Approximately 3.5% to 4% of women with newly diagnosed breast cancer are found to have stage IV disease at presentation according to the Surveillance, Epidemiology, and End Results (SEER) dataset.¹ Despite the fact that this subgroup of patients comprise the minority of the total breast cancer population, this small fraction of breast cancer patients has inspired a heated debate in the literature and at national meetings, fueled by the rapid publication rate on this subject over the past decade. To date, all published reports on this topic are limited to retrospective reviews and meta-analyses. There are several hypotheses as to why extirpation of the primary breast tumor may or may not benefit overall disease-free progression and/or survival despite known distant metastatic sites. There is also a growing body of literature on the potential benefits of metastastectomy of isolated sites. These retrospective data have led to the development of three international, multi-institutional randomized trials to study this question. This chapter will review the published reports to date for both primary tumor removal and distant metastastectomy, discuss the potential beneficial and adverse biological events secondary to primary tumor resection, and summarize the randomized trials currently accruing patients.

Historical Treatment Perspective

Surgery with curative-intent is the cornerstone of treatment for women with stage 0–III breast cancer. Stage IV metastatic breast cancer is defined by the spread of tumor cells beyond the breast, chest wall, and/or regional lymph nodes. The treatment goals in patients with stage IV breast cancer are aimed at controlling the extent of disease, prolonging survival, maintaining quality of life, and limiting the symptoms related to the breast cancer and/or its treatment complications. These goals are typically achieved with systemic therapies, including chemotherapy, endocrine therapy, and/or targeted therapy (i.e., trastuzumab for Her2-amplified disease). Locoregional therapies are generally reserved for palliation. For instance, radiotherapy is often employed for symptomatic bone metastases. Historically, surgical treatment for stage IV breast cancer has been reserved only for cases when the primary tumor has led to complications, such as skin ulceration, infection with foul drainage, or life-threatening bleeding.²

Prognosis

The overall prognosis for patients with stage IV breast cancer is poor, and most patients will die of their breast cancer rather than other noncancer causes. However, the prognosis has dramatically improved over the past several decades, increasing from a 5-year survival of 5% to 10% in the 1970s to 30% to 40% in the early 2000s.^1,3 Further, prognosis can vary widely among patients with stage IV breast cancer according to a myriad of patient and tumor factors. Location of metastatic disease has been shown to correlate with survival in women with stage IV breast cancer: less than 6 months for visceral metastases, 18 months for nodal disease, and 3 to 4 years for bone-only metastases.⁴ The improvements in survival and the survival disparities within stage IV breast cancer patients have led to a surge in the interest surrounding primary tumor removal.

Systemic Therapy Advances

In recent years, the treatment of metastatic breast cancer has undergone considerable advances and changes. Although cure rates after systemic therapy remain poor, the focus is slowly shifting away from palliation and more toward drug discovery resulting in durable progression-free survival, or even a durable cure.^4,5 Multidrug chemotherapy is usually not indicated in stage IV breast cancer patients without life-threatening disease.⁶ Instead, first-line systemic therapy has shifted toward endocrine therapy (for estrogen receptor positive disease), targeted therapies, or monodrug chemotherapy with milder adverse side effects. For patients who experience disease progression while on systemic therapy, a decrease in response occurs with each subsequent line of systemic treatment. Thus, one might hypothesize that the potential beneficial role of primary surgical therapy would have its greatest impact following a specified course of first-line therapy.

Factors Predictive of Survival

Before considering a local surgical treatment for patients with stage IV breast cancer, several predictive factors must be taken into consideration. There is exceedingly low mortality and relatively low morbidity associated with primary breast and/or regional lymph node surgical excision. However, the performance status of the patient, including age and medical comorbidities, must be taken into account. The burden of metastatic disease and the location of that disease should also be considered, as patients who have limited distant disease in more favorable sites (i.e., bone vs. visceral) may fare better. The response to the primary systemic therapy can also provide insight into the likelihood that surgical resection will impact the overall outcome. Finally, the ability to completely resect the local disease, rather than simply debulk it, is also a consideration. Ironically, these factors are also the primary criticism for the retrospective data available on this topic which will be discussed below.

Studies Demonstrating Benefits for Primary Tumor Removal

Sixteen retrospective studies,^7–22 including two large dataset studies from the National Cancer Database (NCDB)⁷ and the SEER program,⁸ have consistently demonstrated that surgical extirpation of the primary breast tumor improves overall survival and decreases progression of systemic disease (Table 80-1). Included in these reports are 30,296 patients, including 15,776 who underwent surgical resection of the primary tumor and 14,520 who did not. These studies have used sophisticated statistical analyses in an attempt to adjust for potential confounders, including age, comorbidity scores, tumor burden (number of metastatic sites), type of metastatic site (visceral vs. bone-only vs. both), type of surgical intervention (breast-conserving treatment vs. mastectomy), margin status (positive vs. negative following surgical removal of the primary tumor), and use of systemic therapy. After controlling for these variables, these studies consistently find that the risk of death is reduced by up to 53% in those women who undergo surgical removal of the primary tumor.

Khan et al⁷ was the first to report the potential survival benefit for surgical resection in stage IV breast cancer patients. Using the NCDB, they found that 57% of 16,023 patients with stage IV disease at diagnosis underwent surgical resection, which resulted in a 39% reduction in the risk of death. The 15 studies which have followed this original report have resulted in similar findings.^8–22 Several patient and tumor characteristics have been identified that both predict the likelihood of undergoing surgical resection, as well as predict the likelihood of observing a survival benefit. Some of these include patient age, patient comorbidities, timing of surgery, extent of surgical resection, margin status, primary tumor biology (e.g., estrogen receptor status), number of and sites of metastatic disease, response to systemic therapy, and extent of adjuvant therapies. Such potential selection bias remains the main criticism of these published reports.

Studies Refuting the Benefit for Primary Tumor Removal

There have been three studies published thus far which have not demonstrated a survival benefit for patients who underwent primary tumor removal in the setting of stage IV disease.^23,24 A single institution study by Cady et al²³ on 808 patients concluded that case selection accounts for most, or possibly all, of the apparent survival advantage reported in the previous analyses. They found that matched-pair analysis significantly narrowed or eliminated the apparent survival benefit secondary to the impact of the sequence of treatment; patients undergoing delayed surgery were preferentially selected following an excellent response to the systemic treatment. In addition, many of the patients in their study were misclassified as stage IV or were selected based on the presence of oligo-metastases or bone-only disease. Dominici et al²⁴ analyzed data from the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database. Eligible patients who did not receive surgery (n=236) were matched to those who received surgery (n=54) based on age at diagnosis, estrogen receptor status, Her2 status, and number of metastatic sites. After matching for the variables associated with a survival benefit in previous studies, surgery was not shown to improve survival.²⁴ Leung et al²⁵ reported that the survival benefit associated with surgery was not seen when their data were adjusted for chemotherapy. The conclusion of these studies was that case-matching appropriately either reduces or eliminates the apparent survival advantage of surgical resection.

Rationale

Similar to the debate that has been occurring with respect to surgical excision of the intact primary tumor in stage IV breast cancer patients, there are also reports describing potential benefits for oligo-metastastectomy. This subgroup of patients is primarily limited to those who had previously undergone curative-intent therapy and then subsequently suffered a metastatic recurrence. The numbers are small in most studies, but there have been consistent findings of improved survival. The largest experience has been in patients with pulmonary and liver metastases, and this discussion will be limited to these two metastatic sites.

Pulmonary Metastastectomy

The lung is one of the most common sites of recurrent metastasis from breast cancer, and 15% to 25% of women with breast cancer metastases will have isolated lung and/or pleural lesions.^26,27 The 5-year survival ranges from 27% to 54%. Freidel et al²⁸ reported the largest study of patients undergoing pulmonary metastastectomy from the International Registry of Lung Metastases which was established in 1997 to monitor the long-term survival of patients after pulmonary resection for numerous types of tumors. There were 467 women who underwent pulmonary resection for breast cancer metastases; the survival rates were 38% at 5 years, 22% at 10 years, and 20% at 15 years. Two-thirds of the patients had solitary metastases, and a complete resection (R0) was performed in 84% of patients. Planchard et al²⁹ analyzed 125 patients who underwent lung resection for breast cancer metastases. They found that a complete (R0) resection was associated with 45% survival at 5 years and 30% survival at 10 years. Similarly, Yoshimoto et al³⁰ reported 54% 5-year survival and 40% 10-year survival in 90 patients undergoing lung resection for breast cancer metastases. One theme that emerges from these studies is that the longer the disease-free interval between the primary tumor and the appearance of the metastases, the better the likelihood of survival.^28–30 This may reflect a more indolent biology of the primary tumor. What remains uncertain is whether these promising findings are secondary to the surgical resection or to the particular selection of patients undergoing surgery.