Breast Cancer - the Evidence for
Current Management
Jane McNicholas
Consultant 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
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
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 LNMeasured 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 metaanalysis
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 nonradiotherapy 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
This was the
first trialet
to al
demonstrate the
Slamon
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
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 23 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
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
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