Prognostic and Predictive Factors: Current Evidence for Individualized Therapy
Predictive Molecular Markers:
Hormone Receptor Status
Presented by
Kathleen I Pritchard
Toronto-Sunnybrook Regional Cancer Centre
and
The University of Toronto
Toronto, Canada
PROGNOSTIC FACTORS
PROGNOSTIC FACTORS
FACTORS WHICH PREDICT THE RISK OF RECURRENCE OR DEATH INDEPENDENT OF THERAPY
PREDICTIVE FACTORS
PREDICTIVE FACTORS
FACTORS WHICH PREDICT THE LIKELIHOOD OF RESPONSE TO A GIVEN THERAPY
ESTROGEN RECEPTOR AND PROGESTERONE RECEPTOR
BOTH PREDICTIVE AND
PROGNOSTIC FACTORS
ESTROGEN RECEPTOR
EXPRESSED IN 60-70% OF BREAST CANCERS
A WEAK BUT FAVOURABLE PROGNOSTIC FACTOR
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
ESTROGEN RECEPTOR
RESPONSE RATES INCREASE WITH
INCREASING LEVELS OF ESTROGEN
RECEPTOR PROTEIN
WITLIFF 1988
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 STILL
POSITIVE
COMPARISON OF ER AND/OR PgR IMMUNOHISTOCHEMICAL METHODS TO OLDER LIGAND BINDING OR BIOCHEMICAL METHODS
EXCELLENT REVIEW BY CRAIG ALLRED et al
MODERN PATHOLOGY 1998; 11 (2): 155-168
STRESSES VALIDATION OF NEW TEST METHODOLOGY WITH CLINICAL OUTCOME AS WELL AS WITH OLDER TEST METHODOLOGY
ESTROGEN RECEPTOR
IHC
PREPARATION OF TISSUE
TYPES OF ANTIBODIES
ARBITRARY
SCORING
INTERPRETATION
REPORTING
ESTROGEN RECEPTOR
LB = LIGAND ASSAY BINDING
IHC = IMMUNOHISTOCHEMICAL
IHC and LB
80-90% CONCORDANT
ESTROGEN RECEPTOR
PROGNOSTIC 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
DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL
THERAPY
DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL
THERAPY
ESTROGEN RECEPTOR
PREDICTIVE VALUE OF ER BY IHC
20 STUDIES
1200 WOMEN
ER +ve ~ 70% RR
ER -ve < 15% RR
PROGESTERONE RECEPTOR
PG-R
AN ER-RELATED GENE PRODUCT
INDICATES WHETHER THE ESTROGEN / E.R. REGULATED PATHWAYS ARE INTACT
PROGESTERONE RECEPTOR
LB vs IHC
~ 70% CONCORDANCE
IHC RR
PgR +ve 70%
PgR-ve < 10%
PROGESTERONE RECEPTOR
IHC
TISSUE PREPARATION
TYPES OF ANTIBODIES
SCORING
INTERPRETATION
REPORTING
PROGESTERONE RECEPTOR
WEAK PROGNOSTIC FACTOR
~ 5% DIFFERENCE IN 713 UNTREATED WOMEN
DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL
THERAPY
DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL
THERAPY
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
ESTROGEN RECEPTOR
PREDICTIVE VALUE FOR CHEMOTHERAPY
PROPOSED AS A PREDICTIVE FACTOR FOR CHEMOTHERAPY RESPONSE
ER -ve
MORE LIKELY TO RESPOND TO CHEMO
LIPPMAN ET AL
NEJM 1978
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
ESTROGEN RECEPTOR
AC vs AC T
DIFFERENCE MAINLY IN ER -ve
LITTLE DIFFERENCE IN ER +ve
HENDERSON ET AL
ASCO 2000
ESTROGEN RECEPTOR
OXFORD OVERVIEW
SUGGESTION IN SOME ANALYSES THAT WOMEN WITH ER NEGATIVE TUMOURS BENEFIT MORE FROM CHEMOTHERAPY
COLE, LANCET 2001
COATES, LANCET 1998
ESTROGEN RECEPTOR MECHANISMS
BREAST CANCER DEVELOPMENT AND PROGRESSION DIRECTLY RELATED TO EFFECTS OF ESTROGEN
ER
A NUCLEAR RECEPTOR
FUNCTIONS AS A TRANSCRIPTION
FACTOR CONTROLLING ESTROGEN
RELATED GENES
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
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
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
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
ESTROGEN RECEPTOR MECHANISMS
CLASSIC HORMONAL THERAPIES
BIOLOGIC AGENTS
ANTI HER-2
HERCEPTIN
OTHERS
ANTI EGF
IRESSA
OTHERS
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
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
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