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Molecular€Pathobiology€of Breast€Canceraz9194.vo.msecnd.net/pdfs/090608/4.4.pdf ·...
Transcript of Molecular€Pathobiology€of Breast€Canceraz9194.vo.msecnd.net/pdfs/090608/4.4.pdf ·...
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Molecular Pathobiology ofBreast Cancer
Celina G. Kleer, M.D.Harold Oberman Collegiate
Professor of Pathology
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EpigeneticEpigeneticchangeschanges
GenomicGenomicinstabilityinstability
TDLUTDLU
hyperplasiahyperplasia
atypiaatypia DCISDCIS
invasiveinvasive
metastasismetastasis
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Outline
•Intraductal Proliferative Lesions•Lobular Carcinoma in situ LCIS•Invasive Carcinoma, pathology and
molecular classification, prediction andprognosis
•Examples of Applications of MolecularBiology into Clinical Practice Today andChallenges
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Intraductal ProliferativeLesions
UsualUsual ductalductal hyperplasiahyperplasia AtypicalAtypical ductalductal hyperplasiahyperplasia
DuctalDuctal Carcinoma in situCarcinoma in situ
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Usual ductal hyperplasia
•Increased cellularity of the ductalepithelium
•Mixture of cells types•Common finding•Often associated with microcalcifications
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Atypical Ductal Hyperplasia(ADH)
•Predictor of increased risk of carcinoma•Structural or cytologic features of DCIS
mingling with hyperplasia•Flat epithelial atypia (also called
columnar cell alteration with atypia)appears to have a similar behavior thanADH
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ADHADH
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FEAFEA
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UDH, ADH and risk of breast ca
•Nurses’ Health Study (2007)•Mayo Clinic Study (2005 and 2007)
“Women with atypical hyperplasia are atsubstantially increased risk (approx 4fold) for breast ca development”
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Ductal Carcinoma insitu
• Malignant cells confined to a duct,without stromal invasion
• Heterogeneous disease• Precursor of invasive carcinoma• No consensus on the criteria required for
diagnosis
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DCISDCIS
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DCISDCIS
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Grading DCIS
Nuclear Grade1 2 3
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Grading DCIS
Nuclear Grade1 2 3
There is probably no progressionfrom low grade (NG1) to high grade
(NG3) DCIS
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DCIS Relationship to invasive ca
•Morphological and molecular similarities•Clonal process•Analogous to epithelial in situ lesions
elsewhere•High frequency of progression of
invasive carcinoma if incompletelyexcised (multiple studies, mean 28%)
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Nurses’ Health StudyDesign:• Casecontrol study of
benign breast diseaseand breast cancer risk
• Review of 1877 breastbiopsies
• 13 had DCIS (of allnuclear grades)
• Received no treatmentbeyond diagnosticbiopsy
Results:• Invasive carcinoma
developed amongwomen with DCIS ofall nuclear grades
• All invasivecarcinomas were inthe same breast thatthe DCIS
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Nurses’ Health Study
Patients with DCIS who received notreatment were at substantiallyincreased risk for developing
ipsilateral invasive ca, and that theincreased risk in this setting was seenin DCIS of low, intermediate, and high
nuclear grades
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The problem
•In order to better understand how ADHand DCIS progress to invasive ca weneed to investigate the molecularalterations of these lesions
•Great difficulty in obtaining ADH andDCIS samples for molecular research
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Genomic alterations
LOH studiesUDH 10% (030%) usually one locusADH 50%
similar loci to low grade DCIS andsimilar alterations found insubsequent invasive ca of samebreast
DCIS 5080% numerous sites (similar toinvasive ca)
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Genomic alterations in DCIS
8p, 11q,13q, 14q
1q 5p 8q17q
high
16q11q
1qIntermediate
16qLow
lossgaingrade
Adapted fromAdapted from BuergerBuerger H, JH, J PatholPathol 1999,187:3961999,187:396402402
Alsoamplification of
11q13 and17q12
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Molecular Markers of DCIS• Gene expression patterns in DCIS,
invasive, and metastatic ca using serialanalysis of gene expression (SAGE)
• Only 8 DCIS cases –they were grouped• 16,430 transcripts analyzed• mRNA ISH to examine gene expression
(18 tumors) and IHC on TMAs (769 cases)• No universal in situ or invasive signature
Adapted from Porter D, Mol Cancer Res 2003;1:362Adapted from Porter D, Mol Cancer Res 2003;1:3627575
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• These data suggest that the different stages ofbreast cancer progression are evolutionary linked
• Genes expressed in ADH and DCIS may induceneoplastic progression
• It appears that the transition from ADH to DCISand invasion is associated with quantitative(rather than qualitative) differences in geneexpression
• There is a strong correlation between thegenomic changes and the grade of the DCIS
Molecular Markers of DCIS
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+1q16q
ADH Low grade DCIS
High grade DCIS
+11q13+17q12
Intermediate gradeDCIS
?
A model forA model forpreinvasivepreinvasiveprogressionprogression
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Molecular Subclasses of DCIS
• 245 cases of DCIS• 61% luminal A (ER+, HER2)• 9% luminal B (ER+, HER2+)• 16% HER2 positive (ER,
HER2+)• 8% basal like (ER, HER2,
EGFR+&/or CK5/6+)• 6% unclassified
Adapted fromAdapted from LivasyLivasy et al, Humet al, Hum PatholPathol 2007;38:1972007;38:197204204
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Molecular Subclasses of DCIS
The clinical implications of themolecular subtypes of DCIS are still
not well defined
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Lobular neoplasiaatypical lobular hyperplasia and lobular
carcinoma in situ• Nonpalpable –Incidental
finding• Multicentric and bilateral
(>50%)• Premenopausal (45 yo)• Involves lobules and
terminal ducts• Calcifications can be seen,
but are uncommon1520%LCIS
8%ALH
Absolute risk(15 years)
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LCISLCIS
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ALHALH
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and remember that…
•ER/PR positive•HER2/neu negative•Ecad negative (useful in differential
diagnosis with DCIS)•LOH at 16q (Ecadherin gene is 16q22)
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EEcadherincadherin
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Is Lobular neoplasia a markerlesion or a precursor?
•Both•Clinical, epidemiological and molecular
data•AbdelFatah et al showed that lobular
neoplasia has similar genetic changesthat invasive lobular carcinomas
Abdel Fatah, AJSP 2007
Mastracci, Genes, Chromosomes, Cancer 2006
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Invasive carcinoma
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Invasive carcinoma
• 1 of 8 women in the US will developbreast cancer
• Most common cancer in women inUS
• 2nd most common cause of cancerdeaths after lung cancer
• 1/3 of these women will die of breastcancer (44,000 deaths a year)
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Genetic predisposition
• Family history• BRCA1 and BRCA2 (17q21 and 13q12)• LiFraumeni syndrome (p53 mutations)• Cowden disease (10q)• Ataxia telangectasia (ATM gene, cr 11)
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BRCA1 BRCA2
Chromosome 17q21 13q12Gene 100kb 70kbFunction Tumor suppr DNA repairMutations >500 >200Risk >70% by 80 yo >60% by 70 yoAge of cancer 4050 yo 50 yoother cancers ovary, prostate male breast,
colon ovary,prostate,pancreas
Pathology medullary, high no specificgrade tumors
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Hormonal Influences and breastcancer
Estrogen excesslong duration of reproductive lifenulliparitylate age at first childfunctioning ovarian tumors
Enviromental factors no specific factor
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Invasive CarcinomaMain Histologic Types
ductal 80%lobular 10%tubularcolloid 10%medullaryadenoid cysticother
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Major histological types ofinvasive carcinoma
I. DUCTAL II. LOBULARIn spite of differences in clinical aspects,
overall prognosis is the same
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Current management of patientswith breast ca
TREATMENT• Surgical (mastectomy /
breast conserving)• Radiation therapy• Hormonal therapy
(based on ER status)• Adjuvant chemotherapy• Neoadjuvant
chemotherapy
CHALLENGES• Prediction of response
to therapy / selection ofspecific treatment
• Identify reliableprognosticators
• Novel targetedtherapies
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Definitions•Prognostic factor: reflect the biology of
the cancer and are associated withoutcome without consideration oftreatment.
•Predictive factor: reflect thesensitivity/resistance of a cancer to aparticular treatment, and are defined asthose factors that predict which patientsare likely to respond to a specifictherapy.
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Pathological features used tomake treatment decisions
•Histological grade (Nottingham,BloomRichardson)
•Tumor size•Lymph nodes•ER/PR and HER2/neu
To supply prognostic and predictive informationTo supply prognostic and predictive information
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0102030405060708090
100
Localized Regional Distant
Fiveyear survival rates by stage atdiagnosis for women with breast
cancer*
*Data from American Cancer Society,Breast Cancer Facts & Figures 20052006,Atlanta: American Cancer Society, Inc.
%%
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Case History: 50 year oldwoman identifies mass on self
examination
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1 cm invasive ductalcarcinoma of lowhistological grade
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Metastasis to the iliac bone 8 years after excision of primary tumor
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Metastasis to the iliac bone 8 years after excision of primary tumor
unable to detect the poor prognosisunable to treat effectively
Need to understand the biology ofbreast ca to improve management
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Estrogen and Progesterone Receptors,and HER2 testing in breast cancer
•ER and PR are weak prognostic factorsbut they are STRONG predictive factorsof response to hormonal therapy
•HER2 is an excellent predictor ofresponse to trastuzumab
•Routinely measured by IHC (ER, PR,HER2) and FISH (HER2) in invasivecarcinoma tissue samples
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Limitations of pathological factorsin prognosis and prediction
•Limited ability to predict individualpatient outcomes
•Most studies do not take into accountpatient treatment
•Patients with similar pathologicalparameters can have markedly differentclinical courses
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Breast cancer biology
•Breast cancer is genetically andgenomically a heterogenous disease
•Likely develops as a continuum•Multiple pathways involved•Our current understanding of the
biology of breast cancer is a majorbarrier to identify novel treatments
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Adapted fromAdapted from www.cellsignal.comwww.cellsignal.com
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Breastcarcinomasamples
Highthroughputanalysis ofRNA and
DNA
What are we learning about breast cancer?Gaining new insights into cellbiologyDeveloping a better classificationImprove treatment
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Molecular signature/Gene expressionprofiling –Seminal papers
• Sorlie et al (PNAS 98:1086974, 2001): 427genes selected from 8102 were used todefine histogenetic subsets of breastcancer (N=78)
• Van’t Veer et al (Nature 2002;415:5306):70 genes selected from 5000 were used todefine prognosis in a set of breast cancerpatients (N=295)
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Applications of Gene ExpressionProfiling
•Better tumor classification•Assess prognosis•Predict response to therapy
Endocrine Adjuvant chemotherapy Neoadjuvant chemotherapy Targeted therapy
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Major Breast Cancer Subtypes Definedby Gene Expression Profiling
+
++/
+++
++
basalHER2Lum BLum AEstrogen Response genes:ESR1, PGR, GATA3, FOXA1
Proliferation genes:CCNB1, FOXA1, MYBL2
HER2 and associated genes
Basal genes:KRT5 and 17, ERBB1
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85%18%Basallike: triple negative
62%14%Her2+
49%20%Luminal B: low levelER+///+/ PR and Her2
21%52%Luminal A: high levelER/PR+///Her2
% Highgrade
FrequencyHistogenetic Subtype
Note: Does not include lobular CA (510% frequency)
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Luminal A• 52% of breast cancers• ER/PR+• HER2 negative• 16q del• Respond to endocrine therapy• Favorable prognosis
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Luminal ALuminal AProgressionProgressionhypothesishypothesis
normalnormal
ADHADHLG DCISLG DCIS FEAFEA LCISLCIS
Tubular caTubular ca Invasive lobular caInvasive lobular ca
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Luminal B Triple positives
•20% of breast cancers•Shares gene clusters with Her2 and
basal groups•Younger age than luminal A•40% node positive•Pathology: extensive DCIS,
“micropapillary” features
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HER2•14 % of breast cancers•HER2 overexpression•Usually ER/PR•Higher grade•Respond to Herceptin•Respond to anthracyclinebased
chemo•Worse prognosis than luminal
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3+ Her2 Stain
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HER2 amplification by FISHHER2 amplification by FISH
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Basallike “triple negative”
•18% of breast cancers•BRCA1 inactivation•More common in African Americans•More common premenopausal•Poor response to endocrine therapy
or Herceptin targeted therapies maybe option in the future
•Poor short term outcome
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Morphology of invasive ductal carcinomasin the molecular basallike group
Associated with:
Pushing margin
Central scar and/ornecrosis
Mitoses andpleomorphism
Lymphocytic infiltrate
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ER
PR Her2/neu
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A Model for Basal like BreastCarcinomas
Permissive mutationsp53, CHK2
Additionalmutations(eg PTEN)
BRCA1+/or reduction
BRCA1 Unstable cellsgenomic chaosHigh proliferationDifferentiation block
BasallikeBreast ca
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Issues that need to be clarified aboutBasallike tumors
• Lacks clear definition at the morphologicaland immunophenotypic levels.
• Heterogeneous group:Invasive ductal ca (triple negatives)Metaplastic caAdenoid cystic caMedullary ca and medullary featuresMost BRCA1 mutated tumors
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MedullaryHigh grade ductal
Metaplastic Adenoid cystic
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EGFR
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Markers of “basal like profile”
• CK 5/6*• EGFR• Vimentin• p53
• Ckit• P63• Pcadherin• MOC31
*Luminal cytokeratins are 8/18
THERE IS NO ACCEPTED MINIMUM DEFINITION
Nielsen, Clin Cancer Res 2004
Livasy, Mod Pathol 2006
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Therapeutic implicationsbasallike carcinoma
• Not all have poor prognosis• Tamoxifen and Herceptin not an option• Respond well to Neoadjuvant
chemotherapy• Association with BRCA1 New
possibilities using DNA repair pathwayscisplatin, PARP inhibitors
• EGFR positivity also offers a newtherapeutic target
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Prognostic Significance of MolecularSubtypes
Adapted fromAdapted from SorlieSorlie et al, PNAS 98:10869et al, PNAS 98:1086910874, 200110874, 2001
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Molecular groups of breast cancer
Adapted fromAdapted from SorlieSorlie et al, PNAS 98:10869et al, PNAS 98:1086910874, 200110874, 2001
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Molecular groups of breast cancer
Adapted fromAdapted from SorlieSorlie et al, PNAS 98:10869et al, PNAS 98:1086910874, 200110874, 2001
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Molecular groups of breastcancer
But not all basalBut not all basallike carcinomaslike carcinomashave a worse prognosishave a worse prognosis
Adapted fromAdapted from SorlieSorlie et al, PNAS 98:10869et al, PNAS 98:1086910874, 200110874, 2001
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Other biologybasedsignatures
•Wound healing signature –Chang 2005
•Hypoxia signature –Chi 2006
• Invasiveness signature –Liu 2007
•Stromal signatures –Finak 2008, Beck 2008
Chang et al, PNAS, 2005 102:3738Chi et al, PLoS Med, 2006 3:e47Liu et al, NEJM, 2007 356:217Finak et al, Nature Med, 2008 14:518Beck et al, Lab Invest, 2008 88:591
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Examples of Applications ofMolecular Biology into ClinicalPractice Today and Challenges
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Modified fromPeto et al.Lancet355:1822, 2000
AdjCTX
AdjHT
Screening
Recent decrease in UK and USA breastcancer mortality at ages 3569 years
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The complexity of assessingprognosis and prediction
Prognostic factors:• Clinical and/or pathologic features that place
the patient into outcomes groups (favorablevs. unfavorable)
• May help guide treatment strategiesClinical (race, detection, bilaterality..)Pathologic (tumor size, type, grade..)
Genetic, somatic and germline(BRCA12, Her2/neu..)
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• Predictive factors: Clinical and/orpathologic features that predict responseto specific treatment interventions.Example, HER2/neu overexpression, ERexpression.
The complexity of assessingprognosis and prediction
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The Problem• Our ability to identify high risk patients
who require systemic adjuvant therapy isnot as adequate at we desire
• Identifying markers to predict response tospecific treatments is a challenge
• Commonly used drugs are ineffective inmany patients, and side effects develop
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Predictive Biomarkers used atpresent
ER and PRER and PR
ERBB2 receptorERBB2 receptor
Response toResponse toendocrineendocrinetreatmenttreatment
Response toResponse totrastuzumabtrastuzumab
So far a limited number of studies have applied aSo far a limited number of studies have applied agenomegenomewide approach using clinical material towide approach using clinical material to
identify predictive gene signaturesidentify predictive gene signatures
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Adjuvant Systemic Therapy forBreast ca
NCCN and St. Gallen Guidelines
•Node Negative Patients–Endocrine Therapy if HR+–Chemotherapy based on size, grade,
perhaps HR•Node positive Patients
–Chemotherapy•ACT, FECT, TAC or similar regimen
–Plus Endocrine therapy if HR +–Plus Trastuzumab if HER2 +
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When is a Marker Clinically Useful?
• It is either prognostic or predictive• The magnitude of effect is sufficiently large that
clinical decisions based on the data result inoutcomes that are acceptable– Greater chance for benefit– Smaller toxicity risk
• The estimate of magnitude of effect is reliable– Assay is reproducible– Clinical trial/marker study design is appropriate– Results are validated in subsequent welldesigned
studies
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ASCO Tumor Marker GuidelinesPanel
• ER, PR Select Endocrine Therapy
• HER2 Select Trastuzumab/
Lapitinib
• UPA/PAI 1 Avoid Chemo if ER+
• Oncotype DX Avoid Chemo if ER+
Harris L., et al. J Clin Oncol. 2007
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Her2 Basics
•Her2 protein; a plasma membranegrowth factor receptor
•overexpression causes spontaneousdimerization, followed by
•constitutive signal transduction (tyrosinekinase activity)
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Her2 Gene Amplification•increased gene copy number relative to
chromosome 17 (>2X by definition)•1530% of breast carcinomas•causally related and proportional to protein
overexpression•Note: 5% of high level overexpression
occurs without amplification
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FISH
HER2/neuHER2/neuCEP 17CEP 17
No HER2 amplificationNo HER2 amplification
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HER2 amplification
A B
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Her2 Amplification Biology
•strong/causal association with chr 17polysomy and DNA aneuploidy; a markerof genetic instability
• intratumoral heterogeneity (protein, copy#, chr 17 polysomy) is “common”, butextent is poorly defined in clinical material
•copy # and protein content well correlatedat population level but not well forindividual cells
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3+ Her2 Stain
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1+ Staining1+ Staining
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HeterogeneityHeterogeneity
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From Romand et al, NEJM 353:16,167384, 2005
•33% reduction in risk of death withTrastuzumab therapy
– High risk local disease (mostly N+)– Trast + Tax/Adria/Cyclophos– 4.1% cardiotox– 3 year follow up
•“On the basis of these results our careof patients with Her2 positive breastcancer must change today.” (editorial)
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Extracellular effects:Extracellular effects:inhibition of HER2 cleavageinhibition of HER2 cleavage
Interference withInterference with dimerizationdimerizationbetween receptorsbetween receptors
Immune mechanismsImmune mechanisms
Intracellular effects:Intracellular effects:
Induction of apoptosisInduction of apoptosisDecrease in proliferationDecrease in proliferationDecreased VEGFDecreased VEGF
PotentiationPotentiation of chemotherapyof chemotherapy
Modulation of downstreamModulation of downstreamsignalingsignaling
Altered cross talkAltered cross talk
HER2HER2
nucleusnucleus
TyrosineTyrosine kinasekinase
Breast Cancer Cell with HER2overexpression
trastuzumabtrastuzumab
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Promising Tumor Markers
• Individual Genes/Proteins– Measures of proliferation (SPhase Fraction, KI67)– PAI1/uPA– p53– Cyclin E– Host of Others– Markers of Progenitor Cells (really new)
• Multigene Expression–DNA array–Multiplex quantitative rtPCR
• Proteomics• Pharmacogenomics
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Emerging Commercial AssaysCompany Veridex Agendia GHINicknames Rotterdam Sig Amsterdam sig OncotypeDX™
Mammaprint™Global gene expr’n Yes Yes NoSignature 76 genes 70 genes 21 genesAssay Array Array RTPCRTreatment No 7% 100% TamTissue Frozen Frozen ParaffinCleared by FDA? No Yes NoAvailable in US No No YesPrice $ 2000 $ 3400
ID N/ER+/Avoid CTX
Validation Trial None MindAct (BIG) TailorRx (NA Intergroup)
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MammaPrint
• Based on Van’t Veeret al (Nature2002;415:5306)
• 70 genes selectedfrom 5000 were usedto define prognosis ina set of breast cancerpatients (N=295)
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MammaPrint
Description & advantages• Agilenttype DNA
oligonucleotide microarray• Independent prognostic
value at multivariable level• Low risk and High risk
groups (89% vs. 70%10 yroverall survival)
Limitations• Needs fresh tissue• Original signature
obtained from nodenegative, < 55yo, nochemo population
• Not completely validated
Limited use in most US institutionsLimited use in most US institutions
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RS = + 0.47 x HER2 Group Score 0.34 x ER Group Score+ 1.04 x Proliferation Group Score+ 0.10 x Invasion Group Score+ 0.05 x CD68 0.08 x GSTM1 0.07 x BAG1
Oncotype DX 21 Gene Recurrence Score
PROLIFERATIONKi67
STK15Survivin
Cyclin B1MYBL2
ESTROGENERPR
Bcl2SCUBE2
INVASIONStromolysin 3Cathepsin L2
HER2GRB7HER2
BAG1GSTM1
REFERENCEBetaactin
GAPDHRPLPO
GUSTFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies16 Cancer and 5 Reference Genes From 3 Studies
RS 31High risk
RS 18 and < 31Int riskRS < 18Low risk
RS (0 –100)Category
Adapted from Paik et al, NEJM 351:2817,2004
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OncotypeDx• Real time PCR test for 21 genes• Performed on paraffin embedded tissues• Gene list derived from published
expression profiles• Main use is in ER+, LN neg breast cancer
to decide if chemotherapy will beefficacious.
Paik et al, NEJM 2004;351:2817Paik et al, NEJM 2004;351:28172626
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NSABP 20 and other data sets: Node Neg, ER+, Tam treatedpatients, 10 yr Distant Recurrence
NSABP:Validation Study of Oncotype DX
0%
5%
10%
15%
20%
25%
30%
35%
40%
0 5 10 15 20 25 30 35 40 45 50
Recurrence Score
Dis
tant
Rec
urre
nce
at 1
0 Ye
ars
Low Risk Group High Risk GroupIntermediate Risk Group
Recurrence Score/Cont. Variable
Also most likely tobenefit from chemoRxPaik S., et al. J ClinOncol 24:37263734, 2006
50% ofPts fall
into thiscategory
Adapted from Paik et al, NEJM 2004;351:2817Adapted from Paik et al, NEJM 2004;351:28172626
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Summary of Clinical Implications ofRecurrence Score for ER+, N0 patients
Greater benefit fromadjuvant chemo
No or minimal benefitfrom adjuvant chemo
Less benefit fromTamoxifen
Greater benefit fromTamoxifen
Greater likelihood ofrecurrence
Less likelihood ofrecurrence
High RSLow RS
Intermediate?Intermediate?
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Node Negative ER and/or PgR (+) BC
Oncotype DX® Assay
RS < 11HormoneTherapyRegistry
RS 11 –25Randomize
RS > 25Chemotherapy
+Hormone Rx(Registry orOther Trials)
n~4400 for randomized arm
Hormone Rx Hormone Rx+ ChemoRx
US Intergroup TailorRx Trial
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Impact of OncotypeDX on ClinicalDecision Making
• Three clinical studies• Treatment recommendations changed in 2025%• Most often results in sparing chemo• Less commonly results in adding chemo
Sparano et al, J Clin Oncol 2008 26:721
18Academic31Kamal et al20Community68Oratz et al
26CommunityandAcademics
89Lo et al
Change intreatment
SettingN of patientsAuthor
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Grading invasive carcinomas: point system
Tubule formation>75% 11075% 2<10% 3
Nuclear pleomorphismSmall, uniform 1Variable 2marked pleomorphism 3
Mitotic count05 1610 2>11 3
Grade 1 –well differentiated –35 pointsGrade 2 –moderately diff 67 pointsGrade 3 –poorly differentiated –89 points
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Relationship between OncotypeDX,pathology, and Nottingham grade
% risk% risk
Nottingham gradeNottingham grade
StrongStrongassociationassociationbetween %between %
risk andrisk andhistologicalhistological
gradegrade(p<0.001)(p<0.001)
Cases withCases withlymphoplaslymphoplas
macyticmacyticinfiltrate hadinfiltrate had
high RShigh RS(p=0.0009)(p=0.0009)
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SWOG 8814/TBCI 0100 Correlative SciencePRIMARY ANALYSISCAUTION NEEDED
• The 21gene RS seems to be prognostic fortamoxifentreated patients with positive nodes
• Chemotherapy is most beneficial in HIGH RS,dominating in the first 5 years, but carriedover longterm
• LOW RS MAY define a group of women withpositive nodes who do not appear to benefitfrom CAF adjuvant chemotherapy (presented atthe San Antonio Breast Cancer Symposium, 2007)
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Conclusions• Molecular tests have great potential to
refine breast cancer classification,enhance our understanding, and improvetreatment
• Their role in daily clinical practice isevolving
• Currently there are clinical trials to furthervalidate OncotypeDX and Mammaprint
• New tests will be coming as well
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Conclusions• Molecular tests have great potential to
refine breast cancer classification,enhance our understanding, and improvetreatment
• Their role in daily clinical practice isevolving
• Currently there are clinical trials to furthervalidate OncotypeDX and Mammaprint
• New tests will be coming as well
These molecular tests need to beused in conjunction with carefulhistopathological examination
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Present challenges•Better understand the molecular
pathogenesis of preneoplasticintraductal proliferations
•Effective strategies to prevent breast cadevelopment
•Better characterization of in situ toinvasive transition
•Better integration between pathology,clinical practice and molecular biology
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The University of Michigan HospitalThe University of Michigan Hospital
THANK YOU!THANK YOU!
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The University of Michigan Cancer CenterThe University of Michigan Cancer Center