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