This document provides an overview of breast carcinoma, including its development, anatomy, risk factors, subtypes, and diagnosis. It begins with the development of the breast from fetal stages through adulthood. It describes the anatomy of the breast including blood supply, lymphatic drainage, and subareolar plexus. Risk factors associated with breast carcinoma include age, family history, personal history, reproductive history, and lifestyle factors. The document discusses the molecular subtypes of breast cancer and genes associated with inherited forms. It provides details on non-invasive and invasive breast carcinomas and concludes with an overview of the clinical examination and workup for diagnosing breast cancer.

1. 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

2. •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

3. DEVELOPMENT OF BREAST praveen tripathi

4. •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

5. •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)

6. •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.

7. praveen tripathi

8. ANATOMY OF BREAST

10. 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

13. 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

14. •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.

15. •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.

16. 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

17. praveen tripathi

18. 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

19. 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

20. 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

21. 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

23. 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 .

24. •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

25. 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

28. •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

29. •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

30. 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

31. 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

32. 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

33. 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. 34
Range of Ductal Carcinoma in situ
Illustration © Mary K. Bryson

35. 35
Ductal Carcinoma in situ (DCIS)
Illustration © Mary K. Bryson
Ductal cancer cells
Normal ductal cell

36. 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

37. 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

38. 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

40. 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)

41. 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

42. 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.

43. 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

44. 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.

45. •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.

46. •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

47. •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.

48. Invasive Lobular Carcinoma (ILC)
48
Illustration © Mary K. Bryson
Lobular cancer cells breaking through the wall

49. Cancer Can also Invade Lymph or Blood Vessels
49
Illustration © Mary K. Bryson
Cancer cells invade lymph duct
Cancer cells invade blood vessel

50. Diagnosis of breast cancer

51. 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

52. 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.

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

54. 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

55. • 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.

56. 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

58. 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

59. RADIOLOGICAL INVESTIGATIONS
•Mammography
•Nuclear Imaging(scintimammography)
•Ultrasonography
•Doppler Flow Studies
•Thermography
•Magnetic resonance imaging
•PET Scan

60. 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

61. 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

62. 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

63. 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

64. mass
microcalcifications

65. •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

66. 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

67. 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

68. 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.

69. 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

70. 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

71. 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

72. •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

73. •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

74. 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.

75. • 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.

76. Modality
Sensitivity
Specificity
P p value
Indications
Mammography
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
Ultrasonography
68-97% (palpable)
74-94% (palpable)
92% (palpable)
Initial investigation for palpable lesions in women younger than 35 years

77. 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
Scintigraphy
76-95% (palpable) 52-91% (impalpable)
62-94% (94% impalpable)
70-83% (83% palpable, 79% impalpable)
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

78. 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.

80. 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.

81. 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

82. 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.

83. 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

84. 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

85. 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

86. 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

87. 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.

88. 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 Oncotype 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

89. 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

90. 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.

91. 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

92. · 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

93. · 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

94. 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

95. 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

96. 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.

97. 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

98. 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

99. 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

100. 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.

101. 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

102. 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

103. 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

104. 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

106. STAGING, GRADING AND MANAGEMENT OF BREAST CARCINOMA

107. (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.

108. (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

109. 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

110. M (Metastasis)
M0
No distant metastasis
M1
Distant metastasis

111. 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

112. 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) )

113. 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

114. 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

115. 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.

116. 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

117. 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

118. 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

119. 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

120. 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

121. 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

122. 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

123. 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

124. 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

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

126. •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

128. 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

129. •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

130. 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)

134. •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

135. 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

136. BREAST CANCER Stage IV Any T any N M1
Examples of distant mestastatic disease

138. 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.

139. 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

140. MEMORABLE PEARLS
•LOCAL RECURRENCE: resection if possible with
ALND +/- RT
•REGIONAL : Radiotherapy
•SYSTEMIC: Chemotherapy+/- endocrine therapy +/- trastuzumab +/- bisphosphonates

141. • 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

142. •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

143. (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

144. 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

146. 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).

147. 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.

148. 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.

150. 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

151. 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

152. 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.

153. 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

154. 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.

155. 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.

156. 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.

157. 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

158. 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

159. 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

160. 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

161. 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

162. 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

163. Premenopausal: Tamoxifen
•Ovaries produce estrogen, sent through bloodstream directly to the breast
•Tamoxifen mimics estrogen
•Attached to receptors, keeping real hormones out

164. 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

165. 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

166. 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.

167. 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.

168. 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

169. 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.

170. 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

171. 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

172. 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

173. 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.

174. 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

175. 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

176. •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.