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

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 STILLPOSITIVE

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

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 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

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 ALNEJM 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 ALASCO 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 TRANSCRIPTIONFACTOR 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