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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 340-347

Impact of breast surgery on response and survival in metastatic breast cancer patients


Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission17-Nov-2013
Date of Acceptance31-Dec-2014
Date of Web Publication31-Aug-2015

Correspondence Address:
Suzy F Gohar
Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Shebin El Kom, Menoufia 32512
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163882

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  Abstract 

Objective
The aim of this study was to assess the impact of primary tumor resection on the survival and quality of life in women with stage IV breast cancer.
Background
About 3-10% of patients with breast cancer have distant metastases (stage IV) at initial presentation. Patients with metastatic or stage IV breast cancer have limited therapeutic options, and the mainstay of treatment remains systemic chemotherapy. Traditionally, the role of surgery has been confined strictly to palliation. However, retrospective studies have shown improved survival in patients who have undergone surgery for their primary tumor. Thus, new clinical questions have emerged in terms of surgery of the primary site in those women with metastatic disease and a resectable intact primary tumor.
Patients and methods
This study included patients with stage IV breast cancer who presented to the Clinical Oncology Department, Menoufia University, from September 2009 till August 2011. Patients were divided on the basis of treatment into two groups: those who underwent surgery and those who did not undergo surgery. All patients then received anthracyclin-based chemotherapy, followed by hormonal treatment according to hormonal status. Patient characteristics and survival were evaluated using univariate and multivariable analyses.
Results
In total, 151 patients were included in this analysis; 61 patients underwent surgery and 90 patients did not. The median survival of the patients who underwent surgery for their primary tumor was significantly longer than that for the patients who did not undergo surgery (39 vs. 24 months). The median time to progression in the surgery group was 26 months versus 13 months in the no-surgery group. The 2-year survival was 73.8% in the surgery group compared with 38.9% in the no-surgery group. A multivariate proportional hazards model identified the grade of tumor as a significant independent prognostic factor.
Conclusion
Primary tumor resection increased survival in patients with metastatic breast cancer. Thus, the role of surgery in women with stage IV breast cancer needs to be re-evaluated.

Keywords: breast cancer, metastases, stage IV, surgery, survival


How to cite this article:
Hashem TA, Abdel Aziz KK, ELsisy AA, Tawfik EA, Elkholy EA, Gohar SF. Impact of breast surgery on response and survival in metastatic breast cancer patients. Menoufia Med J 2015;28:340-7

How to cite this URL:
Hashem TA, Abdel Aziz KK, ELsisy AA, Tawfik EA, Elkholy EA, Gohar SF. Impact of breast surgery on response and survival in metastatic breast cancer patients. Menoufia Med J [serial online] 2015 [cited 2020 Apr 3];28:340-7. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/340/163882


  Introduction Top


About 3-10% of all patients newly diagnosed with breast cancer show evidence of metastatic disease at the time of presentation [1] .

Despite the epidemiological burden of this condition, there are no solid guidelines on how to manage breast cancer patients presenting with systemic spread; for these patients, treatment planning is essentially on the basis of personal preferences rather than reliable clinical data [2] .

The role of surgery in advanced breast cancer will be incomplete without consideration of the management of the intact primary in patients with metastatic disease [3] .

As systemic treatments such as chemotherapy and hormonal therapy have become ever more effective, the median survival of women with metastatic disease has continued to improve, as has the management of symptoms resulting from distant disease sites. Thus, new clinical questions have emerged of surgery of the primary site in those women with metastatic disease and a resectable intact primary tumor [3] .

Traditionally, the treatment for women with metastatic breast cancer and an intact primary tumor is systemic therapy, with surgical treatment reserved for palliation of symptoms or when the primary leads to complications (i.e. skin ulceration, infection, or bleeding) [4] .

However, studies challenge this approach, suggesting that removal of the primary tumor may lead to an overall improved survival [5] .

There are several theories as to why removal of the primary tumor could potentially improve survival. First, it is known that metastatic cancer cells have numerous effects on the immune system. One of these effects is that established malignancies use induction of immune tolerance to avoid immune surveillance [6] .

Second, the breast cancer stem cell theory proposes that specialized tumor-initiating cancer cells have the exclusive potential to proliferate and form new sites of tumor metastasis [6] .

The relatively low morbidity associated with breast surgery makes this an ideal model for a prospective investigation on the surgical excision of the primary in patients with metastatic disease [7] .


  Patients and methods Top


This comparative study included 151 breast cancer patients with stage IV breast cancer and performance status 0 to 2, who were presented to the Oncology Department, Menoufia University Hospital, from 1 September 2009 to 31 August 2011. Sixty-one patients underwent surgery and 90 patients did not undergo surgery. Baseline information collected included demographics, tumor characteristics (size, regional node status, histological characteristics, and grade), sites, and number of metastases, type of operation, and margin status (in the surgery group). Staging was performed on the basis of the clinical TNM classification. On the basis of the site of metastases, patients were divided into three groups: patients with bone metastases versus those with any visceral metastases, and those with mixed visceral and bony metastases. After obtaining consent, all patients received anthracyclin-based chemotherapy, followed by hormonal treatment according to hormonal status. The study was approved by the ethical committee of the faculty of medicine and the patient gave an informed consent.

Quality of life was assessed at baseline and after 6 months of diagnosis using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The items on both measures were scaled and scored using the recommended EORTC procedures.

Statistical analysis

Data were analyzed using the statistical package for social science (SPSS, version 16; IBM Corporation, 1 New Orchard Road, Armonk, NY, USA) program for Windows. Two types of statistics were calculated: descriptive and analytic statistics. Student's t-test and the Mann-Whitney test were used for quantitative variables and χ2 and Fisher's exact test were used for qualitative variables. Two-year survival and time to progression were analyzed using the Kaplan-Meier curves. Multivariate Cox regression test was used for independent prognostic factors. P value less than 0.05 was considered statistically significant.


  Results Top


The characteristics of the 151 patients included in this study are listed in [Table 1]. In the surgery group, 55 patients underwent modified radical mastectomy, five patients underwent wide local excision with axillary evacuation, and only one patient underwent simple mastectomy.
Table 1 Patient characteristics

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Surgery led to a negative margin in 55 patients, a close margin in eight patients, and an involved margin in three patients as shown in [Table 2].
Table 2 Type of surgery and pathological characteristics of the tumor

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Details of the metastatic sites involved, number of metastatic lesions per site, and size of the lesions are shown in [Table 3].
Table 3 Characteristics of metastasis

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There was a statistically significant difference in the overall survival between the two groups (P < 0.001). The mean survival was 39.10 for the surgery group and 28.04 for the no-surgery group [Figure 1].
Figure 1: Kaplan– Meier curve shows that there was a statistically signifi cant difference in overall survival between the two groups; the mean survival was 39.10 for the surgery group and 28.04 for the no-surgery group. (a) Survival function; (b) hazard function

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There was a statistically significant difference in time to progression between the surgery group and the no-surgery group (P < 0.001), with mean time to progression 26.16 (22.1-30.2) in the surgery group and 13.81 (11.5-16.1) in the no-surgery group [Figure 2].
Figure 2: Kaplan– Meier curve shows that there was a statistically signifi cant difference in time to progression between the surgery group and the no-surgery group (P < 0.001), with mean time to progression 26.16 (22.1– 30.2) in the surgery group and 13.81 (11.5– 16.1) in the no-surgery group. (a) Survival function; (b) hazard function

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There was a significant relation between type of metastases, tumor grade, estrogen receptor positivity, and initial tumor marker level [Table 4]. Our results showed that tumor grade was an independent factor for the no-surgery group [Table 5].
Table 4 Probability of survival (surgery group)

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Table 5 Multivariate Cox regression analysis for detection of the independent factors affecting patients' overall survival in the surgery group

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Comparisons between the studied groups in the quality score at initial presentation and 6 months from starting treatment are shown in [Table 6] and [Table 7].
Table 6 Comparison between the studied groups in the quality score pre and post

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Table 7 Kaplan– Meier curve for probability of survival (no surgery group)

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  Discussion Top


Despite major advances in breast cancer treatment, surgery continues to play a major role in the local control of advanced breast cancer as an effective palliation for the pain, bleeding, infection, and malodorous drainage that can accompany locally advanced breast cancer [8] .

One of the critical issues currently impacting surgical consideration in the setting of advanced breast cancer is the marked improvement in the management of patients with metastatic disease [3] .

Recently, multiple studies have retrospectively sought to determine the survival impact of breast tumor resection for patients with metastatic breast cancer. Thus, new clinical questions emerged of surgery of the primary site in those women with metastatic disease and a resectable intact primary tumor. This retrospective study tested this issue.

In terms of the demographic characteristics of the patients, there was a statistically significant difference between the two groups in performance status. In the surgery group, 38 (62.3%) patients had performance score 0, 20 (32.8%) patients had score 1, and only three (4.9%) patients had performance score 2, whereas in the no-surgery group, 23 patients had score 0, 54 had score 1, and 13 had score 2. We believe that this difference could be related to differences in the sample size and that most patients in the surgery group were younger and fit, and all of them were prepared to be treated on a radical basis and were found to be metastatic after surgery.

There was a statistically significant difference between the two groups in performance status. In the surgery group, 38 (62.3%) patients had performance score 0, 20 (32.8%) patients had score 1, and only three (4.9%) patients had performance score 2, whereas in the no-surgery group 23 patients had score 0, 54 had score 1, and 13 had score 2; this difference may be related to differences in the sample size and that most patients in the surgery group were younger and fit, and all of them were prepared to be treated on a radical basis and were found to be metastatic after surgery. Most studies on impact of primary tumor resection excluded patients with poor performance status, thus, a comparison is not possible.

There was a significant difference between the two groups in tumor marker level, which was initially elevated in 18 patients in the surgery group and 54 patients in the no-surgery group. Mostly, this difference could have been because of different tumor bulk as it was measured after surgery. There was a statistically significant difference in the results of the first evaluation of the two groups.

After the first evaluation, three patients achieved a complete response, 38 patients had stable disease, 16 patients achieved a partial response, and three patients showed disease progression in the surgery group, whereas in the no-surgery group, no patient achieved a complete response, 66 patients achieved a partial response, 12 patients had stable disease, and 12 patients showed disease progression, mostly because of differences in sample size and initial tumor bulk. There was a statistically significant difference in the overall survival between the two groups (P < 0.001) [Figure 1].

These results are in agreement with those of Babiera et al. [9] , who analyzed a retrospective single institution cohort of 224 patients, of whom 82 had undergone surgical resection of the primary tumor, and suggested a favorable effect of surgical excision, and Gnerlich et al. [10] , who retrospectively reviewed the 1988-2003 Surveillance, Epidemiology and End Results (SEER) program data, identifying 9734 patients with stage IV breast cancer; 47% underwent surgery, whereas 53% did not. The median survival was 36 versus 21 months (P < 0.001).

Ruiterkamp et al. [2] found that the median survival of the patients who had surgery of their primary tumor was significantly longer than for the patients who did not have surgery (31 vs. 14 months).

These studies all suggested that surgical resection of the breast primary could result in a significant survival advantage for patients with stage IV cancer, but most of these studies did not take into consideration the effect of other treatment lines. However, in our study, we used the same treatment plan for all patients irrespective of the site of metastases to avoid bias related to the type of treatment.

Leung et al. [6] carried out a retrospective single-institution study, in which 157 patients were included and found that the median survival was 25 months for the surgery group and 13 months for the no-surgery group. However, after taking into consideration the impact of chemotherapy, hormonal therapy, and radiation therapy, Leung et al. [6] concluded in the subgroup analysis that hormonal therapy did not play a role in survival advantage for the surgery versus the no-surgery groups, and focused on chemotherapy, which did lead to a difference in survival, and when stage IV patients received chemotherapy and there was no statistically significant survival benefit for surgery, which is not in agreement with our results. We believe that this difference is because of treatment-related bias, which we avoided in our study by providing the same treatment modality to all patients.

There was a significant relation between site of metastases and survival in the surgery group, with the best survival in the bone-only group and the worst in the visceral-only group [Table 4] and in the no-surgery group. These results are not in agreement with those of Leung et al. [6] , who examined differences in survival on the basis of site of metastases and found that there was no difference in survival.

However, Khan et al. [11] showed that resection of the primary tumor yielded a statistically independent survival benefit after adjustment for the extent and type of metastatic disease and type of systemic therapy, and this is in agreement with our study.

In terms of the type of surgery and margin status, Khan et al. [11] found that there was no difference in the survival time between the partial mastectomy and total mastectomy groups, provided that partial mastectomy led to negative margin. McGuire et al. [12] provided further evidence that women with metastatic breast cancer at diagnosis benefit from surgical excision of their primary tumor. Furthermore, patients who underwent total mastectomy versus partial mastectomy showed a statistically significant increase in overall survival because total mastectomy led to a clear margin in almost all patients. Unfortunately, this comparison was not possible in our study because of the small sample size in the surgery group and most patients underwent modified radical mastectomy and achieved a negative margin [Table 2], but the median survival of the three patients with a positive margin was 30 months and the median time to progression was 25 months.

Timing of surgery has been explored previously as a potential factor for survival. Rashaan et al. [13] found that survival for women diagnosed with stage IV breast cancer before surgery was very similar to survival in the no-surgery group (2.40 vs. 2.36 years), whereas improved survival was only observed in women who had already undergone surgery before the metastases were diagnosed.

Bafford et al. [14] subsequently assessed the effect of timing of surgery in two subgroups compared with a cohort of 86 non-operated patients. Data showed a benefit of surgery only in the 'before' group. No significant difference was found between patients in the 'after' group and those in the 'no-surgery' cohort, suggesting that the observed benefit of surgery was because of a stage migration bias.

In our study, two patients were excluded from the no-surgery group after they underwent surgery: one because of lack of response and the other because of ulceration; the median survival of these two patients was 20 months and the median time to progression was 8 months, much lower than that for the surgery group.

There was a significant relation between the site of metastases and survival in the surgery group, with the best survival in the bone-only group and the worst survival in the visceral-only group [Table 6]. This is in agreement with the results of Rapiti et al. [15] , who found that surgery reduces the risk of death in the bone-only group compared with the no-surgery group. These results are not in agreement with those of Leung et al. [6] , who examined differences in survival on the basis of site of metastases and found that there was no difference in survival.

Analyses of other factors related to prognosis for patients with metastatic breast cancer in the surgery group indicated that there was a significant relation between survival and type of metastases, tumor grade, estrogen receptor positivity, and initial tumor marker level [Table 4]. However, multivariate analysis showed that tumor grade was the most independent predictive factor [Table 5], whereas Shibasaki et al. [16] found that triple-negative breast cancer and metastasis to more than three sites were poor prognostic indicators; this difference may be related to differences in the sample size.

In summary, our results are in agreement with those of previous studies and provide additional evidence that surgical removal of the primary tumor is associated with a significantly longer survival time in patients with metastatic breast cancer at diagnosis.

The main limitations of our study are that surgery was not assigned by randomization and the relatively small sample size, especially in the surgery group.


  Conclusion Top


Primary tumor resection did increase survival in patients with metastatic breast cancer and increased time to progression. Thus, the current strategy of treatment, especially the role of surgery in metastatic patients, should be revised.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ernst M, Lonneke V, Fransec V, et al. Trends in the prognosis of patients with primarymetastatic breast cancer diagnosedbetween 1975 and 2002. Breast 2007; 16 :344-351.  Back to cited text no. 1
    
2.
Ruiterkamp J, Ernst MF, van de Poll-Franse LV, et al. Surgical resection of the primary tumor is associated with improved survival in patients with distant metastatic breast cancer at diagnosis. Eur J Surg Oncol 2009; 35 :1146-1151.  Back to cited text no. 2
    
3.
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10.
Gnerlich J, Jeffe DB, Deshpande AD, et al. Surgical removal of the primary tumorincreases overall survival in patients with metastatic breast cancer: analysis of the 1988-2003 SEER data. Ann Surg Oncol 2007; 14 :2187-2194.  Back to cited text no. 10
    
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McGuire KP, Eisen S, Rodriguez A, et al. Factors associated with improved outcome after surgery in metastatic breast cancer patients. Am J Surg 2009; 198 :511-515.  Back to cited text no. 12
    
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Rashaan Z, Bastiaannet E, Portielje J, et al. Surgery in metastatic breast cancer: patients with a favorable profile seem to have the most benefit from surgery. Eur J Surg Oncol 2012; 38 :52-56.  Back to cited text no. 13
    
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Bafford AC, Burstein HJ, Barkley CR, et al. Breast surgery in stage IV breast cancer: impact of staging and patient selection on overall survival. Breast Cancer Res Treat 2009; 115 :7-12.  Back to cited text no. 14
    
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Rapiti E, Verkooijen HM, Vlastos G, et al. Complete surgical excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol 2006; 24 :2743-2749.  Back to cited text no. 15
    
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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Introduction
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