Mike Dixon Edinburgh Breast Unit Breakthrough Research Breast Unit Edinburgh San Antonio Breast Cancer Symposium Update
Mike Dixon
Edinburgh Breast Unit
Breakthrough Research Breast Unit Edinburgh
San Antonio Breast Cancer Symposium
Update
Surgical Removal Of Primary Tumor And Axillary
Lymph Nodes In Women With Metastatic Breast
Cancer At First Presentation :
A Randomized Controlled Trial
PI: R A Badwe
Professor Surgical Oncology(Breast)
Tata Memorial Centre Mumbai , India
Co-Investigators V Parmar, R Hawaldar , N Nair, R Kaushik, S Siddique, A Nawle,
A Budrukkar, I Mittra, S Gupta
Background
• Many recent publications have shown survival
advantage for surgery in Stage IV disease
Benefit of Surgery persists in multivariate analyses
• NOT all series have shown benefit
• Fisher’s animal experiment showed growth of
metastases when primary tumour excised
• Value of Surgery in Stage IV disease uncertain
Aim of Study
• To assess effect of removal of primary tumour on
overall survival in women presenting with metastatic
breast cancer
• Sample size Calculation
Baseline median Survival 18 Months
Expected Improvement 6 months
α = 0.05, 1- β = 80%
N = 350
Trial Schema
R MBC
Anthracyclines +/-
Taxanes
(CR /PR ) No Loco-
Regional
Treatment Stratification
Site of Metastasis
Visceral ,
Bone ,
Visceral + Bone
No of Metastasis
<= 3 ,
>3
ER/PgR:
Positive
Negative
NO Trastuzumab Given to HER2 positive patients
Trial Schema
Randomization
(N=350)
*Loco-regional Therapy : BCT / MRM + supraclavicular node clearance if indicated
** Tamoxifen if pre menopausal +AI in Post menopausal / post Oophorectomy
Loco-regional Treatment (#173)
No Loco-regional Treatment (#177)
LR Surgery* +/-
Ovarian Ablation (40)
Radiotherapy + Hormone Therapy in
Hormone sensitive tumors** (84)
Hormone Therapy (96) whenever indicated including
Ovarian Ablation (34)
Stratification
NO LRT (#177)
N (%)
LRT (#173)
N (%)
TOTAL
Site of Metastasis
Bone
Visceral
Bone + Visceral
50 (50.0)
77 (50.7)
50 (51.0)
50 (50.0)
75 (49.3)
48 (49.0)
100
98
152
Stratification
NO LRT (#177)
N (%)
LRT (#173)
N (%)
TOTAL
Site of Metastasis
Bone
Visceral
Bone + Visceral
50 (50.0)
77 (50.7)
50 (51.0)
50 (50.0)
75 (49.3)
48 (49.0)
100
98
152
No. of Metastasis
<= 3
>3
45 (50.6)
132 (50.6)
44 (49.4)
129 (49.4)
89
261
Stratification
NO LRT (#177)
N (%)
LRT (#173)
N (%)
TOTAL
Site of Metastasis
Bone
Visceral
Bone + Visceral
50 (50.0)
77 (50.7)
50 (51.0)
50 (50.0)
75 (49.3)
48 (49.0)
100
98
152
No. of Metastasis
<= 3
>3
45 (50.6)
132 (50.6)
44 (49.4)
129 (49.4)
89
261
ER/PgR
Positive
Negative
106 (51.0)
71 (50.0)
102 (49.0)
71 (50.0)
208
142
Stratification
NO LRT (#177)
N (%)
LRT (#173)
N (%)
TOTAL
Site of Metastasis
Bone
Visceral
Bone + Visceral
50 (50.0)
77 (50.7)
50 (51.0)
50 (50.0)
75 (49.3)
48 (49.0)
100
98
152
No. of Metastasis
<= 3
>3
45 (50.6)
132 (50.6)
44 (49.4)
129 (49.4)
89
261
ER/PgR
Positive
Negative
106 (51.0)
71 (50.0)
102 (49.0)
71 (50.0)
208
142
Age (Median) 47 48 47
Menopausal status
Pre
Post
88 (54.3)
89 (47.3)
74 (45.7)
99 (52.7)
162
186
NO LRT
(177)
LRT
(173)
TOTAL
Protocol
Violations
3 (1.7%) 9 (5.2%) 12
Palliative
Mastectomy
(per protocol)
18 (10.2%) 1 (0.6%) 19
Treatment Anomalies
p =0.004
Overall Survival
Sub Group Analysis
First Progression Local
First Progression Metastatic
Conclusions
• Loco-regional treatment did not confer any survival
advantage and hence should not be offered as a
routine practice in women presenting with MBC
• The lack of survival benefit is due to a trade off
between local control and distant disease
progression
• Removal of the primary tumor conferred a growth
advantage on distant metastasis
Atilla Soran, Vahit Ozmen, Serdar Ozbas, Hasan Karanlık, Mahmut
Muslumanoglu, Abdullah Igci, Zafer Canturk, Zafer Utkan, Cihangir Ozaslan,
Turkkan Evrensel, Cihan Uras, Erol Aksaz, Aykut Soyder, Umit Ugurlu, Cavit
Col, Neslihan Cabioğlu, Betül Bozkurt, Temel Dagoglu, Ali Uzunkoy, Mustafa
Dulger, Neset Koksal, Omer Cengiz, Bahadir Gulluoglu, Bulent Unal, Can Atalay,
Emin Yıldırım, Ergun Erdem, Semra Salimoglu, Atakan Sezer, Ayhan Koyuncu,
Gunay Gurleyik, Haluk Alagol, Nalan Ulufi, Uğur Berberoğlu, Elizabeth D
Kennard, Sheryl Kelsey, Barry Lembersky.
On behalf of the Turkish Federation of Societies
for Breast Diseases
ClinicalTrials.gov identifier number:NCT00557986.
Early follow up of a randomized trial evaluating
Resection of the Primary Breast Tumor in Women
presenting with de novo stage IV Breast Cancer;
Turkish Study (Protocol MF07-01)
Schema
Patients
Patients
• Average age 51 years
• 56-58% Grade 3 : 39-49% T3 and T4, 80% NST
• 65-73% One site of met only
• No Histological confirmation of mets
• 40-52% Bone Only
• 15-24% solitary bone met
• 25% BCS 75% mastectomy
• XRT to mets in 18-30% in both groups
Overall Survival
Overall Survival in ER +ve vs ER –ve Groups
Survival in Different Groups
SURGERY NO SURGERY
Group N/deaths Survival (95% CI) N/deaths Survival (95% CI) p-value
(Log rank
test
Solitary
bone
33/3 61.4(7.7, 91.1) 20/8 44.0(16.5, 68.8) 0.02
Survival in Different Groups
SURGERY NO SURGERY
Group N/deaths Survival (95% CI) N/deaths Survival (95% CI) p-value
(Log rank
test
Solitary
bone
33/3 61.4(7.7, 91.1) 20/8 44.0(16.5, 68.8) 0.02
Solitary
Lung or
Liver
13/4 55.6(8.6, 86.9) 16/3 67.0(26.1, 88.7) 0.65
Survival in Different Groups
SURGERY NO SURGERY
Group N/deaths Survival (95% CI) N/deaths Survival (95% CI) p-value
(Log rank
test
Solitary
bone
33/3 61.4(7.7, 91.1) 20/8 44.0(16.5, 68.8) 0.02
Solitary
Lung or
Liver
13/4 55.6(8.6, 86.9) 16/3 67.0(26.1, 88.7) 0.65
Multiple
lung or liver
9/7 13.3(0.8, 44.1) 11/3 46.7(7.1, 80.3) 0.003
Conclusions
• No improvement in survival with surgery in Stage IV
disease
• Better outcomes in younger (<55y) + solitary vs multiple
bone mets, and with bone vs other mets
• Surgery possibly disadvantageous for visceral and
advantageous for solitary bone mets
• Patients with aggressive phenotypes in particular had
no benefit from surgery
TBRC13: A prospective Analysis of the
Role of Surgery in Stage IV disease
• Prospective Registry Study
• 127 patients - 14 sites:
112 Stage IV intact primary: Cohort A
15 developed mets <3m surgery: Cohort B
• Median Follow up 25 months
King et al Multicenter
Outcomes for 2 Cohorts
Intact Primary
Mets <3 months
Overall Survival: No Effect of Surgery
Cohort B
Cohort A
Non Responders
A Responder
Surgery
A Responder
No Surgery
Ongoing US Trial New Design
New design planned to detect a 19% in survival 30 vs 49% at 3 years
Based on SABCS data this is unrealistsic
Conclusions
• A large benefit from Primary Surgery to the local site
is unlikely in Stage IV disease
• Assumptions for US trial incorrect
Current design unlikely to meet endpoint
• Pooled analyses of all trials may be needed to
determine whether there is a small benefit from
Surgery in Stage IV Breast cancer
Magnetometer and Iron as a Tracer in
SNBx
• 150 patients having SNBx had both radioisotope and
Iron Injected
Thill et al SABCS P1 O1 O2
Results with Magnetometer
Thill et al SABCS P1 O1 O2
• SN Detection rate
146/150 for radio isotope
147/150 for Iron
• Average nodes 1.8 vs 1.9
• Positive nodes
91.2% for radio isotope
95.6% for Iron
• All patients with a involved SLNs would be
Identified by sampling 2 lymph nodes with
Highest magnetic or radioisotope count
• Iron and Magnetometer works and has potential advantages
Post-operative Radiotherapy In
Minimum-risk Elderly – PRIME II
Kunkler IH, Williams LJ, Jack W, Canney P, Prescott RJ, Dixon JM on behalf of the
PRIME II investigators
San Antonio Breast Cancer Symposium, Dec 10-14th, 2013
Aim
To assess the impact on local control of the
omission of postoperative whole breast radiotherapy
after breast conserving surgery and adjuvant
endocrine therapy in ‘low risk’ older patients
Eligibility: Inclusion Criteria
Age ≥ 65 years
Histologically confirmed Unilateral Invasive breast
cancer
Pathology size ≤ 3cm
Breast conserving surgery
Excision margin of ≥1mm on histological assessment
Oestrogen receptor or progesterone receptor positive
Treated with adjuvant endocrine therapy (including
pre-operative neo-adjuvant endocrine therapy)
No axillary node involvement on histological
assessment
Medically suitable to attend for treatment and follow up
Able and willing to give informed consent
Design
1326
WBI*, N=658
No WBI, n=668
* 40 - 50Gy in 15 – 25 #
Population
No Radiotherapy (n=668) Radiotherapy (n=658)
Age Mean (sd) 71.12 (4.96) 70.78 (4.74)
Tumour size N (%)
0-10mm 258 (38.6%) 265 (40.3%)
10.1-20mm 326 (48.8%) 319 (48.5%)
20.1-30mm 84 (12.6%) 74 (11.2%)
Grade N (%)
1 271 (40.9%) 292 (44.4%)
2 368 (55.6%) 352 (54.6%)
3 23 (3.5%) 13 (2.0%)
LVI N (%)
No 631 (95.2%) 628 (95.9%)
Yes 32 (4.8%) 27 (4.1%)
Pre-operative endocrine therapy N (%)
No 608 (90.9%) 598 (91.7%)
Yes 60 (9.1%) 54 (8.3%)
Local control Local recurrence
5 yr actuarial rate
No RT (n=668)
26 4.1%
RT (n=658)
5 1.1%
Total 31
ER status: Effect of RT
Local recurrence/N (%)
ER* No RT RT p-value
High (7-8) 19/594 (3.2%) 5/602 (0.8%) 0.003
Low (2-6) 7/63 (11.1%) 0/54 (0%) 0.015
* High ER is defined as ER+ve, ER≥7, fmol>20, staining>20%, and +++. Anything else is low ER
Multivariate LR
Variable HR (95% CI) p-value
T size (ref 0-10mm)
1
10.1-20mm 0.53 (0.23,1.22)
0.14
20.1-30mm 1.17 (0.43, 3.20)
0.76
Margins (ref >5mm)
1
<1mm 1.99 (0.25, 16.04)
0.52
1-5mm 0.89 (0.40, 1.98)
0.78
Re-excision 1.05 (0.38, 2.89)
0.92
Radiotherapy (ref Yes)
1
No 5.08 (1.95, 13.24)
0.001
Multivariate LR
Variable HR (95% CI) p-value
Age (ref 65-69) 1
70+ 2.08 (0.95, 4.55)
0.07
Grade (ref G1) 1
G2 1.31 (0.59, 2.90)
0.51
G3 3.48 (0.89, 13.65)
0.07
LVI (ref No) 1
Yes 1.28 (0.29, 5.59)
0.75
ER status (ref High)
1
Low 2.84 (1.21, 6.65)
0.02
Variable HR (95% CI) p-value
T size (ref 0-10mm)
1
10.1-20mm 0.53 (0.23,1.22)
0.14
20.1-30mm 1.17 (0.43, 3.20)
0.76
Margins (ref >5mm)
1
<1mm 1.99 (0.25, 16.04)
0.52
1-5mm 0.89 (0.40, 1.98)
0.78
Re-excision 1.05 (0.38, 2.89)
0.92
Radiotherapy (ref Yes)
1
No 5.08 (1.95, 13.24)
0.001
Regional & distant recurrences /
contralateral IBC, new cancers and 5
year actuarial rates
No RT (n=668)
RT (n=658) Total (n=1326)
Regional recurrence
8 3 11
(1.5%) (0.5%)
Regional & distant recurrences /
contralateral IBC, new cancers and 5
year actuarial rates
No RT (n=668)
RT (n=658) Total (n=1326)
Regional recurrence
8 3 11
(1.5%) (0.5%)
Distant recurrence
5 5 10
(1.0%) (0.5%)
Regional & distant recurrences /
contralateral IBC, new cancers and 5
year actuarial rates
No RT (n=668)
RT (n=658) Total (n=1326)
Regional recurrence
8 3 11
(1.5%) (0.5%)
Distant recurrence
5 5 10
(1.0%) (0.5%)
Contra-lateral BC
4 7 11
(0.7%) (1.5%)
Regional & distant recurrences /
contralateral IBC, new cancers and 5
year actuarial rates
No RT (n=668)
RT (n=658) Total (n=1326)
Regional recurrence
8 3 11
(1.5%) (0.5%)
Distant recurrence
5 5 10
(1.0%) (0.5%)
Contra-lateral BC
4 7 11
(0.7%) (1.5%)
New (non-breast) cancer
29 26 55
(4.3%) (3.7%)
Overall survival
Overall survival (deaths)
5 yr actuarial rate
No RT (n=668)
49 93.9%
RT (n=658)
40 93.9%
Total 87
Deaths
Cause No RT (n=668)
RT (n=658) Total
Breast Cancer 8 4 12
BC present but not cause
2 1 3
No Breast Cancer
36 29 65
Cause unknown 4 5 9
Total 50 (7.5%) 39 (5.9%) 89 (6.7%)
Breast cancer deaths 13.5% of all deaths
Deaths without breast cancer: 73.0%
Conclusions
Omission of WBRT in women ≥65 yrs with pN0, HR positive breast cancer after BCS and endocrine therapy results in a 4.1% 5 year IBTR
RT reduces IBTR significantly, absolute reduction very small in HR rich (3.2% vs 0.8%)
Excluding RT does not compromise overall survival
Omission of postoperative WBRT in HR rich patients based on the 5 year rate of IBTR and overall survival appears a reasonable option
Thank you for your attention