Breast Cancer - the Evidence for Current Management

1. Breast Cancer - the Evidence for Current Management • Jane McNicholas • Consultant Breast and Oncoplastic Surgeon • East Lancashire Hospitals

2. Evidence For Breast Cancer Management • Three major documents that we use • NICE Guidance on Early Breast Cancer • Department of Health “Best practice diagnostic guidelines for patients presenting with breast symptoms” • IOG Breast Cancer 2002

3. Breast Conserving Surgery • What Do We Do? • Offer BCS where feasible and in line with patients wishes

4. Evidence For BCS • NSABP- B06 • Veronesi/Milan Trials • EBCTCG 1995 • Morris et al 1997

5. NSABP-B06 • Showed equivalent survival in patients treated with mastectomy or lumpectomy and radiotherapy

6. Veronesi/ Milan Trials • 1981 and 1986 • Showed survival equivalent for mastectomy or quadrantectomy and radiotherapy

7. EBCTCG 1995 • Systematic Review that looked at 10 year survival from 6 trials (NSABP-B06 was the biggest) comparing BCS and mastectomy. • No difference in survival at 10 years

8. Morris et al 1997 • Meta-analysis of 9 trials • No significant difference of survival at 10 years • No significant difference in rates of local recurrence at 10 years

9. Margins • What Does NICE Say/What Do We Do? • For DCIS - A minimum of 2mm radial margin of excision is recommended, with pathological examination to NHSBSP reporting standards • For Invasive Cancer - Optimal margin is not known, and is not covered in this document.

10. Evidence for Margins • Veronesi 1990 • Singletary

11. Veronesi 1990 • Compared Quadrantectomy with Lumpectomy and showed lower local recurrence with Quadrantectomy

12. Singletary • 10 year follow up of patients being treated with BCS looking at local, regional and systemic recurrence • low annual rate of breast tumour recurrence if margin ≥1mm

13. Surgery to the axilla • What Does NICE Say? • Minimal surgery, rather than lymph node clearance, should be performed to stage the axilla for patients with early invasive breast cancer and no evidence of lymph node involvement on ultrasound or a negative ultrasound-guided needle biopsy • Sentinel lymph node biopsy is the preferred technique

14. Evidence for Sentinel Node Biopsy • NSABP-B32 • ALMANAC Trial

15. NSABP-B32 • SNB + ANC vs SNB +ANC if LN+ • Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes.

16. ALMANAC Trial • Multi-centre, international trial comparing Sentinel Node Biopsy to Standard Axillary Treatment. • Looked at QOL outcomes in patients with clinically LN- • Measured arm morbidity, QOL and Axillary Recurrence rate • Showed reduced lymphoedema and sensory loss (not statistically significant) • Drain usage, length of stay in hospital, resumption of activities was reduced (statistically significant) • QOL and arm functioning scores were increased (statistically significant)

17. Management of the Axilla • What Do We Do? • Currently an area of great controversy. • NICE currently advises that Micrometastatic Disease is treated as a positive axilla, and attracts the recommendation of ANC or RT (depending on local protocol) • Currently in a time of change. Some areas have changed practice, others have continued with this route

18. Evidence for Axillary Management Change • Z11

19. Z11 • Women with ≤3 positive lymph nodes identified on SNB randomised to ANC or observation • With a mean follow up of 6.4 years, there was no difference in DFS or OS • This will probably alter our practice

20. Radiotherapy • What Does NICE Say? • Radiotherapy mandatory after BCS • Radiotherapy in selected patients after mastectomy - those at high risk of recurrence

21. Evidence for Radiotherapy • After BCS- Milan Trial, NSABP-B06, EORTC, Danish Breast Group • After Mastectomy - EORTC meta-analysis

22. After BCS

23. Milan Trial • Women with breast cancer <2cm randomised to mastectomy or quadrantectomy and radiotherapy • No difference in survival,and no significant difference in local recurrence rates • 20 year update published 2002, showed no difference in survival but a significant difference in local recurrence rates

24. NSABP-B06 • 20 year update published 2002, showing no difference in DFS, distant DFS or OS. It did show a significant difference in LR in the radiotherapy and non-radiotherapy groups (14 vs 40%)

25. EORTC 10801 • Randomised to BCS or mastectomy for tumours up to 5cm • 10 year follow up showed no difference in OS or distant DFS. There was no significant in LR rates between mastectomy and BCS groups

26. Danish Breast Group • 850 women randomised to BCS or mastectomy and RT • Results showed no difference in Local Recurrence Rate

27. After Mastectomy

28. EORTC Meta-analysis • Post-mastectomy radiotherapy useful in patients with more than 4 nodes positive, T3 or T4 lesions, and tumours involving skin or muscle

29. Chemotherapy • What Does NICE Say? • Chemotherapy should be offered to lymph node-positive breast cancer

30. Evidence For Chemotherapy • EBCTCG Overview 1998 • EBCTCG 2005 Update

31. EBCTCG Overview 1998 • Systematic review of chemotherapy trials • Benefit of polychemotherapy (CMF or Anthracycline containing regimens) seen in women <50 and aged 50-69. This is unaffected by menopausal status, nodal status or tamoxifen use • 10 year survival improved by about 10% in the <50 age group and about 2-3% in the 50-69 age group

32. EBCTCG 2005 • Anthracycline based chemotherapy significantly more effective than CMF

33. Herceptin • What Do We Do? • NICE - Offer Trastuzumab to HER2-positive early invasive breast cancer following surgery, chemotherapy, and radiotherapy when applicable • Herceptin only given to patients who overexpress the Herceptin receptor (HER-2) • Only licensed for adjuvant or metastatic use, likely to become neo-adjuvant shortly • In adjuvant setting, has to be given alongside chemotherapy, in metastatic setting can be single agent

34. Evidence for Herceptin • Adjuvant - NSABP-B31, NCCTG-N9831, HERA, BCIRG-006 • Metastatic - Slamon et al

35. Adjuvant Trials

36. NSABP-B31 • Herceptin plus taxane given after anthracycline chemotherapy for one year

37. N9831 • Herceptin plus taxane given after anthracycline chemotherapy for one year, together or sequentially

38. NSABP-B31 and N9831 • Reported together by Romond et al • Showed significant increase in DFS and OS at 1 and 2 years • This paper reporting the two trials led to the approval of Herceptin in the adjuvant setting

39. HERA • Herceptin given after any chemotherapy regime for one or two years • Only one year data reported • 34% reduction in risk of death at 2 years

40. BCIRG 006 • Herceptin given with Taxotere and Carboplatin for one year • Showed significant improvement in the DFS and OS

41. Metastatic Trials

42. Slamon et al • This was the first trial to demonstrate the activity of a monoclonal antibody in human breast cancer • Randomised women with metastatic disease to treatment with Herceptin + chemo or chemo alone • Showed use of Herceptin was associated with a longer time to disease progression, higher rate of response to treatment, longer duration of response to treatment, reduction in death rate at 1 year, longer survival and reduction in risk of death by 20%

43. Endocrine Therapy • What Does NICE Say? • ER-positive early invasive breast cancer, postmenopausal women who are not at low risk (excellent or good NPI <3.4) - Offer AI, either anastrozole or letrozole, as initial adjuvant therapy. Offer tamoxifen if AI is not tolerated or contraindicated

44. Evidence For Endocrine Therapy • ATAC • BIG - 198 • IES (Switch) • MA-17 (Extended Adjuvant) • EBCTCG 2005

45. ATAC • Arimidex vs Tamoxifen vs Combination • Combination was dropped at early stage as there it was only as good as Tamoxifen and possibly worse, so it became Arimidex vs Tamoxifen • There was an increased DFS in the Arimidex group, with an absolute benefit of 2.3% • there was a 42% reduction in contralateral Breast Cancers • the benefits have continued to accrue, and data now at 15 years has shown a continued benefit to 5 years of treatment with Arimidex

46. BIG-198 • This studied Tamoxifen vs Tamoxifen/Letrozole vs Letrozole/Tamoxifen vs Letrozole • Showed a 19% decrease in relapse rates with Letrozole (2.6% absolute difference) • Overall survival was improved but not statistically significant

47. IES • Randomised postmenopausal women to either Exemestane or Tamoxifen after 2-3 years of Tamoxifen • In the Exemestane Group, there was a 32% risk reduction of recurrence, contralateral cancers and death • DFS- HR 0.73 • 4.7% absolute benefit • These improvements were shown in both LN+ and LN- patients

48. MA-17 • Letrozole or Placebo given after 5 years of Tamoxifen • Trial stopped early as the interim analysis showed a superior result in the Letrozole group • Significant difference in DFS but not OS

49. EBCTCG 2005 • Summary of polychemotherapy and hormone therapy • For ER-positive disease only, 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, irrespective of the use of chemotherapy and of age, progesterone receptor status, or other tumour characteristics. • 5 years is significantly more effective than just 1–2 years of tamoxifen. • Tamoxifen for 5 years reduces the risk of recurrence by 11.8% and the absolute risk of death by 9.2%

50. Ovarian Suppression • What Does NICE Say? • ER-positive, early invasive breast cancer, premenopausal women - Do not offer ovarian ablation/suppression to women having tamoxifen and chemotherapy. Offer ovarian ablation/suppression in addition to tamoxifen to women who have been offered chemotherapy but chosen not to have it.