The document discusses two studies that evaluated the effects of breast surgery plus systemic therapy versus systemic therapy alone for 624 women with metastatic breast cancer. The average age was 49 years. The studies found no evidence of a difference in overall survival between the two treatment groups. Subgroup analysis found no difference in overall survival based on HER2 or estrogen receptor status, or for those with only bone metastases. Breast surgery plus systemic treatment may improve local progression-free survival but result in shorter distant progression-free survival compared to systemic treatment alone. The document calls for prospective trials and guidelines on the expanding role of surgery for stage IV breast cancer.

1. Breast surgery for Metastatic Breast
Cancer : Cochrane Analysis
Dr KUNDAN
Department of Surgical Oncology
Mahavir Cancer Sansthan

3. Objective
• To assess the effects of breast surgery in
women with metastatic breast cancer.

4. Search methods
• It conducted searches using the MeSH terms ’breast
neoplasms’, ’mastectomy’, and ’analysis, survival’ in the
following databases
1. Cochrane Breast Cancer Specialised Register,
2. CENTRAL, MEDLINE (by PubMed) and
3. Embase (by OvidSP)
4. ClinicalTrials.gov
5. WHO International Clinical Trials Registry Platform
An additional search in the American Society of Clinical
Oncology (ASCO) conference proceedings in July 2016

5. Inclusion criteria
• Randomised controlled trials of women with
metastatic breast cancer at initial diagnosis comparing
breast surgery plus systemic therapy versus systemic
therapy alone.
Outcome
The primary outcomes - overall survival and quality of
life.
Secondary outcomes - progression-free survival (local
and distant control),
breast cancer-specific survival,
and toxicity from local therapy.

6. • GRADE tool to assess the quality of the body
of evidence.
• Risk ratio (RR) to measure the effect of
treatment for dichotomous outcomes
• Hazard ratio (HR) for time-to-event outcomes

8. Mechanism of metastases in breast
cancer
• Halstead theory- extensive locoregional surgery
• Fischer theory - aggressive systemic therapy
• Spectrum theory
• Parallel evolution
• Gene expression profile
• Stem cell model
Lang et al
Circulating tumor cells are present early in
tumorigenesis
metastatic potential of breast tumor is an inherent,
metastatic potential is exclusively present in specialized tumor
initiating caner cells.

9. Metastatic Breast Cancer Survival in USA:
Impact of New Agents
Giordano S et al, Cancer 100:44-52, 2004
women with this diagnosis now live longer, and the survival rate
at five years has increased from 10% in 1970 to about 40% in
women treated after 1995 (Giordano 2004).

10. • Women with metastatic breast cancer treated
between 1995 and 2002 had an 18% lower
risk of death than women treated between
1985 and 1994 (Ernst 2007).
• Median overall survival has improved from 20
months (1988 to 1991) to 26 months (2007 to
2011) in another series (Thomas 2015).

11. • Danna et al demonstrated
immunosuppression in subjects with bulky
primary tumors, which is reversed by removal
of the primary tumor even in the presence of
extensive metastatic disease.

12. • In women with metastatic renal cell carcinoma two
prospective randomised controlled trials showed that
local surgery plus systemic therapy led to longer
survival rates than systemic therapy alone (Flanigan
2001; Mickisch 2001).
• Another recent study showed that local surgery was
beneficial for people with metastatic colorectal cancer
(Anwar 2012).
This has led to the hypothesis that local treatment in metastatic
breast cancer can also improve survival.

13. • Primary breast tumor can be a reservoir of cancer
stem cells, its removal can decrease the
probability of developing new metastatic sites
(Bermas 2009).
• The primary tumor can secrete growth factors
such as tumor-growth factor (TGF)-, which can
send signals that favour implantation and growth
of metastatic sites (Karnoub 2007).
• Studies in animal models suggest that resection
of the primary breast tumor in mice can restore
immunocompetence of the host (Danna 2004).

14. • Historically, the role of surgery for the primary
breast tumor in metastatic breast cancer has
been to alleviate symptoms such as bleeding
or ulceration.
• Retrospective data suggest that the surgical
removal of the primary tumor may improve
overall survival in metastatic breast cancer
(Blanchard 2008; Fields 2007; Gnerlich 2008;
Khan 2002; Rapiti 2006).

19. It is clear that a number of factors affect the decision to
resect the primary tumor in patients with metastatic
breast cancer, including patient age, performance
status, number and location of metastatic sites,
hormone receptor status, and expression of human
epidermal growth factor receptor 2 (HER2).
Despite adjusting for many of those factors, biases—
especially selection bias—cannot be completely
eliminated given the retrospective nature of those
studies.

27. The two studies evaluated a total of 624 women with metastatic breast cancer.
The average age of the women was 49 years.
There were 426 women with ER-positive tumors;
200 women with ER negative tumors;
192 women with HER2-positive tumors;
421 with HER2-negative tumors;
226 women with bone-only metastases.
Most women in both studies received anthracycline-based chemotherapy.

28. The two included studies have the same participants (women with metastatic breast
cancer), the same intervention (breast surgery), and the same main outcome (overall
survival).
The main difference between the studies was that the Indian study included only
women who had responded to systemic therapy (Badwe 2015), while the Turkish
study included women with metastatic breast cancer without previous treatment
(Soran 2016).
Soran 2016 randomised women to upfront breast surgery followed by systemic therapy
versus systemic therapy,
while Badwe 2015 enrolled women who had responded to first-line anthracycline
based chemotherapy and randomised them to breast surgery or continuing medical
therapy.
By excluding those women who did not respond to chemotherapy, Badwe 2015
excluded the cases of worse prognosis, which did not occur in Soran 2016.
Another important difference between the two studies was the fact that most HER2-
positive women were not treated with anti- HER2 therapy in Badwe 2015.
On the other hand, the two treatment groups in Badwe 2015 were well balanced.

30. The estimated number of deaths was 448 per 1000 participants (ranging from
318 to 608 deaths per 1000 participants) in the breast surgery plus systemic
treatment group and 511 per 1000 participants in the systemic
treatment-alone group
There was no evidence of a difference in overall survival between HER2-positive and
HER2-negative subgroups (Chi2 = 0.00, df = 1 (P = 0.97), I2 = 0%).

31. Over all survival : Sub group Analysis
HER2 status
For both HER2-positive and -negative subgroups, the results were consistent with the main
analysis:
HER2-positive: HR 0.85 (95% CI 0.48 to 1.50; 2 studies; 192 women; I2 = 39%; Analysis 1.2);
HER2-negative: HR 0.84 (95% CI 0.50 to 1.40; 2 studies; 421 women; I2 = 79%; Analysis 1.2).
There was no evidence of a difference in overall survival between HER2-positive and HER2-
negative subgroups (Chi2 = 0.00, df = 1 (P = 0.97), I2 = 0%).
Oestrogen receptor status
For both ER-positive and -negative subgroups, the results were consistent with the main
analysis:
• ER-positive: HR 0.83 (95% CI 0.48 to 1.42; 2 studies; 426 women; I2 = 74%; Analysis 1.3);
• ER-negative: HR 1.04 (95% CI 0.70 to 1.55; 2 studies; 200 women; I2 = 19%; Analysis 1.3).
There was no evidence of a difference in overall survival between ER-positive and ER-negative
subgroups (Chi2 = 0.44, df = 1 (P = 0.51), I2 = 0%).
Only bone metastasis
For the subgroup of women with bone metastasis, there was no difference between the
interventions: HR 0.91 (95% CI 0.49 to 1.69; 2 studies; 226 women; I2 = 70%; Analysis 1.4).

35. Breast surgery plus systemic treatment may improve local PFS when compared to systemic
treatment alone (HR 0.22, 95% CI 0.08 to 0.57; 2 studies; 607 women; I2 = 43%; low
quality evidence)
Only Badwe 2015 analysed distant PFS.
The group receiving breast surgery plus systemic treatment probably had a shorter time
to distant PFS compared to the group receiving systemic treatment alone (HR 1.42, 95%CI
1.08 to 1.86; 1 study; 350 women; moderate-quality evidence)

37. Expanding role of surgery in stage IV BC
Take Home Message
• Multidisciplinary treatment and patient
counseling in all stages
• Guidelines to be developed?
• Prospective trial/ RCT?