Transcript No Slide Title

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
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
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