2. GENETICS OF BREAST CANCER
80-90% SOMATIC GENETIC ALTERATIONS-SPORADIC CANCERS
10%-GERMLINE MUTATIONS –HERIDITARY BREAST CANCER
SYNDROME
3. Breast cancer susceptibility genes can be
categorized into three classes according to their frequency and
level of risk they confer:
• rare high-penetrance genes
• rare intermediate-penetrance genes
• common lowpenetrance genes and loci
4.
5. They are traditionally classified on the basis of
• morphological feature,
• histological features,
• tumor grade, and stage
• proliferation status,
• Lymphovascular invasion.
7. • Breast Cancer is caused by
heterogenous group of tumor cells
whose behaviour and response to
therapy depends on biological
features.
• Therefore biologic properties of the
tumor play an important role in its
management
Eliyatkin N et al, Journal of Breast Health 2015; 11: 59-66 Perou, C., Sørlie, T., Eisen, M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000)
8. Molecular Subtyping- Gene Expression Profiling
Measurement of activity (the expression) of thousands of genes
at the level of transcription, at once, to create a global picture
of cellular function.
9. Why do we need to do Molecular Subtyping?
Molecular testing in breast cancer is used to
– Classify tumor types,
–recognize hereditary implications (eg, BRCA1 mutations
– identify appropriate therapeutic agents (eg, HER2+ disease or ER/PR +
disease),
– Determine the prognosis of the disease by giving the risk score,
– Identify biomarkers that can predict or monitor the response to treatment
– To avoid unnecessary treatment to all cancer patients.
Sorlie et al;Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
10.
11. •In Perou’s study two main tumor clusters were identified.
a) ER- positive cluster and was termed luminal in reference to its molecular
similarity to luminal mammary epithelial cells( LUMINAL- A ,LUMINAL- B)
b) ER- negative cluster which exhibited three sub classes -HER 2 positive, basal
like and normal breast type.
Other novel molecular classes claudin-low and apocrine subtypes have triple
negative phenotypes.
12. Intrinsic Breast Cancer Subtypes
• Luminal-like Breast Cancer Types
-Luminal A
-Luminal B
• HER2 enriched breast cancer subtype
• Basal-like breast cancer subtype
• Normal breast like subtype.
Perou, C., Sørlie, T., Eisen, M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000)
Annals of Oncology 23: 2997–3006, 2012 doi:10.1093/annonc/mds586
13. Luminal A
• Approximately50-60% of all breast cancers are classified as luminal A.
• Derives its name from its similarity to the expression profile of normal luminal breast
epithelium.
• Overexpression of ER-regulated genes
• Underexpression of an HER2 gene cluster
• Underexpression of proliferation-related genes.
• Low grade
• include special histological sub types (tubular, mucinous, cribriform,lobular)
• Sensitive to endocrine manipulation( hormonal therapy).
• Less sensitive to cytotoxic agents in both the neoadjuvant and metastatic settings.
• They have favorable prognosis
14. Luminal B
• They represent about 20% of breast cancers.
• Have lower expression of ER-related genes
• Variable expression of an HER2 cluster of genes,
• Relatively higher expression of proliferation related genes Ki67,FGF1,P13K.
• Aggressive phenotype, higher grade,
• They also been shown to have genomic instability, and to harbor mutations in
TP53.
• less sensitive to cytotoxic chemotherapy, sensitive to hormonal therapy
• Associated with a relatively higher risk of relapse.
16. ER ,PR Scoring system and criteria as per Allred
scoring system
17. ER + LOW SUB GROUP
Benefit of HT for tumours with ER 1-10% EXPRESSION ,EXPRESSION
TERMED “ER LOW POSITIVE”
3-9% of all patients
Moderate benefit from tamoxifen in terms of RFS,DFS,OS and TIME TO
RECURRENCE
19. HER2 enriched breast cancer subtype
• It is characterized by high expression of
– HER2
– Proliferation genes
• low expression of luminal clusters.
• Constitute 20% to 30% of all breast
tumors.
• Clinically, they are associated with a
poorer prognosis
20. Basal Like
• Constitute about 15% of invasive ductal breast cancers.
• Its name is derived from shared gene expression patterns with normal basal
epithelial cells.
• They are considered ER/PR and HER2 negative (“triple negative”)
• This subtype is also characterized by relatively high frequency of BRCA1
mutations, increased genomic instability,
• High expression of the proliferation cluster of genes (basal myoepiythelial
markers like CK5,CK14,CK17and laminin. Overexpression P-Cadherin, Fascin ,
Caveolins 1&2 , alphabeta crystallin and epidermal growth factor receptor –EGFR
• A high histologic grade
• High rates of metastasis to the brain and lung.
21. Normal Breast Like
• 5-10% of breast carcinomas
• Clinical significance underdetermined
• Negative for CK5 and EGFR otherwise similar to basal like in expression of
various biomarkers
• Intermediate prognosis between luminal and basal and usually do not respond to
neoadjuvant chemotherapy
22. Summary of the major molecular subtypes
Eliyatkin N et al, Journal of Breast Health 2015; 11: 59-66
23. 2013 ST GALLEN INTERNATIONAL BREAST
CONFERENCE REPORTED THAT
Breast ca should not be treated as single disease but
should be defined by molecular subtypes using genetic
array testing or by IHC
27. Hormonal pathways
• 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
32. Clinical trials implicated in the
development of multigene prognostic
signatures
Vieira AF and Schmitt F (2018) An Update on Breast Cancer Multigene Prognostic Tests—Emergent Clinical Biomarkers. Front. Med. 5:248.
33. Multigene assay
• Oncotype DX
• Mammaprint
• PAM50
• Breast Cancer Index
• Endopredict Index
• IHC4 score
• Next Generation Sequencing
34. Vieira AF and Schmitt F (2018) An Update on Breast Cancer Multigene Prognostic Tests—Emergent
Clinical Biomarkers. Front. Med. 5:248.
35.
36.
37.
38.
39. RESULTS OF TAILOR X TRAIL
• 10273 PTS followed for atleast 5 yrs with a median of 7.5 yrs
• Chemotherapy can safely be avoided in in ER+ ,HER 2 –VE AND NODE
–VE BREAST CANCER WITH 21 GENE RECURRENCE SCORE OF
0-25 , who were post menopausal or older than 50 yrs at diagnosis or
premenopausal 50 yrs or less
40. RX PONDER –ADJ ET +CHEMO in HR + HER 2- EBC
WITH 1-3 POSITVE LYMPHNODES & RS<25
41. 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
42.
43. Growth factor receptor pathways contd…..
• Lapatinib - inhibits tyrosine phosphorylation of both EGFR and HER 2 which in
turn inhibits the activation of proproliferativekinases ERK1/2 and AKT
• IGF – 1R - primary respose mediator for IGF .
• PI3-K Pathway – central signalling pathway downstream of tyrosine kinases and
regulates cell growth and proliferation
Rapamycin - m TOR inhibitors
Raf inhibitor - sorafenib
44. 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
47. 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
