This document discusses the role of local management of the primary site for patients with stage IV breast cancer. It summarizes several studies that have found: 1) Complete surgical excision of the primary tumor is associated with improved survival compared to incomplete excision or no surgery. 2) Resection of the primary tumor may decrease symptoms from local chest wall disease in nearly half of patients who would otherwise not have surgery. 3) Prospective randomized trials are still needed to definitively establish survival benefits, as existing evidence comes from retrospective studies, but surgery may be reasonable for select patients experiencing a good response to systemic therapy.

1. Role of primary site local
management for ABC patients
Virgilio Sacchini
Breast Service
Memorial Sloan-Kettering
Cancer Center - New York

2. Historical arguments against surgery
in stage IV breast cancer
• Patients were debilitated, bulky disease, survival
brief
• Avoid morbidity for unknown benefit
• Measurable disease: can be followed for response
• Fear that removal of the primary tumor would result
in increased angiogenesis and stimulation of
dormant disease

3. National Cancer Database from 1990-93
(Khan SA, Surgery 2002)
6861 (42.8%) no operation
16,023 with
Stage IV
9162 (57.2%) partial
mastectomy or total
mastectomy
Survival
No surgery

4. National Cancer Database from 1990-93
(Khan SA, Surgery 2002)
• Comparing only surgical patients, survival advantage for
those with clear margins (for both total mastectomy
and partial mastectomy)
Survival for Total Mastectomy Patients
Clear margins
Complete excision better then the debulking

5. National Cancer Database from 1990-93
(Khan SA, Surgery 2002)
• Comparing only surgical patients, survival advantage for
those with clear margins (for both total mastectomy and
partial mastectomy) 5 year survival
No operation 6.7%
Involved Margins
Partial Mast 11.3%
Total Mast 11.5%
Clear Margins
Partial Mast 16.6%
Total Mast 18.4%
 Conclusion: complete surgical extirpation of the
Cancer is associated with improved survival

6. Current perspective - primary tumor
surgery in Stage IV Breast Cancer ??
• May not respond to systemic therapy in parallel
with metastatic sites ?
• grow locally and lead to uncontrolled chest
wall disease and impaired quality of life
• May serve as a continued source of tumor stem
cells?
• lead to new metastatic lesions which are
resistant to systemic therapy
• More “earlier stage 4”

7. Current perspective - primary tumor
surgery in Stage IV Breast Cancer ??
• May not respond to systemic therapy in parallel
with metastatic sites ?
• grow locally and lead to uncontrolled chest
wall disease and impaired quality of life
• More “earlier stage 4”

8. Studies assessing distant metastasis detected by conventional imaging
with PET/CT in patients with primary breast cancer
Patients with
Patients with
distant
distant
Patient metastases
First author Type of study No. patients metastases
population detected by
detected by
conventional
PET/CT No. (%)
imaging No. (%)
Primary tumor
Fuster D Prospective 60 3 (5) 8 (13)
>3 cm
Carkaci S Retrospective Primary IBC 41 13 (32) 20 (49)
Alberini J Prospective Primary IBC 62 12 (19) 18 (29)
Suspected
Heusner T Retrospective 40 7 (18) 10 (25)
breast cancer
Groheux D Retrospective Stage II and III 39 0 4 (10)
Stage IIA Upstaged IV in 5.5%
Do we under-treat these early stage IV?)
Naoki Niikura, Naoto T. Ueno J Cancer 2010

9. Overview
(Neuman H, Cancer 2010)
Study Type Years N % surg HR
MSKCC 2011

10. Pooled analysis of hazard ratios for overall mortality for surgery versus no
surgery for patients with stage-IV breast cancer
•10 studies, mostly database or registry driven, with over 30,000 patients studied, about
50% of them had resection of primary
•With all the biases, most studies show some survival benefit in patients having surgery
Jetske Ruiterkamp et Al: Breast Cancer Research and Treatment, 2010

11. MSKCC Experience
(Neuman H, Cancer 2010)
• 2000-2004, database review
• 186 patients stage IV
• Surgery 69 (37%) – No surgery 117 (63%)
• Median f/u 53 months
• Improvement in median survival from
33months to 40months

12. Predictors of Survival of Patients Presenting With Stage IV Breast Cancer
and an Intact Primary Tumor
No. Hazard Ratio 95% CI P
Surgery
Resection 69 (37%) 0.71 0.47-1.1 .10
No resection Reference
ER status
Positive 127 (68%) 0.47 0.29-0.76 .002
Negative Reference
PR status
Positive 74 (40%) 0.57 0.37-0.90 .02
Negative Reference
HER-2/neu
Amplified 59 (32%) 0.51 0.34-0.77 .001
Not amplified Reference
Age at stage IV
1.0 0.98-1.01 .73
diagnosis
Solitary metastasis
Yes 24 (13%) 1.2 0.62-2.4 .57
No Reference
Bone metastases
Yes 122 (66%) 1.7 1.1-2.8 .02
No Reference
Visceral metastases
Yes 111 (60%) 2.3 1.4-3.6 <.001
No Reference

13. Local surgery in Stage IV disease
molecular subtype analysis
Kaplan-Meier survival estimates, by surgery triple_neg
1.00
p = 0.004
0.75
Not
0.50
Triple negative
0.25
p=0.44
Triple negative
0.00
0 20 40 60
analysis time
surgery = 0/triple_neg = 0 surgery = 0/triple_neg = 1
surgery = 1/triple_neg = 0 surgery = 1/triple_neg = 1
Surgery had a benefit in non-triple negative
Surgery had no benefit in triple negative
Conclusion: resection of the primary in stage IV breast cancer is associated
with improved survival in some molecular subtypes Neuman H et al. Cancer 2010

14. for Change in Management
• Resection of the primary may improve survival
• Better local control at diagnosis may
• prevent wound problems in future
• decrease symptoms due to chest wall disease
• better quality of life

15. Surgical resection of the primary tumor, chest wall control, and
survival in women with metastatic breast cancer
Methods: Lynn Sage, Northwestern Memorial Databases from 1995-2005, with
stage IV with intact primary, 27month median f/u, 103 Pts with chest wall information
44 surgery
59 no surgery
H Hazard et Al, Cancer 2008

16. (Hazard HW, Cancer, 2008)
103 patients with 10 (16%)
chest wall info palliative surgery
44 surgery 59 no surgery
13 (21%)
palliative radiation
Chest wall/breast free 36 (82%) 20 (24%) p=0.002
Symptomatic chest dz 8 (18%) 29 (49%) p=0.002
 Conclusion: Nearly half of patients who do not have primary
resected, will become symptomatic. Early resection can significantly
decrease chest wall/ breast symptoms.

17. Conclusion (Facts)
• Retrospective evidence that resection the primary
tumor is associated with improved survival in selected
Pts
• Chest wall symptoms can be improved with resection
of the primary
• Basic science evidence suggesting that resection of the
primary may decrease re-seeding
 For definitive change in standard of care, prospective
randomized trials are needed.

18. Randomized trials open or starting
Location NCT Timing Sample SIZE
India 00193778 After 6 cycle CH 350
Turkey 00557986 Before CH 271
Austria 01015625 Before CH 254
Netherlands 01392586 Before CH 516
USA 01242800 After 6 cycle CH 616
ECOG 2108

19. ECOG 2108 (Seema Khan P.I.)
Register 880 women
Optimal systemic therapy
70% response/stable disease
Randomize 616 women
Palliative local Elective local therapy
therapy, 308 308

20. What do we know about
surgical timing ?
Surgery before vs. after Significant
chemotherapy (n) surgery benefit ?
Boston (Bafford) 36 vs. 24 Before
Boston (Cady) 30 vs. 45 Both
MDACC (Rao) 47 vs. 28 After
Chicago
26 vs. 21 Both
(Hazard)

21. Conclusion (what to do now?)
When Surgery Reasonable
• Good response to metastatic sites/non
response-progression to the primary
• “one almost positive” (ER+/HER2+) with
response to the treatment
• Minimal Stage 4
• Chest wall recurrence without distant
metastasis or good response to the distant
mets