1. Breast cancer is a heterogeneous disease caused by genetic and environmental factors. Global gene expression profiling can classify breast cancers into biological classes associated with survival.
2. Genetic mutations in high, moderate, and low penetrance genes like BRCA1, BRCA2, CHEK2, p53 contribute to hereditary breast cancers.
3. Molecular subtypes including luminal A/B, HER2-enriched, and basal-like have distinct gene expression patterns, responses to treatment, and clinical behaviors.
Carcinoma of breast is the second common killer disease in women after carcinoma of cervix in developing countries like India whereas it is the number one killer in western world. It can also run in families associated with BRCA1 & BRCA2 genes. Early diagnosis is almost curative and that is why they are doing mass screening like mammogram to pick up this cancer early.
The types of breast cancer biomarkers in cancer detection provide a unique view of what is occurring in the bloodstream and can help improve breast cancer detection.
Molecular Subtyping of Breast Cancer and Somatic Mutation Discovery Using DNA...Setia Pramana
Molecular Subtyping of Breast Cancer and Somatic Mutation Discovery Using DNA and RNA sequence
Guess Lecture at Computer Science Department, IPB, Bogor
Carcinoma of breast is the second common killer disease in women after carcinoma of cervix in developing countries like India whereas it is the number one killer in western world. It can also run in families associated with BRCA1 & BRCA2 genes. Early diagnosis is almost curative and that is why they are doing mass screening like mammogram to pick up this cancer early.
The types of breast cancer biomarkers in cancer detection provide a unique view of what is occurring in the bloodstream and can help improve breast cancer detection.
Molecular Subtyping of Breast Cancer and Somatic Mutation Discovery Using DNA...Setia Pramana
Molecular Subtyping of Breast Cancer and Somatic Mutation Discovery Using DNA and RNA sequence
Guess Lecture at Computer Science Department, IPB, Bogor
Audio and slides for this presentation are also available on YouTube: http://youtu.be/ukXhuy5cXrE
Huma Q. Rana, MD, a cancer geneticist with Dana-Farber Cancer Institute, explains the cancer risk associated with BRCA1 and BRCA2 gene mutations. This presentation was originally given on July 23, 2013 as part of the "What Every Woman Should Know" event put on by Dana-Farber's Susan F. Smith Center for Women's Cancers.
Oct. 2013 Via Christi Women's Connection presentation on breast cancer genetic testing featuring Patty Tenofsky, MD, with Via Christi Clinic in Wichita, Kan.
It describes the prevalence of Breast Cancer among BRCA 1/2 mutations with special consideration to biological background, detection and screening, actions taken upon discovering mutation carriers and whether we have a different therapeutic algorithm than sporadic cases. Special emphasis on the role of PARP inhibitors in the management of metastatic disease.
Speaker: Lisette Stork-Sloots, Sr Program Director at Agendia, discusses how their technology, MammaPrint was commercialized.
Part of Dx2010, a workshop at MaRS focused on best practices and regulatory considerations for developing gene-based diagnostic and prognostic tests.
Breast Cancer Theory, Profiling Through Iridology & TherapiesSheldon Stein
Professor Serge Jurasunas offers an in-depth understanding of breast cancer theory, its development, history and treatment. He discusses environmental factors, risk evaluation, genetics and family risk, cellular respiration and treatment innovations back in 2003. You can ask yourself what has happened over the past 13 years since then?
He offers detoxification drinks and formulas, discusses the reversal of mitochondrial damage as well as the need for psychological counseling and support. He then offers several cases.
Please note his new address:
Professor Serge Jurasunas
R.coelho 93 QTA Marinha
2750-008 Cascais
Portugal
Sergejurasunas@hotmail.com
Beyond BRCA Mutations: What's New in the World of Genetic Testing?bkling
Dr. Mark Robson, Clinic Director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, presents a medical update regarding the latest developments in genetic testing as it relates to breast and ovarian cancer. Topics include non-BRCA mutations, including both high-penetrance and so-called moderate penetrance mutations, and a framework for management of these.
Presented in collaboration with FORCE.
Subclassification into type 1 and type 2 is no longer recommended.
PRCC has classic morphology historically in type 1 category.
Criteria of foamy histiocytes and psammoma bodies is not required.
Many tumors previously diagnosed as type 2 PRCC now constitute independent entities
Ca ovary staging(AJCC 8th Edition& FIGO 2014) and classificationDr.Bhavin Vadodariya
Pathological classification of ovary in details.
Principles of Staging in Ca Ovary.
Staging according to AJCC 8th edition & Figo 2014.
Summary of changes in 8th Edition AJCC
Carcinoma breast and its management (1).pptxDr Sajad Nazir
This ppt is about carcinoma breast, its types,presentation, diagnosis, examination,management and recent trends in it.
Sentinel lymph node indications, axillary lymph node management.
Indications for chemotherapy and radiotherapy.
This is mainly for post graduates...
Kindly read anatomy of breast before proceeding for cancer breast and its management
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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