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
NOTES FOR PRESENTERS:
Key points to raise:
For patients with invasive breast cancer, one of the most important prognostic indicators is whether the tumour has spread to the axillary lymph nodes and this is essential in determining subsequent treatment. Current guidelines advise that histological lymph node status should be obtained for all operable invasive breast cancers.
Related recommendations:
Invasive breast cancer
SLNB should only be performed by a team that is validated in the use of the technique, as identified in the New Start training programme.1 (1.4.2)
Perform SLNB using the dual technique with isotope and blue dye. (1.4.3)
Breast units should audit their axillary recurrence rates. (1.4.4)
DCIS
Do not perform SLNB routinely in patients with a preoperative diagnosis of DCIS who are having breast conserving surgery, unless they are considered to be at a high risk of invasive disease.2 (1.4.5)
Offer SLNB to all patients who are having a mastectomy for DCIS. (1.4.6)
Evaluation and management of a positive sentinel lymph node
Offer further axillary treatment to patients with early invasive breast cancer who:
• have macrometastases or micrometastases shown in a sentinel lymph node
• have a preoperative ultrasound-guided needle biopsy with histologically proven metastatic cancer.
The preferred technique is axillary lymph node dissection (ALND) because it gives additional staging information. (1.4.7)
Do not offer further axillary treatment to patients found to have only isolated tumour cells in their sentinel lymph nodes. These patients should be regarded as lymph node-negative. (1.4.8)
1 New Start sentinel lymph node biopsy training programme, The Royal College of Surgeons of England
2 Patients considered at high risk of invasive disease include those with a palpable mass or extensive microcalcifications.

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 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 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.

51. Evidence For Ovarian Suppression
ZIPP
ZEBRA
EBCTCG 2005

52. ZIPP Tam vs Zol vs Tam/Zol vs Nothing
Zoladex prolonged the RFS and showed a trend to increased OS
Benefit greatest in ER+ tumours, irrespective of chemo or Tamoxifen

53. ZEBRA
CMF vs Zoladex
In ER+ Zoladex was equivalent to CMF for DFS and OS
In ER- Zoladex had worse outcome for DFS and OS

54. EBCTCG 2005
Ovarian suppression shows a reduction in the risk of recurrence of 11.5% after 20 years of follow up in women who did not have chemotherapy, but only 0.6% in those who did have chemotherapy

55. Breast Reconstruction
What Does NICE Say?
Discuss immediate breast reconstruction with all patients who are being advised to have a mastectomy
Offer it except where significant comorbidity or (the need for) adjuvant therapy may preclude this option
All appropriate breast reconstruction options should be offered and discussed with patients, irrespective of whether they are all available locally
NOTES FOR PRESENTERS:
Key points to raise:
Breast reconstruction can be carried out at the same time as mastectomy (immediate) or at any point in the future (delayed). Breast reconstruction is not associated with a higher risk of recurrence. Immediate reconstruction has the advantage, to those patients for whom loss of body image is a concern, of having one primary breast procedure and offering the possibility for limited skin removal. The advantage of immediate breast reconstruction, where it is possible, is that fewer operations are required in order to obtain the definitive shape. However, a large quantity of information about reconstruction has to be discussed with patients for them to make informed decisions and this can be difficult when at the same time absorbing the diagnosis of breast cancer. Furthermore, all methods of reconstruction have potential complications which might delay subsequent adjuvant therapy. Chest wall radiotherapy may significantly reduce the cosmetic outcomes of reconstruction.

56. Evidence for Breast Reconstruction
Malata 2000
National Mastectomy Audit
Wilson et al, 2004

57. Malata 2000
Immediate breast reconstruction is a safe and acceptable procedure after mastectomy for cancer; there is no evidence that it has untoward oncological consequences.

58. National Mastectomy Audit
4 years of data now published
Shows approximately 20% of women undergoing IBR after mastectomy

59. Wilson et al
Showed no statistical difference between surgery and first dose of chemo in WLE, mastectomy or mastectomy and IBR

60. Prophylactic Mastectomy
What Do We Do?
No real guidelines as to who should be offered prophylactic mastectomy
Gene carriers often a straightforward decision
Patients with undetermined risk or at low risk are more difficult

61. Evidence for Prophylactic Mastectomy
Cochrane Review - “Prophylactic Mastectomy for the Prevention of Breast Cancer”

62. Cochrane Review for Prophylactic Mastectomy
Prophylactic mastectomy should only be considered for those at very high risk of disease e.g. BRCA1 and 2 mutations
In women who have already had a cancer diagnosis, contralateral mastectomy may reduce the incidence of cancer in the contralateral breast, but there is no evidence it will improve survival
Women generally satisfied with their decision to undergo surgery, but less satisfied with cosmetic outcome. The decreased cosmetic satisfaction was often associated with reconstruction and surgical complications

63. Family History and High Risk Patients
What Do We Do?
NICE Guidance for Family History
Shows who should be referred to primary/secondary/tertiary care
Recommendation for who should have MRI Screening (basically those at highest risk)

64. Evidence for MRI Screening
MARIBS

65. MARIBS Prospective Multi-centre Cohort Study
High Risk Patients (BRCA 1/2, TP53, strong FH, LiFraumeni Syndrome)
Annual Mammo and CE MRI
MRI more sensitive than mammogram
Mammogram more specific than MRI
MRI + mammo - increased sensitivity with some loss of specificity