Prognostic and Predictive Factors: Current Evidence for Individualized Therapy

1. 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

2. PROGNOSTIC FACTORS PROGNOSTIC FACTORS FACTORS WHICH PREDICT THE RISK OF RECURRENCE OR DEATH INDEPENDENT OF THERAPY

3. PREDICTIVE FACTORS PREDICTIVE FACTORS FACTORS WHICH PREDICT THE LIKELIHOOD OF RESPONSE TO A GIVEN THERAPY

4. ESTROGEN RECEPTOR AND PROGESTERONE RECEPTOR  BOTH PREDICTIVE AND PROGNOSTIC FACTORS

5. ESTROGEN RECEPTOR EXPRESSED IN 60-70% OF BREAST CANCERS  A WEAK BUT FAVOURABLE PROGNOSTIC FACTOR

6. ESTROGEN AND PROGESTERONE RECEPTOR OBJECTIVE RESPONSE RATE

7. ESTROGEN RECEPTOR  RESPONSE RATES INCREASE WITH INCREASING LEVELS OF ESTROGEN RECEPTOR PROTEIN WITLIFF 1988

8. 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

9. 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

10. ESTROGEN RECEPTOR IHC  PREPARATION OF TISSUE  TYPES OF ANTIBODIES  ARBITRARY  SCORING  INTERPRETATION  REPORTING

11. ESTROGEN RECEPTOR LB = LIGAND ASSAY BINDING IHC = IMMUNOHISTOCHEMICAL IHC and LB  80-90% CONCORDANT

12. 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

13. DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL THERAPY

14. DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL THERAPY

15. ESTROGEN RECEPTOR PREDICTIVE VALUE OF ER BY IHC  20 STUDIES  1200 WOMEN  ER +ve ~ 70% RR  ER -ve < 15% RR

16. PROGESTERONE RECEPTOR PG-R  AN ER-RELATED GENE PRODUCT  INDICATES WHETHER THE ESTROGEN / E.R. REGULATED PATHWAYS ARE INTACT

17. PROGESTERONE RECEPTOR  LB vs IHC  ~ 70% CONCORDANCE IHC RR PgR +ve 70% PgR-ve < 10%

18. PROGESTERONE RECEPTOR  IHC  TISSUE PREPARATION  TYPES OF ANTIBODIES  SCORING  INTERPRETATION  REPORTING

19. PROGESTERONE RECEPTOR  WEAK PROGNOSTIC FACTOR  ~ 5% DIFFERENCE IN 713 UNTREATED WOMEN

20. DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL THERAPY

21. DISEASE FREE SURVIVAL OF WOMEN RECEIVING HORMONAL THERAPY

22. 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

23. 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

24. 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

25. ESTROGEN RECEPTOR  AC vs AC T  DIFFERENCE MAINLY IN ER -ve  LITTLE DIFFERENCE IN ER +ve HENDERSON ET AL ASCO 2000

26. ESTROGEN RECEPTOR  OXFORD OVERVIEW  SUGGESTION IN SOME ANALYSES THAT WOMEN WITH ER NEGATIVE TUMOURS BENEFIT MORE FROM CHEMOTHERAPY COLE, LANCET 2001 COATES, LANCET 1998

27. 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

28. 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

29. 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

30. 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

31. 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

32. ESTROGEN RECEPTOR MECHANISMS  CLASSIC HORMONAL THERAPIES  BIOLOGIC AGENTS  ANTI HER-2  HERCEPTIN  OTHERS  ANTI EGF  IRESSA  OTHERS

33. PREDICTIVE MOLECULAR MARKERS: HORMONE RECEPTOR STATUSCONCLUSIONS  STILL CRUCIAL IN SELECTION OF HORMONAL THERAPY  MEASUREMENTS MUST BE STANDARDIZED  TISSUE PREPARATON  ANTIBODY USED  SCORING  INTERPRETATION  REPORTING

34. PREDICTIVE MOLECULAR MARKERS: HORMONE RECEPTOR STATUSQUESTIONS ?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

35. PREDICTIVE MOLECULAR MARKERS: HORMONE RECEPTOR STATUSQUESTIONS ?OPTIMAL USE OF COMBINATIONS OF CLASSIC HORMONAL AND BIOLOGIC FACTORS ?OPTIMAL GUIDANCE OF THIS COMBINED THERAPY BY CAREFUL STANDARDIZATION OF LABORATORY MEASUREMENTS