BREAST CARCINOMA Presented by Dr Praveen Kumar Tripathi Moderator Dr C.P.Singh(M.S.,F.I.A.M.S.) Dr Sanjeev kumar(M.S.) praveen tripathi

•The breast is a group of large glands derived from the epidermis • It lies in a network of fascia derived from the dermis and the superficial fascia of the ventral surface of the thorax •Breast formation begins in the 6th weeks of fetal development. •Mammary gland originates from milk streaks, bilateral ectodermal thickenings that extend from the axilla to the groin. •The ectoderm invaginates into the surrounding mesenchyme.

DEVELOPMENT OF BREAST

DEVELOPMENT OF BREAST

praveen tripathi

•During the later part of pregnancy this fetal epithelium further canalizes. •At term birth, the breasts has 6-10 ducts. The ducts contain one layer of epithelium and one layer of myoepithelial •The initial fetal stages of breast development are independent of sex steroid influence. •At birth the withdrawal of maternal steroids results in secretion of neonatal prolactin (PRL) that stimulates newborn breast secretion.

DEVELOPMENT OF BREAST

• Thelarche: the beginning of adult breast development (10 years)

• Ductal growth phase: Club-shaped terminal end buds (TEBs)

• Lobuloalveolar phase: TEBs form alveolar buds. 9-10 alveolar buds empty into terminal ductal lobular units (TDLUs)

• In early puberty, the TDLU is termed a virginal lobule or lobule type 1 (Lob1)

• Under cyclic influence of ovarian hormones: some of the Lob1 will undergo further division and differentiate into a lobule type 2 (Lob 2).

• In Lob 2 the alveolar buds become smaller but four times more numerous than Lob1; these buds are termed ductules or alveoli.

• Lobs develop during late teens but then decline after the mid twenties.

praveen tripathi

ANATOMY OF BREAST

BLOOD SUPPLY

1.Axillary artery(lateral)

•the supreme thoracic branch

• pectoral br. of thoracoacromial a.

• lateral thoracic a.

• mammary br.

2.Internal thoracic

a. (medialupper)

3.Intercostal arteries

LYMPHATIC DRAINAGE

surgeons typically identify six groups at three anatomic levels.

•The axillary vein group or lateral group, lateral and posterior to the axillary vein. Identified at

anatomic confluence of the lateral vein with the latissimus dorsi.

•These nodes receive the majority of lymphatic contents from the upper extremity and ipsilateral back with the exception of lymph that drains into the deltopectoral lymph nodes, a group also referred to as the infraclavicular nodes

•The external mammary group, or pectoral group along lower and lateral border of pectoralis minor in association with the lateral thoracic vessels.

•These nodes receive the principal volume of lymph drainage from the breast parenchyma

praveen tripathi

•The scapular group, near the posterior wall of the axilla in

juxtaposition to the lateral border of the scapula and contiguous with the subscapular vessels

•The central group, nodes that are embedded in the fat of the axilla, usually behind the pectoralis minor muscle.

•These nodes receive lymph from the preceding nodal

groups (axillary, external mammary, and scapular nodal sites).

•This nodal group is the most palpable and numerous of axillary

lymphatics, and because of its superficial position may provide accurate clinical assessment

of metastatic disease.

•The subclavicular group, posterior and partially above the upper border of the pectoralis minor muscle. These nodes receive lymph from all the other axillary lymph node groups.

•Thereafter, these efferent lymphatic vessels from the subclavicular lymph nodes unite to form the

subclavian trunk.

•The interpectoral or Rotter group, between the pectoralis major and minor muscles.

•This group is contiguous with pectoral branches of the thoracoacromial vessels.

• Lymph from these nodes enters the central and subclavicular nodes.

SUBAREOLAR PLEXUS

LATERAL COLLECTING ROUTE

EXTERNAL MAMMARY NODES

SUBSCAPULAR NODE

LATERAL NODE

CENTRAL NODE

SUBCAPULAR NODES

APICAL

SYSTEMIC DISSEMINATION

ROTTER’S

TO CONTRALATERAL BREAST

RECTUS SHEATH AND SUB PERITONEAL PLEXUS

praveen tripathi

BREAST CARCINOMA -OVERVIEW

• Breast cancer is most common malignancy in female

• Second to lung cancer as a cause of death

• Now the mortality rate is decreasing owing to early detection

• Surgery is considered primary treatment for breast cancer

• Etiology of the vast majority of breast cancer is unknown

RISK FACTORS OFBREAST CARCINOMA

• Epidemiologic studies have identified many risk factors to develop breast carcinoma

• The common denominator for many of these risk factors is their effect on the level and duration of exposure to endogenous estrogen.

• Age and female gender are the most significant risk factors for breast cancer

Risk Factors Estimated Relative Risk

Advanced age >4

Family history

Family history of ovarian cancer in women < 50y >5

One first-degree relative >2

Two or more relatives (mother, sister) >2

Personal history

Personal history 3-4

Positive BRCA1/BRCA2 mutation >4

Breast biopsy with atypical hyperplasia 4-5

Breast biopsy with LCIS or DCIS 8-10

Reproductive history

Early age at menarche (< 12 y) 2

Late age of menopause 1.5-2

Late age of first term pregnancy (>30 y)/nulliparity 2

Use of combined estrogen/progesterone HRT 1.5-2

Current or recent use of oral contraceptives 1.25

Lifestyle factors

Adult weight gain 1.5-2

Sedentary lifestyle 1.3-1.5

Alcohol consumption 1.5

Syndrome Gene Inheritance Cancers Other Features

Breast/ovarian BRCA1 AD Breast, ovarian

Cancer syndrome BRCA2 AD Breast, ovarian,

prostate, pancreatic

Fanconi anemia in

homozygotes

Li-Fraumeni

syndrome

TP53 AD Breast, brain, soft-

tissue sarcomas,

leukemia,

adrenocortical,

others

Cowden disease PTEN AD Breast, ovary,

follicular thyroid,

colon

Adenomas of thyroid,

fibroids, GI polyps

Peutz-Jeghers

syndrome

STKII/LKB1 AD GI, breast Hamartomas of bowel,

pigmentation of buccal

mucosa

Ataxia-

telangiectasia

ATM AD Breast Homozygotes: leukemia,

lymphoma, cerebella

ataxia, immune

deficiency,

telangiectasias

Site-specific CHEK2 AD Breast Low penetrance

Muir-Torre MSH2/MLH1 AD Colorectal, breast

PATHOGENESIS OF BREAST CANCER

• Invasive cancers arise through a series of molecular alterations at the cellular level.

• Resulting in the outgrowth and spread of breast epithelial cells with immortal features and uncontrolled growth.

• Genomic profiling has demonstrated the presence of discrete breast tumor subtypes with distinct clinical behavior .

• Proposed molecular subtypes on the basis of DNAmicroarray include:

Basal-like: ER-, PR- and HER2-; also called triple negative breast cancer (TNBC)

Most BRCA1 breast cancers are basal-like TNBC.

Luminal A: ER+ and low grade

Luminal B: ER+ but often high grade

ERBB2/HER2+: has amplified HER2/neu

Normal breast-like

Claudin low: a more recently described class; often triple-negative, but distinct in that there is low expression of cell-cell junctionproteins including E-cadherin and frequently there is infiltration with lymphocytes

Luminal A

Luminal B

HER2+

Basal-like

Intrinsic Breast Cancer Subtypes

Express ↑ amounts Of luminal cyto-Keratins & genetic Markers of luminalEpithelial cells ofNormal tissue

Express ↑ levels of EGFR, c-kit, & growth factors like hepatocyte growth factor and IGF

• Long arm Chm17(17q21)

• autosomal dominant trait with high penetrance

• a role in transcription, cell-cycle control, and DNA damage repair

• 90% lifetime risk of breast cancer

• 40% lifetime risk of ovarian cancer

• Basal like breast cancer

• Chm 13q

• autosomal dominant trait and has a high penetrance

• role in DNA damage response pathways

• Carrier male100-fold increase over the risk in the general male population

• Invasive ductal carcinomas

BRCA1 BRCA2

• High grade,hormone negative receptor,aneuploid,increased S fraction

• early age of onset

• a higher prevalence of bilateral breast cancer; and the presence of associated cancers

BRCA2

• well differentiated

• commonly hormone receptor positive

• early age of onset

• a higher prevalence of bilateral breast cancer; and the presence of associated cancers

BRCA1

The EGFR (erbB) family

Membrane

Extracellular

Intracellular

Receptor

domain

K

EGF

TGF-

Amphiregulin

Tyrosine

kinase

domain

erbB4

HER4

erbB3

HER3

erbB1

HER1

EGFR

erbB2

HER2

neu

Ligands

K

No specific

ligands Heregulins

K

NRG2

NRG3

Heregulins

Histopathology of Breast Cancer

• On the basis of invasion of basement membrane

• CARCINOMA IN SITU

Ductal carcimoma in situ(DCIS)

Lobular carcinoma in situ(LCIS)

• INVASIVE CARCINOMA

Normal Breast

Breast profile

A ducts

B lobules

C dilated section of duct to hold milk

D nipple

E fat

F pectoralis major muscle

G chest wall/rib cage

32

Enlargement

A normal duct cells

B basement membrane (duct wall)

C lumen (center of duct)

Illustration © Mary K. Bryson praveen tripathi

Ductal carcinoma in situ

• Discrete spaces surrounded by basement membrane that are filled with malignant cells and usually with a recognizable, basally located cell layer made up of

presumably normal myoepithelial cells.

• DCIS is divided into

noncomedo cribriform, micropapillary low grade

solid

comedo subtypes high grade

• Five times increased risk of invasive cancer in female

34

Range of Ductal Carcinoma in situ

Illu

str

ation ©

Mary

K.

Bry

son

35

Ductal Carcinoma in situ (DCIS)

Illustration © Mary K. Bryson

Ductal cancer cells

Normal ductal cell

DCIS

Characteristic

Comedo Noncomedo

Nuclear grade High Low

Estrogen receptor Negative Positive

HER2

overexpression

Present Absent

Distribution Continuous Multifocal

Necrosis Present Absent

Local recurrence High Low

Prognosis Worse Better

Lobular carcinoma in situ

• Originates from the terminal duct lobular units and develops only in the female breast

• Normal nuclear:cytoplasmic ratio. • Cytoplasmic mucoid globules are a distinctive

cellular feature • Approximately, 20% of women with LCIS develop

invasive breast cancer within 15 years • Risk of invasive cancers is equal in both breasts • Pleomorphic variant has great potential to

become malignant

Lobular carcinoma in situ(LCIS)

• A. Breast Duct System • B. Lobules • C. Breast Duct System • D. Nipple • E. Fat • F. Chest Muscle • G. Ribs

• A. Cells lining lobule • B. Cancer cells, but all contained

within the lobules • C. Basement membrane

Foot and Stewart Classification for invasive breast cancer

I. Paget's disease of the nipple

II. Invasive ductal carcinoma A. Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST) 80% B. Medullary carcinoma 4% C. Mucinous (colloid) carcinoma 2% D. Papillary carcinoma 2% E. Tubular carcinoma (and ICC) 2%

III. Invasive lobular carcinoma 10%

IV. Rare cancers (adenoid cystic, squamous cell, apocrine)

Paget's disease of the nipple • Chronic, eczematous eruption of the nipple,

which may progress to an ulcerated, weeping lesion.

• Usually is associated with extensive DCIS and rarerly with an invasive cancer.

• Nipple biopsy shows a cells identical to the underlying DCIS cells (pagetoid features or pagetoid change).

• Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget cells) in the rete pegs of the epithelium

Invasive Ductal Carcinoma

Adenocarcinoma of the breast with productive fibrosis (scirrhous, simplex, NST)

• Accounts for 80% of breast cancers

• Axillary lymph node metastases present in up to 60% of cases.

• Occurs in the fifth to sixth decades of life as a solitary, firm mass.

Invasive Ductal Carcinoma (IDC – 80% of breast cancer)

43

• The cancer has spread to the

surrounding tissues

Illustration © Mary K. Bryson

Ductal cancer cells breaking through the wall

INVASIVE CARCINOMA….. Medullary carcinoma

• frequent phenotype of BRCA1 hereditary breast cancer.

• Grossly, the cancer is soft and hemorrhagic.

• A Roughly 30% of patients have lymph node metastasis.

• Typical medullary carcinomas are often associated with a good prognosis despite the unfavorable prognostic features associated with this type of breast cancer.

• Mucinous carcinoma

Excellent prognosis, with a greater than 80% 10-year survival.

66% of mucinous carcinomas display hormone receptors.

Lymph node metastases occur in 33%

• Tubular carcinoma

Low incidence of lymph node involvement and a very high overall survival rate thus patients are often treated with only breast-conserving surgery and local radiation therapy.

•Papillary carcinoma

Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and good prognosis. Invasive micropapillary ductal carcinoma has a more aggressive phenotype, even though approximately 70% of cases are ER-positive. rarely attain a size of 3 cm in diameter Additionally, lymph node metastasis is seen frequently in this subtype (70-90% incidence), and the number of lymph nodes involved appears to correlate with survival

•Invasive lobular carcinoma accounts for 10% of breast cancers.

Special stains may confirm the presence of intracytoplasmic mucin, which may displace the nucleus (signet-ring cell carcinoma). It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammographic features, it is difficult to detect.

Invasive Lobular Carcinoma (ILC)

48 Illustration © Mary K. Bryson

Lobular cancer cells breaking through the wall

Cancer Can also Invade Lymph or Blood Vessels

49 Illustration © Mary K. Bryson

Cancer cells invade lymph duct

Cancer cells invade blood vessel

Diagnosis of breast cancer

Diagnosis of breast cancer Clinical examination

History

This should include the following elements:

• breast mass

• breast pain

• nipple discharge

• nipple or skin retraction

• axillary mass or pain

• arm swelling

• symptoms of possible metastatic spread

2. Past medical history of breast disease in detail.

3. Family history of breast and other cancers with emphasis on gynaecological cancers.

4. Reproductive history:

• age at menarche

• age at first delivery

• number of pregnancies, children and miscarriages

• age at onset of menopause

• history of hormonal viz OCP/HRT

5. Past medical history.

Physical examination Careful physical examination should cover the following: 1. Performance status. 2. Weight, height and surface area. 3. General examination of other systems.

4. Local examination: • breast mass – size – location (specified by clock position and distance from the edge of the areola) – shape – consistency – fixation to skin, pectoral muscle and chest wall – multiplicity • skin changes – erythema (location and extent) – oedema (location and extent) – dimpling – infiltration – ulceration – satellite nodules

• nipple changes – retraction – erythema – erosion and ulceration – discharge (specify) • nodal status – axillary nodes on both sides (number, size, location and fixation to other nodes or underlying structures) – supraclavicular nodes

• local examination of possible metastatic sites.

Signs and Symptoms

Most common: lump or thickening in breast. Often painless

Change in color or appearance of areola

Redness or pitting of skin over the breast, like the skin of an orange

Discharge or bleeding

Change in size or contours of breast

Laboratory investigations

• Complete blood count with differential (CBCD), and renal and hepatic profile. • Bilateral mammography and/or ultrasound. • Chest X-ray ― computed tomography i(CT) of chest if needed. • Abdominal ultrasound •} CT of abdomen. • Bone scan if indicated. • Electrocardiogram (ECG) and echocardiogram or multiple gated acquisition (MUGA)scan if age > 60. • Positron emission tomography (PET) scan optional

RADIOLOGICAL INVESTIGATIONS

• Mammography

• Nuclear Imaging(scintimammography)

• Ultrasonography

• Doppler Flow Studies

• Thermography

• Magnetic resonance imaging

• PET Scan

Mammography • Mammography is a special type of low-dose

(0.1 cGy per study) x ray imaging used to create detailed images of the breast.

• Mammography can demonstrate microcalcifications smaller than 100 µm;

• Reveals a lesion , 1-2 years before it is palpable by BSE.

• Each chest roentgenogram delivers one- quarter of this radiation volume

• Not a substitute for biopsy; rather is an adjunctive

The technique is useful for 1) A screening tool for early detection in asymptomatic female

2) An indeterminate mass that presents as a solitary lesion that

may be a neoplasm

3) Indeterminate mass that cannot be considered a dominant nodule, especially when multiple cysts or other vague

masses are present and the indication for biopsy is uncertain 4) Follow-up examination of breast cancer treated by segmental

mastectomy and radiation therapy

5) Follow-up examination of the contralateral breast after segmental or total mastectomy

6) Evaluation of the large, fatty breast in the symptomatic patient in whom nodules are not palpable

Types of mammography :

• screening

• diagnostic.

Screening mammography is done in asymptomatic womenwhen cancer not suspected

Diagnostic mammography is performed in symptomatic women (eg, when a breast lump or nipple discharge is found during self-examination or an abnormality is found during screening mammography

FINDINGS IN MAMMOGRAPHY • DENSITY- Space occupying lesion seen in only

one projection

- no clinical significance

• MASSES- Space occupying lesion seen in two projections

Round or oval- benign

Irregular or lobulated- malignant

• CALCIFICATIONS – Malignant calcifications are usually<0.5mm, pleomorphic or heterogenous and grouped

mass

microcalcifications

• Benign – Pure and intensely

hyperechoic

– Elliptical shape (wider than tall)

– Lobulated

– Complete tine capsule

– Skin calcifications

– Vascular

– Popcorn

– Punctate

– Eggshell

• Malignant – Hypoechoic,

spiculated,heterogenous

– Taller than wide

– Duct extension

– Microlobulation

– Fine

– Fine and linear

– Linear and branching

Mammogram – Difficult Case

66

• Heterogeneously dense breast

• Cancer can be difficult to detect with this type of breast tissue

• The fibroglandular tissue (white areas) may hide the tumor

• The breasts of younger women contain more glands and ligaments resulting in dense breast tissue

Mammogram – Easier Case

67

• With age, breast tissue becomes fattier and has fewer glands

• Cancer is relatively easy to detect in this type of breast tissue

Xeromammography • Identical with mammography except that the image is recorded on a xerographic plate rather than a conventional transparency. • The image produced is positive rather than negative • Edge enhancement and wide recording latitude allow details of the soft tissues of the breast, chest wall, and thinner peripheral portions of the breast to be recorded with one exposure.

Magnification Mammography •This technique enhances the sharpness of detail and increases diagnostic accuracy for breast cancer. •The optimal magnification is 1.5 times life size • margins of breast masses and the degree and specificity of microcalcifications are clearly defined

•may significantly reduce the number of patients referred for biopsy

Ultrasonography • Useful adjunct to mammography in the

clinical setting

• As a screening device, ultrasound is limited by a number of factors, most notably by the failure to detect microcalcifications and by poor specificity (34%).

• performed primarily to differentiate cystic from solid lesions

• Ultrasonography is also useful for guiding the aspiration of cysts to provide cytologic specimens in FNAC

Magnetic Resonance Imaging • MRI has been explored as a modality for

detecting breast cancer in women at high risk and in younger women.

Indications for MRI

• Characterization of an indeterminate lesion after a full assessment with physical examination, mammography, and ultrasonography

• Detection of occult breast carcinoma in a patient with carcinoma in an axillary lymph node

•Evaluation of suspected multifocal or bilateral tumor •Evaluation of invasive lobular carcinoma, which has a high incidence of multifocality •Evaluation of suspected, extensive, high-grade intraductal carcinoma •Detection of occult primary breast carcinoma in the presence of metastatic adenocarcinoma of unknown origin •Monitoring of the response to neoadjuvant chemotherapy •Detection of recurrent breast cancer and to differentiate from scar • Best imaging modality for the breasts of women with implants

•Contraindications to MRI

Contraindication to gadolinium-based contrast media (eg, allergy, pregnancy) Patient's inability to lie prone(Marked kyphosis or kyphoscoliosis) Marked obesity Extremely large breasts Severe claustrophobia

•LIMITATIONS AS SCREENING TOOL Cost and unreliable depiction of microcalcifications

Above contraindications

Positron Emission Tomography Scanning

• PET scanning is the most sensitive and specific

of all the imaging modalities for breast disease

• At present, its main use to detect recurrences in scarred breasts

• Also useful in multifocal disease, in detecting axillary involvement, and in equivocal cases of systemic metastases.

• Assist in identification of nonaxillary lymph node metastasis (ie, internal mammary or supraclavicular lymph nodes) for staging locally advanced and inflammatory breast cancer before starting neoadjuvant therapy

• Most expensive and least widely available.

Modality Sensitivity Specificity P p value Indications

Mammogra

phy

63-95%

(>95% palpable,

50%

impalpable,

83-92% in

women older

than 50 y)

(decreases to

35% in dense

breasts)

14-90%

(90% palpable)

10-50%

(94% palpable)

Initial investigation

for symptomatic

breast in women

older than 35 years

and for screening;

investigation of

choice for

microcalcification

Ultrasonogr

aphy

68-97%

(palpable)

74-94%

(palpable)

92% (palpable) Initial investigation

for palpable lesions

in women younger

than 35 years

Modality Sensitivity Specificity P PV Indications

MRI 86-100% 21-97%

(< 40% primary

cancer)

52% Scarred breast, implants, multifocal

lesions, and borderline lesions for

breast conservation; may be useful in

screening high-risk women

Scintigraph

y

76-95%

(palpable)

52-91%

(impalpabl

e)

62-94%

(94% impalpable)

70-83%

(83%

palpable,

79%

impalpab

le)

Lesions larger than 1 cm and axilla

assessment; may help predict drug

resistance

PET

scanning

96%

(90%

axillary

metastases)

100% Axilla assessment, scarred breast, and

multifocal lesions

Thermography

•Transmission of detectable heat from the breast is nonspecific, and in malignant lesions results from the hypervascularity that frequently accompanies carcinoma. •Three thermographic methods are used: telethermography, contact thermography, and computed tomography. •Using special heat scanners it is possible to delineate these “hot” perfusion sites on film. • Results are variable and inaccurate, Sensitivity is less than 50 percent and it is not advocated as a routine screening method, because it is unable to detect minimal breast cancer.

DIAGNOSTIC BIOPSY NONPALPABLE LESIONS

• Image-guided breast biopsies are frequently required to diagnose nonpalpable lesion

• Ultrasound localization techniques are used when a mass is present, whereas stereotactic techniques are used when no mass is present (microcalcifications only).

• Combination of diagnostic mammography, ultrasound or stereotactic localization, and FNAB achieves almost 100% accuracy in the diagnosis of breast cancer.

Fine-needle aspiration cytology (FNAC)

• Rapid and least invasive technique of obtaining a cell diagnosis

• 80% diagnostic accuracy

• Invasive cancer cannot be distinguished

from in situ disease

core-needle Biopsy •Permits the analysis of breast tissue architecture and allows the pathologist to determine whether invasive cancer is present. • Core-needle biopsy is preferred over open biopsy for nonpalpable breast lesions because a single surgical procedure can be planned based on the results of the core biopsy. • The advantages of core-needle biopsy include a low complication rate, avoidance of scarring, and a lower cost.

Palpable masses

• FNAC can be done in out patient setting

• USG guided FNAC is preferred in cystic masses and aspirate is sent for cytology if bloody

• Percutaneous vacuum-assisted large-gauge core biopsy (VACNB) with image guidance is preferred

• Incision biopsy can be done in ulcerating masses

Histology The following features are all important in deciding on a

course of treatment :

• Size

• Status of surgical margin

• Presence or absence of estrogen receptors and progesterone receptors

• Nuclear and histologic grade

• DNA content

• S-phase fraction

• Vascular invasion

• Tumor necrosis

• Quantity of intraductal component

Additional Testing HER2 testing

• Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC)

• The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:

3+: Positive HER2 expression - Uniform intense membrane staining of more than 30% of invasive tumor cells

2+: Equivocal for HER2 protein expression - Complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells

0 or 1+: Negative for HER2 protein expression

Current assay of HER2/neu Immunohistochemistry

‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive)

Fluorescence in situ hybridization (FISH)

HER2 gene no amplification

FISH negative :FISH ratio <1.8

HER2 gene amplification FISH positive

FISH ratio >2.2

Oncotype DX

•RT-PCR assay of 16 cancer-related genes and 5 normal comparator reference genes, and is therefore sometimes known as the 21-gene assay. • It was designed for use in estrogen receptor positive tumors. The test is run on formalin fixed, paraffin-embedded tissue. • Oncotype results are reported as a Recurrence Score (RS) . < 18 are considered low risk 18-30 is considered intermediate risk > 30 is considered high risk. • where a higher RS is associated with a worse prognosis, referring to the likelihood of recurrence without treatment. •higher RS is also associated with a higher probability of response to chemotherapy, which is termed a positive predictive factor.

NCCN guidelines include Oncotype DX® testing in the treatment-decision pathway for node-negative and

micrometastatic disease

Adapted from NCCN Practice Guidelines in Oncology – v.1.2010.

• Tumor 0.6-1.0 cm,

moderately or poorly

differentiated,

intermediate or high

grade, or vascular

invasion

• Tumor > 1 cm with

favorable or

unfavorable

pathologic features

Consider

Oncotyp

e DX

Hormone receptor-positive, HER2-negative disease pT1, pT2, or pT3 and pN1mi

No test

RS <

18

RS 18-

30

RS ≥

31

Adjuvant endocrine

therapy

± adjuvant chemotherapy

Adjuvant endocrine

therapy

endocrine therapy

± adjuvant chemotherapy

Adjuvant Adjuvant

endocrine therapy

+ adjuvant chemotherapy

MammaPrint

•The MammaPrint test analyzes 70 genes from an early-stage breast cancer tissue sample to figure out if the cancer has a low or high risk of coming back (recurrence) within 10 years after diagnosis. • A diagnostic test used by physicians to assess the risk that a breast tumor will metastasize to other parts of the body • This helps physicians determine whether or not each patient will benefit from chemotherapy • MammaPrint can be used on cancers that are: stage I or stage II invasive smaller than 5 centimeters in three or fewer lymph nodes

SET (sensitivity to endocrine therapy) index:

• A multigene expression profile that was developed to measure estrogen receptor–related transcription in breast cancer.

RCB (residual cancer burden):An index to estimate the extent of residual invasive cancer in the breast and regional lymph nodes after neoadjuvant chemotherapy.

LEVELS OF INTERVENTION IN BREAST CARCINOMA

1. RISK IDENTIFICATION AND RISK

REDUCTION THERAPY

2. SCREENING

3. STAGING AND MANAGEMENT OF BREAST

CARCINOMA

• SURGERY

• HORMONAL THERAPY

• CHEMOTHERAPY

• RADIOTHERAPY

4. FOLLOW UP

· Familial/genetic factors

Criteria for further risk evaluation:

• Family history

• Early-age-onset breast cancer

Two breast primaries or breast and ovarian/fallopian

tube/primary peritoneal cancer in a single individual

or

• Two or more breast primaries or breast and ovarian/fallopian

tube/primary peritoneal cancers in close relative(s) from the same

side of family (maternal or paternal)

• A combination of breast cancer with one or more of the following:

thyroid cancer, sarcoma, adrenocortical carcinoma, endometrial cancer,

pancreatic cancer, brain tumors, diffuse gastric cancer dermatologic

manifestations or leukemia/lymphoma on the same side of family

• Member of a family with a known mutation in a breast cancer

susceptibility gene

• Populations at risk

• Male breast cancer

• Ovarian/fallopian tube/primary peritoneal cancer

• Known BRCA1/2, p53, PTEN, or other gene mutation associated

with breast cancer risk

· Demographics

• Age.

• Ethnicity/race

Increased incidence of specific BRCA1/2 mutations in Ashkenazi Jewish

decent.

• Body mass index

•· Reproductive history

• Age at menarche

• Parity

• Age at first live birth

• Age at menopause

•· Environmental factors

• Current or prior estrogen and progesterone hormone replacement therapy

• Alcohol consumption

• Other

Atypical hyperplasia

Number of prior breast biopsies

Procedure done with the intent to diagnose cancer, multiple biopsies of the

same lesion are scored as one biopsy.

Breast density

Prior thoracic RT

History of lobular carcinoma in situ (LCIS)

The Gail model

Developed by Gail and colleagues at the National

Cancer Institute now modified

Estimates likelihood that a woman of given age with

certain riskfactors will develop breast cancer over

a specified time interval

• Current age,

• Race,

• Age at menarche,

• Age at first live birth or nulliparity,

• Number of first-degree relatives with breast cancer,

• Number of previous breast biopsies, and histology of the breast biopsies

The modified Gail model is a computer-based

multivariate logistic regression model that uses

Limitations?

It over-predicts the risk of breast cancer among women age 35 to 61 who do not receive annual mammograms

The overestimation is more marked in pre-menopausal women and in those with an extensive family history.

Underestimate the risk for a BRCA1 or BRCA2 mutation carrier and overestimate the risk in a noncarrier.

Not an appropriate breastcancer risk assessment tool for women who received prior thoracicradiation to treat Hodgkin’s disease (eg, mantle radiation),LCIS

The Claus model

• include second-degree relatives and the age of onset,

• does not include nonfamilial risk factors such as

hormonal factors

•Neither model takes into account bilateral breast cancer

or ovarian cancer.

The newest model is the Tyler-Cuzick model.

•This model not only takes into account many of the

relevant details of family history and hormonal factors, but

also includes BMI and the presence of LCIS.

•A computerized version of this model is not yet available.

FAMILIAL RISK ASSESSMENT

Woman meets one or more of the familial risk

criteria

YES NO

Lifetime risk > 20% based on models

largely dependent on family history

or

Pedigree suggestive of genetic

predisposition

or

Known gene mutation associated

with breast cancer risk

and

Life expectancy 10 y

•Prior thoracic RT

•H/O LCIS

•Gail model s/o 1.7%

increased risk of breast

ca. in 5 yr

and

Life expectancy 10 y

Risk reduction counselling

Risk reduction counseling

Woman does not desire risk-reduction

therapy

Woman desire risk-reduction therapy

Breast screening as per NCCN Breast

Cancer Screening and Diagnosis Guidelines

if not done in previous year

Breast screening as per

NCCN Breast Cancer

Screening and Diagnosis

Guidelines

normal abnormal

1. Risk reduction mastectomy 2. Risk reduction salpingo

opherectomy with peritoneal wash 3. Risk reduction agent

m/m accordingly

SCREENING OF BREAST CANCER

• Done to detect disease as early as possible

• Components of screening depends on

1. pt. age medical and family history,

2. breast awareness,

3. Clinical breast examination& physical examination

4. risk assessment,

5. screening mammograpy and MRI in selected cases

BREAST CANCER SCREENING RECOMMENDATIONS American College of Surgeons: •Begin self-examinations and every 3 years clinical breast examination at age 20. •Begin annual mammograms and yearly clinical breast examination at age 40 American College of Radiology •Begin annual mammograms and •yearly clinical breast examination at age 40.

history and physical

examination

s/o asymptomatic

and no physical findings

normal risk

age 20-40

clinical breast examination every 1-3 years

age >40 years

clinical breast examination annually

annual mammogram

increased risk viz.

-prior thoracic RT

-5yr risk of invasive

breast ca. >1.7% in women of>35 yr

-genetic predisposition

-LCIS/atypical hyperplasia

recommendations accordingly

RISK FACTORS

MAMMOGRAPHY

SCREENING

RECOMMENDATIONS PREVENTIVE OPTIONS

Factors Conferring Moderate to High Risk

Age >60 yr Annual Not usually recommended

Atypical hyperplasia (ductal

or lobular)

Annual after diagnosis Tamoxifen, 20 mg/day × 5 yr

LCIS Annual after diagnosis Tamoxifen, 20 mg/day × 5 yr

Personal history of either

DCIS or invasive cancer, age

>40 yr

Annual after diagnosis No specific preventive

recommended[*]

Family history of breast

cancer (1st-degree relative,

age <50 yr; two relatives on

same side of family)

Annual after age 40 Referral for genetic

counseling

Significant Risk Factors for Breast Cancer in Women: Assessment and Recommendations

Factors Conferring Very High Risk

Therapeutic thoracic radiation

(age <30 yr)

Annual at 10 yr after

radiotherapy

No specific preventive

recommended[*]

Personal history of DCIS or

invasive cancer, age <40 yr

Annual after diagnosis No specific preventive

recommended[*]

Family history of breast

cancer (two 1st-degree

relatives, age <50)

Annual after age 35-40 Referral for genetic

counseling

Family history of breast and

ovarian cancer (1st-degree

relatives)

Annual after age 35-40 Referral for genetic

counseling

Known carrier of a mutation

in BRCA1 or BRCA2 or a 1st-

degree relative with a

mutation

Annual after age 25; consider

annual MRI

Genetic testing for relatives;

discuss prophylactic

mastectomy or oophorectomy

for carriers

Indications of MRI for screening

BRCA mutation

First degree relative of BRCA carrier

Lifetime risk of 20-25% as defined by BRCAPRO or any other model which depend on family history

Radiation to chest between 10-30 yr age

Li Fraumeni syndrome in first degree relative

Cowden syndrome in first degree relative

STAGING, GRADING AND MANAGEMENT

OF BREAST CARCINOMA

(p)T (Primary Tumor)

Tis Carcinoma in situ (lobular or ductal)

T1 Tumor ≤2 cm

T1a Tumor ≥0.1 cm, ≤0.5 cm

T1b Tumor >0.5 cm, ≤1 cm

T1c Tumor >1 cm, ≤2 cm

T2 Tumor >2 cm, ≤5 cm

T3 Tumor >5 cm

T4 Tumor any size with extension to the chest wall or

skin

T4a Tumor extending to the chest wall (excluding the

pectoralis)

T4b Tumor extending to the skin with ulceration, edema,

satellite nodules

T4c Both T4a and T4b

T4d Inflammatory carcinoma

American Joint Committee on Cancer Staging System for Breast Ca.

(p)N (Nodes)

N0 No regional node involvement, no special studies

N0 (i-) No regional node involvement, negative IHC

N0 (i+) Node(s) with isolated tumor cells spanning <0.2 mm

N0 (mol-) Negative node(s) histologically, negative PCR

N0 (mol+) Negative node(s) histologically, positive PCR

N1 Metastasis to 1-3 axillary nodes and/or int. mammary

positive by biopsy

N1(mic) Micrometastasis (>0.2 mm, none >2.0 mm)

N1a Metastasis to 1-3 axillary nodes

N1b Metastasis in int. mammary by sentinel biopsy

N1c Metastasis to 1-3 axillary nodes and int. mammary by

biopsy

N2 Metastasis to 4-9 axillary nodes or int. mammary clinically

positive, without axillary metastasis

N2a Metastasis to 4-9 axillary nodes, at least 1 >2.0 mm

N2b Int. mammary clinically apparent, negative axillary nodes

N3 Metastasis to ≥10 axillary nodes or combination of axillary and

int. mammary metastasis

N3a ≥10 axillary nodes (>2.0 mm), or infraclavicular nodes

N3b Positive int. mammary clinically with ≥1 axillary nodes or >3

positive axillary nodes with int. mammary positive by biopsy

N3c Metastasis to ipsilateral supraclavicular nodes

M (Metastasis)

M0 No distant metastasis

M1 Distant metastasis

STAGE TNM

5-YEAR RELATIVE

SURVIVAL RATE (%)[*]

0 Tis, N0, M0 100

I T1, N0, M0 100

IIA T0, N1, M0 92

T1, N1, M0

T2, N0, M0

IIB T2, N1, M0 81

T3, N0, M0

IIIA T0, N2, M0 67

T1, N2, M0

T2, N2, M0

T3, N1, M0

T3, N2, M0

IIIB T4, N0, M0 54

T4, N1, M0

T4, N2, M0

IIIC Any T, N3, M0 [†]

IV Any T, any N, M1 20

Score

1 2 3

A. Tubule formation

>75% 10-75% < 10%

B. Mitotic count per high-

power field

< 7 7-12 >12

C. Nuclear size and

pleomorphism

Near normal

Little variation

Slightly enlarged

Moderate variation

Markedly

enlarged

Marked

variation

Grading System in Invasive Breast Cancer (Modified Bloom and Richardson) )

Grade I cancer if the total score (A + B + C) is 3-5

Grade II cancer if the total score (A + B + C) is 6 or 7

Grade III cancer if the total score (A + B + C) is 8 or 9

Sentinel Lymph Node Biopsy • Sentinel lymph node (SLN) biopsy is a minimally

invasive procedure designed to stage the axilla in breast cancer patients who have clinically negative nodes.

• Sentinel nodes are the first node or first group of nodes that drain from the breast to the axilla.

• SLN biopsy has become the preferred SLN technique for axillary staging, because it offers accuracy equivalent to that of axillary lymph node dissection with less morbidity.

• According to the American College of Breast Surgeons (ACBS), SLN biopsy is suitable for virtually all clinically node-negative T1-2 invasive breast cancers

SLN biopsy technique • The best results with SLN biopsy are

achieved with the combination of careful intraoperative digital examination and lymphatic mapping.

• Technique involves injecting radioisotope (technetium-99m sulfur colloid) alone or radioisotope plus a patent blue dye (Lymphazurin or methylene blue) into the tissues of the breast.

• With SLN dissection, typically 1-3 lymph nodes are removed and tested for nodal metastasis with hematoxylin and eosin (H&E) stain and IHC with an anticytokeratin cocktail.

Relative contraindications • any procedure that potentially alters lymphatic

drainage to the axilla.e.g. breast augmentation, particularly when the implants reside in a subglandular position reduction mammoplasty • Allergy to blue dye or radiocolloid • Pregnancy Absolute contraindications • Inflammatory breast cancer • presence of biopsy proven metastatic axillary

lymphadenopathy

Indications and Contraindications for Breast-Conserving Surgery Indications •T1, T2 (<4 cm), N0, N1, M0 •T2 >4 cm in large breasts •Single clinical and mammographic lesion Contraindications •T4, N2, or M1 (some localized T4 disease and some patients with limited metastatic disease may be suitable for breast-conserving surgery) •Patients who prefer mastectomy •Clinically evident multifocal/multicentric disease · • Prior radiation therapy to the breast or chest wall • Diffuse suspicious or malignant appearing microcalcifications • Widespread disease that cannot be incorporated by local excision through a single incision that achieves negative margins with a satisfactory cosmetic result. • Positive pathologic margin

Relative contraindications

• Active connective tissue disease involving the skin (especially scleroderma and lupus) •Tumors > 5 cm (category 2B) • Focally positive margin • Women < 35 y or premenopausal women with a known BRCA 1/2 mutation: May have an increased risk of ipsilateral breast recurrence or contralateral breast cancer with breast conserving therapy Prophylactic bilateral mastectomy for risk reduction may be considered •Large or central tumors in small breasts

Lobular Carcinoma in Situ Lobular carcinoma in situ (LCIS) identified on breast biopsy

Stage 0 Tis, N0, M0

surgical biopsy

LCIS without other

cancer

Counseling regarding risk reduction

And

observation

6-12 monthly CBE and annual mammogram

pleomorphic LCIS may have a similar biological behavior to that of DCIS. • may consider complete excision with negative margins

Ductal carcinoma in situ (DCIS)

Stage 0 Tis, N0, M0

Lumpectomy without lymph node surgery + whole breast radiation therapy

or

Total mastectomy with or without sentinel node biopsy ± reconstruction

or

Lumpectomy without lymph node surgery without radiation therapy

Consider tamoxifen for 5 years for:

Patients treated with breast-conserving therapy (lumpectomy) and radiation

therapy especially for those with ER-positive DCIS. The benefit of tamoxifen

for ER-negative DCIS is uncertain

Patients treated with excision alone

Interval history and physical exam every 6-12 mo for 5 y, then annually

Mammogram every 12 mo

If treated with tamoxifen, monitor

INDICATIONS FOR SENTINEL LYMPH NODE BIOPSY IN DCIS • Patients with microinvasion • Patients undergoing mastectomy for diffuse disease • Patients with a high suspicion of harboring invasive disease • Extensive high-grade disease or necrosis on core biopsy • Imaging studies suggesting invasion

INDICATIONS FOR MASTECTOMY IN DUCTAL CARCINOMA IN SITU 1. Multicentric disease 2. Diffuse microcalcifications on mammography 3. Large tumor size with predictably bad cosmetic outcome 4. Contraindication to radiation Pregnancy Connective tissue disorder(scleroderma) Previous radiation therapy Patient preference

RADIATION THERAPY AFTER LUMPECTOMY FOR DUCTAL CARCINOMA IN SITU

• Radiation therapy (XRT) reduces ipsilateral breast tumor recurrence by 50% to 60%. • After XRT, the annual rate of an invasive recurrence is 0.5% to 1% per year. • XRT does not improve necessarily survival. PEARLS IN M/M OF DCIS •Complete axillary lymph node dissection should not be performed in the absence of evidence of invasive cancer or proven metastatic disease •Patients found to have invasive disease at total mastectomy or re-excision should be managed as stage l or stage ll disease, including lymph node staging •Margins greater than 10 mm are widely accepted as negative •Margins less than 1 mm are considered inadequate. •There is no evidence that survival differs between the three treatment Options

Stage I

T1, N0, M0

or

Stage IIA

T0, N1, M0

T1, N1, M0

T2, N0, M0

or

Stage IIB

T2, N1, M0

T3, N0, M0

or

Stage IIIA

T3, N1, M0

General workup

If clinical stage

lllA (T3, N1, M0)

consider:

Bone scan

(category 2B)

Abdominal ±

pelvis CT or US or

MRI

Chest imaging

Lumpectomy with surgical

axillary staging (category 1)

(Preferred)

OR

Total mastectomy with

surgical axillary

staging(category 1) ±

reconstruction

Or

If T2 or T3 and fulfills criteria

for breast conserving therapy

except for size

Preoperative Chemotherapy

TREATMENT OF CLINICAL STAGE I, IIA, OR IIB DISEASE OR T3, N1, M0

Lumpectomy with surgical axillary staging

Positive axillary

nodes

Negative axillary

nodes

•Radiation therapy to whole breast with

or without boost (by photons,

brachytherapy, or electron beam) to

tumor bed

• Strongly consider radiation therapy to

infraclavicular region and

supraclavicular area , internal mammary

nodes

•Radiation therapy should follow

chemotherapy when chemotherapy

indicated.

•Radiation therapy to whole breast

with or without boost m (by photons,

brachytherapy, or electron beam) to

tumor bed or

• consideration of partial breast

irradiation (PBI) in selected patients

•Radiation therapy should follow

chemotherapy when chemotherapy

indicated.

+/-Trastuzumab +/- endocrine therapy +/- adjuvant chemotherapy

SYSTEMIC ADJUVANT TREATMENT according to ER/PR, Her/Neu, histology,

•Endocrine therapy is indicated in all ER/PR positive cases •Trastuzumab is added in all Her2 positive cases except microinvasive <0.5cm with Pn0 •Adjuvant chemotherapy is individualised above age 70yrs

UNFAVOURABLE HISTOLOGY

Adjuvant Endocrine Therapy

pT1, pT2, or pT3

and pN0 or pN1mi (≤2 mm axillary node metastasis)

Node positive (≥1 metastases >2 mm to ≥1 ipsilateral axillary lymph nodes)

Tumor ≤0.5 cm or

Microinvasive or

Tumor 0.6-1.0 cm, well differentiated, no unfavorable features

Tumor 0.6-1.0 cm, moderate/poorly differentiated or unfavorable features

Tumor >1 cm

pN0

pN1mi

Adjuvant endocrine therapy ± adjuvant chemotherapy

Adjuvant endocrine therapy

Consider adjuvant endocrine therapy

No adjuvant therapy

Adjuvant endocrine therapy + adjuvant chemotherapy + trastuzumab if HER2+

Consider 21-gene RT-PCR assay

Low score (<18)

Intermediate

Score (18-30)

Not done

High score (≥31)

HR positive disease

•Team includes surgeon, radiologists, nuclear medicine physician,pathologist, and prior discussion

with medical and radiation oncologists on use of sentinel node for treatment decisions.

•Consider pathologic confirmation of malignancy in clinically positive nodes using ultrasound

guided FNA or core biopsy in determining if patient needs axillary lymph node dissection.

•Axillary sentinel node biopsy in all cases; internal mammary sentinel node biopsy optional if

drainage maps to internal mammary nodes

MANAGEMENT OF LOCALLY ADVANCED BREAST CA.

•LABC is defined as either large, bulky primary tumors or extensive adenopathy. •Patients with AJCC T3 or T4 tumors (associated with chest wall fixation, skin ulceration, or both) are classified as LABC. •Patients with AJCC N2 or N3 disease (matted axillary nodes, supraclavicular or internal mammary metastases)

•Interval history and physical exam every 4-6 mo for 5 y, then every 12 mo

Annual mammography

Women on tamoxifen: annual gynecologic assessment every 12 mo if

uterus present

Women on an aromatase inhibitor or who experience ovarian failure

secondary to treatment should have monitoring of bone health with a

bone mineral density determination at baseline and periodically thereafter

Assess and encourage adherence to adjuvant endocrine therapy.

Evidence suggests that active lifestyle, achieving and maintaining an

ideal body weight (20-25 BMI) may lead to optimal breast cancer

outcomes.

SURVEILLANCE/FOLLOW-UP

Intervention Year 1 Year 2 Year 3-5 Year 6+

History & physical examination

q3-4mo q4mo q6mo Annually

Mammography Annually(or 6 mo after post – BCS* irradiation)

Annually

Annually

Annually

CXR Not recommended

Not recommended

Not recommended

Not recommended

Pelvic examination

Annually

Annually

Annually

Annually

Bone density q1-2y

BREAST CANCER Stage IV

Any T any N M1

Examples of distant mestastatic disease

DEFINITIONS Of LOCOREGIONAL RECURRENCE Recurrence: Reappearance of a treated cancer in a patient previously considered NED. Local recurrence: Recurrence in the remaining breast after breast conservation or in the soft tissues of the anterior chest after mastectomy. In-breast tumor recurrence (IBTR): Local recurrence in the breast after breast-conserving therapy although it is not always possible to differentiate IBTR from a second primary tumor. Regional recurrence: Recurrence in the ipsilateral axillary, internal mammary, or supraclavicular lymph nodes. Distant recurrence: Recurrence anywhere outside the ipsilateral breast, chest wall, or regional lymph node basins.

Diagnosis of metastatic breast cancer

Determine site and extent of disease, ER/PR status, age and micronodal status

Hormone responsive or no life threatening disease

Hormone unresponsive or life threatening

First line hormone therapy First line chemotherapy

Progress of disease

No progress of disease

second line chemotherapy

Progress of disease

No progress of disease

third line chemotherapy

Progress of disease

No progress of disease

Progress of disease

second line hormone therapy

No progress of disease

Progress of disease

third line hormone therapy

Progress of disease Supportive care

MEMORABLE PEARLS

• LOCAL RECURRENCE: resection if possible with

ALND +/- RT

• REGIONAL : Radiotherapy

• SYSTEMIC: Chemotherapy+/- endocrine therapy +/- trastuzumab +/- bisphosphonates

• Inflammatory breast cancer is a clinical syndrome in women with invasive breast cancer that is

characterized by erythema and edema (peau d'orange) of a third or more of the skin of the breast and with a

palpable border to the erythema.

• The differential diagnosis includes cellulitis of the breast or mastitis. Pathologically, tumor is typically present

in the dermal lymphatics of the involved skin, but dermal lymphatic involvement is neither required for, nor

sufficient for by itself, a diagnosis of Inflammatory breast cancer

•Chemotherapy should not be administered during the first trimester of pregnancy and radiation therapy should not be administered during any trimester of pregnancy. •Combinations of doxorubicin, cyclophosphamide and fluorouracil can be used •Radiolabeled sulfur colloid appears safe for sentinel node biopsy in pregnancy. •The use of trastuzumab is contraindicated during pregnancy

(Neoadjuvant) Preoperative Chemotherapy Guidelines

Stage IIA

T2, N0, M0

Stage IIB

T2, N1, M0

T3, N0, M0

Stage lllA

T3, N1, M0 Fulfills criteria for

breast

conserving surgery

except for tumor size

Desires breast preservation

Core biopsy of breast tumor, localization of tumor bed for future surgical

management

Clinically negative axillary

lymph node(s), consider

sentinel lymph node

procedure Consider axillary

ultrasound

Clinically positive axillary lymph

node(s), consider core biopsy or

FNA;

Or

consider sentinel lymph node

procedure if FNA or core biopsy

Negative

Preoperative Chemotherapy Guideline

•Lumpectomy or Mastectomy and surgical axillary staging ± reconstruction.

• If sentinel lymph node biopsy performed prechemotherapy and negative

findings, may omit axillary lymph node staging

Consider additional chemotherapy if

recommended

ADJUVANT TREATMENT

Adjuvant radiation therapy post-mastectomy is based on prechemotherapy

tumor characteristics

Endocrine therapy if ER-positive and/or PR- positive

Complete up to one year of trastuzumab therapy if HER2-positive . May be

administered concurrent with radiation therapy and withendocrine therapy if

indicated.

Surveillance/Follow-up

Definitions for response evaluation of primary systemic therapy Clinical definition • Complete: no palpable mass detectable (cCR) • Partial: reduction of tumour area to < 50% (cPR)

Imaging definition • No tumour visible by mammogram and/or ultrasound and/or MRI

Pathological definition • Only focal invasive tumour residuals in the removed breast tissue • Only in situ tumour residuals in the removed breast tissue (pCR inv) • No invasive or in situ tumour cells (pCR) • No malignant tumour cells in breast and lymph nodes (pCR breast and nodes).

POTENTIAL ADVANTAGES TO NEOADJUVANT CHEMOTHERAPY •May allow for breast-conservation therapy in a woman who would otherwise require a mastectomy. • May improve the aesthetic outcome of a lumpectomy by decreasing the volume of tissue needing to be resected. • Allows for an assessment of the response of the tumor to chemotherapy. This may allow for modifications of therapy based on response. In addition, a demonstrable response may also have a positive effect on the patient’s compliance with further treatment and on the patient’s willingness to accept some adverse events. • Allows patients to delay surgery so they have more time to accept the need for mastectomy, consider reconstructive options, or undergo genetic counseling and testing if prophylactic mastectomies are considered. • Allows women in their second or third trimester of pregnancy to delay the surgery and radiotherapy until after delivery. • May reduce distant metastases compared with classic adjuvant systemic therapy.

ADJUVANT CHEMOTHERAPY

• Adjuvant chemotherapy demonstrated reductions in recurrence and death in women 70 years of age with stage I, IIA, or IIB breast cancer

• Minimal benefit to women with negative nodes and cancers 0.5 cm in size and is not recommended.

• Women with negative nodes and cancers 0.6 to 1.0 cm with adverse prognostic factors include blood vessel or lymph vessel invasion, high nuclear grade, high histologic grade, HER-2/neu overexpression, and negative hormone receptor status. Adjuvant chemotherapy is recommended

• Hormone receptor–negative cancers that are >1 cm in size,

• Node-positive tumors or with a special-type cancer that is >3 cm, the use of chemotherapy is appropriate.

• Trastuzumab should also be considered for patients with HER2 positive lymph node negative tumors greater than or equal to 1 cm.

PRINCIPLES OF ADJUVANT CHEMOTHERAPY

• Chemotherapy kills a constant fraction of tumor cells (first-orderkinetics) rather than a constant number of cells (log kill hypothesis).Thus, repetitive cycles of therapy are necessary.

• Combination therapy is superior to single-agent therapy by overcoming drug resistance.

• A dose-response effect exists, thus requiring adequate doses of drug.

• Outcome is dependent on the number of malignant cells present when therapy is

initiated. Even a single metastatic cancer cell, left alive, can lead to death.

• Evidence suggests that anthracycline-based chemotherapy regimens may be

superior to non-anthracycline-based regimens in patients with HER2 positive

tumors.

• In patients with HER2 positive and axillary lymph node positive breast cancer,

trastuzumab should be incorporated into the adjuvant therapy

• Chemotherapy regimens should be given prior to radiotherapy

• If Chemotherapy and tamoxifen used as adjuvant therapy should be given

sequentially with tamoxifen following chemotherapy

Cardiac assessment and anthracyclines Routine pre-anthracycline assessment of left ventricular function is advised for all patients who: • have a cardiac history • are treated for a cardiovascular condition including hypertension • have an obviously abnormal ECG • are 65 or older. •Anthracyclines should be avoided in patients with a baseline left ventricular ejection fraction (LVEF) of < 50%. LVEF should be rechecked after a cumulative epirubucin dose of not more than 400 mg/m2

NON-TRASTUZUMAB CONTAINING COMBINATIONS

PREFERRED ADJUVANT REGIMENS

TAC chemotherapy

Docetaxel 75 mg/m 2 IV day 1

Doxorubicin 50 mg/m 2 IV day 1

Cyclophosphamide 500 mg/m 2 IV day 1

Cycled every 21 days for 6 cycles.

Dose-dense AC followed by paclitaxel

chemotherapy

Doxorubicin 60 mg/m 2 IV day 1

Cyclophosphamide 600 mg/m 2 IV day 1

Cycled every 14 days for 4 cycles.

Followed by

Paclitaxel 175 mg/m 2 by 3 h IV infusion day 1

Cycled every 14 days for 4 cycles.

AC followed by paclitaxel chemotherapy

Doxorubicin 60 mg/m 2 IV day 1

Cyclophosphamide 600 mg/m 2 IV day 1

Cycled every 21 days for 4 cycles.

Followed by

Paclitaxel 80 mg/m 2 by 1 h IV infusion

weeklyfor 12 wks.

OTHER ADJUVANT REGIMENS

FAC chemotherapy

5-Fluorouracil 500 mg/m 2 IV days 1 & 8

or

days 1 & 4

Doxorubicin 50 mg/m 2 IV day 1

(or by 72 h continuous infusion)

Cyclophosphamide 500 mg/m 2 IV day 1

Cycled every 21 days for 6 cycles. CMF chemotherapy

Cyclophosphamide 100 mg/m 2 PO

days 1-14

Methotrexate 40 mg/m 2 IV days 1 & 8

5-Fluorouracil 600 mg/m 2 IV days 1 &

8

Cycled every 28 days for 6 cycles.

TRASTUZUMAB CONTAINING COMBINATIONS

AC followed by T chemotherapy with Trastuzumab

Doxorubicin 60 mg/m 2 IV day 1

Cyclophosphamide 600 mg/m 2 IV day 1

Cycled every 21 days for 4 cycles.

Followed by

Paclitaxel 80 mg/m2by 1 h IV weekly for 12 wks With

Trastuzumab 4 mg/kg IV with first dose of paclitaxel

Followed by

Trastuzumab 2 mg/kg IV weekly to complete 1 y of treatment.

As analternative, trastuzumab 6 mg/kg IV every 3 wk may be used following thecompletion of

paclitaxel, and given to complete 1y of trastuzumab.

Cardiac monitoring at baseline, 3, 6, and 9 mo.

Dose-dense AC followed by paclitaxel chemotherapy

Doxorubicin 60 mg/m 2 IV day 1

Cyclophosphamide 600 mg/m 2 IV day 1

Cycled every 14 days for 4 cycles.

Followed by

Paclitaxel 175 mg/m 2 by 3 h IV infusion day 1

Cycled every 14 days for 4 cycles.

With

Trastuzumab 4 mg/kg IV with first dose of paclitaxel

Followed by

Trastuzumab 2 mg/kg IV weekly to complete 1 y of treatment. As an alternative, trastuzumab 6

mg/kg IV every 3 wk may be used following the completion of paclitaxel, and given to complete 1y

of trastuzumab

PREFERRED CHEMOTHERAPY REGIMENS FOR RECURRENT OR METASTATIC

BREAST CANCER

CAF chemotherapy

Cyclophosphamide 100 mg/m 2 PO days 1-14

Doxorubicin 30 mg/m 2 IV days 1 & 8

5-Fluorouracil 500 mg/m 2 IV days 1 & 8

Cycled every 28 days.

FAC chemotherapy

5-Fluorouracil 500 mg/m 2 IV days 1 & 8 or

days 1 & 4

Doxorubicin 50 mg/m 2 IV day 1

Cyclophosphamide 500 mg/m 2 IV day 1

Cycled every 21 days.

FEC chemotherapy

Cyclophosphamide 400 mg/m 2 IV days 1 & 8

Epirubicin 50 mg/m 2 IV days 1 & 8

5-Fluorouracil 500 mg/m 2 IV days 1 & 8

Cycled every 28 days.

PREFERRED CHEMOTHERAPY

COMBINATIONS

CAF/FAC

(cyclophosphamide/doxorubicin/fluorouracil)

FEC

(fluorouracil/epirubicin/cyclophosphamide)

AC (doxorubicin/cyclophosphamide)

EC (epirubicin/cyclophosphamide)

AT (doxorubicin/docetaxel;

doxorubicin/paclitaxel)

CMF

(cyclophosphamide/methotrexate/fluorouracil

Docetaxel/capecitabine

GT (gemcitabine/paclitaxel)

Docetaxel/capecitabine chemotherapy

Docetaxel 75 mg/m 2 IV day 1

Capecitabine 950 mg/m 2 PO twice daily

days 1-14

Cycled every 21 days.

TRASTUZUMAB(HERCEPTIN) Mechanism of Action • Recombinant humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu growth factor receptor. This receptor is overexpressed in several human cancers, including 25%–30% of breast cancers and up to 20% of gastric cancers. • Downregulates expression of HER-2/neu receptor. • Inhibits HER-2/neu intracellular signaling pathways. • Induction of apoptosis through as yet undetermined mechanisms. • Immunologic mechanisms may also be involved in antitumor activity, and they include recruitment of antibody-dependent cellular cytotoxicity (ADCC) and/or complement-mediated cell lysis. Mechanism of Resistance • Mutations in the HER-2/neu growth factor receptor leading to decreased binding affinity to trastuzumab. • Decreased expression of HER-2/neu receptors. • Activation/induction of alternative cellular signaling pathways, such as IGF-1R. Dosage Range 1. Recommended loading dose of 4 mg/kg IV administered over 90 minutes, followed by maintenance dose of 2 mg/kg IV on a weekly basis. 2. Alternative schedule is to give a loading dose of 8 mg/kg IV administered over 90 minutes, followed by maintenance dose of 6 mg/kg IV every 3 weeks.

Drug Interactions Anthracyclines, taxanes—Increased risk of cardiotoxicity when trastuzumab is used in combination with anthracyclines and/or taxanes. Special Considerations 1. Caution should be exercised in treating patients with pre-existing cardiac dysfunction. Careful baseline assessment of cardiac function (LVEF) before treatment and frequent monitoring (every 3 months)of cardiac function while on therapy. Trastuzumab should be held for ≥16% absolute decrease in LVEF from a normal baseline value. •cardiac function should be assessed every 6 months for at least 2 years following the completion of therapy. 2. Carefully monitor for infusion reactions, which typically occur during or within 24 hours of drug administration. IMPORTANT FACTS •Trastuzumab may be given beginning either concurrent with paclitaxel as part of the AC followed by paclitaxel regimen, or alternatively after the completion of chemotherapy. •Trastuzumab should not be given concurrent with an anthracycline because of cardiac toxicity, except as part of the neoadjuvant trastuzumab with paclitaxel followed by CEF regimen. •Trastuzumab should be given for one year, (with the exception of the docetaxel + trastuzumab followed by FEC regimen in which trastuzumab is given for 9 weeks), with cardiac monitoring, and by either the weekly or every three weekly schedule.

Toxicity •Infusion-related symptoms with fever, chills, urticaria, flushing, fatigue, headache, bronchospasm, dyspnea, angioedema, and hypotension. •Nausea and vomiting, diarrhea. Generally mild. •Cardiotoxicity in the form of dyspnea, peripheral edema, and reduced leftventricular function.. In most instances, cardiac dysfunction is readily reversible. •Myelosuppression,Generalized pain, asthenia, and headache. pleural effusions

Class Toxicity

5-Fluorouracil Antimetabolite Myelosuppression, Mucositis and/or diarrhea, Hand-foot syndrome

(palmar-plantar erythrodysesthesia) , Cardiac symptoms of chest pain,

Metallic taste in mouth

Cyclophosphamide Alkylating agent Myelosuppression, Bladder toxicity in the form of hemorrhagic cystitis,

Nausea and vomiting, Alopecia

Capecitabine Oral fluoro pyrimidine Rash, hand-foot syndrome,diarrhea, mucositis

Docetaxel Antimicrotubule Myelosuppression, alopecia,skin reaction, mucositis,

and fluid retention

Doxorubicin Anthracycline

(antitumor antibiotic)

Myelosuppression, nausea/vomiting, mucositis, diarrhea

cardiotoxicity, alopecia

Doxil (liposomal

encapsulated

doxorubicin)

Anthracycline Less cardiotoxicity, neutropenia, alopecia, stomatitis, hand-foot syndrome

Epirubicin Anthracycline Myelosuppression, mucositis, nausea, vomiting, cardiotoxicity

Gemcitabine Antimetabolite Myelosuppression, nausea/vomiting, flulike syndrome,

elevated LFTs

Paclitaxel Antimicrotubule Myelosuppression, alopecia,neuropathy, allergic reaction

Trastuzumab Monoclonal antibody Fever, allergic reaction cardiotoxicity/congestive heart failure

Vinorelbine Vinca alkaloid Myelosuppression, nausea/vomiting, constipation, fatigue,stomatitis,

anorexia

DEFINITION OF MENOPAUSE •Menopause is generally the permanent cessation of menses,and as the term is utilized in breast cancer

management includes a profound and permanent decrease in ovarian estrogen synthesis.

Reasonable criteria for determining menopause include any of the following:

• Prior bilateral oophorectomy

• Age ≥ 60 y

• Age < 60 y and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene,

or ovarian suppression and FSH and estradiol in the postmenopausal range

• If taking tamoxifen or toremifene, and age < 60 y, then FSH and plasma estradiol level in postmenopausal

ranges

Postmenopausal: Aromatase inhibitors

• Produce most of their estrogen outside the ovaries

• Generated through androgen hormones store in fatty tissue and adrenal glands

• In a biochemical process started by the enzyme aromatase, androgen is converted into estrogen, into bloodstream and to breast

• Aromatase inhibitors “block” the process

Aromatase Inhibitors (AIs)

• Steroidal Ais – Exemestane

• Nonsteroidal AIs • Anastrazole

• letrozole

• Many clinical trials showing significant results in both reduced breast cancer relapse, as well as reduced rates of metastatic disease

• Now being studied in various scenarios with Tamoxifen

postmenopausal agents dose shedule

1 antiestrogen Tamoxifen 20mg Orally everyday

2 Aromatase inhibitor

Anastrazole 1mg Orally everyday

Letrazole 2.5mg Orally everyday

exemestane 25mg Orally everyday

Fulvestrand Megestrol

500mg 250mg 40mg

IM satat f/b IM every month Orally qid

Premenopausal: Tamoxifen

• Ovaries produce estrogen, sent through bloodstream directly to the breast

• Tamoxifen mimics estrogen

• Attached to receptors, keeping real hormones out

ER

X

Selective Estrogen-Receptor Modulators (SERMs): Mechanism

SERMS • Chemical structure resembles estrogen

• Compete with estrogen for ER binding

• Effective treatment for ER+ breast cancer Tamoxifen • First SERM

• Approved for

– Early and advanced ER+ breast cancer and women at high risk for breast cancer

Raloxifene • Currently under investigation for prevention of

breast cancer in postmenopausal women at high risk for breast cancer

Estrogen

SERM

ER-dependent Cell Proliferation

Premenopausal

- bilateral oophorectomy

followed by

class agents dose schedule

Antiestrogen tamoxifen 20mg Orally everyday

Aromatase inhibitor + LHRH

7.5mg IM depot (q28d)

Leuprolide 22.5mg IM (q4mo)

Gosereline 3.6mg s/c depot q28d

Megestrol 40mg Orally qid

Post-mastectomy radiotherapy Objectives • Post-mastectomy radiotherapy reduces the risk of locoregional failure and increases the long-term survival rate for a substantial proportion of women with positive axillary nodes treated with systemic therapy. Indications • Four or more positive axillary lymph nodes. • Tumour > 5 cm in size. • Close or positive margins. • Inadequate axillary surgery (the removal of less than 10 nodes). Consideration • 1 to 3 positive axillary lymph nodes.

Treatment modality: beam energy • Super voltage equipment (4, 6, or 8 MV or cobalt-60) is preferred. • In the patient where the field separation is greater than 22 cm, higher beam energy (10 MV) may give a more homogenous dose distribution. Dosimetry • The aim is to create a homogeneous dose distribution throughout this irregular shaped treatment volume (― 5% variation). Dose/fractionation • A whole breast dose of 45 Gy–50 Gy is prescribed. • This is given in 1.8 Gy–2.0 Gy fractions per day, 5 days per week. Boost • In patients with negative margins, randomized trials demonstrate that the use of a boost is effective, on local control and survival. • This effect was clearer in patients < 50 years of age. • Via the boost, the dose at the tumour bed is increased to 60 Gy–66 Gy. • A boost may be give by electron beam (10 Gy in 5 fractions or 16 Gy/8f) or interstitial implant. • Photons can be used as well.

Radiotherapy technique Target volume • Target definition includes the majority of the breast tissue, and is best done by both clinical assessment and CT-based treatment planning. • The target volume must include the chest wall. • Supraclavicular lymph node group for patients with 4 or more positive axillary lymph nodes. • Axilla if inadequate axillary surgery was done. In addition, the following areas may be included even though there is insufficient evidence to made recommendations: • Drain sites. • Internal mammary chain (IMC).

accelerated partial breast irradiation (APBI) RECOMMENDATIONS FROM THE AMERICAN SOCIETY indicate that APBI may be suitable in selected patients with early stage breast cancer and may be comparable to treatment with standard whole breast RT Patients who may be suitable for APBI are: • women 60 years and older who are not carriers of a known BRCA1/2 mutation, have been treated with primary surgery for a unifocal Stage I, ER positive cancer. •Tumors should be infiltrating ductal or a favorable histology, not be associated with an extensive intraductal component or LCIS, and margins should be negative. •34 Gy in 10 fractions delivered twice per day with brachytherapy or 38.5 Gy in 10 fractions delivered twice per day with external beam photon therapy to the tumor bed is recommended

Radiotherapy for metastatic disease Radiotherapy can be effective symptomatic treatment for: • pain relief from bony metastases; • spinal cord compression; • brain metastases; • leptomeningeal disease; • superior vena caval obstruction; • local control of primary tumour/local or chest wall recurrence; • symptomatic skin metastases.

Bisphosphonates can reduce the incidence of skeletal events and also reduce bone pain in patients with bony metastases. • Their use should be considered in all patients with bony metastases Four bisphosphonates are currently available • Clodronate (800 mg b.d.), a first-generation oral bisphosphonate. • Pamidronate (90 mg i.v. over 90 min every 3–4 weeks), a potent intravenous bisphosphonate. • Zoledronate (4 mg i.v. over 15 min every 3–4 weeks), a potent intravenous bisphosphonate. • Ibandronate, a potent bisphosphonate available in both oral and intravenous preparations •The use of bisphosphonates should be accompanied by calcium and vitamin D supplementation with daily doses of calcium of 1200 to 1500mg and Vitamin D3 400 – 800 IU. • The risk of renal toxicity necessitates monitoring of serum creatinine prior to administration of each dose •Current clinical trial results support the use of bisphosphonates for up to two years •The bisphosphonates are associated with the occurance of osteonecrosis of the jaw

PRINCIPLES OF BREAST RECONSTRUCTION FOLLOWING SURGERY

•The breast can be reconstructed in conjunction with mastectomy using breast implants,

autologous tissue (“flaps”) or a combination of the two (e.g., latissimus / implant

composite reconstructions).

• Breast reconstruction

Immediate

delayed

• As with any mastectomy, there is a risk of local and regional cancer recurrence, and

evidence suggests skin sparing mastectomy is probably equivalent to standard

mastectomy in this regard.

• The nipple-areolar complex is sacrificed with skin sparing mastectomy for cancer

therapy.

•When post-mastectomy radiation is required, delayed reconstruction is generally

preferred after completion of radiation therapy in autologous tissue reconstruction,

because of reported loss in reconstruction cosmesis

•When implant reconstruction is used,immediate rather than delayed reconstruction is

preferred to avoid tissue expansion of radiated skin flaps

•. Immediate implant reconstruction in patients requiring post-operative radiation has an

increased rate of capsular contracture.

•Smoking increases the risk of complications for all types of breast reconstruction

whether with implant or flap

SURGICAL PRINCIPLES OF THE SKIN-SPARING MASTECTOMY

•Excision of the nipple-areolar complex •Excision of the biopsy/lumpectomy incision •Total glandular mastectomy, adhering to the same surgical principles of a total mastectomy •Sentinel node biopsy or axillary node dissection through breast incision (with possible lengthening) or separate incision in the axilla

NOVEL AGENTS • bevacizumab, a humanized monoclonal antibody against the vascular

endothelial growth factor (VEGF) in the treatment of metastatic breast cancer.

• Eribulin is a non-taxane microtubule inhibitor approved by the FDA in November of 2010 for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease.

• Ixabepilone, an epothilone B analogue, is a newer agent for treatment of recurrent or metastatic breast cancer as a single agent or in combination with capecitabine

• Dasatinib (Sprycel) is a novel oral kinase inhibitor that targets the Src family kinases and BCR-abl effective in basal cell type

• HSP90 inhibitor tanespimycin

• Axitinib, another oral Tyrosine Kinase Inhibitor of VEGFR, showed promising antitumor activity in combination with docetaxel

• Other VEGFR TKIs such as pazopanib, vatalanib, cediranib, and motesanib are under investigation.

TREATMENT IN A VIEW NONINVASIVE CA. BREAST

• DCIS BCT+RT+/-Tamoxifen

• LCIS Observation+risk reduction counselling

INVASIVE BREAST CARCINOMA

EARLY

• Stage I,IIa, or IIb lumpectomy/mastectomy+/-ALND+Adjuvant chemo+/-tamoxifen+/-trastuzumab

LATE

• LABC Preop chemo. Mastectomy+axillary staging +adjuvant chemo+RT+/-Tamoxifen+/-trastuzumab

• INFLAMMATORY

• METASTATIC/RECURRENT indvidualised

SUMMARY

• Routine use of screening mammography in women 50 years of age reduces mortality from breast cancer by 33%.

• Tumor estrogen receptor concentration, nuclear grade, histologic grade, tumor type, and markers of proliferation should be considered in patients before choosing between the use of chemotherapy and hormonal therapy

• Anthracycline-based chemotherapy regimens may be superior to

non-anthracycline-based regimens in patients with HER2 positive

tumors.

• Surgery is mainstay of treatment ,BCT is to be done if possible and

pt. can be followed.

• SLN can avoid unnecessary axillary dissection and morbidity

•Surgery should not be performed until leukocyte counts and hemoglobin and hematocrit levels are back to normal, which typically takes 3 to 4 weeks after the last cycle of chemotherapy. •Concurrent radiotherapy and chemotherapy is not used because of increased acute and late local toxicity resulting in a poor cosmetic result. •There is no good evidence that concurrent radiotherapy and endocrine therapy is detrimental. However, concurrent chemotherapy and tamoxifen compromises survival. •Start adjuvant chemotherapy or radiotherapy as soon as clinically possible within 31 days of completion of surgery in patients with early breast cancer having these treatments. • loco-regional recurrence is more likely if radiotherapy is delayed more than 8 weeks following surgery. •Delayed reconstruction is preferred if postmastectomy RT is to be given.