Traditionally, metastatic breast cancer is considered to be incurable, and the goals of treatment are the prolongation of life and the palliation or prevention of symptoms. Within this context, it is not surprising that local therapy is not routinely recommended for patients presenting with stage IV disease and intact primary tumors. Surgery is reserved for patients who develop complications such as bleeding, ulceration, and infection at the primary tumor site, a type of surgery that historically has been described as “toilette” mastectomy. In this issue of the Journal of Clinical Oncology, Rapiti et al¹ present the results of a retrospective, population-based study of the impact of surgical therapy of the primary tumor on survival outcomes in 300 women with metastatic disease at the time of the initial diagnosis of breast cancer. The authors observed that women having surgery of the primary tumor had a 50% reduction in breast cancer mortality compared with women who did not undergo surgery, the survival benefit was limited to women with tumor-free margins of resection, and a significant survival benefit for axillary surgery was not observed.

These results are strikingly similar to those reported by Khan et al² in a retrospective study of 16,023 patients presenting with stage IV disease at initial breast cancer diagnosis. In the work of Khan, surgery of the primary tumor was associated with a 39% reduction in the risk of death, with a 3-year survival of 35% for patients excised to negative margins, 26% for those with positive margins, and 17.3% for those not having surgery (P < .0001). Again, axillary dissection was not found to contribute significantly to survival.

Both Rapiti et al¹ and Khan et al² adjusted for factors such as number of metastatic sites, location of metastases (visceral v bone and soft tissue), and type of systemic therapy that might have differed between patients who had surgical treatment and those who did not. However, both studies concluded that unrecognized selection bias may have accounted for the observed benefit of surgery, and only a large, prospective randomized trial could determine reliably whether surgery of the primary tumor prolongs survival in the patient presenting with metastatic breast cancer.

The merits of prospective, randomized trials are obvious, but in this era of limited research resources, study questions must be selected with care. In considering a trial of surgical management of the primary tumor in metastatic disease, it is reasonable to ask whether a survival benefit for surgery is biologically plausible and whether the conduct of such a trial is feasible. Several lines of evidence suggest that it is time to re-examine the approach to the patient diagnosed with distant metastases at the initial breast cancer presentation. First, improved imaging technology has resulted in the diagnosis of stage IV disease with considerably lower tumor burdens than were seen in the past. This has led to a stage shift, in which women who previously would have been classified as having stage II or III disease and treated aggressively with multimodality therapy are now being classified as stage IV and managed for palliation.

The natural history of this patient population is not well defined. However, limited experience with aggressive multimodal management of patients with limited metastatic disease, sometimes referred to as oligometastases, supports the validity of testing such an approach in patients with stage IV disease and intact primary tumors. M.D. Anderson Cancer Center (Houston, TX) has reported a 15-year disease-free survival rate of 24% in 134 patients with solitary locoregional recurrences or metastases treated with surgical resection, systemic therapy, and in selected cases, radiotherapy.³ Nieto et al⁴ reported the outcome of 60 patients with minimal metastatic disease treated with surgery and/or radiation therapy and high-dose chemotherapy. Included in this group were 17 patients with distant metastases at the time of breast cancer diagnosis. After a median follow-up of 62 months, 51.6% of the entire patient group (95% CI, 39% to 64%) remained alive and free of disease. In the patients with metastatic disease at presentation, 46% of those with distant metastases and three of four with supraclavicular metastases were alive and free of disease. Others have also reported prolonged survival after surgical resection of limited metastatic disease in breast cancer.^5,6

Improvements in systemic therapies for women with breast cancer also raise the possibility of cure for a select group of patients with stage IV disease in the future. Giordano et al⁷ examined survival in patients with metastatic breast cancer who experienced relapse between 1974 and 2000. In multivariate analysis, each more recent year of recurrence was associated with a 1% per year reduction in the risk of death. Rapiti et al¹ also observed improved survival in patients diagnosed as stage IV in more recent time periods. The hazard ratio for death was 0.6 (95% CI, 0.4 to 0.9; P < .01) for those diagnosed between 1992 and 1996 compared with those diagnosed between 1977 and 1981. Neither the data of Giordano et al⁷ nor Rapiti et al¹ include the benefits obtained from newer therapies such as trastuzumab and bevacizumab. As chemotherapy, endocrine therapy, and biologic therapy improve, the potential for reseeding from the intact primary tumor becomes an issue worthy of consideration.

The suggestion that surgery in some patients with metastatic disease may improve survival is not as outlandish as it may initially seem. Prospective randomized trials of postmastectomy radiotherapy demonstrated that local therapy in the form of chest wall and node field irradiation prolonged survival in node-positive women receiving tamoxifen or chemotherapy.^8-10 Although concerns were raised about the extent of surgery and the chemotherapy regimens used in these studies, these observations challenged the prevailing dogma that local therapy has little impact on survival in breast cancer that is likely to be systemic. Instead, the postmastectomy radiotherapy trial results suggest that uncontrolled local disease may act as a source of tumor reseeding, diminishing the effectiveness of systemic therapy. The observation that the increased local recurrence rate after lumpectomy without radiotherapy translates to a decrease in 15-year survival also supports this concept.¹¹ The possible benefit of primary site surgery in metastatic disease is an extension of this line of reasoning.

In aggregate, there is a biologic rationale that supports a proper evaluation of the role of surgery on the primary tumor in stage IV disease. Is such a trial feasible? Data from the Surveillance, Epidemiology, and End Results program indicate that between 1998 and 2002, 6% of women newly diagnosed with breast cancer had stage IV disease.¹² This amounts to 12,674 new cases in the United States in 2005. Somewhat surprisingly, a substantial minority of women in this group do not have locally advanced primary tumors. In the study of Rapiti et al,¹ 31% had T1 and T2 tumors, whereas this figure was 45.7% in the report by Khan et al.² Primary tumors of this size are readily treated by breast-conserving approaches or mastectomy, whereas T3 tumors (12% and 16.9%, respectively) usually require mastectomy.

If removal of the primary tumor improves survival by reducing total body tumor burden then it is logical to assume that reduction of the tumor burden in the axillary nodes will also be beneficial. The failure of the work of Rapiti et al¹ and Khan et al² to show a benefit for axillary dissection is probably related to the small number of axillary dissections that were performed and their correlation with excision to negative margins. Thus, any trial examining the role of surgery would need to incorporate axillary staging and dissection of tumor-bearing nodes. The possibility of modified radical mastectomy in women with stage IV disease may raise concerns about unduly aggressive surgical therapy. It is useful to remember that the 30-day operative mortality of mastectomy as long ago as the 1970s was 0.35%¹³; major complications are infrequent and at present, hospitalizations of longer than 2 days after mastectomy are uncommon. These morbidity and mortality statistics compare favorably with the toxicity profiles of many systemic therapy agents used in the metastatic setting. If the survival benefit of surgery were confirmed in a randomized trial it would represent a safe, low-cost form of treatment, a major advantage in this era of escalating medical expenses.

It would be naïve to believe that surgery will benefit all women with metastatic breast cancer. However, from the limited data that exist, it is not clear whether it is the extent of metastatic disease, the sensitivity to systemic therapy of an individual's tumor, or some combination of these factors that identifies the woman most likely to benefit from surgical resection. The oncology community has come to recognize that trials of new agents targeted toward subsets of breast cancer patients, often defined by molecular characteristics, is the approach most likely to provide useful information for therapy in the future. Ultimately, the size of the stem-cell compartment may predict which patients with metastatic disease are likely to benefit from aggressive multimodal therapy. At present, a study design in which patients are selected for surgery based on an initial response to systemic therapy is a reasonable place to start. Philosophically, the approach to metastatic breast cancer has not changed during the last 20 years. If a new drug with low toxicity were observed in retrospective studies to reduce mortality by 39% to 50% in metastatic disease, it would be rushed into clinical trial.

Patients presenting with intact primary tumors and metastatic disease represent a small proportion of women with metastatic breast cancer. Does the work of Rapiti et al¹ have any implications for the larger population of women with metastatic breast cancer? Hortobagyi¹⁴ has suggested that an aggressive, multimodal approach that includes surgery produces long-term, disease-free survival or cure in a subset of patients with limited metastatic breast cancer. Surgical resection of pulmonary metastases secondary to sarcoma and hepatic metastases from colorectal carcinoma is accepted as standard management, primarily because metastases are often limited to these organs.¹⁵ Oligometastatic breast cancer is uncommon, with autopsy studies documenting an approximately 5% incidence of isolated metastasis in lung, liver, or bone.¹⁶ Although the proportion of patients with limited metastatic disease is low, the absolute number of women who might benefit from combined-modality therapy is high, given that 40,970 breast cancer deaths are expected to occur in the United States in 2006.¹⁷ Just as we have begun to approach primary breast cancer not as a single entity, but as a group of diseases where optimal therapy is defined by molecular characteristics, it is time to recognize that palliation may not be an appropriate goal for all women with metastatic breast cancer. The evidence provided by Rapiti et al¹ confirms that it is an appropriate time to asses the relative benefit of aggressive multimodality therapy for women with stage IV breast cancer and a low disease burden.

Authors' Disclosures of Potential Conflicts of Interest

Section:

ChooseTop of pageAuthors' Disclosures of P... <<Author ContributionsREFERENCES

Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors	Employment	Leadership	Consultant	Stock	Honoraria	Research Funds	Testimony	Other
Lori Goldstein			Genentech (A); Bristol-Myers Squibb Co (A); Sanoti Avenits (A); Novartis (A); Amgen (A); Berlix (A); Pfizer (A); GlaxoSmithKline (A)		Genentech (A); Bristol-Myers Squibb Co (A); Sanofi-aventis (A); Novartis (A); Amgen (A);	Genentech (A); GlaxoSmithKline (A); Johnson & Johnson (A); Wyeth (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) ≥ $100,000 (N/R) Not Required

Author Contributions

Section:

ChooseTop of pageAuthors' Disclosures of P...Author Contributions <<REFERENCES

Conception and design: Monica Morrow

Manuscript writing: Monica Morrow, Lori Goldstein

Final approval of manuscript: Monica Morrow

REFERENCES

Section:

ChooseTop of pageAuthors' Disclosures of P...Author ContributionsREFERENCES <<