Breast Cancer - the Evidence for Current Management

Jane McNicholasConsultant Breast and Oncoplastic Surgeon

East Lancashire Hospitals

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

Breast Conserving Surgery

What Do We Do?

Offer BCS where feasible and in line with patients wishes

Evidence For BCS

• NSABP- B06• Veronesi/Milan Trials• EBCTCG 1995 • Morris et al 1997

NSABP-B06

• Showed equivalent survival in patients treated with mastectomy or lumpectomy and radiotherapy

Veronesi/ Milan Trials

• 1981 and 1986• Showed survival equivalent for

mastectomy or quadrantectomy and radiotherapy

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

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

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.

Evidence for Margins

• Veronesi 1990• Singletary

Veronesi 1990

• Compared Quadrantectomy with Lumpectomy and showed lower local recurrence with Quadrantectomy

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

• 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

Surgery to the axilla

Evidence for Sentinel Node Biopsy

NSABP-B32

ALMANAC Trial

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.

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)

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

Evidence for Axillary Management Change

Z11

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

Radiotherapy

What Does NICE Say?

Radiotherapy mandatory after BCS

Radiotherapy in selected patients after mastectomy - those at high risk of recurrence

Evidence for Radiotherapy

After BCS- Milan Trial, NSABP-B06, EORTC, Danish Breast Group

After Mastectomy - EORTC meta-analysis

After BCS

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

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%)

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

Danish Breast Group

• 850 women randomised to BCS or mastectomy and RT

• Results showed no difference in Local Recurrence Rate

After Mastectomy

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

Chemotherapy

What Does NICE Say?

Chemotherapy should be offered to lymph node-positive breast cancer

Evidence For Chemotherapy

EBCTCG Overview 1998

EBCTCG 2005 Update

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

EBCTCG 2005

Anthracycline based chemotherapy significantly more effective than CMF

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

Evidence for Herceptin

Adjuvant - NSABP-B31, NCCTG-N9831, HERA, BCIRG-006

Metastatic - Slamon et al

Adjuvant Trials

NSABP-B31

Herceptin plus taxane given after anthracycline chemotherapy for one year

N9831

Herceptin plus taxane given after anthracycline chemotherapy for one year, together or sequentially

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

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

BCIRG 006

• Herceptin given with Taxotere and Carboplatin for one year

• Showed significant improvement in the DFS and OS

Metastatic Trials

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%

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

Evidence For Endocrine Therapy

ATAC

BIG - 198

IES (Switch)

MA-17 (Extended Adjuvant)

EBCTCG 2005

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

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

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

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

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%

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.

Evidence For Ovarian Suppression

ZIPP

ZEBRA

EBCTCG 2005

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

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

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

• 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

Breast Reconstruction

Evidence for Breast Reconstruction

Malata 2000

National Mastectomy Audit

Wilson et al, 2004

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.

National Mastectomy Audit

• 4 years of data now published• Shows approximately 20% of women

undergoing IBR after mastectomy

Wilson et al

• Showed no statistical difference between surgery and first dose of chemo in WLE, mastectomy or mastectomy and IBR

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

Evidence for Prophylactic Mastectomy

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

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

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)

Evidence for MRI Screening

MARIBS

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