Surgery of the primary tumor in metastatic breast cancer remains controversial. Several studies have found no survival benefit to surgery, while others have found potential benefits in certain subgroups. The TMH trial found no difference in overall survival between locoregional therapy plus systemic therapy versus systemic therapy alone. However, some retrospective studies have shown improved survival when surgery was performed after systemic therapy, especially in ER-positive tumors. Ongoing trials continue to evaluate the potential benefits of surgery in select patient populations.

1. Surgery of the primary in
MBC
Dr Priyanka Malekar
4/Feb/2018

2. Introduction…
• The incidence of synchronized distant metastatic disease in newly
diagnosed breast cancer (BC) patients is between 3.5% and 10%.
• BC with distant metastases is considered to be a disease with no cure.
Therefore, surgical treatment of the intact primary is indicated only if
it is symptomatic.
• Local complications such as bleeding, ulceration, pain, and hygienic
disturbances are among the palliative indications for locoregional
surgery.
Blanchard DK, Bhatia P, Hilsenbeck SG, Elledge RM. Does surgical management of stage IV breast cancer affect
outcome? (abstract 2110). Breast Cancer Res Treat 2006;100(suppl 1):S118.

3. Introduction…
• Approximately 5% of women with primary breast cancer in the United
States and Western Europe present with de novo stage IV breast
cancer.
• systemic therapy is clearly the primary treatment for women with
overt metastases.
• Retrospective data in past showed improved survival on resection of
primary.

4. • These data, along with the relative lack of morbidity of breast surgical
procedures, and the intuitive appeal of quick elimination of a focus of
often visible and palpable disease, has led to significant enthusiasm
about this approach.
• Additional rationalization regarding the advantages of local therapy
for the primary site include the fact that while metastatic breast
cancer remains an incurable disease, patients are now living longer
with newer therapies.

5. • Solitory metastasis: single metastatic lesion
• Oligometastasis: limited systemic metastatic disease for which local
ablative therapy could be curative.
Ex: single segment of liver with < 3 lesions and < 3 cm, or <3 metastatic
lesions in axial bone
• Denovo metastasis: patient presents with metastasis more than one
site

6. Surgery of the Primary in mBC
• What are the indications, if any?
• Does it have survival advantage?
• Does it have advantage in reducing locoregional recurrences?
• Does it have detrimental effect on distant recurrences?
• Does it improve quality of life?

7. Surgery of the primary in mBC
criticism on qualities of studies conducted….
1. Does surgery of the primary really improve survival?
OR is there a bias in selecting pts?
2. Healthier stage IV are offered surgery vs less
healthy pts.?
3. stage IV may include pts diagnosed early with
modern imaging ( lead time bias ) or shortly after
surgery ( stage migration )?
4. Treatment facility bias – surgery may be a surrogate
for more aggressive multimodal treatment.

8. • TMH Trial ( Badwe ) Lancet Oncol 2015
• Turkish Trial ( Soran ) : SABC 2013.
Surgery of the primary in mBC
Negative Trials

9. • NCDB Study ( Annals Surg 2017 ) :
* All de novo Stage IV CA Breast 2003- 2012 in the US National Cancer
Database.
Of total of 24015 stage IV :
13505 pts – systemic Rx alone : no surgery
10510 pts – surgery of breast.
4552 pts( 19 %) – surgery before sys Rx
5958 pts ( 24.8%)- surgery after sys Rx.
Surgery of the primary in mBC
Positive Studies

10. Consort Diagram

12. • Characteristics of pts receiving sys Rx before Surgery :
- younger ( median age – 55 yrs )
- more pvt insurance
- more often T3 or T4 disease.
- more ER- and PR +ve disease.
- more often offered mastectomy.
Surgery of the primary in mBC
Positive Studies: NCDB Data

13. • Overall survival :
- surgery after sys therapy -52.8 Mo
- surgery before sys therapy – 49 Mo
- systemic therapy alone – 37 Mo.
Surgery of the primary in mBC
Positive Studies: NCDB Data

14. NCDB Data : OS

15. NCDB Data
• After 1 yr of diagnosis : surgery was associated with
improved survival regardless of treatment sequence.
• Greatest benefit seen in ER + tumors who underwent
surgery after sys therapy.
• In 2002, Seema Khan : evaluated 16023 stage IV pts
between 1990 – 1993 from NCDB – reduced risk of
death ( HR= 0.61) in pts undergoing surgery : is surgery
in stage IV only palliative? – questions the surgical
doctrine

16. Limitation of study
• unable to determine why women with metastatic breast cancer went
to surgery either before or after systemic therapy, and whether this
was for palliation, local progression, or a result of shared decision
making between women and their surgeons.
• Unable to include Her2 status given that it was only reliably coded in
the NCDB starting with patients diagnosed in 2010.

18. The TMH Study
• One of the first study conclusively proving that
surgery has no benefit in Stage IV disease.
• Previous evidence of survival benefit of surgery was
retrospective only.
• Open labelled RCT : locoregional vs no locoregional
therapy in Stage IV disease.
• 716 women stage IV :
- 173 : surgery
- 177 : no locoregional therapy

19. • Inclusion criteria:
• Histopathologically confirmed metastatic breast cancer,
• Had not received any previous cancer directed treatment,
• 65 years or younger,
• had an estimated life expectancy of at least 1 year.
• Patients with measurable and non-measureable disease were
included.
• Other eligibility criteria were fitness to receive anthracycline
chemotherapy, defined by adequate cardiac and liver functions

20. Exclusion criteria:
• previous cancer treatment,
• a single focus of metastatic disease amenable to treatment with
curative intent,
• multiple liver metastases with grossly deranged liver function test,
and involvement of more than two visceral organs, because of shorter
life expectancy.

22. The TMH Study: Procedures
• Those eligible for surgery given preop chemotherapy –
6 cycles FEC or FAC or 8 cycles of Anthracycline ( 4 ) followed by
Taxanes ( 4 cycles ).
• Locoregional Rx: mastectomy or BCS with axillary clearance. In SC
nodes – supraclavicular fossa clearance.
• In premenopausal women with persistent periods post-chemo and
receptor +ve : Bilateral oophorectomy.
• Postop : standard doses of RT given
All BCS pts : postop RT
In Mastectomy pts, post op RT given if T> 5 cm, Node +ve and skin
or chest wall involvement.

23. Baseline Characteristics of ITT population

25. TMH Study : Results
• Feb, 7, 2005 to Jan 18, 2013 : 716 pts
• 25 : 1st line endocrine therapy
• 691 : primary systemic therapy
415 ( 60% ) : PR or CR.
• Of 350 randomly assigned pts :
- 173 to locoregional treatment
- 177 to no locoregional treatment.
• Median duration follow up : 23 Mo
data cut off : Nov, 1 , 2013

26. TMH Study : Results
• Median OS :
Locoregional Rx vs no locoregional:
19.2 Mo vs 20.4 Mo ( HR=1.04)
2-yr OS : Locoregional vs no locoregional
41.9% Mo vs 43 % Mo
* Locoregional Progression PFS : benefit seen
Surgery : median not attained
Systemic Rx only : 18.2 Mo ( p < 0.0001 )

27. TMH Study : OS

28. TMH Study : OS

29. TMH Study : comments
• Surgery : detrimental effect on distant PFS.
- growth of the metastatis disease after primary removal.
• 107 of 350 pts ( 31 % ) had HER +ve disease and did not receive anti-
HER Rx ( finance ).
• Most pts received systemic chemotherapy as their 1st line Rx . Use of
endocrine Rx or anti-HER therapy in HER +ve pts could not be
assessed.

30. Journal of clinical Oncology 2016

31. • The MF07-01 trial is a phase III, multicentric, randomized controlled
clinical trial
• All patients receive systemic treatment regardless of their study
assignment.
• 1st arm: locoregional treatment after systemic therapy
• 2nd arm: only systemic therapy.

32. • Inclusion criteria include:
1. Primary breast tumor amenable for complete surgical resection,
2. Patients in good physical condition for receiving protocol driven locoregional
and systemic treatments as well as patients eligible for sentinel lymph node
(SLN) Biopsy
3. Receiving radiotherapy.
• Exclusion criteria:

33. • primary tumor not amenable for complete resection (such as tumor extending to
neighboring tissues; T4a,c or inflammatory breast cancer; T4d);
• Primary tumor with extended infection, bleeding, or necrosis;
• Poor PS
• Synchronous primary cancer at the contralateral breast;
• Previous diagnosis of other cancers (excluding basal cell skin cancer, squamous
cell skin cancer, and cervical intraepithelial neoplasia);
• clinically involved contralateral axillary nodes; patients not suitable for adequate
follow- up; and failure to give informed consent

34. • The MF07-01 trial was activated and patient recruitment was
commenced in October 2007
• 274= n
• 138:- LRS
• 136:- ST
• 36 months survival rates similar
• 40 months median follow up:
• Overall survival 34% higher in LRS group, ER/PR+, Her 2 Neu -, patients <55,
solitary only bone mets.

35. Austrian Trial : Primary surgery followed by systemic therapy in 90 pts.
Trial stopped due to poor recruitment.
Preliminary results ( ASCO 2017 ) : no OS benefit seen.

36. TBCRC 013 Trial (JCO 2016)
Translational Breast Cancer Res Consortium
• A prospective analysis of surgery and survival in stage IV
Breast Ca.
• Tari A. King, Jaclyn Lyman, Mithat Gonen, Sylvia Reyes, Eun-Sil
Shelley Hwang, Hope S. Rugo.
• 127 pts from multicentres.
• All received systemic Rx.
• 3 yr OS was studied. Med Follow up : 54 Mo
• 3 yr OS = 70% ; 85 % pts classified as responders ( PR & CR ).
• 3 yr OS in responders – 78 % vs 24% in non responders( p<0.001)
• Among chemo responders surgery did not impact OS

39. Surgery of Primary in mBC
When ?
• In de novo stage IV after response to systemic
therapy.
• In pts with good PS.
• In pts with oligometastatic disease.
• In pts with no ( or limited ) visceral involvement.
• Luminal or HER +ve disease.