|Year : 2013 | Volume
| Issue : 2 | Page : 181-186
Role of Loco-regional Surgery in metastatic breast cancer
S.V Suryanarayana Deo, Deepak Jha
Department of Surgical Oncology, Dr. BRA-IRCH, AIIMS, Delhi, India
|Date of Web Publication||13-Jun-2013|
S.V Suryanarayana Deo
Department of Surgical Oncology, Dr. BRA IRCH, AIIMS, Delhi
Source of Support: None, Conflict of Interest: None
Approximately 3-10% of patients of breast cancer present with metastatic disease. Traditionally the treatment of these patients has been systemic only with local therapy in form of surgery or RT offered only to palliate local complications like ulceration or haemorrhage, etc. We review and analyse the current literature on surgical removal of primary breast tumor in metastatic disease. Data for this review was compiled by searching the PubMed database. Though current evidence is not strong enough to recommend surgical removal in all MBC patients, there seems a subset of MBC patients who, when carefully selected, have a survival benefit from surgical removal of primary tumor. A carefully structured RCT with large number of patients and long follow up is needed.
Keywords: Breast cancer, in-breast tumour, metastatic, surgery in metastatic setting
|How to cite this article:|
Deo SS, Jha D. Role of Loco-regional Surgery in metastatic breast cancer. J Can Res Ther 2013;9:181-6
| > Introduction|| |
Breast cancer has replaced cervix as the commonest cancer in females in most of the cancer registries in India.  Western studies report that 3-10% of patients of breast cancer present with metastatic disease.  With advent of better multimodality therapy, the survival of metastatic breast cancer (MBC) patients has increased over the years.  Traditionally the treatment of these patients has been systemic only with local therapy in form of surgery or RT offered only to palliate local complications like ulceration or haemorrhage, etc. However, there is now a growing evidence of benefit from offering surgery to intact primary even in metastatic setting in breast cancer, similar to the benefit seen in renal, colorectal, ovarian and gastric carcinoma. 
| > Materials and Methods|| |
Data for this review was compiled by searching the PubMed database using the search terms: breast cancer and metastatic or stage IV and surgery for primary. Full articles were obtained and the respective reference lists were further checked for additional material. Only articles in English were considered.
Mechanism of metastases in breast cancer
The first theory regarding development of metastases in breast cancer was the Halstead theory. It stated that breast cancer starts as localized disease in the breast that spreads from the primary to axillary lymph nodes, and then to metastatic sites. This theory was the basis of extensive locoregional surgery like radical mastectomy initially advocated for breast carcinoma.  The alternative proposed to Halstead theory was the Fischer theory. It described breast cancer as a systemic disease and that tumors that have the capacity to metastasize would do so even before diagnosis. This viewpoint advocated an aggressive systemic therapy with not much survival advantage of local control. 
Both the theories however, represent extremes of a spectrum and neither can explain the disease pattern completely. The ultra radical surgical procedures for local disease have long given way, first to more conservative modified radical mastectomies and recently to breast conservation surgeries. Similarly, the early detection of disease and appropriate multimodality local therapy has definitely shown survival advantage, contradicting the Fischer theory.
With the above inconsistencies in the previously described theories, a third theory, called the Spectrum theory, came forward. It stated that the exact moment of metastases to distant sites is unknown at the time of diagnosis. Hence, it emphasized on both local control and systemic therapy as part of multimodality approach to gain control over the disease. 
The growing understandings of molecular biology and cellular pathways have brought out new concepts to explain the events behind development of metastases in breast cancer. Lang et al. have identified three plausible hypotheses.  The "parallel evolution" model proposes that circulating tumor cells are present early in tumorigenesis and are independent of the primary tumor. This theory would make a case for local treatment of an intact primary in metastatic breast cancer. The "gene expression profile" theory states that metastatic potential of breast tumor is an inherent, genetically predetermined property that is expressed very early in the disease course. Hence, the tumor cells are programmed to metastasize to a certain sites in the presence of a favorable microenvironment. The third hypothesis is the "Stem cell model", which states that metastatic potential is exclusively present in specialized tumor initiating caner cells. It hence, justifies treatment aimed specifically at these cells as well as the primary tumor.
Support to the concept of surgery of intact primary also comes from the work of Danna et al.  They 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. Hence, extirpation of an intact primary may augment the efficacy of immunotherapy. Many other studies have shown a benefit of removal of an intact primary in the setting of metastatic disease in tumors like renal cell cancer, colorectal cancer and gastric cancer. 
However, not all theories support surgical resection of primary breast tumor in metastatic setting. The "tumor dormancy theory" postulates that removal of primary tumour results in proliferation of metastases by induction of angiogenesis, reduction of apoptosis and release of growth factors as a response to surgical intervention. Importantly, this theory is still to be backed by strong clinical evidence. 
The story so far
The first study to evaluate the role of removal of intact primary was by Khan et al. in 2002.  They did a retrospective analysis to evaluate the impact of local therapy on survival of patients with metastatic breast carcinoma. Sixteen thousand and twenty three patients with stage IV disease were identified from National Cancer Data base (NCDB) between 1990 and 1993. Of these 16,023 patients, 57.2% patients underwent partial or total mastectomy. They concluded that women treated with surgical resection with free margins had superior prognosis as compared to those who did not receive any surgical intervention. A multivariate proportional analysis further identified number of metastatic sites, type of metastatic burden, and the extent of resection of the primary tumour as significant independent prognostic covariates.
Other population database and single institute retrospective studies evaluating the impact of surgical extirpation of an intact primary breast tumor in metastatic setting followed the study by Khan et al [Table 1]. A majority of them seconded the view that women who underwent surgical resection of primary did show some survival benefit over women not receiving any surgery and advocated a randomized controlled trial for further evaluation. Surprisingly a significant number (40-60%) of patients had undergone surgery even in presence of metastases, even though the traditional view prevalent was to offer surgery only to prevent or treat local complications of uncontrolled primary disease.
However, all these studies were retrospective database analyses and hence, suffered from inherent weaknesses. The population database reviews (e.g. NCDB, SEER, Geneva cancer registries, etc.) have the large number of patients required for such an analysis. Unfortunately, they also suffer from lack of finer details for each patient included in the study. These details included data like hormone receptor status; details of any radiation therapy received, margin status, etc. These factors have come across as significant in multivariate analyses. Single institute reviews on the other hand have a much detailed patient information allowing an in depth analysis of various prognostic and confounding factors. They however, suffer from lack of substantial number of patients and are more likely to have institutional biases in patient selection. The above reasons make a strong case for a randomized controlled trial for this evaluation.
Is there a survival benefit?
This is the first question that needs to be answered before offering the option of surgery for the "in-breast" tumors. The present literature projects less than six months survival for a patient with visceral metastases, 18 months for nodal disease, and 3-4 years for bone-only metastases. However, most of the retrospective studies have shown an improved survival with surgery of intact primary. Khan et al., in their review of NCDB data observed a 3-year survival of 24.9% for the entire group.  The mean survival recorded in total mastectomy (TM) group was 31.9 months, 26.9 months in partial mastectomy (PM) group, and 19.3 months in no surgery group. The 3-year observed survival was 31.8%, 27.7%, and 17.3%, respectively. They concluded that resection of primary provided a statistically independent survival benefit. Rapiti et al. documented a 50% reduction in breast cancer related mortality in patients undergoing surgical removal of the primary tumor. This effect was restricted to patients with free surgical margins and was more evident in patients with bone only metastases. The SEER review by Gnerlich et al. displayed longer median survival in women who had surgery for their primary tumors.  Twenty four percent of the patients were alive in the surgery group at the end of the study (P < 0.001). This was true for patients who were alive at the end of the study as well for those who had died. Blanchard et al. recorded a median survival of 27.1 months in the surgery group with respect to 16.8 months in no surgery group (P < 0.0001).  McGuire et al. in their single institute review showed 33% overall survival (OS) rate in surgery group vs. 20% in no surgery group ( p 0.0012).  Babiera et al. and Neuman et al. also reported a trend towards increased survival, but it was statistically not significant. ,
Which surgery to offer?
From a dogmatic approach of absolutely no surgery for "in-breast" tumors to contemplating which surgery would be more beneficial is indeed a paradigm shift. When the current surgical practice is shifting towards breast conservation, should a total mastectomy be a blanket treatment to all these patients? Is the survival benefit substantial? The patients in majority of the reviews were more likely to undergo a TM. The percentage of patients undergoing TM varied from 40%-77%, whereas the percentage of PM varied from 22- 59% between the studies. , The most significant result was from the NCDB review that had 31.9 months mean survival in TM group compared to 26.9 in PM group, with observed 3-year survival being 31.8 and 27.7, respectively.  However, given free margin status, the survival was similar in both the groups. Interestingly, patients in TM group were more likely to undergo axillary lymph node dissection (ALND), 78.5% vs. 18.9%, respectively. However, in their final analysis, the benefit of TM remained greater than PM, with free margins adding incremental value. Patients with TM were also more likely to have free margins as compared to PM group. McGuire et al. reported a 37% OS rate in mastectomy group versus 20% in BCT group ( p 0.0275).  Though 34% patients in mastectomy group had preoperative chemotherapy compared to 15% in BCT group, there was no statistical difference in pathological response, site of metastases, receptor status, number of metastases, rate of receiving RT, taxanes or hormonal therapy. Though other reviews have shown a higher rate of patients undergoing TM, with higher rates of free margins, they have not evaluated upon the beneficial effect of TM versus PM/BCT. The above evidence, though limited, has pointed towards a benefit in offering a total mastectomy over conservation surgery. Whether this benefit is due to type of surgery per se or due to the added advantage of ALND and free margins, that are more likely in this group, is yet to be conclusively proven.
Is ALND mandatory?
The details of ALND have not been reported in majority of the reviews. If maximal local control of primary site aides in increasing survival by decreasing the tumor burden, decreasing chances of reseeding, then by same logic ALND should also serve the same purpose and help in increasing the survival of these patients. The obvious trend is that patients undergoing TM are more likely to undergo ALND as part of the surgical procedure as compared to patients undergoing PM. NCDB review had 78.5% rate of ALND in TM group as compared to 18.9% in PM.  However, the extent of ALND was not significantly related to survival. They concluded that ALND may contribute to survival advantage of TM, but is not an independent prognostic factor. Rapiti et al. showed that the risk of death was reduced in patients with and without ALND but the effect was more in ALND group.  This effect however, was not statistically significant. McGuire et al. reported a statistically non-significant trend towards improved survival in patients with node dissection, with 46% of patients having ALND having survived versus 17% in no ALND (p 0.26).  Neuman et al. reported an ALND rate of 47.8% with an axillary recurrence rate of 9%.  This rate is higher than that of axillary recurrence in patients with non-metastatic breast carcinoma but was attributed to lack of post operative Radiation therapy in these patients. The above evidence is still inconclusive about ALND being an independent prognostic factor over and above the type of surgery. This may also be due to the lack of details regarding ALND in the various reviews. Some reviews though have reported ALND in adding to the survival benefit of surgery and hence, may be included as part of the procedure, especially if the patient is being offered a mastectomy.
Are free margins an absolute necessity?
A microscopic margin negative resection is a fundamental concept in oncology. Most reviews lack the detailed data regarding margin status in every procedure; hence, not giving any substantial evidence towards the role of a margin negative resection. The best indication comes from Rapiti et al. who observed reduction in breast cancer mortality only if the entire tumor was removed with negative surgical margins.  They observed no difference in patients with positive margins. Five-year survival was 27% in margin negative group, 16% in margin positive and 12% for patients with unknown margin status or no surgery. This effect was particularly more evident in patients with bone metastases. Khan et al. concluded that margins were more likely to be free in TM group. Importantly, given free margins, the survival was similar in TM and PM group.  Free margin was concluded to have added incremental value to TM in this review. McGuire et al. also observed a higher margin positive rate in BCT (26% versus 3%, P < 0.001).  Neuman et al. observed a higher margin positive rate in PM group but margin status or reason for surgery was not found to be significantly related to local recurrence.  No difference in survival was seen. Though the evidence for free margins is still not concrete, this is more likely due to lack of data and hence, it would be a good practice that a free margin should be obtained in patients undergoing surgery for their "in-breast" tumors.
When to operate?
Once the decision is made on offering surgical removal of the primary to the patient, an equally important decision is when to operate. Most of the reviews have offered surgery to patients who had received chemotherapy as the first line treatment. This fact has also led to the criticism that there may be a selection bias in considering only those patients who had good response on chemotherapy for surgery. Rao et al. in their single institute, retrospective analysis concluded that surgery is associated with an improved metastatic PFS (Progression Free Survival) when performed more than 3 months after diagnosis.  However, all the patients had been treated with anthracycline based chemotherapy and/or hormonal therapy including tamoxifen or anastrazole. Transtuzumab had also been administered to patients whose disease expressed Her2neu gene amplification. Babiera et al. had also recorded that the surgical group patients were more likely to receive chemotherapy as first line of treatment.  Neuman et al. observed a similar median time of 8 months to surgery but they did not find any survival difference due to timing of surgery.  The time gap between diagnosis and surgery allows the oncologist to observe the behaviour of the disease. Hence, some time gap may prevent an unnecessary surgery in patients with aggressive disease biology. However, this issue has not been dealt convincingly in the reviews and is more likely to be resolved by a randomized clinical trial.
Other contributing factors
Surgery has not been the only contributory factor to an improved survival in this subset of patients. Univariate analyses in these reviews have put forward a number of statistically significant factors, with a few of them also showing significance on multivariate analysis. Barbiera et al. reported single metastatic site and lack of Her2neu gene over expression as significant factors on multivariate analysis.  Number of metastatic site was also shown to be significant in multivariate analysis by Blanchard et al., along with hormone receptor status and definite surgery.  Importantly, they did not find any difference in survival in patients with bone only metastases with respect to patients with non-bone metastases. Gnerlich et al. in their review of the SEER database carried out multiple multivariate models and all had surgery as significant factor.  Only bone metastases were not found to be significant in univariate or multivariate analyses. However, Neuman et al. did report the site of metastatic disease to be a significant factor in multivariate analysis of their data.  Ages, method of discovery, regional lymph node status, visceral or CNS metastases were the significant factors in multivariate analysis by Rapiti et al.  The above data points to the fact that there probably is a subset of patients with presence of other positive contributory factors, which is going to get the maximum survival advantage from a well-timed surgery. A randomized controlled trial is needed to separate out the effect of these factors from the survival benefit that is being associated with surgery of "in-breast" tumors.
A selection bias?
Selection bias is the most often cited criticism of retrospective reviews. It is argued that some form of unconscious selection bias might have taken place when considering which patient to be considered for surgery. Hence, there should be dissimilarities in the surgery and non-surgery group of the majority of the reviews. Babiera et al. found that patients in the surgery group were younger, had less nodal involvement, fewer metastatic sites, had liver metastases, and had received chemotherapy as first line of treatment.  The SEER database had younger, white, married, less than five cm primary tumor, receptor status positive patients in their surgery group but had no information on site of metastases, margin status, or use of systemic therapy.  Khan et al. in their review had patients with single metastatic site and bone metastases that were more likely to offered surgery.  The patients in surgery group were older in the reviews by Blanchard et al. and McGuire et al., contrary to younger patients in virtually all other reviews. , McGuire et al. did not find any difference in tumor size, site or number of metastases or hormone receptor status in the surgery group.  Blanchard et al. found that older patients, hormone positive, smaller tumors, were more likely to undergo surgery. 
Case against surgical removal
A vast majority of literature points towards a survival benefit due to surgical resection of "in-breast" tumors but there have been a few studies that have not shown the similar results. The first study was by Cady et al. who conducted a retrospective, matched pair analysis of 622 patients from the tumor registries at Massachusetts general hospital (MGH) and Brigham and Women's Hospital (BWH) over a period of 40 years.  They observed that case matching either reduced or eliminated the survival advantage of surgical resection. A 90% 2-year survival was seen in patients receiving chemotherapy first, suggesting selection after an excellent chemotherapy response. Among the 5-year survivors, the high frequency of patients with surgery after excellent chemotherapy response, stage III patients incorrectly classified as stage IV, and oligo-metastases, all indicated bias. The critics to this study however, point out to the observation that case matching did not completely negate the survival benefit shown by surgery. The second study negating the effect of surgery was by Bafford et al. They carried out a retrospective review of 147 patients from Clinical Research Information system (CRIS) between1998 and 2005. They reported an unadjusted survival of 3.52 years in the surgery group versus 2.36 years in no surgery group. On multivariate, survival was significantly superior in the surgery group. However, this benefit was restricted to patients diagnosed with stage IV disease postoperatively and hence, was likely due to stage migration bias. The survival in patients with preoperative diagnosis of stage IV disease was same as no surgery group.
The MF07-01(NCT 00557986) trial is a phase III randomized controlled trial which compares breast cancer patients with distant metastases at presentation, who receive locoregional treatment for intact primary with those who do not receive such treatment.  The primary objective is to assess whether locoregional treatment of the primary tumor provides better overall survival. It is a multi centric trial with central randomization, activated in October 2007. The accrual target is 271 patients. The short-term interim results were presented from the RCT in the ASCO breast symposium, 2010 which reported no evidence that surgery promotes tumor progression and post op 30 day mortality.  However, a similar prospective trial (NCT 00193778) from India failed to show any such benefit in their interim results.  Long-term results are awaited from these trials that would go a long way in creating a consensus towards the role of surgery in intact breast primary.
| > Conclusion|| |
The current evidence is still not strong enough to advocate surgery for primary in all MBC patients. However, there seems a subset of MBC patients who, when carefully selected have a survival benefit from surgery of primary tumor. A carefully structured RCT with large number of patients and long follow up is needed but, based on present literature; surgical removal of primary in-breast tumor should be considered as a viable option even in metastatic setting to maximize survival in this group of patients.
| > References|| |
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