1. How Do We Treat HR positive Breast Cancer in Postmenopausal Women?

2. Oestrogen Receptors Oestrogen Target Cell (e.g. Breast, Uterine lining, Liver, etc.) Non-Target Cell (contains no oestrogen receptor)

3. Dominant Pathway in Postmenopausal Women Cholesterol Pregnenolone Androstenedione Oestrogen AROMATASE Aromatase Inhibitors Adrenal Adipose

4. Her2neu Positive Breast Cancer and Herceptin (Trastuzumab) Her2 receptors send signals telling cells to grow and divide Too many Her2 receptors send more signals, causing cells to grow too quickly Herceptin stops the Her2 receptors from signaling the cell to grow Her2-normal breast cancer cell Her2+ breast cancer cell Herceptin

5. Subtypes of Breast Ca Luminal A Luminal B Erb-B2 Overexpression ‘Basal-like’

6. Normal mammary development Breast tumour subtype Signatures Stem cell Bipotent progenitor Myoephithelial progenitor Luminal progenitor Late luminal progenitor Differentiated luminal cells Differentiated myoephithelial cells Claudin-low Basal-like HER2 -enriched Luminal B Luminal A Mesenchymal Luminal Basal- like

7. Subtypes of Breast Ca Intrinsic SubtypeClinico-Pathological DefinitionTreatment

8. Subtypes of Breast Ca Luminal A Intrinsic SubtypeClinico-Pathological DefinitionTreatment ER and/or PgR positive HER2 negative Ki-67 low

9. Subtypes of Breast Ca Luminal AET Intrinsic SubtypeClinico-Pathological DefinitionTreatment HR positive HER2 negative Ki-67 low

10. Subtypes of Breast Ca Luminal A Luminal B Erb-B2 Overexpression (non-Luminal) Basal-like ER and/or PgR positive HER2 negative Ki-67 high Triple-negative (ductal) ER and PgR absent HER2 negative Special Hist Types ET ET +/- CT CT + anti-her2 CT CT + anti-her2 + ET Intrinsic SubtypeClinico-Pathological DefinitionTreatment ER and/or PgR positive HER2 negative Ki-6 Ki-67 low (<14%) HER2 over-expressed or amplified ER and PgR absent ER and/or PgR positive Any Ki-76 HER2 over-expressed or amplified

11. We need Oncotype Dx to differentiate between some types at least

12. Variable / StudyTamoxifenTamoxifen + Chemotherapy 10 yr DRFS B20 N0* Low Recurrence Score High Recurrence Score 97 % 60 % 93 % 73 % 10 yr BCSS S8814 N+** Low Recurrence Score High Recurrence Score 93 % 54 % 88 % 73 % Remarkably Similar Significant Interaction between Chemotherapy Benefit and Recurrence Score in B20 (N0) and S8814 (N+)

13. Case Studies

14. Case Study 1 70 Pleomorphic Lobular cancer - aggressive subtype HR positive and her2 negative Stage 2 with no nodes involved

15. 1.Nothing as she is elderly and early stage 2.ET alone 3.CT + ET 4.Don’t know

16. Subtypes of Breast Ca Luminal A Luminal B Erb-B2 Overexpression (non-Luminal) Basal-like HR positive HER2 negative Ki-67 high Triple-negative (ductal) HR absent HER2 negative Special Hist Types ET ET +/- CT CT + anti-her2 CT ET or CT ET + anti-her2 + CT Intrinsic SubtypeClinico-Pathological DefinitionTreatment HR positive HER2 negative Ki-67 low HR absent HER 2 positive HR positive HER2 positive Any Ki-76

17. CT + ET ET alone Don’t know Suggestions?

18. Genomic Grade 21 Gene Recurrence Score (RS) 70 Gene Other Prognostic Signatures… Relative Endocrine “Resistance” Relative Chemo “Sensitivity” BUT… Only RS tested in Phase III trials N0, N+

19. Very early tumours: Factors to consider

20. Age </=35 LVI HER2 + Triple negative subtype Luminal with high risk genomic profile Comorbidities

21. Premenopausal Adjuvant Therapy 38 RA and severe depression. ‘FA’ excised: T2 (23mm) N – HR strongly positive + Her2negative cancer. G1 Ki 67 High Very worried about developing suicidal depression again

22. Subtypes of Breast Ca Luminal A Luminal B Erb-B2 Overexpression (non-Luminal) Basal-like ER and/or PgR positive HER2 negative Ki-67 high Triple-negative (ductal) ER and PgR absent HER2 negative Special Hist Types ET ET +/- CT CT + anti-her2 CT ET or CT ET + anti-her2 + CT Intrinsic SubtypeClinico-Pathological DefinitionTreatment ER and/or PgR positive HER2 negative Ki-67 low (<14%) HER2 over-expressed or amplified ER and PgR absent ER and/or PgR positive Any Ki-76 HER2 over-expressed or amplified

23. CT + ET ET alone Don’t know Suggestions?

24. Adjuvant Online – S D Age: 38 ER: Positive Grade: 1 Size: 2.1 - 3.0 cm Nodes : 0 CT: AC x 4 → T x 4 Decision: No Additional Therapy Decision: Hormonal Therapy Decision: Chemotherapy Decision: Combined Therapy 87/100 women alive 09/100 women died - cancer 04/100 women died - other 03/100 women alive because of therapy 04/100 women alive because of therapy 05/100 women alive because of therapy

26. Node Negative, ER-Positive Breast Ca Chemotherapy Benefit

27. Which hormonal therapy?

28. Oestrogen Receptors Oestrogen Target Cell (e.g. Breast, Uterine lining, Liver, etc.) Non-Target Cell (contains no oestrogen receptor)

29. Pathway in Premenopausal Women Pituitary Oophorectomy OestrogenOvariesHypothalamus LHRH Agonist FSH LH

31. Post-mastectomy RT No benefit proven if stage 4 Reduces LR recurrence by 2/3

32. Oxford Overview

34. Oxford Overview NO

35. Indications for Post-Mx RT Nodes Positive T 3 or 4 or muscle invasion Margins

36. Relapsed Late Stage 3 Stage 4 Treatment of Advanced Breast Cancer

37. Hormones Chemotherapy Biologicals Radiotherapy Surgery Bisphosphanates for bone secondaries

38. Treatment of Advanced Disease Rx = ET Elderly & unfit HR+ Long DFI Bones & Soft Tissue Rx = CT Young & fit HR- Short DFI / Rapid progress Visceral / Life-threatening

39. Case 3 46 Premenopausal Mx Lt 2009 for T2 ca with micromet in node HR positive and her2 negative : CT x 3 (poorly tolerated )then Tam Now presented severe RUQ pain CXR mass in lung and ultrasound 3 liver lesions = mets

41. Liver and lung secondaries PS: 3 Hospitalised for symptom control Reluctant to see counsellor or St Lukes Case 3 cont’d

42. 1.Symptomatic care 2.Chemotherapy 3.Endocrine therapy

43. Liver and lung secondaries PS: 3 Hospitalised for symptom control Reluctant to see counsellor or St Lukes CT – patient choice Case 3 cont’d

44. Performance Status 0 Symptom-free 1 Symptomatic, fully active 2 Resting < 50% of day 3 Resting > 50% of day 4 Bedridden

45. Painful Rib metastasis 7 years after primary treatment HR positive Her2 negative Case 4

46. 1.CT 2.ET 3.Other 4.Combination

47. Painful Rib metastasis Rx ET + RT with control of symptoms Case 4

48. Obese Looked after her about 10 years with bone secondaries HR positive Her2 negative Case 5

50. How would you try to control this long term?

51. 2 -3 operations to spine + RT + BP + CT + ET Lifestyle Still works Case 5 cont’d