Prognostic and Predictive Factors: Current Evidence for Individualized Therapy
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Prognostic and Predictive Factors: Current Evidence for Individualized Therapy
Predictive Molecular Markers:Hormone Receptor Status
Presented byKathleen I Pritchard
Toronto-Sunnybrook Regional Cancer Centreand
The University of TorontoToronto, Canada
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PROGNOSTIC FACTORS
PROGNOSTIC FACTORS
FACTORS WHICH PREDICT THE RISK OF RECURRENCE OR DEATH INDEPENDENT OF THERAPY
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PREDICTIVE FACTORS
PREDICTIVE FACTORS
FACTORS WHICH PREDICT THE LIKELIHOOD OF RESPONSE TO A GIVEN THERAPY
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ESTROGEN RECEPTOR AND PROGESTERONE RECEPTOR
BOTH PREDICTIVE AND
PROGNOSTIC FACTORS
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ESTROGEN RECEPTOR
EXPRESSED IN 60-70% OF BREAST CANCERS
A WEAK BUT FAVOURABLE PROGNOSTIC FACTOR
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ESTROGEN AND PROGESTERONE RECEPTOR
OBJECTIVE RESPONSE RATE
0%10%20%30%40%50%60%70%80%90%
100%
ER-ve, PgR-ve ER+ve, PgR-ve ER-ve, PgR+ve ER+ve, PgR+ve
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ESTROGEN RECEPTOR
RESPONSE RATES INCREASE WITH INCREASING LEVELS OF ESTROGEN
RECEPTOR PROTEIN
WITLIFF 1988
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ER AND PgR MEASUREMENT METHODS
LIGAND BINDING OR BIOCHEMICAL DONE ON A “SLURRY” OF TISSUE YIELDS AN AVERAGE VALUE
IMMUNOHISTOCHEMICAL DONE ON A SECTION CAN LOCALIZE RECEPTOR 1-10% OF CELLS STAINING STILLPOSITIVE
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COMPARISON OF ER AND/OR PgR IMMUNOHISTOCHEMICAL METHODS TO OLDER LIGAND BINDING OR BIOCHEMICAL METHODS
EXCELLENT REVIEW BY CRAIG ALLRED et alMODERN PATHOLOGY 1998; 11 (2): 155-168
STRESSES VALIDATION OF NEW TEST METHODOLOGY WITH CLINICAL OUTCOME AS WELL AS WITH OLDER TEST METHODOLOGY
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ESTROGEN RECEPTOR
IHC
PREPARATION OF TISSUE
TYPES OF ANTIBODIES
ARBITRARY SCORING INTERPRETATION REPORTING
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ESTROGEN RECEPTOR
LB = LIGAND ASSAY BINDING
IHC = IMMUNOHISTOCHEMICAL
IHC and LB 80-90% CONCORDANT
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ESTROGEN RECEPTORPROGNOSTIC VALUE OF ER BY IHC
~ 10-15% RECURRENCE/SURVIVAL BENEFIT IN WOMEN WHO DO NOT RECEIVE HORMONAL ADJUVANT THERAPY
CONFIRMED IN AT LEAST FOUR TRIALS INVOLVING UNTREATED WOMEN
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DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL
THERAPY
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DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL
THERAPY
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ESTROGEN RECEPTOR
PREDICTIVE VALUE OF ER BY IHC
20 STUDIES
1200 WOMEN
ER +ve ~ 70% RR
ER -ve < 15% RR
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PROGESTERONE RECEPTOR
PG-R
AN ER-RELATED GENE PRODUCT
INDICATES WHETHER THE ESTROGEN / E.R. REGULATED PATHWAYS ARE INTACT
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PROGESTERONE RECEPTOR
LB vs IHC
~ 70% CONCORDANCE
IHC RR
PgR +ve 70%
PgR-ve < 10%
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PROGESTERONE RECEPTOR
IHC TISSUE PREPARATION
TYPES OF ANTIBODIES
SCORING
INTERPRETATION
REPORTING
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PROGESTERONE RECEPTOR
WEAK PROGNOSTIC FACTOR
~ 5% DIFFERENCE IN 713 UNTREATED WOMEN
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DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL
THERAPY
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DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL
THERAPY
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PREDICTIVE VALUE OF RECEPTORS
PHENOTYPE INCIDENCE RESPONSE RATE
ER + PgR+ 58% 77%
ER + PgR- 23% 27%
ER - PgR+ 4% 46%
ER - PgR- 15% 11%
McGuire 1991
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ESTROGEN RECEPTOR
PREDICTIVE VALUE FOR CHEMOTHERAPY
PROPOSED AS A PREDICTIVE FACTOR FOR CHEMOTHERAPY RESPONSE
ER -ve MORE LIKELY TO RESPOND TO CHEMO
LIPPMAN ET ALNEJM 1978
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ESTROGEN RECEPTOR
PREDICTIVE VALUE FOR CHEMOTHERAPY
SUBSEQUENTLY REJECTED AS A PREDICTIVE FACTOR BASED ON CONTRADICTORY DATA FROM A SERIES OF SMALL STUDIES IN METASTATIC DISEASE
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ESTROGEN RECEPTOR
AC vs AC T
DIFFERENCE MAINLY IN ER -ve
LITTLE DIFFERENCE IN ER +ve
HENDERSON ET ALASCO 2000
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ESTROGEN RECEPTOR
OXFORD OVERVIEW
SUGGESTION IN SOME ANALYSES THAT WOMEN WITH ER NEGATIVE TUMOURS BENEFIT MORE FROM CHEMOTHERAPY
COLE, LANCET 2001
COATES, LANCET 1998
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ESTROGEN RECEPTOR MECHANISMS
BREAST CANCER DEVELOPMENT AND PROGRESSION DIRECTLY RELATED TO EFFECTS OF ESTROGEN
ER A NUCLEAR RECEPTOR FUNCTIONS AS A TRANSCRIPTIONFACTOR CONTROLLING ESTROGEN RELATED GENES
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ESTROGEN RECEPTOR MECHANISMS LIGAND BINDING
RECEPTOR CONFORMATION INTERACTION OF RECONFORMED
RECEPTOR WITH COREGULATORS RESPONSE ELEMENTS IN
PROMOTOR REGIONS OF TARGET GENES (ERE)
ALL CONTRIBUTES TO NET ESTROGENIC EFFECTS IN A CELL
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ESTROGEN RECEPTOR MECHANISMS
POLYPEPTIDE GROWTH FACTORS AND THEIR MEMBRANE RECEPTORS ALSO
CONTRIBUTE TO BREAST CANCER DEVELOPMENT AND PROGRESSION
SIGNALS THROUGH VARIOUS PROTEIN KINASE PATHWAYS ENHANCE CELL SURVIVAL AND PROLIFERATION
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ESTROGEN RECEPTOR MECHANISMS
THESE PATHWAYS ALSO INTERACT WITH ESTROGEN RECEPTOR
KINASES IN GROWTH FACTOR CASCADE CAN PHOSPHORYLATE AND ACTIVATE
ER
ER IN TURN ACTIVATES AND AUGMENTS SIGNALING IN GROWTH FACTOR PATHWAYS
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ESTROGEN RECEPTOR MECHANISMS
SIGNALING THROUGH GF PATHWAYS MAY CONTRIBUTE TO HORMONAL RESISTANT STATES BY LIGAND - INDEPENDENT ACTIVATION OF ER
THUS TARGETING GF PATHWAYS IN ADDITION TO ER MAY PROVIDE
BETTER THERAPY
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ESTROGEN RECEPTOR MECHANISMS
CLASSIC HORMONAL THERAPIES
BIOLOGIC AGENTS ANTI HER-2
HERCEPTIN OTHERS
ANTI EGF IRESSA OTHERS
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PREDICTIVE MOLECULAR MARKERS: HORMONE RECEPTOR STATUS
CONCLUSIONS STILL CRUCIAL IN SELECTION OF
HORMONAL THERAPY
MEASUREMENTS MUST BE STANDARDIZED TISSUE PREPARATON ANTIBODY USED SCORING INTERPRETATION REPORTING
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PREDICTIVE MOLECULAR MARKERS: HORMONE RECEPTOR STATUS
QUESTIONS? ER / PgR
ROLE IN SELECTING CHEMOTHERAPY
? Her 2 - Neu ROLE IN SELECTING CHEMOTHERAPY ROLE IN SELECTING HORMONAL THERAPY
? EGF - R (Erb - B1) ROLE IN SELECTING THERAPY
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PREDICTIVE MOLECULAR MARKERS: HORMONE RECEPTOR STATUS
QUESTIONS
? OPTIMAL USE OF COMBINATIONS OF CLASSIC HORMONAL AND BIOLOGIC FACTORS
? OPTIMAL GUIDANCE OF THIS COMBINED THERAPY BY CAREFUL STANDARDIZATION OF LABORATORY MEASUREMENTS