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WRAP UP BREAST CANCER
Stefania Redana
Divisione Universitaria di Oncologia Medica
IRCC - Candiolo
Bologna, 20 Giugno 2010
Wrap Up Breast Cancer
Outline
•
Loco-regional treatment
–
–
•
Endocrine therapy
–
•
The role of sentinel node dissection in clinically N0 patients
Radiotherapy: time for changing clinical practice?
Chemopreservation of ovarian function
Metastatic disease
–
–
–
–
–
HER2 positive disease: beyond trastuzumab and lapatinib
Biopsy of metastatic sites
Multi-targeted therapies
Role of bevacizumab in first line treatment
New drugs
Loco-regional treatment
The role of sentinel node dissection

ACOSOG Z0010 A multicenter prognostic study of sentinel node (SN) and
bone marrow (BM) micrometastases in women with clinical T1/T2 N0 M0
breast cancer. Abs CRA 504
SN not found
cT1
or
cT2
N0
M0
R
E
G
I
S
T
E
R
E
D
BCT, SLND,
bilateral
iliac crest
BM
aspiration
YES:
enrolled in
Z0011
SN positive
SN negative
N=5210
ALND
Consent
for Z0011
IHC
NO
NO ALND
and no
specific
axillary
therapy
F
O
L
L
O
W
E
D
Loco-regional treatment
The role of sentinel node dissection

ACOSOG Z0010: main results
–
–
–
–
5 years overall survival: 93% among patients with
H&E+ SN
The detection of IHC+ SN mets has no impact on
overall survival
The detection of IHC+ bone marrow mets is predictive
for a reduced overall survival
No clinical implication on daily clinical practice
Loco-regional treatment
The role of sentinel node dissection

cT1
or
cT2
N0
M0
ACOSOG Z0011 A radomized trial of axillary node
dissection in women with clinical T1/T2 N0 M0 breast
cancer who have a positive sentinel node. Abs CRA 506
BCT,
SLND
with
positive
SN
N=891 of the planned 1900
R
A
N
D
O
M
ALND
Breast
radiation
NO
furhter
surgery
Adjuvant
Systemic
therapy
F
O
L
L
O
W
E
D
Loco-regional treatment
The role of sentinel node dissection

ACOSOG Z0011: main results
– No difference in the rate of local recurrence between ALND
and SLND (4.1% vs 2.8%, respectively)
– Loco-regional recurrence rate is independent from the
number of nodes removed, positive nodes or the size of
nodal disease
– No impact on disease free survival (83.2% vs 82.2% in
SLND and ALND respectively)
– No impact on overall survival (92.5% vs 91.8% in SLND
and ALND respectively)
– Hard to believe that 0.9% increased risk of regional
recurrence and 2.8% increased risk of loco-regional
recurrence might influence survival
Loco-regional treatment
The role of sentinel node dissection

NSABP B32 A randomized phase III clinical trial to compare sentinel
node resection to axillary dissection in clinically node-negative
breast cancer patients. Abs LBA 505
Clinically
negative
node
disease
R
A
N
D
O
M
SLND
+
ALND
SLND
SLND
positive
SLND
negative
Intraop cytology
and postop H&E
FOLLOW-UP
N=1975
SLND
positive
SLND
negative
FOLLOW-UP
N=2011
Loco-regional treatment
The role of sentinel node dissection

NSABP B32: main results
–
–
–
–
No difference in the rate of local (2.7% vs 2.4%) and axillary
recurrence (0.1% vs 0.3%) between ALND and SLND
No impact on disease free survival (HR 1.05, p=0.542), no
difference even according to stratification factors (type of
surgery, tumor size, age)
No impact on overall survival (HR 1.20, p=0.117), no
difference even according to stratification factors (type of
surgery, tumor size, age)
More morbidty was seen after ALND
Loco-regional treatment
Radiotherapy: time for changing clinical practice?

CALGB 9343 comparison of lumpectomy plus tamoxifen with or
without irradiation in women 70 or older with stage I, ER+ breast
carcinoma. Abs 507
Age≥70
Clinically node
negative
Lumpectomy, negative
margins
Tumor size ≤2cm
ER positive or
indeterminate
R
A
N
D
O
M
I
Z
A
T
I
O
N
TAMOXIFEN +
RADIATION
THERAPY
TAMOXIFEN +
NO
RADIATION
THERAPY
N=631
Median follow-up 12 years
Loco-regional treatment
Radiotherapy: time for changing clinical practice?

CALGB 9343: main results
Breast recurrence
Ultimate breast preservation
Secondary primary
Distant metastaes
Breast cancer specific death (3%)
Death from any cause (46%)
~7%
NS
NS
NS
NS
NS
Endocrine therapy
Chemopreservation of ovarian function

Role of luteinizing hormone-releasing hormone analog (LHRHa)
triptorelin (T) in preserving ovarian function during chemotherapy
for early breast cancer patients: Results of a multicenter phase III
trial of Gruppo Italiano Mammella (GIM) group. Abs 528
281 pt
Age 18-45
Stage I-III
HR + or -
R
A
N
D
O
M
CHT
133
CHT
+ OS
148
Main Results
Early
menopause
No
menopause
CT
32.3%
58%
CT + T
13.5%
77%
Absolute reduction of early
menopause: ~19%
Metastatic disease
HER2 positive breast cancer

A phase Ib/II trial of trastuzumab-DM1 (TDM-1) with pertuzumab
for women with HER2 positive locally advanced or metastatic
breast cancer who were previously treated with trastuzumab.
Abs 1012
Metastatic disease
HER2 positive breast cancer
Efficacy results
Cohort 1 (n=3)
Complete response
Cohort 2 (n=25)
Total (n=28)
0
0
0
Partial response
2 (66.7%)
8 (32%)
10 (35.7%)
Stable disease
1 (33.3%)
12 (48%)
13 (46.4%)
Progressive disease
0
4 (16%)
4 (14.3%)
Missing
0
1 (4%)
1 (3.6%)
Safety Results
1 grade 5 event
2 grade 4 evets (4.5%)
Most common grade 3 events were: fatigue (13.6%),
thrombocytopenia (6.8%), increase of AST (6.8%), nausea and
vomiting (4.5% each)
Metastatic disease
Biopsy of metastatic sites

Tissue confirmation of disease recurrence in patients with
breast cancer: pooled analysis of two large prospective
studies. Abs 1007
Recurrence or progression
• DESTINY STUDY
• Single institution study (Canada)
• ER/PgR determined according to
ASCO guidelines with IHC
• HER2  FISH
• Re analysis of primary
Written informed consent
Oncologist post-biopsy questionnaire
• BRITS STUDY
• Multicentric study (UK)
• ER/PgR determined with IHC
according to Allred score
• HER2  FISH
• Re analysis of primary
N=271 patients
BIOPSY
Central revision of ER/PgR/HER2
Oncologist post-biopsy questionnaire
Metastatic disease
Biopsy of metastatic sites

Should liver metastases of breast cancer be biopsied to
improve treatment choice? Abs CRA 1008
–
–

TRIAL DESIGN: retrospective analysis on 255 liver biopsy
performed on metastatic recurrent breast cancer at a single
institution
AIM: quantify discordance of ER, PgR and HER2 expression
between primary tumor and metastases from breast cancer
Discordance in hormone receptor status in breast cancer
during tumor progression. Abs 1009
–
–
TRIAL DESIGN: retrospective analysis of 486 patients for whom
assessment of ER and PgR was available on both primary tumor
and mets
AIM: determine if hormone receptors (ER and PgR) change
between the primary tumor and recurrence
Metastatic disease
Biopsy of metastatic sites
AMIR
LOCATELLI
KARLSSON
LITTERATURE
Overall discordance (%)
38.8
N.R.
N.R.
29% (17.7-55)
Overall ER discordance (%)
12.6
14.5
35
N.R.
ER gain (%)
14.0
25.9
8
N.R.
ER loss (%)
12.1
11.2
27
N.R.
Overall PgR discordance (%)
34.1
48.6
43
N.R.
HER2 gain (%)
4.6
5.9
N.R.
N.R.
HER2 loss (%)
12.5
31.5
N.R.
N.R.
Change in treatment decision
15%
12%
N.R.
N.R.
Amir: less discordance among triple negative tumors (6.8%)
Karlsson: correlation between ER status in relapse and OS
Metastatic disease
Multi-targeted therapies


SUN 1064. Sunitinib (SU) in combintion with docetaxel (D) versus
D alone for the first-line treatment of advanced breast cancer
(ABC). Abs LBA 1010
SUN 1099. Phase III trial of Sunitinib (SU) in cmbination with
capecitabine (C) versus C alone in previously treated advanced
breast cancer (ABC). Abs LBA 1011
SUN 1064
Measurable
or non
measurable
disease
≥12 months
from
neo/adjuvant
taxanes
No CHT for
ABC
Primary End Point: PFS
R
A
N
D
O
M
D+
SUN
D
Measurable
or
SUN 1099
non
measurable
disease
Prior
neo/adjuvant
anthracyclines
and taxanes
1-2 prior CHT
for ABC
R
A
N
D
O
M
Secondary: ORR, OS,safety
C+
SUN
C
Metastatic disease
Multi-targeted therapies

Efficacy results
SUN 1064
• Safety results
•
•
SUN 1099
D+
SUN
D
C+
SUN
C
PFS (months)
8.7
8.3
5.5
5.9
HR (95% IC)
0.92 (0.721.19)
P=0.904
ORR (%)
55
42
54
59
24.8
25.5
16.4
16.5
OS (months)
1,22 (0.95-1.58)
P=0.941
Most grade 3-4 AE were registered in the experimental arms
More frequent AE were: neutropenia, thrombocytopenia,
asthenia/fatigue, diarrhea, HFS, nausea and vomiting
Metastatic disease
Role of bevacizumab in first line therapy

A meta-analysis of overall survival data from three randomized trials
of bevacizumab (BV) and first-line chemotherapy for treatment of
patients with metastatic breast cancer(MBC). Abs 1005
E2100
Paclitaxel
Previously
untreated
MBC
AVADO
Docetaxel
RIBBON-1
Capecitabine,
anthracyclines
or taxanes
R
A
N
D
O
M
I
Z
E
CT + NO
BV
Treat
untill
PD
CT + BV
PRIMARY END POINT: PFS
Optio
nal
2nd
line
with
BV
Metastatic disease
Role of bevacizumab in first line therapy

Main results
No BV (1008)
AVADO
E2100
Median PFS (months)
HR (95% IC)
Median
PFS
OS
NO BV
BV
6.7
NO BV
5.8
11.3
7.926.4
Stratified
HR (95% HR
IC)
P
valuesurvival (%)
1 year
0.48 (0.39-0.61)
Median
ORR* FU for OS
35
P<0.0001
BV (1439)
RIBBON-1
Capecitabine
BV
8.8
BV
BV
0.64NO
(0.57-1,07)
5.7
8.6
0.62 (0.48-0.79) 0.97 (0.86-1.08)
0.69 (0.56-0.84)
P=0.0003
P=0.0002
77
29
32%
* Only patients with measurable disease
23
RIBBON-1
Anthra/Tax
9.2
NO BV
BV
9.2
26.78.0
0.64 (0.52-0.80)
82
P<0.0001
49%
26
Metastatic disease
New drugs


A Phase III study (EMBRACE) of eribulin mesylate versus
treatment of physician's choice in patients with locally recurrent
or metastatic breast cancer previously treated with an anthracycline
and a taxane. Abs CRA1004^
Metastatic disease
New drugs
Efficacy results
Eribulin
Median OS (months)
TPC
13.12
HR (95% IC)
0.81 (0.66-0,99)
1 year survival (%)
53.9
43.7
Median PFS (months)
3.7
2.2
HR (95% IC)
ORR (%)
Clinical benefit (CR + PR +
SD≥6 months) (%)
Safety results
10.65
Adverse Events (%)
0.87 (0.71-1.05)
12
4.7
22.6
16.8
Eribulin (503)
TPC (247)
All AE
98.8
93.1
Serious AE
25.0
25.9
Fatal AE
4.0
7.3
Take home messages
Early Breast Cancer
1.
2.
3.
4.
Patients with early breast cancer clinically N0 should not
undergo ALND but only SLND
Patients with clinically N0 but positive SLND could safely
be spared ALND without an increased risk of progression
or death
Old women with HR+, cN0, free margins after lumpectomy
could be spared RT if given hormonal therapy
Young women should be offered OS during adjuvant
chemotherapy either they are HR+ or not
Take home messages
Metastatic disease
1.
2.
3.
4.
5.
TDM-1 + Pertuzumab is a reasonable option for patients with
HER2+ disease progressing after trastuzumab and lapatinib
Biopsy of metastatic sites could be changing practice
Sunitinib should not be considered for the treatment of ABC
1st line bevacizumab increases PFS and ORR but has no effect
on OS (hard to see in 1st line treatments)
Eribulin increases OS in heavily pre-treated metastatic breast
cancer patients (new drugs can impact OS in further lines of
therapy)