Does Resection of an Intact Breast Primary Improve Survival in Metastatic Breast Cancer?

The recommended primary treatment approach for women with metastatic breast cancer and an intact primary tumor is the use of systemic therapy. Local therapy of the primary tumor is recommended only for palliation of symptoms. However, a series of retrospective studies examining practice patterns for this problem show that about half the women presenting with de novo metastatic disease undergo resection of the primary tumor, and suggest that women so treated survive longer than those who do not undergo resection of the intact primary. In analyses that adjust for tumor burden (number of metastatic sites), types of metastases (visceral, nonvisceral), and the use of systemic therapy, the hazard ratio for death is reduced by 40% to 50% in women receiving surgical treatment of the primary tumor. The benefit of surgical treatment appears to be confined to women whose tumors were resected with free margins. However, these results may simply reflect a selection bias (ie, younger, healthier women with a smaller tumor burden are more likely to receive surgical treatment). In addition, the role of other locoregional therapy such as axillary dissection and radiotherapy is not addressed in these studies. In view of these data, the role of local therapy in women with stage IV breast cancer needs to be reevaluated, and local therapy plus systemic therapy should be compared to systemic therapy alone in a randomized trial.

Despite improvements in breast cancer survival over the past decade or so, the Surveillance, Epidemiology, and End Results (SEER) program, reports that 3.5% of the 200,000 women with newly diagnosed breast cancer in the United States present with stage IV disease, and have an intact primary tumor. This amounts to almost 7,000 women annually, for whom the traditional approach has been systemic therapy. Oncologic dogma has so far dictated that local treatment should be recommended only if the primary tumor is symptomatic, and that therapy directed to the primary tumor will not change the course of the distant disease.

In 2001, provocative data from the Southwest Oncology Group challenged this concept in a trial that examined the benefit of nephrectomy in patients with stage IV renal cell carcinoma, by randomizing patients to interleukin therapy with or without nephrectomy.[1] An improvement in survival for the nephrectomy group was observed, with overall median survival increasing from 8 to 11 months, raising the possibility that aggressive local therapy may contribute to prolongation of survival in other tumors.

In the area of breast cancer, retrospective data have recently accumulated regarding the frequency with which women presenting with stage IV disease and an intact primary receive surgical resection of the primary tumor, and whether such ablation has any impact on survival. As reported in three separate retrospective studies in the past 4 years, substantial numbers of these women undergo surgical extirpation of the primary tumor (Table 1). These studies are based on data from the National Cancer Database (NCDB), representing a varied hospital setting in the United States,[2,3] a European tumor registry,[4] and a large comprehensive cancer center.[5] They show that 30% to 55% of women with de novo stage IV breast cancer undergo surgical therapy for the primary tumor. Data on the use of follow-up radiation therapy in this setting are very sparse. Two other studies have been reported in abstract form: one based on SEER data, and the other from the breast cancer database of the Baylor College of Medicine.[6,7]

These studies, summarized below, are remarkably consistent in the finding that women who undergo surgical therapy for the primary tumor in the setting of metastatic disease fare better than those whose primary tumor is left intact. However, the entire published literature on this topic consists of retrospective reviews, all subject to the same selection bias-ie, healthier women with lower disease burden were offered surgery. Despite the reassuring concordance in the studies reported so far, no retrospective study will settle this issue, and definitive proof of this concept awaits a randomized clinical trial testing systemic therapy alone against systemic therapy plus local therapy to the primary tumor.

Retrospective Studies

National Cancer Database Study

The first formal analysis of local therapy in women with de novo metastatic disease was performed by Khan et al utilizing data from the National Cancer Database (NCDB) of the American College of Surgeons.[2] They examined the current patterns of surgical care for women with stage IV breast cancer at initial presentation, analyzing the relationship between the use of surgical resection of the primary tumor and duration of survival.

The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, providing information about cancer management and outcomes. In addition to demographics (age, race, etc), recorded tumor characteristics include primary site, histology, grade, clinical and pathologic AJCC (American Joint Commission on Cancer) stage, date and type of recurrence, and sites of distant metastasis. Treatment information includes the use of surgery, radiation, chemotherapy, hormonal agents, biologic modifiers, and other approaches; and follow-up data provide last contact date, vital status, and tumor status at last follow-up.

During the years examined in this study, the NCDB did not include detailed information regarding the type, dose, or duration of chemotherapeutic agents, although nonsurgical therapy was recorded as part of the primary treatment. Additionally, although the use of radiotherapy was recorded, it was not possible to determine whether this was directed at the primary tumor or at a metastatic site such as bone.

Over the 4-year period from 1990 to 1993, 16,024 women were identified (mean age: 62.5 years) who presented with stage IV breast cancer (4.1% of the total number of breast cancer cases accrued during this period). AJCC (5th ed) staging information was fairly complete for these women: The size of the primary tumor was unknown in 11.2% of women; the remainder was evenly divided between T1/2 (45.7%), and T3/4 (43.1%). Pathologic nodal status was unknown in a majority (63%) of patients. When reported, it was N0 in 7.1% of the total population, N1 in 20.8%, N2 in 8.0%, and N3 in 1.1%.

Of the 16,024 women identified, 6,861 (42.8%) received no surgical resection of the primary tumor other than a breast biopsy, and 9,162 (57.2%) underwent surgical resection of the primary tumor. Therapeutic breast procedures consisted of partial mastectomy in 3,513 (38.3%), and some form of total mastectomy in 5,649 (61.7%). Surgical margin data were available on 5,957 patients (69.5%) of the surgical therapy group. The free-margin rate was 45% in women undergoing partial mastectomy (913/2,025) and was significantly higher (63%) in the total mastectomy group: 2,483/3,932. Women undergoing total mastectomy were also much more likely to undergo nodal dissection, which was performed in 78.5% of the total mastectomy group and 18.9% of the partial mastectomy group.

Women who had single-organ involvement were significantly more likely to receive surgery than those with multiorgan involvement (P < .0001), as were those with soft-tissue/bone metastases rather than visceral metastases (see Figure 1). The majority of patients received systemic therapy: endocrine therapy alone (6,880 patients) and chemotherapy, either alone or in combination with other treatment modalities, in 7,779 patients.

Analysis of these data (with death from any cause as the endpoint) revealed a 3-year survival rate of 24.9% for the entire group. The mean survival duration was 19.3 months for the no-surgery group, 26.9 months for the partial mastectomy group, and 31.9 months for the total mastectomy group. Corresponding 3-year survival rates were 17.3%, 27.7%, and 31.8%, respectively. Further analysis of the benefits of total mastectomy over partial mastectomy demonstrated that the strength of the survival benefit experienced by surgically treated patients was entirely explained by the status of the pathologic resection margins. When margins of resection were involved, the 3-year survival rate was equivalent, regardless of the type of resection (26.4% and 26.1 %). When margins were free, the 3-year survival rates were also equivalent-34.7% for partial, and 35.7% for total mastectomy (see Figures 2A and 2B).

In the final model, therefore, the data for the partial and total mastectomy groups were collapsed by margin status, and the no-surgery group was compared to those who underwent surgery with involved margins and those who had surgery with free margins. A multivariate Cox proportional hazards model showed that in addition to surgical resection, three other factors were independently and significantly associated with survival: the administration of systemic therapy, the number of metastatic sites, and the type of metastatic disease. The adjusted hazard of death was significantly lower in the surgical than in the nonsurgical group: If margins were free, the hazard ratio (HR) was 0.61 (95% confidence interval [CI] = 0.58-0.65), and if margins were involved, the HR was 0.75 (95% CI = 0.71-0.79). In this model, the type of surgery (partial or total mastectomy), tumor size (AJCC T), the extent of surgical dissection of regional lymph nodes, or the number of involved axillary nodes were not independently predictive of survival.

Subsequently, the same group of investigators examined NCDB data for the 2-year period from 1994 to 1995, with identical findings. In this analysis, the HR was also adjusted for age, with no substantial differences in the results.[3]

Geneva Cancer Registry Study

The canton of Geneva, Switzerland, has 420,000 residents, and the Geneva Cancer Registry has tracked all incident cases of cancer since 1970. Rapiti et al utilized this resource to examine the breast cancer-specific survival of women diagnosed with de novo stage IV breast cancer over the period 1977 to 1996, and identified 300 such women.[4] Their study methods were very similar to those used in the NCDB study discussed above; AJCC tumor staging was used for the tumor and nodal status, and the metastatic sites were coded in a roughly similar fashion-by number of organ sites involved (one, two, three, or more) and by sites of metastases (bone, soft-tissue, visceral, and central nervous system [CNS]). The breast cancer diagnosis was based on tissue sampling in 87% of women. Of the 300 women identified, 173 (58%) did not receive any surgical therapy, 29% underwent total mastectomy, and 13% received partial mastectomy. Among those in the surgical group, 48% had free margins of resection.

Factors influencing the use of surgery were also similar to the NCDB results: Younger women, those with smaller tumors, and those with less evidence of nodal involvement underwent surgical resection significantly more frequently, as did those with fewer sites of metastatic involvement. Local radiotherapy was used in 21% of the surgical group, as opposed to 5% of the nonsurgical group, and was largely associated with the use of breast-conserving surgery.

Five-year breast cancer-specific survival was 27% in women who underwent surgery with free margins, 16% for those who had surgery with involved margins, and 12% for those whose margin status was unknown (log rank P = .0002). In univariate analysis, the hazard ratio for the risk of death from breast cancer for women with surgical resection and free margins was 0.5 (95% CI = 0.3-0.7), whereas women with positive or unknown margins derived no significant survival benefit, with hazard ratios of 0.8 and 95% CIs of 0.5-1.1 and 0.6-1.3, respectively.

The multivariate Cox model showed that surgical resection with free margins had a favorable impact on the hazard of death from breast cancer (HR = 0.6, 95% CI = 0.4-1.0), as shown in Figure 2C. Other factors that were significantly and independently associated with the hazard of death were the use of chemotherapy (HR = 1.2 when chemotherapy was not used), use of endocrine therapy (HR = 2.6 when not used), radiotherapy (HR = 1.6 when not used), and the presence of CNS metastases (HR = 1.9).

These authors then compared the survival benefit observed in women with bony metastases to that seen in women with metastases at other sites. The adjusted HR for women with bony metastases was 0.2 (95% CI = 0.1-0.4), which was superior to the benefit seen in women with metastases at other sites (HR = 0.7, 95% CI = 0.4-1.2). They also examined the effect of axillary dissection on the value of surgical resection of the primary tumor, and found a trend toward improvement in survival with the addition of axillary surgery to resection with free margins (HR = 0.2, 95% CI = 0.02-1.9), the wide confidence limits doubtless being related to small numbers in this group.

M.D. Anderson Cancer Center Study

A third retrospective study has been reported, by Babiera and colleagues, from the M.D. Anderson Cancer Center.[5] These investigators performed a single-institution retrospective review of women presenting with stage IV breast cancer, either at initial diagnosis, or within 3 months of the primary surgery. Also included in the surgical group were women who underwent surgical extirpation of the primary tumor and metastatic lesions at any point in their course, following diagnosis of metastatic disease. All patients received chemotherapy, with endocrine therapy and trastuzumab (Herceptin) being added as appropriate, based on tumor characteristics.

The study included 244 women, of whom 37% were treated surgically. As in the previous studies, women who received breast surgical treatment were younger, and had a lower tumor burden (fewer involved nodes, fewer metastatic sites). They were also more likely to have hepatic metastases, and to have tumors with HER2/neu amplifications. Mean follow-up duration was 31 months. Independent determinants of survival on Cox proportional hazards modeling included the presence of only one metastatic site, and HER2/neu positivity. There was a trend toward improved survival with surgical resection of the primary tumor.

These authors were also able to evaluate the time to progression, which was not available for the previous two studies. They found that tumor size, site of metastatic disease, use of chemotherapy, estrogen receptor status, and use of surgery for the primary tumor were all independent and significant predictors of longer time to progression. The hazard ratio for surgical therapy was 0.5 (95% CI = 0.4-0.8). A repeat analysis was performed, excluding those women who had been rendered free of evaluable metastatic disease, either by systemic therapy or by the resection of metastatic sites. This analysis also showed a significant improvement in progression-free survival with the use of surgical therapy for the primary tumor.

Analysis of SEER Data

Gnerlich et al analyzed data from the National Cancer Institute's SEER program and presented their findings at the 2007 meeting of the Society of Surgical Oncology.[6] This fourth retrospective study of local surgical therapy in stage IV breast cancer covered the period from 1988 to 2003 and involved 9,734 women, accounting for 3.6% of the breast cancer cases reported to SEER over that period of time. This is very close to the 4% incidence of de novo stage IV disease reported to the NCDB over the period 1990 to 1993, and over a second 2-year period, 1994 to 1995. Surgical resection of the primary tumor was performed in 43% of the SEER population, and slightly more than half (54.3%) underwent total mastectomy. Surgical margin data were not available.

These authors attempted to identify factors associated with the use of surgery and found that women who underwent surgery were more likely to be younger, of European ancestry, married, with smaller tumors, and with a higher proportion of grade III and hormone receptor-positive lesions. However, data on tumor grade were missing for a large number of women in the nonsurgical group. The crude hazard ratio for death in the surgical group was 0.57 (95% CI = 0.55-0.60); adjusted hazard ratios ranged from 0.55 to 0.63. However, in the SEER data, adjustments for systemic therapy and surgical margin status were not possible, and the major adjustments made in these analyses were for factors that influenced the use of surgery (see above).

Baylor College of Medicine Study

In an abstract presented at the 2006 San Antonio Breast Cancer Symposium, Blanchard et al described findings from an existing database of over 10,000 breast cancer patients, which was searched for women who presented with stage IV breast cancer.[7] They identified 807 such women (8.1% of the database population), and then excluded from analysis those women with more than 120 days between biopsy and entry into database, or death within 90 days of diagnosis. They found 427 evaluable women, of whom 258 (60.4%) underwent surgical resection of the primary tumor as part of initial therapy. Surgical margin data were not available, but 78% of women in the surgical group were treated with mastectomy.

The interval from diagnosis to death was 27.1 months for the surgical group and 16.8 months for the nonsurgical group (P < .0001). The significant terms in their final multivariate model included surgical therapy (HR = 0.7, P = .0059), ER positivity (HR = 0.6, P = .0007), PR positivity (HR = 0.7, P = .0015), and the number of metastatic sites (HR = 1.3, P = .0084).

Discussion

A substantial accumulation of retrospective data has established the association of surgical resection of the primary tumor and improved survival in women who present with metastatic breast cancer. The hazard ratios for death in women who undergo surgery for their primary tumor are remarkably constant in these studies, hovering around 0.6, although a single-institution study did not find an improvement in overall survival, presumably because only 17% of women had died at the time of reporting.[5] Bolstering the significance of these findings is the fact that in two studies where surgical margin status was analyzed,[2,4] the benefit of surgery was explained almost entirely by the presence of free surgical margins, demonstrating internal consistency of the data and adding strength to the hypothesis that local therapy is valuable even in the presence of distant disease.

Study Characteristics

In the four studies[2,4,6,7] that have reported an overall survival benefit in this group of patients, the authors have adjusted the survival analyses for a variety of parameters, in an attempt to account for a presumed selection bias driving the use of surgery in women who are younger and have better overall health, lower disease burden, and better access to care. The authors of each study have attempted, to the extent allowed by retrospective data, to adjust for obvious indicators of tumor burden and prognosis.

The NCDB and Geneva studies were better able to adjust for treatment and prognostic factors (the number of sites of metastatic disease, visceral vs soft-tissue organ involvement, and the use of chemotherapy and endocrine therapy). Each of these features, as anticipated, affected the hazard of death, but the impact of surgical resection of the tumor persisted in multivariate models that included these parameters. In the population-based study utilizing the SEER program, data on the number/type of metastatic sites, the use of systemic therapy, and the status of the surgical margins were not available, but .the authors attempted to adjust for other social and demographic factors that determine access to care. They found very little attenuation of the diminished hazard ratio in the surgical group.[5]

Thus, at the present time, five retrospective studies (three published and two presented in abstract form) involving over 26,000 women present us with compelling evidence that either surgical therapy of the primary tumor has a substantial therapeutic benefit in women with metastatic breast cancer, or there is a strong and consistent selection bias driving the use of surgery in women who have less aggressive disease. Another possible explanation of the apparent beneficial effect of surgical resection is that the use of surgery is a surrogate indicator of more aggressive therapy overall, including more aggressive systemic therapy, which translates into better survival. It is unlikely that new retrospective analyses will allow us to refute one or more of these explanations.

The settings of the five studies completed so far are varied. The NCDB receives tumor registry data from hospitals around the United States; these are small and large, urban and rural, academic and community centers. The data are carefully monitored, and the quality of the submission is audited by the Cancer Program of the American College of Surgeons. The SEER database provides high-quality, population-based diagnosis and outcomes data from 11 regions of the United States. The Geneva Tumor Registry tracks cancer diagnoses and outcomes in the entire population of the canton of Geneva, Switzerland. The M.D. Anderson Cancer Center is a large Comprehensive Cancer Center drawing patients from the state of Texas, but with additional referrals from all over the United States and else where. And the Baylor College of Medicine has a large and mature database with high-quality hormone-receptor data.

Despite the diversity of these settings, the findings of all five studies are remarkably similar and leave no doubt regarding the strength of the association between improved survival and surgical resection of the primary tumor in women with metastatic breast cancer. They therefore pose the urgent question, addressable only with a prospective randomized trial, of whether this is a causative association.

Resection and Local Control

The frequent use of surgical resection in women presenting with stage IV disease is somewhat surprising. The main justification for surgical extirpation of the primary tumor in this setting so far has been the so-called "toilette" resection, but many of the patients undergoing partial and total mastectomy had T1 or T2 tumors. This trend highlights the fact that both physicians and patients are concerned about uncontrolled local disease because of its significant impact on quality of life.

The literature available to date provides little insight into the frequency with which uncontrolled chest wall disease occurs in women who present with distant metastases, and whether or not this is influenced by the use of surgical resection. It is reasonable to assume that no (or incomplete) resection is a risk factor for the occurrence of uncontrolled chest wall disease, but relevant direct data are limited to a study of 28 women in which the authors did evaluate the quality of local control in resected and unresected patients with stage IV disease and concluded that there was a benefit for local control and survival.[8] Other data on local control and survival in women with an analogous situation (synchronous local and distant recurrence following breast-conserving therapy for an initial breast carcinoma) showed that women undergoing resection of the in-breast recurrence, whether by mastectomy or repeat breast conservation, experienced better local control and overall survival.[9]

The rationale for resection of the primary tumor in women with metastatic disease is based on the tacit assumption that resection will improve local control. It is then assumed that axillary dissection and follow-up radiotherapy are usually not justified because women will die of metastatic disease before local control becomes a problem. In the NCDB study, although the extent of nodal disease was not significantly related to survival, women undergoing total mastectomy were much more likely to have nodal dissection, and this may have contributed to the survival advantage observed in the total mastectomy group. In the Geneva study, axillary dissection was performed in 24% of patients, and the investigators found a trend toward greater benefit for women who had both negative surgical margins and axillary dissection (HR = 0.2, 95% CI = 0.02-1.9).

Similarly, regional radiotherapy data are lacking in the published studies, although local irradiation was used in women undergoing breast-conserving surgery in Geneva, and the lack of radiotherapy increased the hazard of death independently. The inability to distinguish local radiation from radiation to metastatic sites is a limitation of the data in the NCDB, as well as in the SEER program, where radiotherapy to local or distant sites is not distinguishable.

The lines of evidence providing theoretical support for the hypothesis that local therapy is useful in women with metastatic breast cancer include the time course of local failure and metastatic disease in studies of postmastectomy radiotherapy,[10] and the survival benefit of postmastectomy radiotherapy to the chest wall and nodal fields, compared to patients treated with adjuvant systemic therapy alone,[11-13] suggesting that uncontrolled local disease may act as a source of continued seeding of distant metastases. Thus, it appears plausible that total tumor burden is a major predictor of treatment outcome for patients with locoregional, or overt metastatic disease, and this presents a logical basis for surgical removal of the primary tumor.

The parallel debate regarding treatment of oligometastatic breast cancer is relevant here: Single-institution data regarding the value of aggressive local therapy to the metastatic site, combined with systemic therapy in women with metastatic breast cancer continue to accumulate.[14] In one such study involving systemic therapy plus resection and radiotherapy to a single metastatic site, 10- and 15-year survival rates of 26% and 24% were achieved.[15] A more recent study reported that 51.6% of patients with limited metastatic disease were disease-free at a median follow-up of 62 months.[16] These results far surpass those generally reported for women with stage IV breast cancer,[17] and are consistent with the argument presented above that the intact primary tumor can be considered as a resectable metastatic site, particularly in women with limited metastatic disease.

Arguments For and Against a Prospective Randomized Trial

Despite decreases in the age-adjusted incidence of breast cancer in recent years, at least 3.5% of the anticipated 200,000 new cases annually will have metastatic disease at diagnosis, generating 7,000 such women in the United States alone, and many more worldwide. The trend toward more intense surveillance for metastatic disease in newly diagnosed breast cancer patients has resulted in the diagnosis of a higher frequency of "oligometastases" and, in fact, in the M.D. Anderson study,[5] 11 women underwent "curative" surgery to the breast with no evidence of residual metastatic lesions elsewhere. If the recommendation of how much (if any) local therapy these women should receive is to be based on scientific evidence, a prospective randomized trial is required.

The design of a prospective study will need to address the full gamut of local therapy for the primary tumor: surgical resection with free margins, axillary control, and radiotherapy. Even if one were to concede that it is a simple matter (because of low cost and low morbidity) to recommend surgical extirpation of the local tumor in women who demonstrate a response to initial systemic therapy, questions regarding recommendations of axillary and radiation therapy cannot be made based on the available data. In addition, as women with metastatic disease are diagnosed earlier and survive longer,[21] failure to consolidate local therapy exposes them to the risk of chest wall disease over a longer period of time.

Thus, the assumption that surgical resection alone provides sufficient protection against uncontrolled chest wall disease needs to be supported with empirical evidence, which at the moment is relatively weak. The present retrospective evidence suggesting a survival benefit from surgical resection is likely to lead to the increased use of surgical resection in this group of patients. The addition of axillary therapy and radiotherapy poses economic and personal burdens that cannot be justified in the absence of firm data to support this. It is sobering to note that resection of the primary tumor appears to be widely practiced in the United States despite the lack of prospectively acquired evidence regarding its benefits, either for survival, or for local control.

Arguments against a randomized trial include questions as to whether limited cooperative group resources should be devoted to a small minority of patients; whether randomization will be accepted by patients and physicians; and whether systemic therapy can be standardized sufficiently in a heterogeneous patient population in the present era of targeted therapy. However, given the apparent large effect of surgery, it appears unlikely that specific systemic therapy regimens will have a great enough impact on survival to confound the effects of surgery. One solution would be to provide general guidelines for systemic therapy for women entered onto such a trial (eg, all women with HER2-positive disease would need to have trastuzumab as part of their regimen, all women with receptor-positive disease should receive endocrine therapy, etc).

With regard to the acceptance of randomization by physicians and patients, this is less likely to be a barrier if axillary dissection and radiotherapy are part of the question, since these interventions are not widely used in this group of patients at the moment. Additionally, innovative trial designs could be considered, in which surgeons are randomized, rather than patients, with crossover to the other arm after accrual of a given number of patients. Preliminary sample size calculations based on a 10% improvement in 3-year survival suggest that such a trial would require about 800 patients, and if adopted across cooperative groups, with 3% of eligible women participating, could be completed in 5 years. A similar trial by Flanigan et al took 6 years to complete but provided invaluable data for patients with advanced renal cell carcinoma.[1]

Conclusions

Whether local therapy should be incorporated into the management of de novo metastatic disease as the standard of care is an important question for thousands of women worldwide. Although surgical resection of a breast tumor-particularly after a good response to systemic therapy-is a fairly straightforward therapeutic intervention, with low morbidity and reasonable cost, the question of local therapy does not end with resection of the primary tumor. To be carried to its logical conclusion, this also requires a decision regarding the use of axillary dissection and radiotherapy for optimal local control.

A randomized trial of aggressive vs minimal local therapy in women with metastatic breast cancer and intact primary tumors, who also receive optimal systemic therapy, appears necessary. Such a trial would provide valuable data regarding the survival benefit of local therapy, and the true frequency and impact of uncontrolled and symptomatic local disease. The inclusion of cost and quality-of-life data would further enhance the value of such a study.

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