RISK FACTORS

1. Female gender BREAST CANCER

2. Increasing age
3. Family history of breast cancer at a young age
4. Early menarche
5. Late menopause
6. Older age at first live child birth
7. Prolong HRT
8. Exposure to chest wall irradiation → Cancer risk occurs 8-10 years later
9. Benign proliferative breast disease
10. Increased mammographic breast density
11. Genetic mutations - BRCA1/2

PATHOLOGY ASSESSMENT
• How to send a specimen?
◦ Orientation of the specimen is very important!
◦ All specimens should be sent immersed in 10% Formal saline → Fixative that prevents degradation of cellular structures
‣ Formalin penetrates tissue 1mm per hour - very slow → therefore for mastectomies make one incision through
the tumour starting at deep surgical margin up to skin, but keep skin intact! → Insert some gauze in to the incision
◦ Send in proper containers
‣ Appropriate sized wide mouthed leak proof
‣ send as separate specimens - Mastectomy separate, level 1, 2, 3 in separate containers for each
‣ Proper labelling of container
◦ Request form - include
‣ Patient identification
‣ Type of specimen and side
‣ If WLE what quadrant
‣ Previous investigation findings (USS, Mammo, FNAC, Core biopsy)
‣ Neo-adjuvant chemotherapy
‣ Orientation sutures
• Types of breast cancer
◦ Proliferative abnormalities of breast occur from
‣ Lobular epithelium and
‣ Ductal epithelium
• Both epithelia can give rise to a spectrum of proliferative abnormalities
◦ hyperplasia → atypical hyperplasia → insitu carcinoma → invasive carcinoma
◦ Types
‣ Ductal carcinoma - 85-90% are these
• Invasive ductal NOS (= Invasive breast cancer NST)
• Other less common types
◦ Favourable histologies
‣ Tubular - unlikely to spread outside the breast
‣ Mucinous - less likely to spread to LNs
◦ Adenoid cystic
◦ Signet ring cell cancers - mucin produced inside the cell within a vacuole that pushes the nucleus to
periphery (SRCC in gastric and colorectal cancers are aggressive where as SRCC in breast are slow
growing)
◦ Medullary - not as less aggressive as it was thought to be and should not be included as a favorable
histology anymore
◦ Papillary
◦ Metaplastic carcinoma - similar to invasive ductal
‣ Lobular carcinoma - 10% of breast cancer
• Incidence is rising than the rate of ductal carcinoma - possibly because of the strong association of post-
menopausal HRT
• Classic → noncohesive cells that infiltrate the stroma in a single file pattern (non-cohesiveness is due to lack
of E-cadherin expression in the tumor cells that will result in deregulation in cell-cell adhesion)
• Non-classic
◦ Pleomorphic
◦ Apocrine
◦ Histiocytoid
◦ Signet ring cell
‣ Mixed
 ◦ Main differences b/w Ductal and Lobular cancer
‣ Lobular cancers - No mass lesion is grossly evident
‣ Lobular is usually bilateral and multicentric
‣ Lobular arises mainly in older women
‣ Lobular cancers generally tend to have features associated with good prognosis
• Grade - usually low to intermediate
• ER +ve as a rule!
• HER-2 negative
• Ki67 - low
‣ Initially thought as lobular's outcome is equal to ductal, but now at least for the short term lobular is considered
to have a favorable outcome compared to ductal, but some variants of lobular cancer have poorer prognosis than
ductal!
‣ Lobular cancers metastasize later compared to ductal, but they spread to unusual locations - peritoneum,
meninges, GIT, ovarian tissue!
• Pathology report
◦ Pathology reporting should be standardized according to CAP (College of American Pathologists) protocols
‣ Tumour type
‣ Tumour size
‣ Resection margins - After surgical resection → standard for negative surgical margins is "NO INK ON A
TUMOUR"
‣ Nodal involvement
‣ Pathological grading
‣ Prognostication
‣ IHC

◦ Pathology grading - ELSTON-ELLIS modification of the Scarff-Bloom-Richardson grading system

‣ Scoring is based on ‣ If score is
• Glandular formation (1-3) • 3,4,5 - Grade 1 (well differentiated)
• Nuclear features (1-3) • 6,7 - Grade 2 (moderately differentiated)
• Mitotic count (1-3) • 8,9 - Grade 3 (poorly differentiated)
◦ Prognostication - NPI (Nottingham Prognostic Index)
‣ How the score is made • Score values and prognosis
• Tumour grade (1, 2, 3) ◦ 2-2.4 → 93% 5 year survival
• Lymphnodes (No LN = 1, 1-3 LNs = 2, >3 LN = 3) ◦ 2.4-3.4 → 85%
• Tumour size in centimeters x 0.2 ◦ 3.4-5.4 → 70%
◦ >5.4 → 50%
◦ IHC should be routinely done and documented in the report
‣ ER PR HER2/Neu Ki 67

‣ ER and PR status
• Checked with IHC
• ER status should be determined for all samples of ductal carcinoma in situ (DCIS)
• ER and PR status should be determined for all invasive breast cancer
• Breast cancers that have at least 1% of cells staining positive for ER should be considered ER positive
• How to check?
◦ Percentage of cells that stain by IHC for ER - on a scale of 0-5
◦ Intensity of staining - on a scale of 0-3
◦ If total score is 0-2 → ER negative
◦ If total score is 3-8 → ER positive
◦ PR is the same
• ER/PR Negativity - carries a bad prognosis
• ER/PR Positivity - allows the use of Tamoxifen or an Aromatase inhibitor as adjuvant hormonal therapy

‣ HER2 status
• Marker of sensitivity to Trastuzumab
• Should be determined for all newly diagnosed invasive breast cancer + first recurrences of breast cancer
• 2 methods to detect this
◦ IHC - evaluates the over expression of this receptor at the surface of the cells
‣ 0 an 1+ negative
‣ 2+ weakly positive
‣ 3+ strongly positive for HER2
 ◦ FISH (Fluorescent in situ hybridization) - evaluates the status of the HER2 gene in the nucleus → 2
indications to do this!
‣ if specimen is put in formalin for <4-6 hours or >48 hours IHC cannot be done and then FISH is
needed to detect HER2
‣ Weakly positive IHC HER2 results should be checked with FISH
• HER-2 Negativity - carries a good prognosis
• HER-2 Positivity - allows the use of monoclonal antibody - Trastuzumab (Herceptin®)
‣ Ki-67 status
• Non histone protein that increases in the cell when it prepares to divide → used to evaluate the proliferate
activity of the breast cancer
• If Ki67 <10% - tumor growth rate is low
• 10-20% - borderline
• >20% - high growth rate
◦ if high it confers a higher risk of relapse and poor survival in early breast cancer
• In triple negative breast cancer - high Ki-67 suggests better response to neoadjuvant therapy than low Ki-67,
but if Ki-67 is very high, the response will be poor again = Ki-67 has a non-linear effect on treatment!
• In hormone positive breast cancer - Ki-67 index is used to decide on addition of chemotherapy to endocrine
therapy!

STAGING
• TNM
• Manchester classification
◦ Stage 1 - T1 N0 M0 (or N1mic)
◦ Stage II - T2 N1 M0 (but T3 N0 M0 is also included in stage IIb)
◦ Stage IV - AnyT AnyN M1
◦ Stage III - Everything inbetween II and IV
‣ IIIa - N2 (but also has T3 N1 M0 which is considered as early breast cancer)
‣ IIIb - T4
‣ IIIc - N3

CLINICAL FEATURES

SPREAD
• Local spread
• Lymphatic spread
◦ To axillary nodes
◦ To internal mammary nodes (posterior 1/3 tumours
◦ Advanced cancer - to supraclavicular nodes and contralateral nodes
• Haematogenous spread
◦ Bone (osteolytic) - Lumbar vertebrae > Femur > Thoracic vertebrae > Ribs > Skull
◦ Liver
◦ Lung
◦ Brain
◦ Rarely - adrenals, pancreas, ovaries

TREATMENT APPROACH
Can be discussed under 5 topics
1. Noninvasive carcinomas
A. LCIS
B. DCIS
2. Invasive locoregional operable cancer
A. Early breast cancer - Stage I, II
B. Locally advanced - Stage IIIA's T3N1M0
3. Invasive locoregional inoperable cancer - Locally advanced breast cancer (Stage III → Stage IIIA
except T3N1M0, IIIB, IIIC)
4. Invasive Metastatic (Stage IV)
5. Recurrent carcinoma
 (1) NON-INVASIVE CARCINOMAS
(1) LCIS
Workup
• (1) H&E
• (2) Diagnostic bilateral mammography
• (3) Core biopsy
Treatment
• Classic LCIS with <4 terminal duct lobular units in a single core → Surveillance
• Other LCIS (pleomorphic LCIS, LCIS associated with necrosis) → Surgical excision
◦ Reason to excise is to look for
‣ Invasive breast cancer
‣ DCIS component
◦ If DCIS → manage as DCIS
◦ If Invasive breast cancer → manage as invasive breast cancer
◦ If LCIS only → Surveillance
Surveillance
• CBE 6-12 months
• Annual mammogram
• Risk reduction strategies
• Breast awareness

(2) DCIS
• Characterised by proliferation of presumably malignant epithelial cells with in the mammary ductal system without any
evidence of invasion
• Major differences between DCIS and LCIS
◦ Presentation
‣ DCIS - Incidental, mammographic abnormality, occasionally palpable, unifocal
‣ LCIS - Incidental, multifocal
◦ Location
‣ DCIS - Ducts
‣ LCIS - lobules
◦ Cell size
‣ DCIS - Medium or large
‣ LCIS - Small
◦ Principle types
‣ DCIS - Comedo (with central necrosis - mammographically detectable calcifications, higher chance of
invasiveness, recurrence), cribriform, micro papillary, papillary, solid
‣ LCIS - Solid
◦ Calcification
‣ DCIS - Yes or no
‣ LCIS - No
◦ Invasive cancer risk
‣ DCIS - High
‣ LCIS - Low
◦ Location if becomes invasive
‣ DCIS - Ipsilateral
‣ LCIS - Ipsilateral or contralateral
Workup
• (1) H&E
• (2) Diagnostic bilateral mammography
• (3) MRI breast is optional -
◦ Detects DCIS better than mammogram
◦ But has not
‣ increased negative margins following WLE
‣ decreased "conversion to mastectomy" rates
• (4) Core biopsy
• (5) ER status (HER 2 status has not proven to be prognostically significant in DCIS)
• (6) Genetic counseling for high risk patients for hereditary breast cancer
Treatment
• General guideline is based on Van Nuys Prognostic index
◦ Age (>60, 40-60, <40)
◦ Tumour grade and calcification (non high grade without calcification, non high grade with calcification, high grade with
or without calcification)
◦ Tumour size (<15mm, 16-40mm, >40mm)
◦ Resection margin (>10mm, 1-9mm, <1mm)

◦ Usual guideline was

‣ If score 4,5,6 - WLE only
‣ If score 7,8,9 - WLE + RT
‣ If score 10, 11, 12 - Mastectomy +/- Reconstruction

• But now with evidence, following factors are suggested

◦ If tumour is in more than one quadrant → mastectomy
◦ Current evidence suggests RT after any WLE has shown to reduce recurrence significantly even in low risk (Van Nuys
score 4, 5, 6 group)
◦ Place for axillary surgery
‣ There is no place for ALND in DCIS management
‣ but what about SLNB?
• Some patients with DCIS on core biopsy will end up having invasive cancer when WLE is done for DCIS
which would eventually require addressing the axilla → therefore SLNB is done in DCIS in following situations
◦ if DCIS requires mastectomy (Van Nuys 10, 11 or 12, DCIS in more than one quadrant) or
◦ WLE for DCIS is done at an anatomical location which could compromise future SLNB
• Accepted margin in DCIS
◦ NO INK ON THE TUMOUR is what is accepted as the negative margin
◦ <1mm is not adequate and >10mm is a good clearance
◦ But at least having a 2mm margin has shown to reduce recurrence in WLE + RT group
◦ Margin for WLE alone group is not well established, but should be at least 2mm or probably more → this is why RT is
now recommended (category 1) following WLE for DCIS
◦ If accepted margin is not there → re-excision → if comes positive again → may require mastectomy

Risk reduction in DCIS

• Reduction of Post WLE/BCS recurrence risk for • Risk reduction therapy for contralateral
ipsilateral breast breast
◦ Endocrine therapy ◦ Counseling regarding risk reduction options
‣ Duration → for 5 years ‣ Risk reduction agents
‣ For ‣ Risk reduction surgery
• WLE + RT group if ER+ve ‣ Life style modifications
• WLE alone group
‣ Agents
• Tamoxifen for premenopausal
• Tamoxifen or aromatase inhibitors for post-menopausal

Followup in DCIS
• H&E 6-12 months for 5 years → then annually
• Annual mammogram
◦ For WLE + RT group → 1st mammogram in between 6-12 months after surgery
• Monitor patients started on endocrine therapy
◦ Tamoxifen
‣ Endometrial cancer risk → gynecological screening
• If PV bleeding → prompt evaluation for endometrial cancer if uterus intact
• if cancer diagnosed → stop the drug → hysterectomy → recommence after hysterectomy
• If no cancer → continue
‣ Cataract and retinopathy risk → Ophthalmology screening if cataract or vision problems
‣ Thromboembolism risk → DVT/PE/CVA features or prolonged immobilization → stop tamoxifen
‣ Hot flashes and other perimenopausal symptoms → symptomatic treatment → continue drug
◦ Anastrozole (AI)
‣ Arthralgia → symptomatic treatment → continue the drug
 (2) INVASIVE LOCOREGIONAL OPERABLE
Early breast cancer - Stage I, II Locally advanced - Stage IIIA's T3 N1 M0
Aim of management
• To reduce the risk of local recurrence • To reduce the risk of metastatic spread
Workup
• Diagnosis
◦ (1) History and clinical examination
◦ (2) Bilateral diagnostic mammography
◦ (3) Breast ultrasonography with axillary assessment
◦ (4) Breast MRI
‣ Absolute indications
• Clinically positive axillary nodes and occult primary breast cancer
• Paget's disease of the nipple with breast primary not identified on mammogram/US/Physical examination
• To evaluate cancer response to neoadjuvant chemotherapy and decide on BCS
• ?Pregnancy
‣ In other instances it is not helpful because
• MRI findings can alter the decision to go for BCS if it detects mammographically occult satellite disease which
results in mastectomy, which actually could have been treated with post BCS radiotherapy
• RCTs have shown MRI usage doesn't improve post-lumpectomy re-excision rates (margin -ve resections)
• MRI use has not shown any difference in local recurrence or OS
◦ (5) Core biopsy of breast lesion +/- axillary nodes if suspicious on imaging
‣ Pathological review
‣ Receptor status - ER/PR/HER2
• Staging and metastatic screening
◦ Asymptomatic stage I and II → no place for imaging and no place for LFT even (chance of metastasis is <3%)
◦ If symptomatic I and II
‣ FBC
‣ Metabolic panel including LFT and ALP
‣ Chest CT if pulmonary symptoms (cough, hemoptysis)
‣ Abdominal CT/MRI if
• ALP high or
• abnormal LFT or
• abdominal symptoms or
• abnormal physical examination in abdomen/pelvis or
• CT chest/abdomen/pelvis only if lobular carcinoma, otherwise for ductal CT chest/abdomen only!!
‣ Bone scan if
• localized bone pain or • FDG PET/CT has no place in early breast cancer
• High ALP
◦ If Stage IIIA (T3 N1 M0) even if asymptomatic → routine imaging can be considered
‣ All of above for symptomatic I and II
‣ FDP PET/CT is optional
◦ If patient is a candidate for neo-adjuvant → All of above for symptomatic I and II
• Other aspects
◦ (1) Genetic counseling for high risk patients for hereditary breast cancer
◦ (2) Psychological distress assessment
◦ (3) Fertility counseling
‣ 2 things to bear in mind
• After breast cancer treatment
◦ Child bearing does not affect mother's OS or recurrence rates
◦ Child conceived and born after BCa treatment will not have any birth defects or serious illnesses
• During breast cancer treatment
◦ It can affect success of conceiving
◦ Conceiving should not happen while patient is on systemic treatment for BCa to ensure fetal safety
‣ Therefore premenopausal women should be informed about chemotherapy + endocrine therapy and consequent
reduction in fertility and ask about the desire to have children in the future → if they desire → refer to a fertility
specialist before initiating systemic therapy (Chemo and endocrine therapy) → He should
• Discuss available options
◦ Starting GnRH agonist Goserelin (ovarian stimulation) before CT and during CT can reduce the CT
induced ovarian failure (effect is more in hormone receptor negative BCa than positive BCa)
◦ Embryo or oocyte cryopreservation
• Advise not to get pregnant while on breast cancer treatment to ensure fetal safety
Locoregional treatment
• Surgery • Radiotherapy
◦ Surgery to breast ◦ Surgery to axilla
‣ Mastectomy ‣ Axillary clearance
‣ BCS ‣ SLNB
‣ Breast reconstruction
(1) Surgery
(A) Surgery to breast
• Different types of surgery in breast cancer
A. Preventive surgery
a. Contralateral mastectomy at the time of surgery for primary breast cancer → improved breast cancer specific
mortality only in (according to SEER database)
1. Young population (18-49)
2. ER negative cancer
b. Currently recommendation - Risk reduction prophylactic contralateral mastectomy after MDT and careful
counseling only for
1. < 35 breast cancer patients
2. Premenopausal patients with breast cancer who have BRCA 1/2 mutations
B. Diagnostic surgery
a. When investigations fail to diagnose
C. Therapeutic surgery
a. Breast conservative surgery for DCIS, Early breast cancer, Locally advanced breast cancer after neoadjuvant
b. Mastectomy for breast cancer patients not candidates for BCS or not willing for BCS
D. Oncoplastic surgery - combination of plastic surgery and oncological principles to improve the cosmetic outcome following
therapeutic breast surgery without compromising the oncological clearance
E. Damage control surgery
a. For local recurrence
b. For metastasis
c. For treatment related complications
• (i) BCS
◦ Mastectomy is equal to BCS (WLE + WBRT) in Stage I and II in terms of survival (category 1 statement)
◦ Absolute contraindications
‣ Pregnancy (as RT cannot be given during pregnancy)
‣ Inflammatory breast cancer
‣ Diffuse microcalcifications
‣ Multicentric disease (more than 1 quadrant)
‣ Diffusely positive pathological margins
◦ Relative contra-indications
‣ Previous radiation to breast or chest wall
‣ Active connective tissue disorders involving breast skin
‣ Tumours >5cm
‣ Focally positive pathological margins
◦ These are not contraindications
‣ Skin dimpling
‣ Nipple areolar retraction
‣ Tumour location
‣ Young age
◦ Some studies have shown doing BCS for young women with breast cancer increases risk of local recurrence
‣ But studies have shown there is no difference in survival outcomes in them compared to mastectomy!
◦ Types of BCS
‣ WLE
• Tumour + rim of at least 1cm normal breast tissue should be taken
‣ Quadrantectomy
• Entire segment of the breast that contains the tumor is taken out
‣ Lumpectomy
• Reserved only for excision of benign breast lesions
◦ When BCS is done whole breast irradiation is mandatory to reduce the risk of local recurrence (by 50%)
‣ Following BCS (WLE + WBRT) chance of recurrence increases by 1% every year, so by 10 years it is 10%. If
radiation isn’t given it will be 20-30%. Following mastectomy LR rate is 1-2%.
◦ If margins +ve 3 options
‣ Further local excision
‣ Mastectomy
‣ Booster RT
• (ii) Mastectomy
◦ Indications
‣ For those who are not candidates for lumpectomy
‣ For those who prefer mastectomy over lumpectomy
◦ Different types of mastectomy
‣ Radical Halsted Matectomy
• Breast, Axilla, Pec major and pec minor
‣ Extended radical mastectomy
• Above + internal mammary nodes + supraclavicular nodes
‣ Simple mastectomy
• Breast and axillary tail only (no ALND)
‣ Modified Radical Mastectomy
• Patey - Cut pec minor and take level III
• Scanlon - Retract pec minor and take level III
• Auchincloss - The one we usually do
‣ Skin sparing mastectomy
• Spares inframammary fold for reconstruction
‣ Nipple sparing mastectomy
• SSM with saving of nipple areolar complex (NAC)
‣ Subcutaneous mastectomy
• Subtotal removal of breast tissue leaving behind 1-2cm of breast tissue on mastectomy flaps and NAC
‣ Prophylactic mastectomy
• Risk reduction prophylactic contralateral mastectomy at the time of surgery for primary breast cancer
should be done only after MDT and careful counseling → indicated for only following 2 situations
◦ < 35 year old breast cancer patients
◦ Premenopausal patients with breast cancer who have BRCA 1/2 mutations
◦ Extensive DCIS

• (iii) Breast reconstruction/Oncoplastic surgery

◦ Is an option for any woman receiving surgical treatment for breast cancer
◦ It does not affect the oncological outcome in breast cancer (recurrence or cancer related mortality), but significantly
improve quality of life
◦ All women should be educated about it and allowed to consult a reconstructive plastic surgeon
◦ BR should not interfere with appropriate surgical treatment for BCa
◦ Relative contraindications
‣ Smoking
‣ Obesity
• Both lead to partial or complete failure of flaps due to poor wound healing
◦ Advantages
‣ Ability to achieve adequate surgical clearance with less fear of cosmetic results
‣ Reduce unacceptable cosmetic effects following radiation
◦ Without oncoplastic procedures → deformities that can occur
‣ With large volume resections, resections at certain sites like lower quadrants, RT following BCS → lead to
unsightly deformities
• Bird beak deformity (lower pole deformity)
• Skin pectoral adherence deformity
◦ Oncoplastic ladder/toolbox
‣ For BCS
• If volume resection is <20% of breast volume → primary closure
• If volume resection is 20-40% → volume displacement techniques
• If volume resection is >40% → volume replacement techniques
‣ For Mastectomy
• Volume replacement techniques
◦ Implants (Inside a solid silicon envelop either saline or silicon gel or both)
◦ Autogenous tissue/Flaps
‣ Pedicled flaps
‣ Free flaps
◦ Use of both implants and autogenous tissue/flaps
◦ Steps in oncoplastic procedures
‣ Decide excision volume
‣ Decide type of breast according to BIRADS classification of breast composition
• Type A - almost entirely fat
• Tybe B - scattered glandular 25-50%
• Type C - heterogeneously glandular 50-75%
• Type D - almost entirely glandular >75%
‣ Decide level of repair
• 1 stage - at the time of primary surgery for → "Immediate breast reconstruction"
• 2 stage procedure → "Delayed breast reconstruction"
‣ Decide type of repair based on tumor location
‣ Decide on contralateral symmetry procedures
• Reduction
• Augmentation
• Mastopexy
◦ Principles of breast reconstruction after mastectomy
‣ Mastectomy leads to
• loss of breast for breast feeding
• loss of sensation in the breast skin and nipple areolar complex (NAC)
• loss of breast for cosmetic, body image and psychosocial purposes
◦ This can be partially overcome by breast reconstruction
‣ Options → Volume replacement techniques
• Implants (Inside a solid silicon envelop either saline or silicon gel or both)
◦ Immediate placement of a permanent sub pectoral implant
◦ Initial placement of a subpectoral expander → gradual expansion of the implant causing stretching of the
overlying muscle and skin → followed by replacement of the expander with a permanent sub pectoral
implant
• Autogenous tissue/Flaps
◦ Pedicled flaps - TRAM, LD
◦ Free flaps - DIEP (Deep inferior epigastric perforator flap), Superior gluteal artery flap (Gluteus
maximus myocutaneous flap)
• Composite of autogenous tissue and implant
‣ These could be done following
• Standard modified radical mastectomy
• Skin sparing (SSM) mastectomy or Nipple sparing mastectomy (NSM)
◦ SSM and NSM give rise to better cosmetic outcome
‣ Scar is less
‣ Breast shape is more natural when flaps are used
‣ NSM preserves the nipple sensation
◦ And they allow immediate reconstruction possible as well
‣ If RT is to be given
• RT can affect the reconstruction cosmesis
• For autogenous tissue reconstruction (flaps) - some advocate immediate breast reconstruction and then RT
while others first give RT and then do a delayed reconstruction - NCCN recommendation is 2B
• For Implants → NCCN prefers a staged approach to reduce the risk of capsular contracture, malposition,
implant exposure and poor cosmesis associated with RT
◦ Instead of immediate placement of a permanent sub pectoral implant → initial placement of a sub
pectoral expander → followed by replacement of the expander with a permanent sub pectoral implant
before or after RT
‣ If patient has been previously irradiated
• Implants are contraindicated due to high rates of capsular contracture, malposition, implant exposure and
poor cosmesis
• Only option is Flaps
◦ Principles of breast reconstruction after lumpectomy/BCS
• If volume resection is <20% of breast volume → primary closure
• If volume resection is 20-40% → volume displacement techniques
• If volume resection is >40% → volume replacement techniques
◦ Thoraco epigastric flaps
◦ Mini LD flaps
◦ Intercostal perforator flaps
Figures in the last page
(B) Surgery to Axilla (Surgical axillary staging)
• For early breast cancer management, surgical axillary staging is a must
• Presence of axillary LNs is the single most important prognostic factor in BCa
• Axillary surgery provides
◦ Staging information to ascertain the need for systemic therapy
◦ Prognostication
◦ Local control of the disease to a certain extent
• 2 ways to address the axilla in BCa
◦ SLNB
◦ ALND
• If clinically palpable or radiologically suspicious (enlarged size, thickened cortex, compression of fatty hilum) nodes
→ FNAC or core biopsy should be done on them to confirm tumor deposits
◦ If Positive → ALND
◦ If negative → SLNB
• 3 studies on surgery to axilla
◦ ALMANAC (Axillary lymphatic mapping against nodal axillary clearance)
‣ SNB provides accurate assessment of axilla with few false negatives (5-11%)
‣ SNB is associated with significantly low surgical morbidity to axilla
◦ Z0011 trial
‣ Axillary dissection or no axillary clearance in women with +ve SNLB?
‣ Cohort of women with SLNB +ve, but low risk of getting non-SLN involvement → no difference in local
recurrence, DFS, OS by doing ALND → therefore if the patient has following criteria fulfilled → even if SLNB is
positive (SLNB positivity should be in <3 nodes), no need of ALND!
• <3 SLN positive
• T1 (<2cm)
• Grade 1 or 2 tumor
• ER/PR +ve and HER2 negative (Luminal A) - this is not in the original trial!
• Patient is undergoing BCS and WBRT
• Should not have received neo-adjuvant before BCS!
◦ AMAROS (After Mapping Axilla Radiotherapy Or Surgery?)
‣ If SNLB is positive → performing ALND or axillary RT will give equal control of axilla if
• T1/T2 tumor
• No palpable LNs
‣ Axillary RT is better than ALND as it reduces morbidity to axilla!
• (i) SLNB
◦ Definition: First tracing LN to which cancer cells are most likely to spread from the primary tumor
◦ Rationale: If SLN is negative for mets, remaining should be free of tumor too → So no further action is needed
◦ Prerequisites
‣ Axilla should be clinically negative, if clinically positive → FNAC/Core biopsy should be done and it should be
negative
‣ SNL expert team should be there
◦ Technique
‣ Peri-areolar injection of Tc labelled nano colloid (To carry Tc, colloid is needed) subdermally/peritumoural/
subareolar on the day before (40 MBq) or same day (20 MBq)
‣ When patient is anaesthetised 2 mL of patent blue or methylene blue 0.2% is injected
‣ Massage for 10 minutes
‣ Intra-operatively check with gamma probe to detect the hot nodes (one with 10 times the background activity)
‣ Transverse incision in the axilla along the inferior axillary line
‣ To identify the SLN
• Blue node
• Several blue nodes
• Node to which blue lymphatic reaches
‣ If failed to locate the LN → send 4 lymph nodes
‣ To increase the chance of identification preoperative lymphoscintigraphy can be done to visualize the lymph
draining pattern
◦ Microscopic examination
‣ Current decision making is based on H&E
‣ If equivocal only Cytokeratin IHC can be tried
‣ Intra-operative methods
• Frozen section • One step nucleic acid amplification
• Imprint cytology
 ◦ If SLN is positive for
‣ Macromets (>2mm) or Micromets (0.2 - 2mm)
• ALND is indicated
• If tumor is T1/T2 and nodes were not palpable clinically → ALND or Axillary RT (AMAROS)
• If positivity is in only 1-2 nodes (<3 nodes), T1 tumor, Grade 1 or 2 tumor, BCS and WBRT is going to be
done, no neoadjuvant, Luminal A → No need of ALND (Z0011)
‣ ITC/Isolated tumor cells (<0.2mm mets or <200 tumor cells in a single cross section)
• No need of ALND
• But if this was in lobular carcinoma → ALND is indicated (as lobular cancers grow in non-cohesive patters,
they can have ITC is many nodes)
• (ii) ALND
◦ 4 important recommendations in terms of ALND
a. Level I and II axillary dissection should be done when
1. Clinically +ve nodes at the time of diagnosis confirmed by FNA or Core biopsy!
2. SLN cannot be identified!
3. SLN mapping is contraindicated as in inflammatory breast cancer
4. SLN is positive in patients who do not fulfill the ZOO11 criteria
b. If RT is planned after mastectomy (for tumor factors) → axillary radiation can replace ALND
c. Traditional ALND requires at least 10 LNs to provide pathological staging of axilla
d. ALND should be extended to include level III only if gross disease is present in level II or III
◦ Morbidities
‣ Short term
• Uncomfortable post-op drains
• Seromas
‣ Long term
• Division of intercostobrachial nerve - pain/neuropathies
• Functional limitation of arm abduction
• Lymphoedema requiring
◦ Physio for shoulder girdle
◦ Diet modifications
◦ Compression garments
◦ Avoidance of excessive small muscle use of hand!!!! (Increased blood flow to upper limb → more lymph
produced)

(2) Radiotherapy
• RT should be given with in 1 month after surgery
• If chemo is planned, it should be given before RT, except CMF which can be given with RT
• If neo-adjuvant chemotherapy is given and then surgery done, post-operative RT decision should be based on pre-
chemotherapy stage, and not on the tumor that responded to neo-adjuvant
• SE of RT
◦ Breast shrinkage
◦ Telangiectasia
◦ Breast edema
• Types
◦ Whole breast irradiation (for BCS)
◦ Chest wall irradiation (for mastectomy including breast reconstruction)
◦ Regional nodal irradiation
• (i) Whole breast RT (WBRT)
◦ WBRT reduces risk of Local Recurrence (LR) and additional booster dose of radiation to tumor bed in BCS further
reduces it!
‣ Types of LR in BCS
• True LR - with in primary tumor bed
• Marginal miss - with in the same quadrant, just outside the tumor bed
• Elsewhere recurrence - in another quadrant of the same breast
‣ >75% of all recurrences occur with in 5 years!
◦ Additional methods to reduce unwanted exposure of heart and lungs
‣ CT based treatment planning
‣ Respiratory control techniques
• Deep inspiration breath-hold
• Prone position
 ◦ Schedules
‣ Standard schedule - 50Gy in 25 fractions (2 Gy per fraction) → 25 fractions means 25 days → 5 week schedule
(only 5 days per week)
‣ Hypofractionated schedule - 42.5 Gy in 16 fractions (2.65 Gy per fraction) → 3.2 week schedule
• This was found equally effective to standard dose
• This was found with less SE of RT
• This is what is preferred by NCCN if WBRT alone is done (no axillary RT)
‣ Booster dose to tumor bed in higher risk patients to reduce local recurrence - 10 to 16 Gy in 4-8 fractions
• Age <50
• High grade tumor
• Focally positive margins after BCS
• (ii) Chest wall RT (CWRT)
◦ Targets
‣ Ipsilateral chest wall
‣ Mastectomy scar
‣ Drain sites
◦ Special techniques using photons and electrons if breast reconstruction is done
◦ Schedules
‣ Standard schedule only 50 Gy in single fractions of 2 Gy per day → 5 weeks
‣ Booster dose to scar for higher risk patients - 2 Gy per fraction to a total dose of 60 Gy
• (iii) Regional nodal irradiation
◦ Targets
‣ Axilla
‣ Infraclavicular nodes
‣ Internal mammary nodes
‣ Supraclavicular nodes (upper axillary nodes)
◦ Has shown to reduce recurrences compared to WBRT/CWRT alone

• RT clinical circumstances
◦ RT after BCS
◦ RT after Mastectomy
• (A) RT after BCS
◦ WBRT to everyone following BCS
‣ node positive patients → category 1 recommendation
‣ node negative patients → 2A recommendation
◦ Boost to tumor bed in high risk patients - Age <50, High grade tumor, Focally positive margins
◦ Regional nodal irradiation (Axillary bed, infraclavicular, supraclavicular, internal mammary nodes) if axillary nodes
positive
‣ Category 1 recommendation if >4 LNs positive
‣ Not recommended for node negative disease
◦ RT is not always necessary if woman is >70 years old having an ER positive, node negative, T1 breast cancer →
Lumpectomy and Adjuvant Tamoxifen/AI alone is adequate (Category 1 recommendation)
• (B) RT after Mastectomy
◦ Node positive disease
‣ CWRT (Category 1 recommendation) + Regional nodal irradiation (all 4 areas - axillary bed, infraclavicular,
internal mammary, supraclavicular) (Category 1 if >4 LNs, Category 2A if 1-3 nodes)
◦ Node negative disease
‣ CWRT + Regional nodal irradiation (only supraclavicular and internal mammary areas) if features that predict high
rate of LR in node-negative disease are present
• Tumour size >5cm AND/OR
• Positive pathological margins
‣ CWRT alone if
• Tumour size is <5cm AND
• Negative margins, but margin clearance is <1mm
◦ RT is not indicated
‣ Nodes negative
‣ Tumour <5cm AND
‣ Resection margin clearance >1mm
Systemic Therapy
• Neo-adjuvant/Preoperative • Adjuvant
◦ Endocrine therapy
◦ Chemotherapy
(1) Neo-adjuvant/Preoperative systemic therapy ◦ Biological therapy
• Principles
◦ Rationale
‣ RCTs have shown no difference in long term outcome when systemic chemotherapy is given before or after
surgery
◦ Benefits of preoperative chemotherapy
‣ renders inoperable tumors resectable
‣ downstage operable breast cancer to make BCS possible
‣ provides prognostic information about the aggressiveness of the tumor based on response to therapy
• If pathologic complete response (pCR) can be achieved → favorable disease free and OS
◦ This correlation is best seen in Triple negative disease, than HER 2 positive disease but least for
hormone positive disease
‣ Allows time for appropriate genetic testing
‣ Allows time to plan breast reconstruction in patients proceeding with mastectomy
◦ Selecting patients
‣ Inoperable breast cancer to make them resectable
• T4
• N2 and N3
• Inflammatory breast cancer
‣ Operable cancer with features suggestive of needing adjuvant chemotherapy following surgery, but BCS is not
possible due to the relative size of the tumor to the breast, and patient requests for BCS
‣ Even if BCS is not possible, for operable tumors that will need post op chemotherapy - neo-adjuvant is acceptable
◦ Deselecting patients
‣ Extensive in situ disease
‣ When extent of the tumor is poorly delineated
‣ In those whose tumors are not palpable
◦ Neo-adjuvant options
‣ Chemotherapy
• Regimens for HER2 negative disease
◦ AC (Doxorubicin + Cyclophosphamide) given together on day 1 followed by Paclitaxel given over 3
hours on day 1 and this cycle is repeated every 2 weeks for 4 cycles
‣ Another option is → AC given together on day 1 followed by Paclitaxel over 1 hour given on day 1
then AC cycled 2 weekly for 4 cycles, while Paclitaxel cycled weekly for 12 cycles
◦ TC (Docetaxel + Cyclophosphamide)
◦ CMF (Cyclophosphamide + Methotrexate + 5-fluorouracil)
• Preferred regimens for HER2 positive disease
◦ AC followed by T (Taxane - Paclitaxel) + Trastuzumab +/- Pertuzumab
‣ Anthracycline based CT is better than non-anthracycline based CT for HER2 positive BCa
◦ TCH (Docetaxel + Carboplatin + Trastuzumab) +/- Pertuzumab
‣ Endocrine therapy
• Can be offered as neo-adjuvant endocrine therapy for hormone receptor positive tumours
• Aromatase inhibitor or Tamoxifen
• For post-menopausal women - AI preferred
‣ Biological therapy
• For HER2 positive tumors if the patient is a candidate for neo-adjuvant chemotherapy, then
Trastuzumab + chemotherapy should be given (at least 9 weeks)
• Chemotherapy + Dual anti HER2 blockade with Trastuzumab + Pertuzumab is better than Chemotherapy +
Single anti HER2 blockade with Trastuzumab in achieving pCR
◦ Neosphere trial
◦ TRYPHAENA trial
‣ Therefore NCCN recommends the Chemo + Trastuzumab + Pertuzumab option for Neo-adjuvant
in down-staging strong HER2 positive early breast cancer if tumor is
• >T2 OR
• >N1
◦ Response assessment
‣ Routinely while on neo-adjuvant by clinical examination
‣ Imaging only if tumor seems to be progressing → in which case neo-adjuvant should be stopped and patient taken
for surgery promptly
 ◦ Algorithm of neo-adjuvant for operable breast cancer - Stage IIA, IIB, IIIA (T3 N1 M0) fulfilling
criteria for BCS except for tumor size (DOWN STAGING)
‣ Work up - same as for early breast cancer work up for surgery
• Additional points
◦ FDG PET/CT is optional and has a place here if standard staging studies are equivocal or suspicious but
not conclusive in the setting of locally advanced or metastatic disease
◦ When core biopsy of breast is performed placement of image detectable markers → to demarcate the
tumor bed
◦ Axilla USS → if +ve FNAC/Core biopsy
‣ If FNA/Core biopsy negative → SLNB before or after neo-adjuvant
‣ If FNA/Core biopsy +ve → Neo-adjuvant → Restage axilla after neo-adjuvant →
• If Axilla is still +ve → ALND
• If Axilla is now negative → ALND or SLNB (but >10% false negativity if SLNB is done in this
situation, and this can be reduced by marking previously core biopsied LNs, using dual tracer,
and removing >2 sentinel nodes) - (ACOSOG Z1071 trial)
‣ Proceed with neo-adjuvant therapy
‣ Assess response and do surgery accordingly
• If disease is progressing → Stop neo-adjuvant → Mastectomy done promptly
• If disease has responded,
◦ Partially, but BCS is not possible → Mastectomy
◦ Partially, but BCS is possible → BCS
◦ pCR → BCS
‣ Post operative adjuvant therapy
• Chemotherapy → Planned full course of CT to be completed (if not already completed pre-operatively)
• RT depending on the pre-operative staging of the disease
• Endocrine therapy sequentially after CT (if ER/PR positive)
• Trastuzumab → complete one year of therapy (to be continued if started pre-operatively) - can be given
concurrently with RT and Endocrine therapy
◦ Algorithm of neo-adjuvant for inoperable or locally advanced breast cancer - Stage IIIA's N2
disease, IIIB/T4 disease, IIIC/N3 disease (INOPERABLE → OPERABLE)
‣ Work up is similar to work up of invasive locoregional inoperable cancer
‣ Proceed with neo-adjuvant therapy
‣ Assess response
• if responded
◦ Total mastectomy + ALND
◦ BCS if feasible only + ALND
• If not responded → Continue additional systemic chemotherapy +/- RT
◦ If responded → as above
◦ If no response → Individualised treatment
‣ Post-operative adjuvant therapy - same as above
• RT
◦ if mastectomy → CWRT + Regional nodal irradiation (All 4 areas)
◦ if BCS → WBRT +/- Boost to tumor bed + Regional nodal irradiation (All 4 areas)

(2) Adjuvant
• Strongest prognostic factors that determine future recurrence or death from BCa
A. Age
B. Co-morbidity
C. Tumour size
D. Grade
E. Number of axillary LNs - single most important prognostic factor
F. HER2 status
a. if positive Trastuzumab can be used in the treatment
b. anthracycline based chemo is superior to non-anthracycline based chemo in HER2 positive tumors!
G. Hormone receptor status (ER/PR status)
• DNA microarray technologies allow breast cancer classification by gene expression profile → 4 types according to
The Cancer Genome Atlas Network (TCGA)
◦ ER/PR positive, HER2 negative - Luminal type A
‣ Most common
‣ Less aggressive, low grade, good prognosis, and advanced age patients
◦ ER/PR positive (sometimes PR-), HER2 positive - Luminal type B
‣ Poorer prognosis than Luminal A
 ◦ ER/PR negative, HER2 negative - Basal subtype (triple negative/cancer cells share gene expression just like basal
epithelial cells)
‣ Cytokeratin 5/6+, EGFR + in these!
‣ Aggressive, high grade, young and premenopausal (<40)
‣ 20% of breast cancers! 20% tend to have BRCA1 mutations!
◦ ER/PR negative, HER2 positive - HER2 enriched
‣ Rare, highly aggressive, high grade and young age!
• 21 gene RT-PCR assay → is the best validated prognostic assay
◦ Is predictive of loco-regional or distant recurrence for postmenopausal women treated with Tamoxifen or AI
◦ It also has the ability to predict who is likely to best benefit with chemotherapy - TAILORx study
‣ If score <18 - unlikely to benefit with CT and risk of local or distant recurrence is very low
‣ If score >30 - will benefit with CT in reducing the risk of distant recurrence
• Above factors determine the use of adjuvant therapies judiciously on patients

• Adjuvant options
(A) Endocrine therapy
◦ ER/PR status should be checked on all primary invasive breast cancers
◦ Options
‣ Selective ER modulators - Tamoxifen
• Action of Tamoxifen → binds to estrogen receptors and blocks the proliferative action of estrogen on the
mammary epithelium
• Side effects:
A. Commonest issues are postmenopausal symptoms (hot flashes, night sweats, vaginal dryness, irritation,
irregular menses)
B. 3 most significant problems are
a. Vascular problems - DVT and PE
b. Endometrial cancer
c. Cataract and retinopathy risk
• Reduces annual odds of recurrence by 39%, annual odds of death by 31% regardless of use of other adjuvant
therapy, age, menopausal status, LN status
• If patient is to get chemotherapy also, chemo should be given first followed by Tamoxifen sequentially
• Trials
◦ B-14 was the trial (Tamoxifen given for 5 years, placebo given for 5 years) that showed Tamoxifen was
effective in reduction of breast cancer DFS, distant DFS and overall survival

◦ An extension of B-14 trial was done for those who were given 5 years of Tamoxifen. Half was
continued on Tamoxifen for another 5 years and the rest was stopped at 5 years. It showed at the end
of 10 years, giving Tamoxifen for 10 years did not significantly improve breast cancer DFS compared to 5
year group. Therefore the standard treatment of Tamoxifen for 5 years was established.

◦ BUT then, despite B-14 other trials on longer duration of Tamoxifen continued beyond 10 years →
ATLAS (Aduvant Tamoxifen Longer Against Shorter) and aTTom (adjuvant Tamoxifen Treatment offers
more)
◦ ATLAS study followed up patients for 15 years and found that although effects of continuing Tamoxifen
after 5 years was not evident during the 5-9 year follow up period, the effect became statistically
significant after 10 years of follow up with reduction in breast cancer recurrence and breast cancer
related mortality in that category compared to just 5 years of Tamoxifen. (Absolute benefit in terms of
reducing breast cancer related mortality is just 2.8% only, but still statistically significant. Comparing with
side effects, continuing the therapy for 10 years should definitely be discussed with women as the added
benefit is just 2.8%)

‣ Aromatase inhibitors (AI)

• Action → binds to aromatase enzyme reversibly (also called estrogen synthase enzyme) which competitively
blocks the aromatisation of androgens to estrogen in peripheral tissue (extra-gonadal tissue)
◦ Does not act on pre-menopausal women and therefore should be only used when ovarian estrogen
production has stopped (post menopausal women)
• Drugs
◦ Non - steroidal AI
‣ Anastrozole
‣ Lestrozole
◦ Steroidal AI - Exemestane
 • Side effects:
A. Similar to Tamoxifen - hot flashes, night sweats, vaginal dryness, irritation, irregular menses
B. Osteoporosis and fractures
C. Arthralgia
• Trials
◦ ATAC (Aramidax-Tamoxifen-Alone or in Combination) has shown Aromatase inhibitor alone to be
statistically better than Tamoxifen alone or Tamoxifen + AI combination in improving
breast cancer disease free survival, reducing distant metastasis and contralateral breast cancer
occurrence.
‣ Tamoxifen + AI combination tends to have a deleterious effect from weak estrogenic effect of
Tamoxifen and that's why the combination was not good.
◦ TEXT-SOFT - has shown AI (Exemestane) + ovarian suppression is better than Tamoxifen + ovarian
suppression in premenopausal women in reducing recurrences!
◦ BIG 1-98, ITA, IES, Arimidex Nolvadex (ARNO 95) trial - Multiple studies on switching therapy
(crossing over from Tamoxifen to AI, AI to Tamoxifen etc.) → All these show use of 3rd generation AI in
postmenopausal women with hormone receptor positive breast cancer lowers the risk of
‣ ipsilateral breast cancer recurrence
‣ contralateral breast cancer
‣ distant metastatic disease
• When used as
◦ initial adjuvant OR
◦ sequential therapy OR
◦ extended therapy
‣ Ovarian suppression/ablation
• Ovarian ablation/suppression is as good as giving chemotherapy (CMF - Cyclophosphamide/Methotrexate/
Fluorouracil) for hormone receptor sensitive BCa
◦ But CMF has better effects on hormone receptor negative cancer!
• Methods
◦ Ovarian suppression achieved by → LHRH agonists (Goseralin as monthly depot injection) - inhibits the
pulsatility of LHRH release that is required to release LH and FSH from ant. pituitary
◦ Ovarian ablation achieved by
‣ Oophorectomy OR
‣ Ovarian RT
◦ NCCN recommendations
‣ At the start of therapy Pre-menopausal
• 1) Tamoxifen for 5 years with or without ovarian suppression
• 2) Ovarian suppression + AI for 5 years for high risk of recurrence patients
◦ Young age
◦ High grade tumor
◦ LN involvement
• To start AI, "True Postmenopausal Status" should be ensured. Premenopausal women who were started on
chemotherapy can become amenorrhoeic due to chemo effects but continue to secrete estrogen from
ovaries → For them either
◦ Oophorectomy OR
◦ Serial measures of FSH and/or estradiol levels to ensure levels in postmenopausal range should be done
‣ At the start of therapy post-menopausal
• Criteria to determine menopause
◦ Prior bilateral oophorectomy
◦ Age >60
◦ Age <60 with amenorrhoea for >12 months in the absence of chemo, tamoxifen or ovarian suppression
+ FSH/estradiol levels in postmenopausal range
◦ If taking tamoxifen and age <60 → FSH/estradiol levels in postmenopausal range
• 4 possible options of endocrine therapy
◦ 1) AI as initial therapy for 5 years ◦ 3) Tamoxifen for 4.5-6 years followed by
◦ 2) Tamoxifen for 2-3 years followed by ‣ 5 years of AI
‣ AI to complete 5 years ◦ 4) For those who decline or have CIº for AI
‣ 5 years of AI ‣ Tamoxifen for 5 years → consider up to 10
‣ At the beginning pre-menopausal, but after 5 years of therapy post-menopausal
• Extend the therapy for 5 more years with AI (Category 1 recommendation) OR
• Continue tamoxifen for 5 more years
‣ At the beginning pre-menopausal, and after 5 years of therapy still pre-menopausal
• Consider continuing tamoxifen up to 10 years
 (B) Chemotherapy
◦ Regimens for HER2 negative disease - Same as neo-adjuvant
‣ AC (Doxorubicin + Cyclophosphamide) followed by T (Pacletaxel)
‣ TC (Paclitaxel + Cyclophosphamide)
‣ CMF (Cyclophosphamide + Methotrexate + 5-FU)
◦ Regimens for HER2 positive disease - Same as neo-adjuvant
‣ AC followed by T + Trastuzumab +/- Pertuzumab
‣ TCH (Docetaxel + Carboplatin + Trastuzumab) +/- Pertuzumab
(C) Biological therapy
◦ Trastuzumab
‣ Humanised monoclonal antibody that binds to extracellular domain of HER2
‣ Side effects: Cardio toxicity
◦ Trials
‣ HERA - OS with Trastuzumab is higher in HER2 positive disease
‣ ALTTO - Although Neosphere and TRYPHAENA trials in neoadjuvant setting showed benefit of use of dual
antiHER2 therapy, same benefit is not seen in adjuvant setting.
◦ NCCN recommendations
‣ Trastuzumab should be given with chemotherapy concomitantly and then continued as a mono therapy to
complete a period of 1 year!
‣ Should be used for HER2 positive
• Node positive disease
• Node negative but tumors >1cm
‣ Suggests use for HER2 positive
• Node negative tumors of 0.6-1cm
• <0.5cm tumors with axillary nodal micromets
◦ Because the recurrence rate for these tumors compared to HER2 negative group is higher
‣ Preferred regimens are (same as above said chemo regimens in HER2 positive disease)
• AC (Doxorubicin + Cyclophosphamide) followed by T (Paclitaxel) and Trastuzumab
◦ Trastuzumab 4mg/kg IV given with the first dose of Paclitaxel and continued as 2mg/kg IV weekly for 1
year while Paclitaxel is given weekly for 12 weeks and AC given in 21 day cycles for 4 cycles
• TCH → This is preferred in patient with poor cardiac profile as Anthracycline + Trastuzumab combination is
not good for them (although Anthracycline based chemo + Trastuzumab for HER2 positive tumors is better
than non-anthracycline based chemo + Trastuzumab)
• Because of the unprecedented improvement in OS in metastatic breast CA and significant improvement in
pCR in neo-adjuvant setting → Pertuzumab can be considered even in adjuvant setting as a second anti HER2
drug in addition to Trastuzumab in the same above regimens, provided patient has not received Pertuzumab
as part of neo-adjuvant!
‣ Should check left ventricular function - baseline and 3 monthly while on the medication

• Algorithms
◦ Patient stratification for adjuvant therapy is based on ER/PR status and HER2 status
‣ Then further decisions are based on other tumor characteristics
• Tumour type
• Tumour grade
• Tumour size
• ALN status
• LVI invasion
◦ Adjuvant algorithm in DUCTAL, LOBULAR, MIXED, METAPLASTIC breast cancer
‣ ER/PR positive HER2 Negative (Luminal A type)
• Node positive (>2mm one or more mets positive in an ipsilateral LN)
◦ Chemotherapy → then Endocrine therapy
• Node negative
◦ Tumour >0.5cm → do 21-gene RT-PCR assay (Oncotype-Dx)
‣ Low recurrence score <18 → Endocrine therapy alone
‣ Intermediate recurrence score 18-30
• Endo alone OR
• Chemo + Endo
‣ High recurrence score >30 → Chemo + Endo
‣ If assay not done
• Endo alone OR
• Chemo + Endo
 ◦ Tumour <0.5cm
‣ Micromets absent
• No therapy OR
• Consider Endo alone to reduce a second contralateral BCa
‣ Micromets present
• Endo alone OR
• Chemo + Endo
‣ ER/PR positive HER2 Positive (Luminal B type)
• Node positive → Chemotherapy with Trastuzumab followed by Endocrine therapy
• Node negative
◦ Tumour >1cm → CT + Trastuzumab followed by Endo
◦ Tumour <1cm
‣ <0.5 and micromets absent
• No therapy OR
• Consider Endo alone OR
• Consider CT + Trasuzumab followed by Endo
‣ <0.5 and micromets present OR tumor size is 0.5-1cm
• Endo alone OR
• CT + Trasuzumab followed by Endo
‣ ER/PR negative HER2 negative (Basal type/Triple Negative Breast Cancer - TNBC)
• Node positive → Chemotherapy
• Node negative
◦ Tumour >1cm → Chemotherapy
◦ Tumour <1cm
‣ <0.5cm and no micromets → No therapy
‣ <0.5cm with micromets OR 0.5-1cm
• No therapy OR
• Consider chemotherapy
‣ ER/PR negative HER2 positive (HER2 Enriched type)
• Node positive → Chemotherapy with Trastuzumab
• Node negative
◦ Tumour >1cm → Chemo with Trastuzumab
◦ Tumour <1cm
‣ <0.5cm and no micromets
• No therapy OR
• Consider Chemo with Trastuzumab
‣ <0.5cm with micromets OR 0.5-1cm
• Consider Chemo with Trastuzumab

◦ Adjuvant algorithm in Favorable histologies - Tubular OR Mucinous breast cancer

‣ ER/PR positive
• Node positive
◦ Endocrine therapy alone OR
◦ Chemotherapy followed by endocrine therapy
• Node negative
◦ Tumour >3cm → Endocrine therapy alone
◦ Tumour <3cm
‣ <1cm
• No therapy
• Consider Endo to reduce risk
‣ 1-3cm
• No therapy
• Consider Endo
‣ ER/PR Negative - manage as usual breast cancer
• Repeat ER/PR status
◦ ER/PR Positive → as above
◦ ER/PR Negative → Do HER2 status
‣ If HER 2 Positive → Manage as ER/PR negative HER2 Positive (HER2 Enriched) usual breast cancer
‣ If HER 2 Negative → Manage as TNBC
 (3) INVASIVE LOCOREGIONAL INOPERABLE
Locally advanced breast cancer (Stage III except IIIA's T3N1M0)

Work up - almost like early breast cancer

• Diagnosis
◦ History and examination
◦ Diagnostic bilateral mammogram
◦ USS of breast and axilla
◦ MRI for mammographically occult tumour
◦ Core biopsy of breast lesion is a must and guided FNAC of axillary nodes
‣ Core biopsy is a must because it gives the diagnosis, grade, and receptor status and following neo-adjuvant 9% can
get cPR (complete pathological response), in which case there won't be tissue to do receptor study!
• Staging (Chance of mets is 33%)
◦ Lab tests
‣ FBC, LFT including ALP
◦ Chest CT with contrast
◦ Abdominopelvic CECT or Contrast MRI
◦ Bone scan or NaF PET/CT
◦ FDG PET/CT is optional (if this is done and bone mets are seen, Bone scan or NaF PET/CT is not necessary)
• Other aspects
◦ Genetic counseling for high risk for hereditary breast cancer
◦ Fertility counseling for pre-menopausal
◦ Distress assessment

Management
• Same as what is discussed under neo-adjuvant for inoperable locoregional invasive cancer
• Systemic therapy
◦ ER +ve, HER 2 -ve
‣ Chemotherapy followed by Endocrine therapy
• AC (Doxorubicin + Cyclophosphamide) followed by T (Paclitaxel)
• TC (Docetaxel + Cyclophosphamide)
• CMF
◦ ER +ve, HER 2 +ve
‣ Chemotherapy + Trastuzumab +/- Pertuzumab followed by Endocrine therapy
• AC followed by T + Trastuzumab +/- Pertuzumab
• TCH (Docetaxel + Carboplatin + Traztuzumab) +/- Pertuzumab
◦ ER -ve, HER 2 -ve
‣ Chemotherapy alone
• AC followed by T
• TC
• CMF
◦ ER -ve, HER 2+ve
‣ Chemo + Trastuzumab
• AC followed by T +/- Pertuzumab
• TCH +/- Pertuzumab
• Response assessment
• Surgery depending on response
◦ If responded
‣ Mastectomy + level II AC
‣ BCS + level II AC
◦ If not responded → continue systemic therapy again +/- RT (Palliative breast irradiation)
‣ If responded → As above
‣ If not → individualized treatment
• Adjuvant after surgery
◦ Chemotherapy - to complete the course if preoperatively not completed
◦ Endocrine therapy for Hormone receptor +ve patients sequentially once CT is over
◦ Trastuzumab up to 1 year if HER2 +ve
◦ RT → CWRT/WBRT (depending on mastectomy or BCS) + regional nodal irradiation
Post-Therapy Surveillance for Invasive locoregional operable and inoperable cancer
(Stage 1, II, III)
• The risk of developing a recurrence or another primary breast cancer after surgery for breast cancer is 7 fold higher than
the normal population → thus proper surveillance is required
• Same treatment team should do the surveillance
• History and examination every 4-6 months (1-4 times per year) up to 5 years, and then annually thereafter
• Mammogram annually for BCS patients
◦ Should wait 6-12 months after the completion of RT for the post therapy 1st mammogram
• No need of any other investigations in the absence of symptoms and signs
◦ No Lab tests including LFTs and ALP
◦ No tumour markers
◦ No bone scans
◦ No CT scans
◦ No MRI scans except in those women who have BRCA1/2 with high life time risk of developing a second breast cancer
◦ No PET scans
◦ No USS
• Surveillance on endocrine therapy patients
◦ Tamoxifen - Yearly gynecological assessment for women with intact uteri (endometrial cancer)
‣ If vaginal spotting - rapid evaluation
◦ Aromatase inhibitors
‣ Serial estradiol and FSH levels if AI started to ensure postmenopausal status
‣ Bone mineral density
• Level at baseline and periodically thereafter
• Medication to improve bone mineral density
◦ Bisphosphonate (Zoledronic acid)
‣ Should under go a dental examination prior to initiation of Bisphosphonate because of risk of
osteonecrosis of jaw (ONJ) with poor baseline dental health
‣ Should take supplemental calcium and vit D
◦ Denosumab
‣ Should under go a dental examination for the same reason as bisphosphonates (ONJ risk)
◦ Symptom management of endocrine therapy
‣ Hot flashes - Venlafaxine (Serotonin-norepinephrine reuptake inhibitor - SNRI)
• Fluoxetine (SSRI) should not be used as it decreases endoxifen → the active metabolite of tamoxifen
‣ Concurrent depression
• Checking compliance on medication
• Lymphoedema management
◦ Risk is high with
‣ Axillary clearance
‣ Axillary radiation
‣ Infection
‣ Obesity
◦ Action
‣ Educate
‣ Monitor
‣ Refer for lymphoedema management
• Patient education on
◦ Compliance
◦ Lymphedema
◦ Contraception for pre-menopausal women → methods other than hormonal birth control methods should be used
regardless of the hormone receptor status of the tumor
‣ IUCD
‣ Barrier methods
‣ If no intent for future pregnancy - LRT
◦ Breast feeding → Not to breast feed the child while on adjuvant CT and ET
◦ Life style modification
‣ Control BMI at 20-25
• High fruit and vegetable consumption
• Low fat diet (more effective with hormone receptor negative patients)
• Physical activity
‣ Stop smoking
‣ Stop alcohol consumption
 (4) INVASIVE METASTATIC (STAGE IV) BREAST CANCER

Work up
• History and examination
• Lab tests
◦ FBC
◦ LFT including ALP
◦ Metabolic panel - S.Cr, Calcium, Phosphorus, Magnesium
• Visceral mets
◦ Chest CT
◦ Abdomiopelvic CECT or Contrast MRI
◦ Brain MRI if suspicious CNS symptoms
• Bone mets
◦ Spine MRI if back pain or symptoms of cord compression
◦ Bone scan or NaF PET/CT
◦ FDG PET/CT (if this is done, bone scan or NaF PET/CT is not necessary)
◦ X-rays of symptomatic long bones or long bones abnormal on bone scan
• Biopsy of first recurrence
◦ ER/PR HER2 status of the metastatic site

Management
• Mainstay of treatment is systemic therapy
◦ Since these patients have non-curable disease → use of less toxic systemic treatment is preferred (Endocrine over
Chemotherapy)
• Options
◦ Bone targeted therapy → Anti resorptive agents
‣ They target osteoclast activity to prevent "skeletal related events/SRE" in metastatic bone disease in BCa (4 SREs)
• bone fracture
• bone pain requiring RT
• spinal cord compression
• hypercalcemia
‣ Agents
• Denosumab RANK-Ligand inhibitor
• Bisphosphonates
◦ Zoledronic acid
◦ Pamidronate
‣ Should be started if
• survival is expected >3 months AND
• renal function is adequate
‣ Precautions
• All should be given with calcium and vit D supplementation
• Dental examination prior to treatment with these drugs is needed because of risk of osteonecrosis of the
jaw (ONJ) specially if
◦ Poor baseline dental health
◦ Dental procedures done during treatment
◦ Concomittant administration of chemotherapy or corticosteroid
‣ Dosing for zoledronic acid - monthly for 12 months then quarterly

◦ Endocrine therapy
‣ Premenopausal
• Selective ER Modulators/SERM (Tamoxifen or Toremifene)
• Ovarian ablation/suppression + ET as for post menopausal
‣ Postmenopausal
• AI
◦ Non-steroidal - Anastrozole or Letrozole
◦ Steroidal - Exemestane
• SERM (Tamoxifen or Toremifene)
• Palbociclib + Letrozole (category 1 recommendation)
• Ribociclib + Letrozole (category 1 recommendation)
• Selective ER down-regulators (Fulvestrant)
 ◦ Chemotherapy
‣ Single agents given sequentially is preferred over combined agents
• Anthrcycline - Doxorubicin
• Taxanes - Paclitaxel
• Antimetabolites - Capecitabine or Gemcitabine
• Microtubule inhibitors - Vinorelbine
◦ Surgery for local disease
• Since surgery for primary breast tumor in patients presenting with metastatic disease does not improve OS,
after primary treatment with systemic therapy surgery for primary breast tumor is only for
◦ Palliation of symptoms
◦ To address complications
‣ Skin ulceration
‣ Bleeding
‣ Fungation
• Surgery should be done only if
◦ Local clearance of tumor can be achieved AND
◦ Other sites of tumour are not immediately life threatening to the patient
◦ Therapies local to metastatic sites
‣ Types of therapies
• Surgery
• Radiation
• Regional chemotherapy (e.g.: intrathecal methotrexate)
‣ Indicated for localized metastatic scenarios
• Brain mets
◦ If resectable, mets elsewhere are not life threatening, and patient has good performance status →
Surgery + Whole brain RT
◦ If unresectable, but patient has good performance status → whole brain RT
◦ If poor performance status → palliation
• Leptomeningeal disease
• Choroid mets
• Pleural effusion
• Pericardial effusion
• Biliary obstruction
• Ureteral obstruction
• Spinal cord compression
• Impending pathological fractures
◦ Prophylactic long bone fixation
• Localised painful bone
◦ EBRT in single fraction to treat bone pain

• Algorithm in using systemic therapy

◦ Patient stratification for management purposes depends on
‣ Presence or absence of bone mets
‣ Then receptor status

◦ For patients with bone mets

‣ Add Denosumab or Bisphosphonates (Zoledronic acid or Pamidronate)
• Add Calcium and Vit D supplements
• Dental assessment prior to initiation
◦ ER/PR positive Her2 Negative (luminal A), ER/PR positive HER2 Positive (luminal B)
‣ If bone mets alone → Endocrine therapy
• If previously endocrine therapy given with in 1 year
◦ Premenopausal → Ovarian ablation or suppression + ET regimen as for postmenopausal women and
continue until progression of the disease → if progression occurs → change to a different regime up to 3
times → still no benefit → switch to chemotherapy
◦ Postmenopausal → one of the ET regimens which wasn't used before until progression → if progression
occurs → change to a different regime up to 3 times → still no clinical benefit → Switch to chemotherapy
• If previously endocrine therapy not given with in 1 year
◦ Premenopausal
‣ Selective ER modulators (SERM) - Tamoxifen or Toremifene OR
‣ Ovarian ablation/suppression + ET regime as for a postmenopausal woman
 ◦ Postmenopausal
‣ One of the above options
◦ Continue the ET until progression just like above and if progression of the disease occurs change over
to another regimen up to 3 times → if still no clinical benefit → switch to chemotherapy
‣ If visceral mets also → Straight away chemotherapy
◦ ER/PR negative HER2 negative (Basal)
‣ Bone mets alone
• Try with endocrine therapy even if ER/PR negative as long as patient is not endocrine refractory OR
• Chemotherapy → if no benefit after 3 sequential lines of chemotherapy or ECOG status is >3 (>50% of the
time spent in bed) → Palliation
‣ Visceral mets also → Chemotherapy → if no benefit or poor ECOG status → Palliation
◦ ER/PR negative HER2 positive (HER2 enriched type)
‣ Bone mets alone
• Try with endocrine therapy even if ER/PR negative as long as patient is not endocrine refractory OR
• Trastuzumab + chemo
‣ Visceral mets also
• Pertuzumab + Trastuzumab + Taxane → if no benefit after 3 sequential lines of targeted therapy or ECOG >3
→ Palliation

(5) RECURRENT BREAST CANCER

• Recurrent Disease
◦ Local Recurrence
‣ True Local Recurrence
‣ Marginal Miss
‣ Elsewhere Recurrence
◦ Regional Recurrence
‣ Axillary Recurrence
‣ Supraclavicular Recurrence
‣ Internal mammary node Recurrence

• Local Recurrence in a patient with

◦ Initally WLE + RT
‣ Total Mastectomy + SLNB if axillary clearance was not done before
◦ Initially Mastectomy + LII ALND + RT
‣ Surgical resection of the recurrence if possible
◦ Initially Mastectomy without RT
‣ Surgical resection of the recurrence if possible
‣ Then RT
◦ Then Systemic Adjuvant Therapy for all patients similar to metastatic disease

• Regional Recurrence
◦ Axillary Recurrence
‣ Surgical resection if possible
‣ RT to chest wall (if not given before), supraclavicular and infraclavicular nodes, axilla
◦ Supraclavicular Recurrence
‣ RT to chest wall (if not given before), supraclavicular and infraclavicular nodes
◦ Internal mammary node Recurrence
‣ RT to chest wall (if not given before), supraclavicular and infraclavicular nodes, internal mammary nodes
◦ Then Systemic Adjuvant Therapy for all patients similar to metastatic disease
Surveillance of metastatic and recurrent disease
• Aims
◦ To monitor for disease progression to see if treatment is providing benefit or not
◦ To find out whether patient is developing toxicity from the treatment
• Definition of disease progression
◦ Progression of disease can be identified through evidence of growth or worsening of the disease at previously known
sites or occurrence of disease in new sites
◦ Evidence
‣ H&E
• Worsening symptoms (pain, dyspnoea)
• Evidence of worsening disease or new disease found on physical examination
• Reducing performance status
• Unexplained weight loss
‣ Lab tests
• Increasing ALP, ALT, AST, Bilirubin
• Hypercalcemia
• Increasing tumor markers (CEA, CA 15-3, CA 27.29)
‣ Imaging
• Radiographic evidence of increase in size of a previous abnormality or appearance of a new abnormality
• New areas of abnormality on functional imaging (Bone scan, PET/CT)
• Principles of monitoring
◦ Same method of assessment should be used over time (e.g.: if an abnormality found on chest CT, it should be
monitored with a chest CT)
◦ Use of RECIST criteria (Response evaluation criteria in solid tumors) to evaluate
‣ Response
‣ Stability
‣ Progression of the disease
◦ Functional imaging (bone scan) can be challenging when used to assess response as responding disease itself can result
in a flare/increased activity on the scan → can misinterpret as disease progression
◦ Frequency of monitoring
‣ History and examination, performance status, weight, LFT and CBS
• Prior to each Chemo cycle
• Every 3 monthly with Endocrine therapy
‣ CECT
• Every 2-4 cycles of Chemo
• Every 6 monthly with ET
‣ Bone scan
• Every 4 cycles of Chemo
• Every 6 monthly with ET