2. Introduction
• Breast cancer - extremely heterogeneous disease caused by
interactions of both inherited and environmental risk factors
• Progressive accumulation of genetic and epigenetic changes in
breast cancer cells
• Tumors with similar clinical and pathological presentations may
have different behaviors
• Global gene expression profiling (GEP) studies - for classifying
breast cancer into distinct biological classes associated with patient
survival, based on gene expression patterns
4. Genetics
• Low penetrance high frequency breast cancer predisposition genes
o FGFR 2, LSP1, TOX3
• Moderate penetrance low frequency breast cancer predisposition
genes
o CHEK 2 ,BRIP1, ATM , PALB2
• High penetrance low frequency breast cancer predisposition genes
o BRCA1, BRCA 2, TP53, PTEN, CDH 1, STK11/LKB1
5. BRCA -1Breast
Cancer 1,Early
onset ( Chr.17)
BRCA-2, Breast
Cancer 2,Early onset(
Chr.13)
p53( Chr.17) CHEK2( Chr. 22)
FUNCTIONS:
1. Transcription
2. DNA Repair of
double
stranded
breaks
3. Ubiquitination
4. Transcriptional
regulation.
FUNCTIONS:
1. Stability of
the human
genome
2. DNA double
strand break
repair.
FUNCTIONS
1. Cell cycle
control
2. DNA
replication
3. DNA repair
4. Apoptosis.
FUNCTIONS
1. Cell cycle
checkpoint
kinase,
recognition and
repair of DNA
damage.
2. Activates
BRCA1 and p53
by
phosphorylation
Germline point
mutations/Deletions
of BRCA1 gene
Hereditary breast &
ovarian cancers.
Mutations 20%
Hereditary breast
cancer, ovarian
cancer, increased
cancer risk in male
carriers.
Mutations
Sporadic breast
cancers.
Li fraumeni
syndrome
Mutations - rare
(<5%).
Li fraumeni variant
Increase breast
cancer risk after
radiation exposure
6.
7. Differential Chemotherapeutic Sensitivity for
Breast Tumors With BRCA
• BRCA1 and BRCA2 germline mutations have an important role in DSB
repair of DNA
• Defective BRCA1 or BRCA2 functions and subsequently impair DNA
repair capacity
• Differentially more sensitive to DNA-damaging chemotherapeutic agents
• Resistant to taxanes
8. PATHOGENESIS – HORMONAL FACTORS
• Hormones breast growth during
puberty, menstrual cycles, pregnancy
cycles of proliferation cells at
risk for DNA damage.
• If premalignant or malignant cells are
present, hormones - stimulate their
growth + growth of normal epithelial
and stromal cells tumour
development.
• Metabolites of estrogen mutations
/ generate DNA-damaging free
radicals.
10. DUCTAL CARCINOMA IN SITU
Most DCIS detected by
calcifications on
mammography/mammographic density
- periductal fibrosis surrounding a
DCIS/rarely palpable mass/ nipple
discharge/incidental finding on a biopsy
for another lesion.
Spreads through ducts & lobules
extensive lesions entire sector of a
breast.
DCIS – involves lobules – acini
distorted, unfolded appear as small
ducts.
12. Comedocarcinoma
Solid sheets of pleomorphic cells
with high grade hyperchromatic
nuclei.
Areas of central necrosis +nt.
Necrotic cell membranes – calcify
clusters/linear & branching
microcalcifications on
mammography.
Periductal concentric fibrosis &
chronic inflammation.
Extensive lesions – palpable as
vague nodularity.
13. Noncomedo DCIS
Monomorphic cell population –
nuclear grades low to high.
CRIBRIFORM DCIS
Intra-epithelial spaces –evenly
distributed, regular in shape.
COOKIE CUTTER – LIKE
• SOLID DCIS
Completely fills the involved
spaces.
14. Noncomedo DCIS
PAPILLARY DCIS
Grows into spaces along
fibrovascular cores lack
myoepithelial cell layer.
• MICROPAPILLARY DCIS
Bulbous protrusions without a
fibrovascular core arranged in
complex intraductal patterns.
Calcifications – assoc.with
necrosis/form on intraluminal
secretions.
15. PAGET’S DISEASE OF NIPPLE
• Malignant cells/PAGET CELLS
Extend from DCIS within ductal
system – via lactiferous sinuses
nipple skin without crossing the
BM.
• Tumour cells – disrupt tight
squamous epithelial barrier – ECF
seeps out onto nipple surface
oozing scaly crust.
• Paget’s cells – detected by nipple
Bx/cytological preparation of the
exudate.
• Poorly differentiated, ER Negative,
HER2/neu overexpression.
• Prognosis – depends on features of
underlying Ca.
17. MANAGEMENT AND PROGNOSIS OF DCIS
Major risk factors for recurrence:
1. Grade
2. Size
3. Margins
In ER + ve DCIS Post-op. radiation + Tamoxifen
recurrence risk – low.
18. LOBULAR CARCINOMA IN SITU
Incidental biopsy finding -no
calcifications /stromal reactions
mammographic densities.
Bilateral - 20% to 40% .
Young women.
Loss of expression of E-
cadherin(transmembrane cell
adhesion protein cohesion of
normal breast epithelial cells).
19. LOBULAR CARCINOMA IN SITU - MORPHOLOGY
• Dyscohesive round cells with oval
or round nuclei and small nucleoli.
Absence of atypia, pleomorphism,
mitoti activity, necrosis.
Involved acini – recognizable as
lobules.
Mucin-positive signet-ring cells.
ER and PR +ve.
20. Invasive Carcinoma, No Special Type
(NST; Invasive Ductal Carcinoma)
Majority (70% to 80%).
Gross appearance: Most
tumors - firm to hard
,irregular border . Less
frequently - well-circumscribed
border , softer consistency.
When cut / scraped
characteristic grating sound
d/t small, central pinpoint foci
or streaks of chalky-white
elastotic stroma and occasional
small foci of calcification.
21. Invasive Carcinoma – NST- HPE
Features Well diff. Ca Mod. diff.Ca Poorly diff. Ca.
Tubule formation Prominent Less,solid
clusters/single
infiltrating cells
Ragged nests/solid
sheets of cells
Nuclei Small,round,mono
morphic
Greater nuclear
pleomorphism
Nuclei –
enlarged,irregular.
Mitotic figures Rare Present Numerous
Proliferation rate - - High
Tumour necrosis - - Present
22. INVASIVE LOBULAR CARCINOMA
Well-differentiated and moderately
differentiated carcinomas diploid, ER
positive, HER2/neu overexpression - rare
Poorly differentiated carcinomas
aneuploid, lack hormone receptors, may
overexpress HER2/neu.
Different pattern of metastasis than other
breast cancers. Metastasis peritoneum
,retroperitoneum, the leptomeninges
(carcinoma meningitis), the
gastrointestinal tract, ovaries and uterus.
23. MEDULLARY CARCINOMA
MC - 6th decade.
May closely mimic a benign lesion
clinically and radiologically/
present as a rapidly growing mass.
MORPHOLOGY : Well –
circumscribed,soft,fleshy mass -
little desmoplasia more yielding
on palpation and cutting. (medulla
=>“marrow”).
24. MEDULLARY CARCINOMA - HPE
1. Solid, syncytium-like sheets of large
cells with vesicular, pleomorphic
nuclei, prominent nucleoli > 75%
of the tumor
2. Frequent mitotic figures;
3. Moderate to marked
lymphoplasmacytic infiltrate
surrounding and within the tumor.
4. Pushing (noninfiltrative) border
• Poorly differentiated.
26. MUCINOUS/COLLOID CARCINOMA
Older women (median age 71)
grow slowly - many years.
Morphology: Tumor –
soft/rubbery . Consistency &
appearance of pale gray-blue
gelatin. Borders - pushing /
circumscribed.
27. MUCINOUS CARCINOMA - HPE
Tumor cells - arranged in clusters
and small islands within large lakes
of mucin.
Mucinous carcinomas diploid,
well to moderately differentiated,
and ER positive.
Lymph node metastases -
uncommon.
Overall prognosis is slightly better.
28. INVASIVE PAPILLARY & MICROPAPILLARY
CARCINOMA
Rare - 1% or fewer of all invasive
cancers.
More commonly seen in DCIS.
INVASIVE PAPILLARY CA.
ER positive.
Favorable prognosis.
INVASIVE MICROPAPILLARY
CA.
ER negative,HER2 positive.
Lymph node metastases - very
common
Prognosis is poor.
29. METAPLASTIC CARCINOMA
Includes a variety of rare types of
breast cancer (<1% of all cases)
matrix-producing carcinomas,
squamous cell carcinomas, and
carcinomas with a prominent spindle
cell component.
ER-PR-HER2/neu “triple negative”.
Lymph node metastases - infrequent.
Prognosis - poor.
30. TUBULAR CARCINOMA
• Uncommon.
• Morphology: Well-formed tubules
+ nt, myoepithelial cell layer, BM -
nt tumor cells in direct contact
with the stroma. Apocrine snouts -
typical.Calcifications - within the
lumens.
• > 95% of all tubular carcinomas -
diploid, ER + ve,HER2/neu –ve .
• Well differentiated. Excellent
prognosis.
31. INFLAMMATORY CARCINOMA
Tumors swollen, erythematous
breast - caused by extensive
invasion and obstruction of
dermal lymphatics by tumor
cells.
Underlying carcinoma - diffusely
infiltrative - does not form a
discrete palpable mass
confusion with true inflammatory
conditions a delay in diagnosis.
Many patients metastases at
diagnosis / recur rapidly.
Overall prognosis poor.
32. Disease patterns in ER +ve
• Have better outcomes
• Potential for recurrence over a long period (half recurrences in between 6 to
15 years )
• Better survival even in a recurrence or a metastatic setting
• predilection for osseous metastasis – women who relapse after a decade do
so in bones in majority of cases
33. Impact of histology
• Invasive ductal vs invasive lobular
• Invasive lobular associated with older age at presentation , larger
tumors of lower grade with less LVI
• ILC more likely to be bilateral and multicentric and exclusively ER
PR positive and HER 2 negative
• ILC tend to be mammographically occult
• ILC more likely to involve bone, ovary and the body cavities
• Rare sites like skin, adrenal, GB, pancreas more often with ILC
Loss of
CDH
35. HER2/neu
• Human Epidermal growth factor Receptor 2
• Member of ErbB protein family.
• HER2 is a cell membrane surface-bound receptor tyrosine kinase -
normally involved in signal transduction pathways cell growth and
differentiation.
• Approximately 30 % of breast cancers amplification of
the HER2/neu gene/ overexpression of its protein product.
36. HER 2 status
• More likely to be detected symptomatically
• Younger age, high nuclear grade, more LN and negative hormone
status
• Inferior OS
• Following BCS locoregional recurrence rates are higher and re
excision rates are higher
• Distant mets to liver and lungs
• CNS acts as a sanctuary site present in more than 50 % with mets
37. Triple negative status
• 15% of the breast cancers
• Relatively younger population
• Larger tumors, mostly grade 3, aggressive phenotype, less likely to
have lymph nodes
• Overall poorer prognosis
• OS from diagnosis of mets - 7- 12 months
• OS from diagnosis of CNS disease - 4 -5 months
40. Luminal like
• ER-positive group - relatively high expression of many genes
expressed by breast luminal cells (ER-responsive genes, luminal
cytokeratins and other luminal associated markers)
• Luminal A - 50- 60 % of all breast types
• low histological grade, low degree of nuclear pleomorphism, low
mitotic activity (low Ki 67)and include special histological types
(i.e., tubular, invasive cribriform, mucinous and lobular) with good
prognosis.
41. • Luminal B 15- 20 % -
• increased expression of proliferation-related genes FGFR1, PI3K
• ER-positive, HER2-negativeand Ki 67 high or ER and HER-2
positive tumors
• more aggressive phenotype, higher histological grade, proliferative
index and a worse prognosis
• Ki 67 cut off 14% differentiates the two
42. Basal like
• 8- 37% of all breast cancers
• Most of these tumors are infiltrating ductal tumors with solid growth
pattern, aggressive clinical behavior and high rate of metastasis to
the brain and lung
• Express high levels of basal myoepithelial markers, such as CK5,
CK 14, CK 17 and laminin, triple-negative.
• They also overexpress P-cadherin, fascin, caveolins 1 and 2,
alphabeta crystallin and epidermal growth factor receptor (EGFR).
43. Basal like
• triple-negative and basal-like are not completely synonymous
• frequent mutations in the tumor protein 53 (TP53) gene,
retinoblastoma (Rb)
• constitute approximately three quarters of breast cancer 1 (BRCA1)
gene related breast cancers.
44. Normal breast-like
• 5%-10% of all breast carcinomas.
• clinical significance remains undetermined
• negative for CK5 and EGFR otherwise similar to basal type on
expression of various markers
• intermediate prognosis between luminal and basal-like cancers and
usually do not respond to neoadjuvant chemotherapy
45.
46.
47. TNBC status
• Higher loco regional recurrence rates
• Significant excess visceral involvement – pulmonary and CNS
• metastatic TNBC - 33- 46 % CNS
• Rarely there is a recurrence after 5 years compared to other subtypes
with recurrence even at 17 years
• Triple-negative breast cancer is highly responsive to primary
anthracycline and anthracycline/taxane chemotherapy
• A more profound initial response to chemotherapy compared with
other phenotypes despite poorer overall survival
48. CLINICAL GENE EXPRESSION BASED
ASSAYS
• PAM 50 –
• a 50 gene expression assay based on microarray and quantitative
real time (qRT)-PCR
• provide a risk of relapse score that predicts relapse-free survival for
node-negative breast cancer patients who had not received adjuvant
systemic therapy
49. MammaPrint
• a microarray based gene expression profiling assay
• The genes that comprise the MammaPrint assay are
proliferation genes and genes associated with invasion and
angiogenesis
• 70-gene signature
• Stage Ⅰ/Ⅱ, 5 cm, ER (+), Node (-)/[1-3 Node (+)]
• FDA approved - Yes
50. Oncotype DX
• most widely used prognostic and predictive
• 21 gene qRT-PCR based assay
• hormone receptor positive, node-negative breast cancer
• 21 selected genes essentially related to proliferation, ERand HER2
signaling
• absolute clinical benefit of adjuvant chemotherapy in lymph node
negative (N-) breast cancer is modest, estimated absolute benefit of
4% in terms of 10-year distant recurrence
• The Trial Assigning IndividuaLized Options for Treatment (Rx)
51.
52. • GENOMIC GRADE INDEX
• MapquantDx is defines the tumoral histological grade by gene
expression features, used to assign a grade index to ER-positive
breast cancers in attempt to refine their molecular classification.
• to classify grade 2 tumors into low and high genomic grades
• BREAST CANCER INDEX
• the likelihood of distant recurrences in patients diagnosed with ER-positive,
node-negative breast cancer.
54. Therapeutic targets
• Estrogen signalling - therapeutic success story
• SERMs, aromatose inhibitors and ovarian ablation
• Highly effective and have a made a significant impact on breast
cancer mortality and morbidity
• Oncotype DX - adds additional insight
55. Growth factor receptor
pathways
• HER2 (EGFR 2 or Erb2 ) -
• HER2 amplification is associated with deregulation of G1/S phase
cell cycle control via up-regulation of cyclins D1, E, and cdk6, as
well as p27 degradation
Trastuzumab-
• disrupts heterodimeric interaction of HER2 with other EGFR family
members
• modulate host immunity, activating natural killer cells involved in
antibody-dependent cellular cytotoxicity
• decrease tumor-associated microvessel density
56. • Lapatinib - inhibits tyrosine phosphorylation of both EGFR and
HER 2 which in turn inhibits the activation of proproliferative
kinases ERK1/2 and AKT
• IGF – 1R - primary response
mediator for IGF
57. • PI3-K Pathway – central signalling pathway
downstream of tyrosine kinases and
regulates cell growth and proliferation
Rapamycin - m TOR inhibitors
Raf inhibitor - sorafenib
58. Angiogenesis
• VEGFR 2 mediates most of the functions
• Bevacizumab - humanized monoclonal antibody
• First line metastatic setting
Multi targeted agents
Sunitinib - VEGFR, PDGFR and c- kit
Sorafenib - VEGFR, RAF kinase
59. Summary
• The histological appearance of the tumors may not be sufficient to
establish the underlying complex genetic alterations and the
biological events involved in cancer development and progression
• Defining more detailed biological characteristics to improve patient
risk stratification and to ensure the highest chance of benefit and the
least toxicity from a specific treatment modality
