genes (eg TP53, CHK2,
H2AX), leading to defective repair of damaged DNA. Cancers may result from
improper DNA repair.
• OTHERS; HNPCC, CHEK2, CDH1, STK11, LKB1

• Family history:
• 15% of breast CA patients have a positive family history. There is no family
history in remaining 85% of cases
• Patients with one 1st degree relative with breast cancer (grandmother,
mother, sister or daughter) have twice or three fold risk of breast CA.
• Risk is much higher if affected first-degree relatives had premenopausal onset
and bilateral breast cancer..
• Risk decreases quickly in women with distant relatives affected with breast
cancer (cousins, aunts, grandmothers).
• The +ve family history may be familial or hereditary

• Previous breast disease
• Breast CA in contra-lateral breast: associated with 16 times increased risk.
• 6% of all patients with breast CA have had Rx for breast CA in the contra-
lateral breast
• Fibroadenosis with atypical hyperplasia
• 15% and 16% of patients who survive 20 and 30 years respectively after
treatment of breast cancer develop cancer in the other breast.
• Patients who have had cancers of the ovary, uterus, bowel, prostate and soft
tissue sarcoma have an double risk of developing breast CA in the future: due to
the BRCA mutations. Ovarian/Uterine CA also share the risk factor of chronic
estrogen exposure with breast CA

• Prolong exposure to oestrogen
• Early menarche and late menopause: early menarche (before 12yrs) or late
menopause (> 55yrs) has one and a half times greater risk than those with
menarche at normal age or menopause by 45.
• Age at 1st pregnancy: those having the first child < 18yrs have less risk
compared to those who have at the average age of 24yrs. The risk is tripled if
1st pregnancy is > 35yrs
• Nulliparity/low parity: Associated with increased risk. Unmarried nulliparous
women have a greater risk than those who are married.
• Each childbirth reduces the risk by 7%/child
• Risk is tripled in nulliparous women
• Breast feeding for prolonged period: reduces the risk by 4.3%/breastfed year
• Hormonal contraceptives and hormone replacement therapy: associated with
increased risk of breast and ovarian CA if used for more than 5 yrs. The risk
disappears 5-10yrs after cessation of HRT

• RADIATION
• Previous irradiation exposure to the chest. The risk is higher in women <
30yrs, in whom the breast is still in development.
• Mantle radiation

DIET & SOCIAL HABITS:
• Smoking:
• Cigarette smoke contains
• > 70 carcinogens such as polycyclic aromatic hydrocarbons like benzopyrene, benzene, tar, arsenic,
nitrosamines, cadmium, formaldehyde, polonium-210, 1,3-butadiene, acrolein etc.
• Nicotine: addictive. Also causes vasoconstriction, which can adversely affect wound healing
• Hydrogen cyanide, carbon monoxide, nitrogen oxides, ammonia
• The carcinogens (especially PAH) directly damage DNA and cause mutation in cell-repair genes
(such as P53). Susceptible individuals have a genetic defect with inability to detoxify the
carcinogens in the cigarette smoke
• Risk is higher in pre-menopausal women
• Alcohol:
• Causes increased androgen and oestrogens levels
• Enhances mammary gland susceptibility to carcinogens
• Can act as a carcinogen, thereby causing increased mammary DNA damage and increasing the
metastatic potential of breast CA cells. Acts as a carcinogen via:
• Ethanol is metabolised to Acetaldehyde in the liver. The acetaldehyde is mutagenic
• Induction of CYP2E1
• Nutritional deficiencies
• Impairment of retinoic acid metabolism
• Obesity (after menopause):
• Due to the peripheral aromatization of fat and other steroids into oestrogens
• Due to increased insulin levels in obese individuals.

RISK ASSESSMENT MODELS
• They calculate the risk of cancer in a patient;
• Gail model:
• Claus model
• Hereditary models
• Couch model

GAIL MODEL
• Provides 5-year and lifetime (to age 90) risk estimate
• Risk evaluation is based on patient’s
• Age,
• Age at menarche
• Age first childbirth,
• Number of first degree relatives with breast cancer,
• Number of previous breast biopsies and and pathology exhibiting atypical hyperplasia
• A woman's risk factors are translated into an overall risk score by multiplying
her relative risks from several categories. This risk score is then compared
with an adjusted population risk of breast cancer to determine the woman's
individual risk.
• Best used in women undergoing annual screening (mammography).

• PITFALL OF THE GAIL
• It excludes paternal family history and age of onset of cancer in relatives.
Thus, it is not applicable if family history suggests hereditary breast cancer
• This model is not appropriate for use in women with a known BRCA1 or
BRCA2 mutation or women with lobular or ductal carcinoma in situ.
• Overestimates risk in women who aren’t screened regularly
• Cannot be used for patients with prior breast cancer, DCIS or LCIS

CLAUS MODEL:
• Predicts lifetime risk of developing breast cancer based solely on
family history (1st and 2nd degree relatives with breast cancer and age
of onset in them).
• Useful for women with a strong family history of breast cancer with
unknown BRCA1 and BRCA2 status
• Problem is it relies only on family history
• A drawback to both the Claus and Gail models is that they are entirely based on
Caucasian populations, making risk assessment in non-Caucasian populations
potentially inaccurate.

• HEREDITARY MODELS:
• BRCAPRO and BOADICEA predict chance of being BRCA-1 and BRCA-2 gene-
mutation carriers.
• Problem is that only 5-10% of breast cancers are linked to those genes.
• 20% of breast cancer is linked to as yet unidentified hereditary factors.
• 70% of breast cancers are thought to be sporadic or non-hereditary
• BRCAPRO is the most frequently used, identifies 50% of mutation negative,
avoiding unnecessary genetic testing, reducing the cost
• COUCH MODEL: uses ethnicity, average age of onset, family history of breast
and/or ovarian cancer, and the presence of breast and ovarian cancer in a single
individual to estimate the probability of finding a mutation in BRCA1.

PATHOLOGY
• NON-INVASIVE
• Lobular carcinoma in situ (LCIS) (2-5%)
• Ductal carcinoma in situ (DCIS) or intraductal carcinoma (5-10%)
• Non-comedo; Papillary, cribriform, solid,
• comedo types
• INVASIVE
• Invasive lobular carcinoma (10%-15%)
• Invasive ductal carcinoma
• Invasive ductal carcinoma, NOS (50%-70%)
• Tubular carcinoma (2%-3%)
• Mucinous or colloid carcinoma (2%-3%)
• Medullary carcinoma (4%)
• papillary carcinoma (1%-2%)
• Paget’s disease of the nipple (2%)
• Inflammatory breast cancer
• Rare cancers; Adenoid cystic carcinoma, apocrine, squamous cell
• MIXED CONNECTIVE TISSUE AND EPITHELIAL TUMOUR
• Phylloides, Angiosarcoma, Carcinosarcoma, Adenocarcinoma

Non-invasive
• LOBULAR CARCINOMA IN-SITU
• Originates from the terminal duct lobular units and develops only in the female
breast
• Multifocal and bilateral
• Predominantly pre-menopausal, with average age of 45 years.
• Rarely metastasise and Is not palpable
• Invasive cancer develops in 25% to 35% of patients, which may develop in either
breast regardless of the breast harbors the LCIS, and is detected synchronously in 5%
of cases.
• It has no mammographic features (no calcification etc unlike DCIS).
• Discovered by chance from biopsy for other purposes
• It rarely expresses the C-erb2 oncogene, unlike ductal carcinoma in situ
• LCIS is not directly considered as a form of cancer but is a risk factor for invasive CA
• 65% of the subsequent CA are ductal, hence not an anatomical precursor.

• DUCTAL CARCINOMA IN-SITU
• Ductal carcinoma in-situ: intraductal CA
• 75% of in-situ CA.
• In DCIS, malignant breast epithelial cells are confined to the duct system, and
does not invade the basement membrane or surrounding tissues
• If untreated, 50-60% progress to invasive CA over the course of 40 years
• Types
• Non-comedo ; solid (duct filled malignant cells); Cribriform (has a sieve-like
appearance), Papillary (has papillary projections);
• Comedo; central necrosis in the lesion. Comedo carcinoma is the most likely
to become invasive and has the greatest expression of both DNA aneuploidy
& C-erb2 oncogene, may show calcifications.

INVASIVE CARCINOMA
Current histologic classifications recognize special types of
breast cancers (10% of total cases), which are defined by specific
histologic features. To qualify as a special-type cancer, at
least 90% of the cancer must contain the defining histologic
features.

• INVASIVE DUCTAL CARCINOMA
• (scirrhous, simplex, NST) accounts for 80% of breast cancers
• Presents with macroscopic or microscopic axillary lymph node metastases in
up to 25% of screen-detected cases and up to 60% of symptomatic cases.
• occurs most frequently in perimenopausal or postmenopausal women in the
fifth to sixth decades of life as a solitary, firm mass.
• It has poorly defined margins and its cut surfaces show a central stellate
configuration with chalky white or yellow streaks extending into surrounding
breast tissues.

• PAGET'S DISEASE OF THE NIPPLE
• Most patients > 50yrs
• It is ductal CA in-situ with eczema-like skin changes affecting the nipple,
areola and surrounding skin. Results from ductal CA in-situ that spreads
within the ducts and reaches the epidermis of the nipple, areola and
surrounding skin with resultant inflammatory reaction, crusting and scaling
• Pathology: paget cells (large, irregular malignant cells)
• Usually associated with an underlying breast CA.

MEDULLARY CARCINOMA
• Medullary carcinoma is a special-type breast cancer; it accounts for 4% of all
invasive breast cancers and is a frequent phenotype of BRCA1 hereditary
breast cancer.
• Grossly, the cancer is soft and hemorrhagic.
• It contains malignant cells with dispersed lymphocytes.
• large pleomorphic nuclei that are poorly differentiated and show active
mitosis
• Women with this cancer have a better 5-year survival rate than those with
NST or invasive lobular carcinoma.
• Approximately 50% of these cancers are associated with DCIS
• Medullary variant with some features of pure form shows uniformly high
grade aggressive tumour cells with negative ER, PR, HER2 NEU cell surface
receptors (triple negative). They express molecular markers of basal/
myoepithelial cells and so now termed as basal-like breast cancers.

MUCINOUS CARCINOMA
• Mucinous carcinoma (colloid carcinoma), another special type breast
cancer, accounts for 2% of all invasive breast cancers and typically presents
in the elderly population as a bulky tumor.
• This cancer is defined by extracellular pools of mucin, which surround
aggregates of low-grade cancer cells. The cut surface of this cancer is
glistening and gelatinous in quality.
• Fibrosis is variable, and when abundant it imparts a firm consistency to the
cancer.
• Over 90% of mucinous carcinomas display hormone receptors
• Lymph node metastases occur in 33% of cases, and 5- and 10-year survival
rates are 73% and 59%, respectively.
• Because of the mucinous component, cancer cells may not be evident in all
microscopic sections, and analysis of multiple sections is essential to
confirm the diagnosis of a mucinous carcinoma.

• INFLAMMATORY BREAST CANCER
• Most aggressive type of carcinoma breast.
• It is 2% common.
• It is common in lactating women or pregnancy.
• It mimics acute mastitis because of its short duration, pain, warmth and tenderness.
• Clinically, it is a rapidly progressive tumour of short duration, diffuse, painful, warm often
involving whole of breast tissue with occurrence of peau d’ orange, often extending to the skin
of chest wall also.
• More than 1/3rd of skin over the breast is involved; diffuse lymphoedema is due to tumour
emboli within dermal lymphatics. Underlying localised palpable mass is not evident clinically. It
should be differentiated from other LACB with skin involvement where underlying palpable
mass is well evident.
• Mammography may not show any finding except skin thickening. Inflammatory carcinoma of
breast is a clinical diagnosis.
• Ductal or lobular type with cancer cells in dermal lymphatics is the histology.
• It rapidly metastasises to chest wall, bone and lungs.
• It is always stage IIIB carcinoma (T4d).
• FNAC confirms the diagnosis—it contains undifferentiated cells. Punch biopsy is ideal and better
which shows undifferentiated cells.
• Total count is normal.

PAPILLARY CARCINOMA
• Papillary carcinoma is a special-type cancer of the breast that accounts
for 2% of all invasive breast cancers.
• It generally presents in the seventh decade of life and occurs in a
disproportionate number of nonwhite women.
• Typically, papillary carcinomas are small and rarely attain a size of 3 cm
in diameter.
• These cancers are defined by papillae with fibrovascular stalks and
multilayered epithelium.
• In a large series from the SEER database 87% of papillary cancers have
been reported to express estrogen receptor.
• Showed a low frequency of axillary lymph node metastases and had 5-
and 10-year survival rates similar to those for mucinous and tubular
carcinoma

TUBULAR CARCINOMA
• Tubular carcinoma is another special-type breast cancer and accounts for
2% of all invasive breast cancers. It is reported in as many as 20% of
women whose cancers are diagnosed by mammographic screening and
usually is diagnosed in the perimenopausal or early menopausal periods.
• 94% of tubular cancers were reported to express estrogen receptor.
• Approximately 10% of women with tubular carcinoma or with invasive
cribriform carcinoma, a special-type cancer closely related to tubular
carcinoma, will develop axillary lymph node metastases.
• The presence of metastatic disease in one or two axillary lymph nodes does
not adversely affect survival.
• Distant metastases are rare in tubular carcinoma and invasive cribriform
carcinoma.
• Long-term survival approaches 100%.

INVASIVE LOBULAR CA: 5-10% OF BREAST CA
• Up to 10% of lobular cancers have a coexisting ductal component.
• Five main subtypes (CAMPTS): classic (commonest-40%), alveolar
(5%), mixed (40%), pleomorphic, tubulolobular (5%), solid (10%)
• Overrall 5-year survival rate was approximately 85% in 2003
• Loss of E-cadherin is common in lobular carcinoma but is also seen in
other breast cancers

GRADING
• Tumour grade (level of differentiation): well, moderate and poorly differentiated
• The tumour grade refers to the measure of similarity of the tumour to normal breast tissue
• Bloom–Richardson grading system:
• Each is given a score between 1-3. The scores are added up (maximum of 9, minimum of
3) to give a bloom-richardson grade.
• Tubule formation:
• 1- tubule formation in > 75% of tumour;
• 2- tubule formation in 10-75% of tumour;
• 3- tubule formation in < 10% of tumour
• Nuclear pleomorphism (variation in size, shape and staining intensity of the nuclei):
• 1- nuclei with minimal variation in size and shape,
• 2- moderate variation in size and shape of the nuclei,
• 3- marked variation in size and shape of the nuclei
• Mitotic count/HPF:
• 1 - <6
• 2 – 7-15
• 3- >15
• Grade 1 (well differentiated)- 3-5;
• Grade 2 (moderately differentiated)- 6-7,
• Grade 3 (poorly differentiated)- 8-9

NOTTINGHAM PROGNOSTIC INDEX (NPI):
( 0.2 × tumour size in cm)+ lymph node stage + tumour grade
• NPI score— < 3.4 Good prognosis with 80% survival (15 years)
• NPI score— 3.4 –5.4 Moderate prognosis with 40% survival
• NPI score—> 5.4 Poor prognosis with 15% survival

MOLECULAR SUBTYPE OF BREAST CANCER
• Pathologic classification based on the molecular subtype (receptor status-
ER, PR, Her/neu2) of the tumour: Immunohistochemistry is used
• Luminal A: ER+, ± PR+, Her-. Low grade. 20% in Nigeria
• Luminal B: ER+, ± PR+, HER+. High grade. 11% in Nigeria
• HER2+ enriched: HER2+, ER-, PR-). 19%
• Basal-like breast CA: triple negative breast CA (ER-, PR-, HER2-). 25% in
Nigeria
• Also CK5/6+, ± EGFR+)
• Aggressive, fast-growing, poor prognosis.
• Most have BRCA1 mutation
• Unclassified: negative for all five markers. 24%
• Claudin-low: Recent. Triple negative but there is low expression of cell-cell
junction proteins including E-cadherin. Associated lymphocyte infiltration

STAGING
• Staging-TNM
• Tx: primary tumour cannot be assessed
• Tis: LCIS, DCIS, Paget’s disease of nipple without underlying mass
• T0: no clinically palpable tumour. (screen detected tumour)
• T1: < 2cm
• T1mic: tumour < 0.1cm
• T1a: Tumour 0.1-0.5cm
• T1b: Tumour 0.5-1.0cm
• T1c: Tumour 1-2cm
• T2: tumour 2-5cm
• T3: tumour > 5cm
• T4: tumour of any size with:
• T4a: involvement of underlying chest wall, while sparing P. major
• T4b: skin involvement (peau d’orange, nipple retraction, ulceration, cancer en-currasse)
• T4c: combination of T4a and T4b
• T4d: Inflammatory breast CA

• Nx: regional nodes cannot be assessed
• N0: no clinically palpable regional lymph node involvement (needs SLN biopsy)
• No (i+): isolated tumour cells (ITC)- small clusters of cells < 0.2mm
• No (mol-): regional lymph nodes have no metastasis histologically, but have positive molecular
findings
• N1: mobile, ipsilateral axillary nodes
• N2
• N2a: matted ipsilateral axillary nodes
• N2b: internal mammary nodes in absence of axillary nodes
• N3:
• N3a: Infraclavicular lymph node involvement (with or without axillary nodes)
• N3b: both ipsilateral axillary and internal mammary nodes involved
• N3c: Supraclavicular lymph node involvement
• Mx: metastasis cannot be assessed
• M1: no distant metastasis
• M2: distant metastasis present
• Note: contralateral axillary lymph node involvement is taken as metastasis

AJCC GROUP STAGING
• Stage 0: T is, N 0, M 0
• Stage 1: T 1, N 0, M 0
• Stage II A:
• T0, N1, M0
• T1, N1, M0
• T 2, N 0, M 0
• Stage II B
• T 2, N 1, M 0
• T 3, N 0, M 0
• Stage III A: T <4, N2
• T0-T3, N2, M0
• T3, N1, M0
• Stage III B: T4, N <3, M0
• T 4, N0-N2, M0
• Stage III C: Any T, N 3, M0
• Stage IV: Any T, Any N, M 1 (metastatic breast cancer)

STAGING: MANCHESTER
• Stage 1:
• Tumor confined to the breast; no attachment to the underlying muscle. No axillary
node involvement.
• Stage 2:
• Stage 1 + mobile axillary lymph nodes
• Skin involvement in continuity with the tumour and not extend beyond it.
• Stage 3:
• Skin involvement is beyond the periphery of the tumour, or
• The tumour is attached to the underlying muscle, or
• Axillary lymph nodes are fixed.
• No distant metastases.
• Stage 4:
• Lymphatic spread is beyond the ipsilateral axilla or
• Distant blood-borne metastases are present.
• Draw-back: no cognisance for size of primary tumor, so emphasy is shifting from it to
TNM

CERTAINTY FACTOR IN STAGING
• Reflects validity of classification according to diagnostic
methods employed. Usually used for research.
• The certainty factor (C-factor) gives evidence of dx extent.
• It is based on:
• C 1 : Hx, PE (inspection, palpation) & plain X-Rays for
metastases
• C 2: Special imaging diagnostic tests such as mammograms,
breast USS, MRI, CT scan, bone scintigraphy
• C 3: Surgical exploration like biopsy and cytology
• C 4: Definitive surgery & pathological examination of resected
specimens
• C 5: Autopsy

SPREAD
LOCAL INVASION:
Affects surrounding breast tissue, overlying skin, underlying muscle, and chest wall.
• Occurs via:
• Direct infiltration into the surrounding parenchyma: causes macroscopic stellate appearance
• Direct infiltration along the lactiferous ducts: leads to nipple retraction
• Involvement of the ligaments of astley-cooper leads to dimpling of the skin
• Local spread within the breast: leads
• Multifocality: other cancer within the same quadrant as the primary tumour. It is present in
up to 50% of patients with breast cancer. Its extent depends on tumour size. It accounts for
the unacceptable high incidence of local recurrence if breast conservation is performed
without adjuvant radiotherapy
• Multicentricity: other carcinoma outside the quadrant containing the primary tumour.
• Skin involvement leads to skin tethering (skin attachment), peau d’orange (obstruction of
dermal lymphatics), skin ulceration

• LYMPHATIC SYSTEM:
• Involves axillary (75%) or internal mammary lymph nodes (25%)
• Spread to axillary nodes is the most important prognostic indicator of breast cancer
• Tumours in the inner breast quadrants and peri-areolar tumours have a higher
incidence of internal mammary node involvement.
• Routine excision of internal mammary nodes in breast CA patients has not been
associated with an overall improvement in survival
• The size of the primary breast CA is the most important determinant for lymph node
spread
• Metastases as a rule have their origin in the primary tumour and not from other
metastases. However, spread is from one lymph node to another unless obstruction
of lymph flow by tumour causes directional change. This is the basis for the sentinel
lymph node biopsy technique.
• Lymph node spread may also lead to some skin changes:
• Peau d’orange: results from lymphedema of the breast skin from infiltration and obstruction
of the dermal lymphatics secondary to axillary metastasis. It is not due to direct infiltration of
the skin by tumour. It must also be differentiated from inflammatory breast cancer (in which
cutaneous lymphatics contain tumour emboli)
• Cancer-en-cuirasse: refers to skin nodules, from extensive, dermal lymphatic spread

BLOODSTREAM:
• Spreads to distant sites through the bloodstream such as lungs, liver,
bones, brain, peritoneum.
• Invasive lobular CA and signet-ring ductal CA have a high incidence of
metastasis to peritoneum
• The commonest site for metastasis is the bones.

DIAGNOSIS
• Triple assessment is used for the diagnosis of breast CA, which involves
• Clinical evaluation (History, and Physician Examination),
• Imaging
• Pathology
• HISTORY:
• Age: commonest between 45-65yr age –group
• Sex: 99-100 times commoner in females
• Painless, progressive breast swelling, most common site being the upper outer quadrant of the breast.
• The swelling may be painful in inflammatory breast CA
• Ulceration of overlying skin, axillary swelling, upper limb swelling (lymphedema)
• Blood-stained nipple discharge.
• Nipple changes: deviation, retraction, destruction
• Complications
• Metastasis
• CNS: headache, blurring of vision, altered consciousness, vomiting
• Chest: cough, dyspnoea
• Abdomen: jaundice, ascites (abdominal distension)
• MSS: bone pains, weakness in limb, backache, numbness/tingling sensation in lower limbs
• Anemia

• HISTORY OF RISK FACTORS
• Chronic oestrogen exposure
• Family history
• Social habits: smoking, alcohol
• Irradiation exposure, previous breast CA in contralateral breast
• PHYSICAL EXAMINATION
• General
• Head and neck
• Alopecia
• Chest
• Breasts: examine the normal breast before the diseased breast
• Breast symmetry: ask the woman to gradually lift both hands up
• The breast may be bigger than the normal breast or smaller (from attachment of the tumour to the
underlying chest wall).
• Skin changes: peau d’orange (from blockage of dermal lymphatics), Dimpling of skin due to infiltration of
ligament of Cooper, Retraction of nipple due to infiltration of lactiferous duct, Ulceration, discharge
from the nipple and areola, Skin ulceration and fungation, Cancer-en-cuirasse: Skin over the chest wall
and breast is studded with cancer nodules appearing like an armour coat, nipple changes
• In Paget's disease, there is eczema-like excoriation or ulceration of the nipple and areola. The nipple
may be eroded. A lump is palpable in the breast in about 50% of patients and in over 90% of these there
is a co-existing invasive cancer. When a lump is present, axillary nodes may be felt. A mammogram may
reveal a lump.

• Inflammatory breast cancer: the breast is diffusely swollen, painful,
tender, indurated , erythematous and warm. There is diffuse oedema
of the overlying skin. It may be confused with acute mastitis.
However, there are usually skin nodules from infiltration of subdermal
lymphatics and nodes are invariably involved.
• Lump/swelling: location, tenderness, differential warmth, size, shape,
consistency (hard or firm/soft in medullary, mucoid or intraductal
comedo-carcinoma), edge (indefinite), surface, attachment to skin or
underlying chest wall
• The axillary, supraclavicular, cervical and infraclavicular regions are
palpated for enlarged lymph nodes. If nodes are palpable, check for
tenderness, mobility and consistency. They may be firm and mobile or
hard and fixed.

• CVS
• Abdomen
• Hepatomegaly and ascites from liver metastases.
• Rectal examination is done for pelvic metastases.
• Extremities and back
• The spine and skull are examined for tenderness or swelling.
• Gait

• DIFFERENTIAL DIAGNOSIS
• TB OF THE BREAST
• PHYLLODES TUMOUR: sarcoma of the breast
• BREAST LYMPHOMA: commoner in younger age group, around 20yrs. Both breasts are
simultaneously affected. Presents with multiple swellings which are smooth, hard and discrete
without attachment to skin or underlying muscle. The overlying skin is hot with distended veins.
Lymph nodes are not involved.
• CHRONIC BREAST ABSCESS: There may be a history of breast infection. It is tender and owing to
fibrosis around the abscess, it feels hard and the edges are indefinite. There may be peau d'orange.
Axillary lymph nodes may also be palpable. Differentiation from carcinoma can only be by biopsy.
• TRAUMATIC FAT NECROSIS: firm or hard with an indefinite edge. Clinically indistinguishable from
early carcinoma.
• CHRONIC FUNGAL INFECTIONS- Actinomycosis
• GIANT FIBROADENOMA: usually firm, well-defined and mobile without any attachment to skin or
surrounding tissue.
• DUCT ECTASIA: It has the same physical features as carcinoma and can only be distinguished by
biopsy.
• BENIGN MAMMARY DYSPLASIA (fibroadenosis): one or both breasts are affected. The affected
segment is diffusely lumpy and granular and is best palpated with the tips of the fingers. It is firm
and ill-defined but without any attachment to skin or underlying tissue.
• CYST: usually associated with B.M.D. It is soft or tense and fluctuant with definite edges.
• GALACTOCELE: The patient is lactating. The lump is soft or tense and fluctuant with definite edge.

INVESTIGATIONS
• IMAGING
• BREAST USS: useful to differentiate solid from cystic breast lesions. Can also
be an adjunct to mammography, to examine suspicious areas in detail. Useful
in women < 35yrs with dense breast tissue. Sensitivity is 70-90%, specificity is
80-95%. It is operator dependent.
• MAMMOGRAPHY (Screen-film mammography-SFM)
• Useful after 35yrs of age when the breast tissue contains less dense glandular tissue
(but comprises more of fat)
• 10-15% of breast cancers are not seen on mammography
• Two views of each breast are taken: cranio-caudal and oblique
• Low x-ray dose (0.5-1.0mGy or 0.1cGy) is involved

• INDICATIONS
• Community screening
• Elderly patients with breast complaints -lumps, pain
• To determine the presence of muticentricity or multifocality in a patient being
considered for breast conservation surgery.
• To determine the presence of malignancy in the opposite breast before
initiating treatment. This is especially relevant where there is a clinical
suspicion or the existence of lobular carcinoma.
• Follow-up after previous treatment for breast cancer. The second breast has a
greater risk of developing cancer.
• Suspicious lesions may show as distortion of normal breast
architecture, tissue asymmetry, micro-calcification, soft tissue
densities with irregular margins, nipple inversion or skin thickening

• DIGITAL MAMMOGRAPHY
• Has better ability to detect lesions in dense breasts, than conventional
mammography
• Has better image quality and can be used in premenopausal patients and
women with dense breasts.
• Other advantages over SFM include display, storage and advanced
applications (such as computer-aided detection and diagnosis, contrast-
enhanced mammography and tele-mammography.

 MRI
 Useful for determining the extent of multi focal or multicentric disease, for
identifying primary foci in non-palpable lesions, axillary metastases
apparently without a primary focus, for assessing response to neoadjuvant
chemotherapy, for recurrence in breast after surgery and/or radiotherapy and
also for screening high-risk and BRCA-positive patients especially younger
than 50 years.
 It is also useful for detecting bone marrow metastases and spinal cord
compression.
 The rate of false-positive cases is however high.

BIRAD- Breast imaging reporting and data system
• Category 0: assessment incomplete; additional imaging needed
• Category 1: Negative. Routine annual screening mammography is recommended for
women > 40 years
• Category 2: Benign findings; routine annual mammography is recommended for
women older than 40 years
• Category 3: probably benign finding; initial short-term imaging follow-up(usually 6-
month) recommended. Malignancy rate < 2%
• Category 4: suspicious abnormality; consider biopsy. Malignancy rate in this category
ranges between 3% and 94%
• 4A-low suspicion
• 4B- intermediate
• 4C- moderate but not classic
• Category 5: highly suspicious for malignancy
• Category 6: known biopsy-proven malignancy

• CYTOLOGY:
• To determine if the lesion is benign or malignant.
• Can also distinguish ductal from lobular CA, though cannot distinguish in-situ from
invasive CA
• Yield increased by USS-guided FNAC or mammography-guided FNAC
• False-negative rate- 5%; false-positive- 2%
• Specimen collection
• Use a 21G or 23G needle and 10-ml syringe
• Negative pressure is created in the syringe, and multiple passes made through the lump
in order to obtain an aspirate
• The aspirate is then smeared on to a slide, which is air dried or fixed

• Advantage
• Fast/Rapid
• Least invasive technique of obtaining a cell diagnosis
• Accurate, if both operator and cytologist are experienced
• Disadvantage
• It is operator-dependent: the operator may miss the lesion and sample normal breast tissue,
make a bloody tap or aspirate too few cells to enable the cytologist make a diagnosis
• There may be false-negative results: mainly through sampling error
• Invasive cancer cannot be distinguished from in-situ disease.

• CORE-TISSUE BIOPSY
• Useful to make a definitive diagnosis of breast CA, differentiates DCIS from
invasive CA, determines the histologic grade, level of differentiation and also
in determining the hormone receptor status (ER, PR and Her-2/neu receptor
status of the tumour. The BRCA 1 gene can also be done if indicated.
• Hormone receptor status:
• For its full growth and development, the breast depends on oestrogen, progesterone,
prolactin and growth hormone. Cortisol is required for lactation to be initiated.
• 75% of breast carcinomas are hormone-dependant i.e. depend for their growth on the
presence of hormones usually needed for normal breast development
• About 45 % of tumours are positive for both oestrogen and progesterone receptors, 70%
for oestrogen and 50% for progesterone; 25 % are negative.
• Metastases usually have the same status as the primary tumour, but there is 10%
discordance.
• 25% of breast tumours show over-expression of HER/neu receptor. HER 2 testing is done
using two methods- Immunohistochemistry (measures receptor over-expression) and
fluorescence in-situ hybridisation (FISH) which measures gene amplification.

• In the interpretation of HER 2 by Immunohistochemistry;
• Results of 0 and 1+ are negative (weak, incomplete or no stain)
• 2+ is equivocal (uniform staining of < 30% clarified FISH test)
• 3+ is positive (uniform staining more than 30% of tumour cells )
• Interpretation of ER/PR
• If value is more than 10 units (f/mols) per gram of tissue it is called as ER +ve
status
• If value is less than 10 units per gram of tissue it is called as ER –ve status.

• TYPES OF BIOPSY INCLUDE:
• Tru-cut biopsy: a core of tissue is cut using a special tru-cut needle. Local
anaesthesia is given before biopsy and it can be performed in the consulting
room.
• Open biopsy
• Incisional biopsy
• Wedge biopsy: in ulcerated lesions
• Excisional biopsy: done for most clinically benign breast lumps or masses eg
fibroadenoma, residual mass after aspirating a cyst, recurrent cysts and duct ectasia. If
malignancy is suspected, it is better to perform a FNAC or Tru-cut biopsy unless facilities
are not available.
• Wire-localization excision: done in patients with impalpable, image detected breast
lesions. Under image-guidance, a hooked wire is inserted into the 'lesion'. The surgeon
excises the area of the breast corresponding to the "lesion" by following the wire and
mammographic images in theatre
• Core biopsy, stereotactic biopsy: where facilities exist; image guided, for impalpable
lesions.

• FURTHER INVESTIGATIONS ARE DONE TO STAGE THE DISEASED BREAST.
• CXR: it may show secondaries in the chest (canon-ball metastases in the lungs, pleural
effusion or in the rib cage).
• Abdominal USS: secondaries in the liver, ascites
• LFT: abnormal LFT parameters, especially a raised ALP may be due to metastasis to the liver
• SKELETAL SURVEY: Involve x -rays of the spine, pelvis and skull. Useful where facilities for
scintigraphy are not available. It is done to find the presence or otherwise of asymptomatic
osseous metastases. However, requires 50% bone de-mineralization for it to detect the bone
metastasis, so it doesn’t pick up small deposits yet to cause up to 50% bone de-
mineralization
• SKELETAL SCINTIGRAPHY: refers to bone scan using 87Sr or 18F. Picks up bony metastases 3-
6 months before they become demonstrable by conventional X-ray. 20% of negative skeletal
X-rays are positive on skeletal scintigraphy scan
• CT-scan of the brain: in suspected cranial metastasis
• PET/CT scan: if available, it is considered the most accurate and useful imaging modality for
staging metastatic breast cancer because it provides whole-body assessment of soft tissue,
visceral and bony sites at a single examination. The need for multiple imaging modalities to
assess different anatomical sites is thereby obviated.

• Other investigations
• FBC
• Urinalysis
• E/U/Cr
• ECG
• Grouping and xmatch
• PT: if pregnancy is suspected. A decision about terminating the pregnancy to enable
treatment will then have to be taken with the patient.

TREATMENT
• The Rx is multidisciplinary, involving surgeons, radiotherapists, medical
oncologists, pathologists, and other professionals such as counsellors and
breast care nurses
• The principal treatment modalities are:
• Loco-regional therapy:
• Surgery: Breast conserving surgery, mastectomy (simple, radical, modified radical)
• Radiotherapy
• Systemic therapy: cytotoxic chemotherapy, hormonal therapy, immunotherapy,
targeted therapy (tumour cell specific therapy)
• The systemic therapy can be neo-adjuvant or adjuvant
• Adjuvant chemo/hormone therapy is indicated for
• All node +ve patients
• > 1cm primary lesion
• >0.5 cm /adverse factors (vessel invasion, high grade, Her2 over expression)
• The Rx given depends on the stage, grade and location of the cancer,
history of prior disease and general health of the patient

SURGERY
• Surgery on the breast in pre-menopausal women should be done
from the fourth week of the menstrual cycle to the third day of
menstruation when the level of oestrogen (a stimulant of local growth
factors) is low and the progesterone level is high and apoptosis is
marked. This reduces the risk of local recurrence in pre-menopausal
women
• Oophorectomy, at or before mastectomy is also preferable

• SURGICAL OPTIONS INCLUDE:
•BREAST CONSERVING SURGERY ;
• (Wide local excision or segmental mastectomy; Quadrantectomy) with SLNB,
and subsequent axillary clearance or radiotherapy.
• Wide local excision (Segmental mastectomy): excise the tumour with a margin of at least
5cm down to pectoralis fascia
• Quadrantectomy: the affected breast quadrant is removed
• The breast, supraclavicular, infraclavicular and internal mammary lymph nodes are then
irradiated with 4500cGy
• The axilla is not irradiated if axillary clearance was done, but it is irradiated if no axillary
clearance was done
• Indications:
• Screen-detected (impalpable) tumours or tumour < 3cm size without skin changes,
attachment to underlying muscle nor palpable axillary nodes
• Unicentric tumours
• Tumour not central in breast, breast size adequate

Contra-indications to breast conservative surgery
• PATIENT CHOICE: some patients prefer simple mastectomy to breast conservation
so as to avoid emotional concerns of recurrence post-op
• TUMOUR CHARACTERISTICS:
• Size >3cm
• Multicentric tumours
• Widespread micro-calcification on mammography (this is indicative of widespread additional ductal
carcinoma in situ).
• High grade histology, or micro-papillary or comedo histology. These are associated with multicentricity
• Poor cytological differentiation.
• Lymphatic vessel invasion.
• Tumour location: centrally situated tumour. The breast may shrink after radiation and
become distorted.
• A small breast. The breast remnant may be distorted especially after radiation
• Heavy pendulous breasts may provide poor cosmetic results after conservation because of the oedema
and fibrosis which may follow irradiation
• PREGNANCY. Radiation is contra-indicated.
• Where there are no facilities for radiotherapy.

• ADVANTAGES
• Improved cosmesis
• Reduced psychological trauma: preserves body image, sexuality and self esteem
• COMPLICATIONS
• The breast may become less attractive with time.
• Fibrosis and gross asymmetry may occur.
• Radiation ulcer or necrosis, transient pericarditis in left-sided tumour and spontaneous rib fracture
may occur.
• Rarely, sarcoma may be induced.
• There may be lymphoedema, nodularity or firmness of the skin which makes detection of local
recurrence, even by mammography, difficult.
• The patient, afraid that there may be a local recurrence, may suffer from anxiety.
• Recurrence: the 10-year local recurrence rate 5-10%.
• IMPEDIMENTS TO CONSERVATIVE SURGERY
• Poor radiotherapy services
• Lack of expertise
• Advanced disease on presentation
• Concerns with loco-regional recurrence
• Follow-up post mastectomy easier for rural women living far from hospital
• Inability to afford subsequent treatment after initial funds for surgery

SIMPLE MASTECTOMY WITHOUT AXILLARY SURGERY:
• indications include:
• Bilateral prophylactic simple mastectomy- done in high risk patients to reduce the risk of
developing breast cancer
• Diffuse, multicentric, ductal carcinoma in-situ of the breast
• Fungating, metastatic breast CA: simple mastectomy serves as a form of local control to
palliate the bleeding, pain and smell, thus improving the quality of life of the patient
• Breast reconstruction should be done (except maybe in 3rd indication above).

• SIMPLE MASTECTOMY WITH AXILLARY RX (SNLB, AXILLARY
SAMPLING, AXILLARY CLEARANCE OR AXILLARY
RADIOTHERAPY)
• The axillary status is important because;
• it acts as a guide to staging and prognosis,
• it dictates the need for adjuvant Rx (chemotherapy, hormonal therapy or
radiotherapy), prevents morbidity from subsequent untreatable axillary
metastasis
• However, there is no evidence that good therapeutic control of the axilla
correlates with survival. This is because axillary nodal involvement is a marker
of likelihood of systemic spread

THE AXILLARY OPTIONS INCLUDE:
• Axillary clearance
• Remove the axillary fat and lymph nodes en-bloc with the breast
• However, full axillary clearance from axillary dissection over treats the 60% of women with
tumour-negative palpable axillary lymph nodes
• Adjuvant radiotherapy is not required after clearance because it does not improve local
control or prognosis but is associated with unacceptable limb oedema.
• Axillary sampling
• Surgical removal of at least 4 nodes (but up to 10 if possible) of the level 1 axillary lymph
nodes in order to determine the presence or absence of metastatic deposits in them.
• This is dependent on the fact that skip metastases to higher nodes are rare (about 2%) in the
absence of involvement of level 1 nodes
• Patients with positive nodes on axillary sampling then have adjuvant radiotherapy. Patients
who are node negative after sampling do not benefit from adjuvant radiotherapy.
• However, axillary sampling does not provide as much quantitative prognostic information as a
full nodal assessment from axillary dissection

• SLNB: Sentinel Lymph Node biopsy
• Sentinel lymph node refers to the 1st lymph node that drains a tumor bearing area
• SNLB of the breast refers to the histologic examination of the 1st lymph node that drains a tumour bearing area of the
breast, which is the axillary nodes in 90% of breast CA cases
• Done for patients with small (<4cm) or impalpable (screen-detected) breast tumours with clinically impalpable axillary
lymph nodes
• Importance:
• In 25% of clinically impalpable axillary nodes, metastases are present (while in 50% of clinically palpable axillary
nodes, there is no metastasis)
• Morbidity associated with axillary clearance. Thus, axillary clearance should be done only if metastasis is present in
the axillary nodes
• The Sentinel Lymph Node (SLN) can be identified by lymphatic mapping via
• Injection of a dye such as isosulphan blue (or patent blue -V dye) which is injected around the tumour just before
commencement of surgery. The dye rapidly enters the lymphatic vessels and is visualized in the lymphatic vessels and
the SLN with little diffusion into the soft tissues. With time, the dye will reach other lymph nodes.
• Use of lympho-scintigraphy: a radiolabelled colloid (such as technetium–sulphur colloid) is injected around the
tumour 30mins before surgery. The SLN is then detected using a probe in the axilla
• The SLN is excised for histological examination.
• Paraffin sections (H & E stain) or immunohistochemistry (more sensitive) is used for the histology
• The histologic examination can be by frozen section (after which axillary clearance proceeds if positive) or may be via
conventional biopsy (in which when the result is obtained at a later date, the axilla is subjected to radiotherapy if the
SLN was positive)
• Adv: prevents the morbidity associated with axillary clearance
• Contraindications to SLN
• Clinically palpable axillary nodes
• Large tumours (> 4 cm)
• Tumour in axillary tail or in medial quadrant of the breast. (Such tumours require a prior lymphoscintigram to identify
the area of primary drainage)

SIMPLE MASTECTOMY WITH AXILLARY CLEARANCE
(MODIFIED RADICAL MASTECTOMY)
• The breast, axillary lymph nodes and fat are removed en-bloc,
preserving the intercostobrachial nerve if possible to prevent
numbness of the shoulder and upper limb
• Modified radical mastectomy of Auchincloos, Scanlon and Patey
• Auchincloos: Retract the Pectoralis minor muscle. Remove the level 1 and 2 nodes only
• Scanlon: incise the P. minor. Remove the level 1, 2 and 3 nodes
• Patey: excise the P. minor. Remove the level 1, 2 and 3 nodes

•Indications:
• When breast conserving surgery is contra-indicated
• Local recurrence in the breast after breast-conserving surgery for invasive cancer; or new
primary tumour after a wide excision.
• Multiple carcinomas.
• Large carcinoma relative to the breast: Carcinoma more than 30% of the size of the
breast. An adequate wide excision would leave a very deformed breast.
• Central carcinoma: A wide excision, in effect, would amount to a mastectomy.
• Lobular carcinoma: Often present with multifocal, synchronous tumours in either breast.
May develop metachronous tumours in the future.

• POST-OP CARE AFTER MASTECTOMY
• IV-fluids till awake and tolerating orally
• Analgesics; Antibiotics
• Drain: regular charge, remove by POD 7-10, effluent <30mls/day
• Wound inspection- POD 4-5
• Remove drain between POD 7-10.
• Stitches removal: POD 10-14
• Adjuvant care: Chemotherapy, Radiotherapy
• Physiotherapy: helps early return to normal function in the upper limb on affected side
• FOLLOW UP:
• Retrieve histology result
• Adjuvant chemotherapy and radiation therapy
• Breast reconstruction: immediate or late
• Counselling, genetic testing of other family members

• MASTECTOMY COMPLICATIONS
• Intra-op
• Anaesthetic
• Surgical: excessive primary haemorrhage, damage to nerves
• Post-op
• Early
• Reactionary haemorrhage
• Seroma; Haematoma:
• Seroma: treated by repeated aspiration
• SSI
• Late
• Lymphedema of upper limbs; later complicated by lymphangiosarcoma (stewart-treve’s syndrome)
• Numbness, pain, weakness, stiffness of the shoulder, upper arm and axilla. Due to severance of the intercostobrachial nerve
and lateral branch of 3rd & 4th intercostal nerves
• Neurovascular injury resulting in axillary or upper arm sensory deficits and shoulder weakness
• Axillary webs.
• Chyle leak.
• Skin flap necrosis.
• Axillary vein thrombosis.
• Chronic incisional pain.
• Brachial plexopathy from positioning
• Recurrence
• Psychological: anxiety, depression (25% of patients), loss of self esteem, sexual dysfunction (35%), marital problems (some men
desert or divorce their wives)
•

• BREAST RECONSTRUCTION AFTER MASTECTOMY
• All women undergoing simple mastectomy should be offered reconstruction, even if
they have advanced disease because it reduces the psychological sequelae of
mastectomy
• Breast reconstruction is usually not needed after breast conserving surgery. If
reconstruction is required after breast conservation therapy, there must be doubts as
to whether the original surgical operation was appropriate.
• Breast reconstruction reduces psychiatric morbidity by improving the patient's
appearance and self-esteem.
• Timing of breast reconstruction: can be immediate or delayed till after 6months-
2years after surgery (to allow for wound healing and adjuvant radiotherapy)
• Immediate reconstruction: it is the standard treatment following mastectomy.
• Advantages
• Only one surgical procedure is required
• The woman does not undergo a period of loss of the breast
• Disadvantages
• Unfavourable cosmetic comparisons against the original breast
• Doubts over the ability to detect local recurrence

• METHODS OF RECONSTRUCTION
• No single method is perfect
• Counsel the woman before surgery, so that she has a realistic expectation
• Reconstruction may provide a satisfactory cosmetic appearance, but the reconstructed
breast will not have sensation or mobility like the original.
• Counsel on nipple reconstruction
• There may be need for reduction mastopexy in the contralateral breast after
reconstruction in order to achieve equality

OPTIONS FOR RECONSTRUCTION INCLUDE:
• BREAST IMPLANTS:
• Easiest technique. The implant is placed in the subcutaneous or subpectoral space
(under Pectoralis major)
• Types of breast implant: Adjustable silicon or saline implant
• Silicon gel: adv is that it is inert and has a relatively natural feel.
• Saline implant: gives an undesirable soft, striated, and 'flabby' result. Leakage of saline can
also occur in the long term.
• Disadv
• Skin necrosis and implant extrusion may occur (especially after irradiation and if a
subcutaneous position is used)
• Cosmetic problems
• Capsule formation: unsightly and also imparts a very hard texture to the breast. Less
common if 'textured' implants are used Excess capsule formation is treated by surgical
fracturing or excision
• Nipple reconstruction must be done
• Lack of ptosis: ptosis occurs in the normal breast, especially with increasing age.

• TISSUE EXPANSION
• Overcomes the problems of breast implants (lack of natural ptosis and
complications in irradiated skin)
• A tissue expander is 1st used followed by insertion of a permanent prosthesis
or the use of combined tissue expander/permanent prosthesis
• Becker expander/mammary prosthesis: consists of an outer lumen filled with
silicone gel and an inner chamber connected to a removable, self-sealing, side
port (through which normal saline is injected)

• PEDICLED AND FREE MYOCUTANEOUS FLAPS
• Pedicled latissimus dorsi myocutaneous flap
• Commonest, because of its proximity, good blood supply, and ease of creation.
• Disadvantages:
• The bulk of muscle transposed is often quite small and there may be need to combine it with
a breast implant
• It leaves a scar on the back
• May be associated with skin mismatch
• Often complicated by seroma formation.
• Latissimus dorsi miniflap:
• A modification of the pedicled latissimus dorsi myocutaneous flap. It utilizes the
latissimus alone on its neurovascular pedicle without overlying skin. Its
tendinous insertion into the humeral head is divided to allow mobility for the
muscle bulk to be used to fill a defect in the lateral part of the breast after partial
mastectomy.
• Rectus abdominus myocutaneous flap.
• A longitudinal or transverse incision can be used.
• Longitudinal rectus abdominis myocutaneous flap: a pedicled graft is swung on its axis to
provide tissue bulk on the chest wall.
• Transverse rectus abdominus myocutaneous flap: a horizontal, elliptical, sub-umbilical incision
is used for access

• Free transverse rectus abdominis flap (with microvascular
anastomosis between epigastric and thoracodorsal vessels): preferred
by some surgeons because of the precarious blood supply in this
region
• The free transverse rectus abdominis myocutaneous flap has the best
cosmetic results, thus it should be regarded as the 'gold standard' by
which other methods of reconstruction are judged. However, it is
time-consuming, requires specific expertise with microvascular
anastomosis and relatively contraindicated in patients who are very
obese or very thin, in those who have a pre-existing lower abdominal
scar, in those who are heavy smokers, and in those who are above age
55.
• Gluteal flap: used in patients with contraindications to free transverse
abdominis myocutaneous flap

NIPPLE RECONSTRUCTION
o Important because the nipple is the most important part of the breast and the
methods of breast reconstruction outlined above fail to provide appropriate nipple
reconstruction.
 Only subcutaneous mastectomy routinely preserves the nipple–areola complex; but
has the disadvantages of not being an oncologically adequate surgery, because it
leaves residual tumour
o Options for nipple reconstruction
 Use of any excessive skin on the reconstructed breast or a free graft from a distant site (groin
or thigh)
 Adhesive prosthesis
 Tattooing: useful if the reconstructed nipple is pale in comparison to that on the opposite side

RADIOTHERAPY
• It reduces the incidence of loco-regional metastases in "early" breast
cancer, but does not generally improve the overall survival rates except in
small tumours, primarily because of the presence of distant micro-
metastases when some patients are first seen.
• INDICATIONS FOR RADIOTHERAPY
• After breast conserving surgery (wide local excision) and axillary lymph node
clearance: irradiation of the breast is mandatory to destroy any cancer remnants in
order to reduce the incidence of recurrence. (the supraclavicular, infraclavicular and
internal mammary nodes are also irradiated, but the axilla is not irradiated in order
not to cause/worsen lymphedema.
• After mastectomy in patients with high risk of loco-regional recurrence
• Patients with 4 or more positive nodes
• Advanced primary tumour >5cm
• One invading the underlying muscle or adjacent skin
• Poorly differentiated tumour or one with lymphovascular invasion.
• Advanced metastatic carcinoma: Radiotherapy is beneficial for alleviating bone
pains and for controlling or treating the local disease or recurrence.

• SIDE EFFECTS
• Pulmonary fibrosis and insufficiency
• Transient pericarditis: especially after irradiation of the left breast
• Brachial plexopathy
• Poor cosmesis
• Spontaneous rib fractures
• Lymphedema of the arm

CHEMOTHERAPY
• ER/PR receptors status does not make any significant difference in response to
chemotherapy
• However, HER-2 + patients benefit more from taxane and anthracycline based
chemotherapy than HER-2 negative patients. They do not benefit from alkylating
agent based therapy or hormonal therapy
• The greatest effect is on patients < 50yrs with positive nodes
• Cyclical combination chemotherapy is more effective than single drug therapy as
the different drugs attack the tumour cells in different phases of their growth and
different essential components of the cell. The cycles also ensure that cells which
are dormant during one cycle and become active later are attacked during
subsequent cycles.
• They Antracycline based (CAF,CEF), non-anthracycline(CMF) based and taxane
based. OR first, second and third line

• ANTHRACYCLINE BASED REGIMEN (1ST LINE):
• There is very good response in small tumours with high proliferation rate and
over expression of HER-2/neu.
• P53 mutation gives poor response.
• Options: CAF, CEF
• CAF (Cyclophosphamide, Adriamycin/doxorubicin and 5-FU)
• CAF: 1
• Cyclophosphamide 125mg/m2 orally on days 3,4,5,6, 7 and 8.
• Adriamycin 40mg/m2 IV on day 1.
• 5-fluorouraciI 400mg/m2 IV on days 3 and 8.
• The cycle is repeated every 28 days for six cycles.
• CAF: 2
• IV Cyclophosphamide 500mg/m2 on day 1 and 8
• Adriamycin 50mg/m2 on day 1
• F-FU 500mg/m2 on day 1 and 8
• The cycle is repeated every 21 days
• CEF (Cyclophosphamide, Epirubicin, 5-FU). Epirubicin is as effective as adriamycin but
has a safer profile. CEF is given 3-weekly for 6 cycles
• CA (cyclophosphamide, adriamycin): given 3-weekly for 4 cycles

• TAXANE BASED (2ND LINE):
• Taxane based chemotherapy (paclitaxel and docetaxel) are used for 2nd line
therapy, in treatment of advanced breast cancer refractory to other
chemotherapy or in patients with operable breast cancer with axillary lymph
nodes
• Regimens include:
• PAC-Taxol: AC given 3-weekly for 4 cycles followed by paclitaxel given either 3-weekly for
4 cycles or weekly (at a smaller dose) for 12 weeks
• DAC: Taxotere (docetaxel), Adriamycin (doxorubicin) and cyclophosphamide given 3-
weekly for 6 cycles
• DC: Taxotere (docetaxel) and cyclophosphamide given 3-weekly for 4 or 6 cycles
• D-CEF: CEF is given 3-weekly for 3 cycles followed by docetaxel given 3-weekly for 3
cycles
• Taxane + capecitabine

• Other combinations
• Platinum –based combination (cisplatin/carboplatin) : in 3- negative breast cancer.
• Mitoxantrane plus vinorelbine: also effective especially in patients who have previously
had adjuvant chemotherapy
• Third-line; Gemcitabine - based (in combination with paclitaxel)
• Trastuzumab (Herceptin) + chemotherapy; a humanized murine monoclonal antibody
to HER-2/neu may be added to combinations if the tumour over-expresses the human
epidermal growth factor receptor (HER-2/neu). Such tumours are usually ER-.

INDICATIONS FOR CHEMOTHERAPY
• All node positive patients.
• Primary tumour more than 1 cm in size.
• Presence of poor prognostic signs of any tumour—vascular and
lymphatic invasion; high nuclear and histologic grade; Her 2/Neu
overexpression; negative hormone receptor status.
• In advanced carcinoma breast as a palliative procedure.
• In postoperative period after simple mastectomy in stage III
carcinoma breast with fixed axillary nodes.
• In inflammatory carcinoma of breast.
• In stage IV carcinoma breast with secondaries in bone, lungs,
liver.
• In premenopausal age group with poorly differentiated tumours.

NEO-ADJUVANT CHEMOTHERAPY (NAC)
• Helps to down-stage many tumours and also eradicate distant micro-metastasis. This
may make an unresectable tumour to become resectable and can also make a tumour
that was initially not amenable to breast conserving surgery to become amenable to
breast conserving surgery
• NAC also helps to reduce rapid growth and tumour dissemination after mastectomy. It
has been shown that cancers secrete anti-angiogenic factors which inhibit their
growth and spread. It is believed that surgical removal of the primary tumour
removes the inhibitory factors, leading to angiogenesis in the micro-metastatic
tumour bed. This leads to rapid growth and dissemination of the tumour. NAC
prevents this phenomenon.
• Tumours likely to have pathologic complete response after NAC are those that are
small, well differentiated and in women less than 50 years.
• After NAC, MRI is the most accurate method for assessing residual disease which may
be either concentric or honeycombed.
• There are several NAC combinations but currently the most effective is an
anthracycline (eg. adriamycin) and cyclophosphamide combination (four courses at 3-
week intervals), followed by docetaxel (a taxane) for four courses.

• Adjuvant chemotherapy: refers to chemotherapy administered post-
operatively. Helps to eradicate distant micro-metastasis, thereby
improving quality of life, prevents recurrence and increase disease
free interval (5-yr survival is better)

RESPONSE TO CHEMOTHERAPY
RESPONSE WHO RECIST (response
evaluation criteria in
solid tumours)
COMPLETE RESPONSE (CR) WITHOUT DISEASE
(Disappearance of all disease)
WITHOUT DISEASE
PARTIAL RESPONSE (PR) 50% RESPONSE
(≥50% decrease from baseline)
30% RESPONSE
PROGRESSION (PD) 25 % INCREASE
(≥ 25% increase in one or more
lesions or appearance of new
lesions)
20 % INCREASE
STABLE RESPONSE WITHOUT PD or PR (no change) WITHOUT PD or PR
Measures 2 measures 1 measure

HORMONAL THERAPY
• If the tumour is ER +, hormonal therapy is given postoperatively.
• It aims at reducing the level of oestrogen in the body, thereby depriving the
tumour of oestrogen which is essential for its growth.
• 60% of ER+ and 80% of PR+ tumours and their metastases respond to
hormonal Rx, while none of receptor negative tumours respond to hormonal
therapy.
• Cytotoxic chemotherapy is given before hormonal therapy in patients with a
high risk of relapse i.e those with metastatic axillary nodes , vascular invasion
or positive family history.
• Indications for hormonal therapy
• Post-menopausal patients with ER + tumours with or without positive axillary nodes.
Premenopausal patients may be similarly treated, but oophorectomy is advised in
developing countries.
• For palliation in patients with advanced ER+ carcinoma
• Preoperatively to shrink large ER + tumours and make them operable.
• During 3 months of tamoxifen, the tumour shrinks rapidly and there may not be any evidence o f
tumour in the mastectomy specimen. The tumour shrinks by 25-50% in 2 weeks if 100mg is
given daily.

•HORMONAL THERAPY
• Drugs Used:
• Anti-oestrogens:
• Tamoxifen: better used in pre-menopausal women
• SAI (selective aromatase inhibitors): better used in post-menopausal women
• Reversible: Anastrozole/Arimidex
• Irreversible: Exemestane, Formestane
• Pure anti-oestrogens: Fulvestrant (Faslodex), given IM, once monthly. They are steroids that
bind oestrogen receptor and prevent oestrogen receptor dumerization and DNA binding
• Progestins:
• Medroxyprogesterone acetate (500-1000mg/day)
• Megestrol acetate (80mg b.d)

• Surgery: adjuvant oophorectomy in premenopausal women
• In drug Rx, start with tamoxifen, 20mg daily for 2-5 years.
• If there is relapse after initial response, then the next step is to give an SAI
(Anastrozole, exemestane or formestane). The response is 30-40% and lasts
18 months.
• If there is relapse again after further response, then progestins are
administered.
• Clinical responses to antiestrogen are evident in >60% of women with
hormone receptor-positive breast cancers but in <10% of women with
hormone receptor-negative breast cancers.

• TAMOXIFEN
• An oestrogen receptor modulator (just like Raloxifene and Idoltifene)
• Tamoxifen is a synthetic, non-steroidal, peripheral oestrogen receptor modulator (oestrogen
agonist-antagonist) that also reduces circulating oestradiol level, has a potent antiestrogenic
effects in the breast.
• Mech of action:
• Dependent on oestrogen receptor
• It binds the oestrogen receptors, thereby inhibiting uptake of the growth-promoting
oestrogen by the tumour cells.
• It down-regulates oestrogen receptor content of tumour cells.
• Independent of oestrogen receptor (thus exerts some effects even on ER negative tumours)
• Causes breast epithelial cells to rest in the Go phase.
• Stimulates fibroblasts to produce TGF-B, which acts in paracrine fashion to stimulate peri-
tumoral proliferation of fibroblasts, resulting in more fibrous tissue around the tumour, with
less chances of spread to other part of the breast
• Reduces the level of circulating IGF-1/Insulin-like growth factor 1 (somatomedin C). IGF-1
normally stimulates the growth and spread of malignant cells.
• Inhibits angiogenesis
• Direct toxic effect to cause apoptosis of breast tumours.
• Other theoretical advantages of tamoxifen (from its oestrogenic effects)
• It reduces low-density lipoprotein cholesterol by 20%, thus it may lessen deaths from coronary
artery disease.
• Stabilizes bone density and protect against the effects of osteoporosis.

• Benefits/Adv of Tamoxifen: these benefits are irrespective of age or menopausal status, but better with
ER tumours. (Response is 60% in soft tissues and 30% in bone).
• Reduces the incidence of CA in the contralateral breast by 47% irrespective of the ER status, when used for 5
years
• Reduces risk of recurrence and improves 10-yr survival. The absolute improvement in 10-yr survival is nearly 11%
for node positive and 5.6% for node-negative tumours.
• Indications for Tamoxifen use
• Used as first line in hormonal therapy in postmenopausal patients with ER/PR positive tumours. The dose is
20mg daily. If there is response, which is evident in 6 weeks, it is continued normally for about 1-2 years then
replaced with aromatase inhibitor for 3years.
• It has also been found to be more effective in premenopausal patients. (In developing countries, oophorectomy
may be preferable in premenopausal patients because tamoxifen is expensive, compliance is uncertain and
follow-up is often irregular).
• Side effects of tamoxifen
• Nausea, vomiting
• Areola pigmentation
• Hot flushes
• Pruritus vulvae
• Fluid retention and weight gain
• Thrombocytopaenia, thrombotic complications
• Dryness of the skin.
• Uterine bleeding may occur when the drug is stopped.
• Hepatotoxic: when used over a long period
• Can cause irreversible endometrial, colorectal or gastric cancer.
• Cause of Rx failure in patients with ER + tumours: over-expression of the ER receptor subtype B causes it

Selective Aromatase Inhibitors (SAl)
 They inhibit aromatase, the adrenal enzyme that catalyses the conversion of
androstenedione to oestrone (and so do not interfere with production of corticosteroids) and
of testosterone to oestradiol. They therefore prevent the production of oestrogens by
peripheral (i.e non-ovarian) tissues especially adipose tissue. The oestrogen level is thereby
markedly reduced usually by about 90%.
 The SAI can be
 Reversible: Anastrozole/Arimidex. Anastrozole is a non-steroidal, reversible, selective aromatase
inhibitor. Dose is 1mg daily
 Irreversible: Exemestane, Formestane. They are both steroidal, irreversible SAls.
 Steroid supplementation is not necessary as the drug is selective.
 Side-effects: hot flushes, vaginal dryness , hair thinning , somnolence, headache, weight gain,
rash , vomiting and diarrhoea.
 Indication
 Used in post-menopausal or oophorectomized patients following relapse during tamoxifen therapy.
 SAls may be used as first line hormonal agents with better survival than tamoxifen.
 Recent reports suggest that survival is better if its use is preceded by two years of tamoxifen
treatment.
 It is expensive.

• PURE ANTI-OESTROGENS
• They are steroids which bind oestrogen receptors and prevent oestrogen receptor
dimerization and DNA binding. They also degrade the receptor proteins.
• These anti-oestrogens may be used for second line hormonal treatment after tamoxifen
relapse instead of SAIs.
• PROGESTINS: Medroxyprogesterone acetate (500-1000mg/day), Megestrol
acetate (80mg b.d). Both are synthetic progesterone agents
• They reduce the concentration of both oestrogen and progesterone receptors and so
have a direct cytotoxic effect on breast cancer cells.
• They also have anti-oestrogen, anti-prolactin, anti-androgen and anti-gonadotrophin
actions.
• Response is 30%.
• Side-effects are weight gain, moon face, rise in blood pressure and breakthrough vaginal
bleeding
• Progestins are used in patients who have previously responded to tamoxifen
and anastrozole.

• Targeted therapy
• Useful as an adjunct to other treatment modalities that reduce tumour
burden.
• 20% of tumours express the human epidermal growth factor receptor gene
(HER2/neu gene). This receptor encodes a protein that accelerates the growth
of metastatic breast cancer.
• Trastuzumab (Herceptin) is a recombinant monoclonal antibody against the
HER2/neu gene. It inhibits growth of tumour cells that overexpressed HER-
2/neu. It is thus used for Rx of advanced breast cancer in tumours that
express the HER-2/neu gene. As adjuvant or for metastatic disease.
• Trastuzumab is given intravenously weekly or 3-weekly for a total duration of
1 year
• It is used in combination with cytotoxic drugs.
• About 50% of tumours with HER-2/neu gene shrink by 50% or more and
survival is prolonged. In about 10% the tumour regresses completely.
• It has got cardiac side effects.

TREATMENT OF DIFFERENT FORMS OF BREAST CA
• Ductal CA in-situ, Lobular CA in-situ (Tis, No, Mo)
• Breast conserving surgery (wide local excision) + Radiotherapy
• Simple mastectomy with appropriate axillary surgery
• Early invasive ductal or lobular CA: tumour < 3cm, no metastasis
• Localized lesion (from mammography): wide local excision with appropriate
axillary surgery. Radiotherapy is then performed on the internal mammary,
supraclavicular and infraclavicular lymph nodes. Mammography follow-up is
then done at 3-6months, and then yearly. Simple mastectomy is then done for
recurrence
• Multicentric lesion: simple mastectomy + appropriate axillary surgery. Give
adjuvant cyclical combination chemotherapy + hormonal therapy (Tamoxifen)
in those with ER+ tumours

• Advanced (tumour > 3cm)/Metastatic/Recurrent CA: the primary
treatment is palliative
• Neoadjuvant chemotherapy (+ hormonal therapy in ER+ tumours). Add
Trastuzumab if the tumour expresses HER-2/neu oncogene
• The tumour may shrink sufficiently for simple mastectomy (or wide local
excision) with axillary clearance to be undertaken. If not, the tumour is
irradiated.
• Give adjuvant cytotoxic chemotherapy for another 3 months if there was
preoperative response. Add hormonal therapy if ER+

TRIPLE NEGATIVE BREAST CANCER
• This is a clinical subtype of breast cancer which does not express ER, PR,
and HER 2 neu receptors
• Characterized by aggressive behaviour
• Distinct patterns of metastasis,
• No well defined targeted therapies.
• Epidemiologically: younger women of African descent show a high
prevalence of triple-negative breast cancer.
• Majority of triple-negative breast cancers carry the “basal-like” molecular
profile on gene expression arrays. (with 30% discordance rate)
• Majority of BRCA1 (80%) breast cancers are triple-negative and basal-like.
• Although sensitive to chemotherapy, early relapse is common
• predilection for visceral metastasis including brain metastasis.

RX:TRIPLE NEGATIVE BREAST CANCER
• Platinum based chemotherapy plus taxol
• The overall response of platinum is 30%
• Targeted agents
• PARP [poly (ADP-ribose) polymerase] inhibitors,
• VEGFR blocker- bevacizumab; binds to VEGFR and blocks tumour blood vessel
growth.
• Ongoing trials include the following:
• Ixempra vs Taxol
• Bendamustine hcl and Erlotinib hcl
• Bevacizumab and abraxone + carboplatin
• Temosirolimus and neratinib
• Does not respond to radiotherapy

PAGET'S DISEASE OF THE NIPPLE:
• Simple mastectomy is done. If associated with invasive CA and axillary lymph
node enlargement, do modified radical mastectomy
• Wide local excision and nipple reconstruction: being advocated by some
authorities
• Prognosis: excellent

• OCCULT BREAST CARCINOMA:
• Refers to the presence of enlarged axillary nodes without palpable breast
mass.
• The enlarged axillary lymph node is biopsied (to establish the diagnosis)
• Modified radical mastectomy is then done, followed by adjuvant
chemotherapy (and hormonal therapy if ER +)

• Rx of complications of advanced breast CA
• Bony metastasis:
• Occurs in up to 75% of breast cancer.
• The metastasis are osteoclastic, leading to bone resorbtion and hypercalcemia
• Leads to severe pain, immobility, disability, pathological fractures, spinal cord compression
and hypercalcaemia.
• Hypercalcaemia: caused by widespread bony metastases and occasionally by "tumour flare" soon
after tamoxifen is started
• Bone pains: Local radiotherapy, NSAlDs and analgesics are beneficial
• Pathological fractures: requires immobilization of the fracture (with internal fixation if necessary).
Palliative radiotherapy to the fracture site is beneficial.
• Cord compression: Root pain usually precedes paraplegia. Local radiotherapy is efficacious before
the onset of paraplegia. Surgical decompression is urgent if paralysis occur
• Rx by biphosphonates (IV/oral ibandronale, i.v zoledronic acid, pamidronate). These
drugs inhibit osteoclastic activity, thereby preventing bone complications.

• Lymphedema of the arm:
• It is caused by removal of axillary nodes, radiotherapy to or metastases to the axillary
lymph nodes.
• May undergo malignant change into lymphangiosarcoma (stewart’s treves syndrome)
• Rx:
• Elevation of the arm
• Compression elastic sleeve or bandage
• Jobst pump or massage

• Pleural effusion:
• 50% of patients develop pleural effusion
• Rx by chest tube thoracostomy drainage, then pleurodesis
• Pleurodesis is done using sclerosants such as tetracycline 1g, cyclophosphamide, bleomycin
125mg/kg in 50mls N/S, povidone iodine or talc (best)
• Add lignocaine to it, since the procedure is painful
• The chest tube is clamped for 6hrs, and then drained for 24hrs before it is removed.
• Cerebral metastasis:
• The patient may present with symptoms of a space-occupying lesion.
• Improvement may occur with steroids. Anticonvulsants (phenytoin) may be needed if
convulsions occur. Give analgesics for headache
• Definitive treatment (craniotomy + excision) can then follow if the tumour if localised and
resectable
• Pain: Paracelamol, dihydrocodeine, toradol and NSAIDs are useful in moderate pain.
Morphine is needed in severe pain.
•

FACTORS AFFECTING PROGNOSIS
• Lymphovascular involvement
• Presence or absence of axillary nodes: this is the most important prognostic index. The
regional nodes are important in the immune response of the host. Metastatic involvement is
an expression of a breakdown of host-resistance to the disease often with widespread micro-
metastases.
• Presence or absence of systemic dissemination.
• Histologic sub-type of tumour and grade of the tumour (different biologic
propensity):
• 20% of all tumours are slow-growing and almost non-metastastic.
• Intraductal mucinous, papillary, cribriform & tubular carcinomas have a slower growth and
better prognosis. Medullary carcinoma with lymphocytic infiltration also has a good
prognosis. (pure variant of medullary has poor prognosis)
• Invasive ductal CA Nos (not otherwise specified) is the commonest form of invasive ductal
CA. It has an intermediate prognosis
• Some rare forms of breast cancer (e.g. sarcomatoid carcinoma, inflammatory carcinoma)
have a poor prognosis.
• Tumour grade is determined by Bloom–Richardson grading system and modified Bloom–
Richardson grading system (aka Nottingham grading system)
• Well-differentiated adenocarcinoma have a better prognosis
• Poorly-differentiated tumours (high grade, Grade 3) have a poor prognosis.

• Size of the tumour at the time of diagnosis: small tumours have a
better prognosis than big tumours which have genetically unstable
cells with propensity to metastasize. Tumours < 1cm are unlikely to
metastasize
• Hormone receptor status: tumours with oestrogen receptors have a
better prognosis within the first 5 years and over than those without.
They have > 70% response rate to hormonal therapy
• Over-expression of oncogenes such as HER-2/neu gene: poor
prognosis. Such tumours are usually ER and PR negative.
• Menstrual status of the patient: pre-menopausal patients do better
than post-menopausal patients. Women between 35 and 49 have on
the whole a better prognosis than those over 50yrs or less than 35.
• Age & Sex

• DNA analysis: less reliable predictors of spread than size, histology,
and lymph node involvement
• DNA analysis indicates the amount of DNA in cancer cells and how fast the
cancer is growing.
• DNA testing indicates the rate of growth by determining the number of cells in the
synthetic phase (S Phase). An S-phase > 10% means a higher chance of spreading
• Cells with the normal amount of DNA are called diploid. Cells with too much
or too little DNA are called aneuploid. Aneuploid cells are more likely to
spread than diploid cells.
• Thus, a diploid tumour has a better prognosis than an aneuploid one

PREDICTIVE FACTORS
• These predict the probability of tumour response to a particular drug or
class of drugs.
• ER and PR positive tumours have a good response (70%) to hormonal
manipulation.
• HER-2/neu over-expression: they do not respond to hormonal
manipulation, are resistant to CMF and show partial resistance to
anthracyclines. However, they respond to trastuzumab (herceptin)
• p53 mutation: shows resistance to anthracyclines, but have greater
sensitivity to taxanes.
• Age below 35years tend to have high grade tumours with poor response to
treatment.

INFLAMMATORY BREAST CA
• It is an AJCC stage IIIb breast CA that has characteristic skin changes
involving > 1/3rd (33%) of the breast
• It is an aggressive, rapidly fatal tumour, seen in relatively younger
patients (40-59yrs)
• Accounts for <3% of breast cancers
• Occurs in all adult age groups, but commoner in 40-59year age group
• Overall rate: 1.3 cases per 100000. Black women have the highest
rate; 1.6/100000. Asian and Pacific Islander women the lowest rates
(0.7/100000)
• Risk factors: Risk increased by prolonged breast-feeding. However,
this effect is far outweighed by the protective effect breastfeeding
has against more frequent breast cancer types.

• PATHOLOGY
• Inflammatory breast cancer is a high grade aneuploid cancer, with mutations
and over-expression of p53, high levels of E-cadherin and abnormal cadherin
function.
• Caveolin-1 and -2 are overexpressed and may contribute to tumour cell motility
• E-cadherin is overexpressed and paradoxically associated with especially aggressive type.
• RhoC GTPase is overexpressed, possibly related to overexpression (hypomethylation)
of caveolin-1 and -2. Caveolin is paradoxically tumour promoting. NF-κB pathway
activation overexpression may contribute to the inflammatory phenotype.
• It is often regarded as a systemic cancer.
• Most are triple negative breast cancer. Estrogen and progesterone receptor
status is frequently negative, corresponding with poor survival.
• The tumors are highly angiogenic and vascular, with high levels
of VEGF and bFGF expression.

CLINICAL FEATURES
• Diffuse breast enlargement rapidly increasing in size, associated with skin
changes such as erythema with a raised edge, brawny induration, skin edema
(peau d'orange), nipple retraction, satellite skin nodules, persistent itching,
with warm/hot skin
• There may be associated pain
• There may be an associated breast mass
• > 75% of women who have inflammatory breast cancer present with palpable
axillary lymphadenopathy (unlike in non-inflammatory breast CA when 50%
have axillary lymph nodes at presentation).
• Distant metastases are also frequently present (25% of cases).
• There can be spontaneous fluctuation of symptoms

• Differentials
• Mastitis
• Locally advanced scirrhous carcinoma that has invaded the dermal lymph vessels in
the skin to produce peau d'orange and lymphangitis
• Inv
• Imaging (mammography, breast USS) & FNAC are not helpful in diagnosis because
there may be no breast mass
• Core biopsy (incisional biopsy): helpful in diagnosis; it is one of the few indications
for incision biopsy: it is characterised by the presence of cancer cells in the
subdermal lymphatics on incisional (skin) biopsy.
• Rx
• Neoadjuvant Rx
• Chemotherapy: using anthracycline (doxorubicin) based chemotherapy (eg CAF every 21
days).
• Hormonal therapy if ER+: estrogen antagonist or aromatase inhibitors. There is dramatic
regression in 75% of cases

• Targeted therapy:
• Trastuzumab (if over-expresses HER-2/neu oncogene).
• Promising new therapeutic agents:
• Lapatinib - a Her2/neu receptor antagonist
• VEGF receptor antagonists
• Tipifarnib: a farnesyltransferase inhibitor
• Surgery: modified radical mastectomy: used to remove residual cancer from the chest
wall and axilla.
• Adjuvant Rx
• Chemotherapy may be indicated depending on final pathologic assessment of the breast and
regional nodes.
• Adjuvant radiotherapy: the chest wall, supraclavicular, internal mammary and axillary lymph
nodes (if simple mastectomy was done) receive radiation therapy. 5000-6000cGy for 6 weeks is
delivered.
• Hormonal Rx
• Targeted therapy
• This multimodal approach results in 5-year survival rates that approach 30%.
• Inflammatory breast cancer is known to respond to antibiotics and progesterone, and
reaction to other medications or hormones cannot be excluded

• Prognosis
• Oetrogen and Progesterone receptor positive cases have better prognosis.
• Loss of heterozygosity, stage IV disease and appearance of symptoms
resembling extensive inflammation are markers of poor prognosis.
• Premenopausal cases have significantly worse prognosis. In postmenopausal
cases lean women have significantly better prognosis than obese women.

Pregnancy Associated breast Cancer (PABC)
• PABC is breast cancer that occurs during pregnancy; up to one year after delivery (during
lactation, up to a year post-delivery).
• Epidemiology;
• Accounts for about 1% of breast CA cases
• PABC is the most common malignancy in pregnant women; occurring in 1:3000 pregnancies.
• Age group is usually 32 –38 years.
• Characterized by delay in detection & presentation because:
• It is rare
• Difficulty in evaluating the pregnant or lactating breast due to the physiologic and anatomic
changes of pregnancy
• Anatomic
• Hypertrophied breast, with increase in lobulo-alveolar growth & increased ductal and lobular proliferation
• Engorged blood vessels (mammary blood flow at term is 180%)
• Weight of the breast is doubled
• The breast has a dense and multi-nodular consistency.
• At 20 weeks Uterus ---- at Umbilicus; At 36 weeks, uterus is at costal margin
• 1st trimester uterus is protected bony pelvis. 2nd Trimester uterus is outside pelvis

• PATHOLOGY
• PABC is not caused by pregnancy!
• Less than 25% are Estrogen Receptor (ER) Positive
• Estrogen is normally elevated in pregnancy. ER may be saturated. Little
regulation of ER and Pregesterone Receptor (PR) act at the tumour level.
• BRCA1 or BRCA2 mutations. Early first pregnancy is not protective. In fact the
risk is increased if pregnancy occurs before the age of 40 years.
• CLINICAL FEATURES
• Rapidly growing breast swelling during pregnancy, lactation or up to 1yr after
delivery
• 70-75% have axillary nodes at first diagnosis.

• INVESTIGATIONS
• Screening Mammography of the contralateral breast: usually patients are too young for this. (Mammography
is preferred after the age of 35 years and upwards, when the breast tissue is being replaced by fat )
• Diagnostic mammography with abdominal shielding to look for microcalcification, masses, and multicentricity.
• Sonography:
• To differentiate cysts from solid masses in affected breast
• To screen contralateral breast in women < 35yrs with more dense, glandular breast with less fat
• Biopsy: About 70 – 80% of biopies in a pregnant breast are benign. But pregnancy should not stop this from
being performed. Any palpable dominant mass must be biopsied even when mammography is interpreted as
normal!
• Fine Needle Aspiration (FNA)
• Core Needle Biopsies: there is danger of milk fistula formation
• Trucut biopsy
• Incisional biopsy
• Excisional biopsy using an image-guided biopsy when possible.
• Pre-Natal Monitoring: foetal assessment throughout pregnancy is mandatory. Sonography is
essential. Amniocentesis is indicated if foetus abnormality is suspected.

• Rx
• SHOULD NOT BE DELAYED BECAUSE OF PREGNANCY, BUT TREATED LIKE NON-
PREGNANT PATIENTS WITH SOME MODIFICATIONS.
• Full explanation to patient and husband; including risk to foetus and maternal
benefits
• Informed Consent
• Rx depends on the stage of the disease, stage of the pregnancy and the desire
of the couple on whether or not to terminate the pregnancy
• The view of the woman and her husband about keeping the pregnancy or aborting it
should be respected
• Abortion: NOT usually recommended, because it does not improve survival. However,
there may be need to abort the foetus in the 1st trimester because of chemotherapy and
radiotherapy

• 1st trimester
• Modified radical mastectomy (+ axillary clearance) is the best Rx, as this would avoid the need for
adjuvant irradiation. If nodes were found to be positive, then consideration would have to be given to
termination of the pregnancy and provision of adjuvant chemotherapy. Adjuvant chemotherapy and
radiation therapy can be given after delivery if pregnancy was not terminated
• For very advanced tumours, pregnancy should be terminated (after consent) and patient commenced on
neo-adjuvant chemotherapy (and hormone therapy if ER+). Based on response, modified radical
mastectomy or wide local excision (+ appropriate axillary surgery) can then be done
• 2nd trimester
• The choice of management is more difficult.
• A full discussion with the patient and her partner is required and a treatment policy formulated which
takes into account not only the state of the disease but also the patient's wish regarding the pregnancy.
• 3rd trimester
• Surgical treatment can be provided using normal criteria (breast conserving surgery or simple
mastectomy + appropriate axillary surgery). Adjuvant chemotherapy or irradiation can be delayed until
after delivery.

• Lactation
• Breast cancers occurring during lactation present special problems.
• Lactation may be suppressed with bromocriptine and treatment of the cancer based
on standard principles.
• It is felt that there is nothing contraindicated to a woman getting pregnant
again if she so desires after she has been successfully treated for breast
cancer. The only thing is that she should wait for at least 2 years after full
treatment because if recurrence will occur, it will occur within 2 years after
treatment
• Prognosis:
• Prognosis is poor because >75% have axillary nodes at 1st diagnosis
• Women < 35yrs with PABC had same long-term outcomes as women who were not
pregnant when diagnosed. However, the patients with PABC were more likely to be
diagnosed with later-stage cancer

SCREENING FOR BREAST CA
• Screening by mammography can significantly reduce absolute mortality from
breast cancer by up to 25% in those who attend. About 11% of the cancers are
diagnosed in earlier.
• Self breast examination: done on 7th-10th days of the cycle, in supine position
• Mammography
• Done every 1—2yrs
• Indications
• Women > 50yrs
• Patients who have had breast conservation for breast CA. Both breasts should be screened
• Those who have had mastectomy. The other breast is screened yearly as about 10% develop cancer of
the other breast.
• Patients with a high risk of developing breast cancer eg strong family Hx.(starts screening in 30-35 years)
• Detects small lesions, sometimes not yet palpable. These are biopsied
• Suspicious features include:
• Stellate or irregular densities
• Altered breast architecture
• Micro-calcification (> 2mm), which may be clustered, punctate, microlinear or branching and
concentrated in an area > 1cm in diameter.

• Problems
• May give false reassurance that there is no tumour. 10-15% of cancers are not detected
by mammography. Cancer may also occur in-between screening (interval carcinoma).
• Difficult to detect lobular carcinoma, because of minimal calcification
• False alarm: many women may go through psychological and physical trauma from
unnecessary consultation and biopsies

BREAST CANCER PREVENTION
1. Early detection and treatment; screening and surveillance
2. Chemoprevention
• Tamoxifen; recommended only for women who have a Gail relative risk of 1.66% or
higher, who are aged 35 to 59, women over the age of 60 or women with a diagnosis
of LCIS or atypical ductal or lobular hyperplasia. When taken for 4-5 years, it reduces
the incidence of invasive breast cancer
• 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.
3. Risk reducing surgeries
• Prophylactic bilateral mastectomy: recommended for BRCA 1 and 2 mutation carriers
and other high-risk patients after genetic counselling. It reduces breast cancer risk by
90%.
• Prophylactic bilateral oophorectomy (in premenopausal women): reduces risk by
50%.

REFERENCES MATERIALS
• Text books ;
• Schwartzs principles of surgery 10th edition
• Sabiston textbook of surgery 19th edition
• BAJA
• ABC of breast diseases
• Medscape

An overview of breast cancer risk factors and diagnosis

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