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10.1245/ASO.2006.03.033
Annals of Surgical Oncology 13:776-782 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Effect of Primary Tumor Extirpation in Breast Cancer Patients Who Present With Stage IV Disease and an Intact Primary Tumor

Gildy V. Babiera, MD1, Roshni Rao, MD1, Lei Feng, MS2, Funda Meric-Bernstam, MD1, Henry M. Kuerer, MD1, S. Eva Singletary, MD1, Kelly K. Hunt, MD1, Merrick I. Ross, MD1, Karin M. Gwyn, MD3, Barry W. Feig, MD1, Frederick C. Ames, MD1 and Gabriel N. Hortobagyi, MD3

1 Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
2 Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
3 Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

Correspondence: Address correspondence and reprint requests to: Gildy V. Babiera, MD; E-mail: gvbabiera{at}mdanderson.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Currently, therapy for breast cancer patients with stage IV disease and an intact primary tumor is metastasis directed; the primary tumor is treated only when it causes symptoms. A recent review suggested that surgery may improve long-term survival in such patients. We evaluated the effect of surgery in such patients on long-term survival and disease progression.

Methods: We reviewed the records of all breast cancer patients treated at our institution between 1997 and 2002 who presented with stage IV disease and an intact primary tumor. Information collected included demographics, tumor characteristics, site(s) of metastases, type/date of operation, use of radiotherapy, chemotherapy and hormonal therapy, disease progression (time to progression and location of progression) in the first year after diagnosis, and last follow-up. Overall and metastatic progression-free survival were compared between surgery and nonsurgery patients.

Results: Of 224 patients identified, 82 (37%) underwent surgical extirpation of the primary tumor (segmental mastectomy in 39 [48%] and mastectomy in 43 [52%]), and 142 (63%) were treated without surgery. The median follow-up time was 32.1 months. After adjustment for other covariates, surgery was associated with a trend toward improvement in overall survival (P = .12; relative risk, .50; 95% confidence interval, .21–1.19) and a significant improvement in metastatic progression-free survival (P = .0007; relative risk, .54; 95% confidence interval, .38–.77).

Conclusions: Removal of the intact primary tumor for breast cancer patients with synchronous stage IV disease is associated with improvement in metastatic progression-free survival. Prospective studies are needed to validate these findings.

Key Words: Breast cancer • Surgery • Stage IV disease • Metastasis • Outcome • Synchronous stage IV disease


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Traditionally, surgical treatment of the breast in patients who present with stage IV breast cancer and an intact primary tumor has been palliative. Potentially curative surgical treatment of the primary tumor or site(s) of metastasis has not been considered. However, Khan et al.1 recently challenged this approach. In a retrospective review of data from the National Cancer Database of the American College of Surgeons covering the years 1990 through 1993, these authors found that women who were treated with surgical resection of the primary tumor with free margins had a better 3-year survival rate than women not surgically treated (35% vs. 26%). To our knowledge, this is the only significant study investigating the role of breast in patients presenting with stage IV disease and an intact primary tumor.

Other investigators, in studies of patients with other types of cancer presenting with stage IV disease and an intact primary tumor, have demonstrated improved survival for patients who undergo surgical extirpation of the primary tumor, site(s) of distant metastasis, or both. Multiple studies have demonstrated an improvement in survival after colectomy and resection of liver metastases in patients with colon cancer metastatic to the liver.2–6 Flanigan et al.7 demonstrated in a randomized trial that survival among patients with metastatic renal cell carcinoma was better for those who underwent nephrectomy followed by interferon than for those who received interferon alone. The purpose of our study was to evaluate the effect of surgery in a contemporary series of patients who presented with stage IV breast cancer and an intact primary tumor at a large national comprehensive cancer center.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After institutional review board approval was granted, we reviewed the complete comprehensive medical records of breast cancer patients who presented to The University of Texas M. D. Anderson Cancer Center between 1997 and 2002 with stage IV disease and an intact primary tumor or with surgical removal of an intact primary breast tumor within 3 months after the diagnosis of stage IV disease. Baseline information collected included demographics, tumor characteristics (size, regional node status, histological characteristics, grade, estrogen and progesterone receptor status, and Her2/neu status), site(s) and number of metastases, type and timing of operation, use of radiotherapy, and use and types of chemotherapy and hormonal therapy. In addition, information was collected on disease progression (time to progression and location of progressive disease) in the first year after diagnosis and at last follow-up. The response evaluation criteria in solid tumors guidelines8 were used to assess response to therapy of the intact primary tumor and sites of metastasis. The breast cancer staging guidelines in the AJCC Cancer Staging Manual, 6th edition,9 were used to describe tumor size and lymph node involvement.

All patients had known metastatic disease at the time of or within 3 months after breast cancer diagnosis. The patients were divided into two groups: the surgery and nonsurgery groups. The surgery group included patients who underwent breast surgery within 3 months of the diagnosis of stage IV disease or at any point during active treatment or long-term follow-up for stage IV disease. This group also contained patients who underwent surgery to remove distant metastases. The nonsurgery group included patients who did not undergo breast surgery at any time. All patients were treated with some form of systemic therapy that included anthracycline-based chemotherapy or anti-hormonal therapy with tamoxifen or anastrozole. Trastuzumab was also administered if the patient had gene amplification for Her2/neu. Surgical removal of the intact primary breast tumor was considered curative when the site(s) of distant disease were eradicated (no evidence of disease) by surgery, systemic therapy, or both. The time to surgery was calculated from the date of diagnosis to the date of surgery of the intact primary breast cancer.

Two hundred twenty-four patients fulfilled the inclusion criteria for this study. Eight of the 224 patients had synchronous bilateral breast cancer. For statistical analysis, information on the breast with the larger tumor and higher nodal stage was used. Study end points were death and progression of metastatic disease. Time-to-event analyses were reported for both end points. Kaplan-Meier curves were plotted, and the log-rank test was used to compare the difference in survival between the surgery and nonsurgery groups. Cox proportional models were fitted for multivariate analysis. Patient characteristics were compared between the surgery and nonsurgery groups by using the {chi}2 test. The difference in age between the two groups was tested by using the t test. All tests were two sided, and P values < .05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographic, tumor, and treatment characteristics for the 224 patients in the study are listed in Table 1Go. The median age was 52 years (range, 22–88 years). One hundred forty-two patients (63%) were treated without surgery and 82 (37%) with surgery. Of the 82 patients who had breast surgery, 39 (48%) underwent segmental mastectomy, and 43 (52%) underwent mastectomy. Twenty-nine patients underwent excision of the primary tumor for diagnosis, 41 underwent breast surgery for definitive treatment to the breast, 7 underwent breast surgery for palliation, and 5 underwent breast surgery for other reasons. Of the 41 patients who underwent definitive surgery, 11 (27%) underwent surgery with curative intent (meta-static sites were eradicated with surgery, systemic therapy, or both).


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  		TABLE 1. Patient characteristics (n = 224)
 
Patient characteristics for the surgery and nonsurgery groups are compared in Table 2Go. There were significant differences between the surgery and nonsurgery groups. Compared with patients in the nonsurgery group, patients in the surgery group were younger, had less nodal involvement, had fewer sites of metastases, were more likely to have metastases to the liver, were more frequently positive for Her2/neu gene amplification by fluorescence in situ hybridization, and were more likely to receive chemotherapy as first-line systemic therapy. The two groups were similar with respect to race, family history, history of cancer, breast tumor size, estrogen and progesterone receptor status, and histological subtype. For the surgery group, the median time to operation was 24 days.


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  		TABLE 2. Patient characteristics by surgery groupa
 
Overall, the median follow-up time was 32.1 months (95% confidence interval, 30.4–35.5 months). At last follow-up, there had been 38 deaths; 33 patients died of disease, 1 died with no evidence of disease, and 4 died of unknown causes. Univariate analysis indicated that clinical tumor size, number of metastatic sites, and Her2/neu status had significant effects on overall survival. Multivariate analysis indicated that the presence of only one site of metastasis and the lack of Her2/neu gene amplification were associated with better overall survival (Table 3Go). Although this was not statistically significant, there was a trend towards better overall survival for patients who underwent operation. This trend was observed in the univariate analysis (P = .091; Fig. 1Go) and in the multivariate analysis (P = .12; Table 3Go).


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  		TABLE 3. Cox proportional hazards model for overall survival
 

Figure 1
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  		FIG. 1. Overall survival by surgery status. Kaplan-Meier curves show overall survival in the surgery (Y) and nonsurgery (N) groups. E/N, number of events/total sample size.

 
On univariate analysis, metastatic progression-free survival seemed to be associated with clinical tumor size, site of metastasis, estrogen receptor status, receipt of chemotherapy vs. other therapy as first-line systemic therapy, and treatment with breast surgery. Multivariate analysis demonstrated improved meta-static progression-free survival only for patients who had a positive estrogen receptor status and underwent breast surgery (Table 4Go). Kaplan-Meier curves demonstrating the difference between the surgery group and the nonsurgery group in metastatic progression-free survival are shown in Fig. 2Go. When the 11 patients who underwent surgical removal of the intact primary breast tumor with curative intent were excluded from the analysis, metastatic progression-free survival was still better for patients who underwent definitive or excisional surgical treatment of the intact primary breast tumor (Fig. 3Go).


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  		TABLE 4. Cox proportional hazards model for metastatic progression-free survival
 

Figure 2
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  		FIG. 2. Metastatic progression–free survival by surgery status. Kaplan-Meier curves show metastatic progression–free survival in the surgery (Y) and nonsurgery (N) groups. E/N, number of events/total sample size.

 

Figure 3
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  		FIG. 3. Metastatic progression–free survival by surgery status after removal of the curative group. Kaplan-Meier curves show metastatic progression–free survival in the surgery (Y) and non-surgery (N) groups after exclusion of the 11 patients who underwent removal of the primary breast tumor with curative intent. E/N, number of events/total sample size.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although our study demonstrated only a trend toward improvement in overall survival with primary tumor extirpation in breast cancer patients presenting with stage IV disease and an intact primary tumor, our study demonstrated a statistically significant improvement in metastatic progression-free survival for these patients.

The role of primary breast tumor surgery in the setting of metastatic breast cancer has been questioned, at least in part because of a concern that surgery may modify the growth kinetics of breast cancer metastases.10 It has been proposed that surgical extirpation of the primary breast tumor may accelerate relapse through two mechanisms: (1) an angiogenic surge due to removal of inhibitors of angiogenesis and (2) the release of growth factors in response to surgical wounding.11 This hypothesis was supported by a study in an animal model, in which lung metastases started to grow rapidly after the primary tumor was resected.12 However, the results of our study suggest that removal of the primary tumor does not lead to a clinically relevant enhancement of distant metastatic growth. On the contrary, we observed a prolongation of metastatic progression–free survival in patients who underwent surgical removal of their intact primary tumor. Our findings are supported by a study by Danna et al.,13 who noted that in a mouse model, surgical removal of the primary tumor restored immunocompetence even in the presence of disseminated metastatic disease. The possibility that the primary tumor may actually enhance progression of distant metastases, by release of growth mediators or by modulating the immune system, or that it may lead to the development of new metastases by providing a continued source for circulating tumor cells needs to be addressed.

The survival after diagnosis for patients with metastatic breast cancer is 16 to 24 months.14 Recent reports suggest that survival in this group of patients is improving.15,16 In our series, more than half of the patients were still alive after 2 years, thus suggesting that our patients are living longer than what is expected. However, caution should be made in interpreting our data because we have not reached our median survival as a result of short follow-up. Despite the inability to demonstrate a significant improvement in survival in the surgery group, our study does demonstrate that there is an association between surgical removal of the intact breast primary breast tumor and decreased progression of metastatic disease. Therefore, there does seem to be a role for surgery in improving outcome in these patients. A study by Carmichael et al.16 of a small series of 20 patients with stage IV disease who underwent surgical extirpation of the intact primary breast tumor reached a similar conclusion.

Overall, there were statistically significant differences between the surgery and nonsurgery groups. Surgical resection of the intact primary breast tumor was more likely to be performed in patients who were younger, were Her2/neu receptor positive, received chemotherapy, had less nodal involvement, had only a single site of distant metastasis, and had liver metastases. Despite these differences, this study still demonstrated that surgical removal of the intact primary breast tumor was independently associated with improved metastatic progression–free survival on multivariate analysis.

This study has limitations, including the bias inherent to a retrospective review. Other bias that could affect our findings relates to the belief that at M. D. Anderson Cancer Center a cure can be sought for some patients with limited local and metastatic breast cancer.17 In a review by Singletary et al.18 of the literature investigating surgical resection of the metastatic site in patients presenting with stage IV disease long after achievement of local-regional and systemic control of breast cancer, the authors noted improved long-term outcomes for selected patients metastectomy of the lung, liver, brain, or sternum. At M. D. Anderson, surgical resection of sites of distant metastasis is performed in carefully selected patients for palliation and for potential cure.19–21 In our series, the 11 patients selected for surgical extirpation of the intact primary breast tumor with curative intent were so selected because their distant disease seemed to have completely responded to treatment with either systemic therapy alone or systemic therapy and surgery. To eliminate any potential bias associated with inclusion of these patients, we conducted a second analysis with these patients excluded. On this second analysis, however, we still noted a statistically significant improvement in metastatic progression–free survival for patients who underwent surgical treatment of the intact primary breast tumor.

Determining which patients with stage IV disease will definitely benefit from surgical removal of an intact primary breast tumor is the key question. Other important questions that should be addressed are the optimal timing of surgery, the optimal chemotherapy regimen, and methods of and indications for resection of site(s) of metastasis. Further analyses are under way at M. D. Anderson Cancer Center to determine the optimal patient population and timing of surgery. Randomized clinical trials should be developed that will attempt to determine whether surgical treatment of the intact primary tumor ultimately does affect outcome, to determine the association between the primary tumor and metastatic sites, and to determine whether novel markers may play a role in predicting who will most benefit from surgery. Our study, together with the study by Khan et al.,1 challenges the paradigm that surgery has no effect on outcome in patients with metastatic disease. Perhaps by challenging this paradigm and using surgery as a tool, we will be able to learn more about the mechanisms of metastasis and the association between the intact primary breast tumor and sites of metastasis.


   ACKNOWLEDGMENTS
 
The authors thank Stephanie Deming for her editorial assistance, Marlen Banda for assistance with manuscript preparation, and Alam Khuwaja for data management. Supported by the Nellie B. Connally Breast Cancer Research Fund.


   FOOTNOTES
 
Presented in part at the Annual Meeting of the Society of Surgical Oncology, Atlanta, Georgia, March 3–6, 2005.

Received for publication March 4, 2005. Accepted for publication November 14, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  6. Tanaka K, Shimada H, Matsuo K, et al. Outcome after simultaneous colorectal and hepatic resection for colorectal cancer with synchronous metastases. Surgery 2004; 136:650–9.[CrossRef][Medline]
  7. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001; 345:1655–9.[Abstract/Free Full Text]
  8. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205–16.[Abstract/Free Full Text]
  9. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. 6th ed. New York: Springer-Verlag, 2002.
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  11. Retsky M, Bonadonna G, Demicheli R, et al. Hypothesis: induced angiogenesis after surgery in premenopausal node-positive breast cancer patients is a major underlying reason why adjuvant chemotherapy works particularly well for those patients. Breast Cancer Res 2004; 6:R372–4.[CrossRef][Medline]
  12. O’Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79:315–28.[CrossRef][Medline]
  13. Danna EA, Sinha P, Gilbert M, et al. Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 2004; 64:2205–11.[Abstract/Free Full Text]
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  16. Carmichael AR, Anderson ED, Chetty U, Dixon JM. Does local surgery have a role in the management of stage IV breast cancer? Eur J Surg Oncol 2003; 29:17–9.[CrossRef][Medline]
  17. Hortobagyi GN. Can we cure limited metastatic breast cancer? J Clin Oncol 2002; 20:620–3.[Free Full Text]
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