Surgery for the Primary in Patients with Distant Metastases
Surgery for the Primary in Patients with Distant Metastases
Tari A. King
The traditional dogma that surgery is reserved for the palliation of symptoms in stage IV breast cancer is being challenged by advances in breast cancer diagnosis and treatment. Widespread mammographic screening and increased awareness have resulted in fewer patients presenting with inoperable disease; improved imaging technologies have resulted in the detection of low-volume metastatic disease in patients who would have previously been classified as having early-stage disease; and improved efficacy of modern chemotherapy regimens, including the use of targeted hormonal and biologic therapies, has resulted in prolonged survival for women with metastatic disease. Thus, in modern breast cancer treatment, the goals of therapy for patients with metastatic disease often extend beyond palliation; however, the role of local treatment in this setting remains uncertain.
Although the mean survival for patients with metastatic breast cancer remains 18 to 24 months, the range of survival extends from a few months to many years, and reports of improved survival in the more-recent decades of treatment raises the possibility of cure for a select group of patients in the future. Andre et al. (1) reported survival rates over two time periods for 724 consecutive breast cancer patients presenting with metastatic disease at diagnosis; overall 3-year survival for patients treated from 1987 to 1993 was 27%, which increased to 44% for those treated from 1994 to 2000. Clinical characteristics were similar in the two time periods, suggesting that the survival trend was related to treatment advances that occurred after 1993. Giordano et al. (2) also demonstrated a trend toward improved survival with more-recent year of recurrence and treatment in a multivariate analysis of 834 women who developed recurrent breast cancer between 1974 and 2000. Each more-recent year of recurrence was associated with a 1% per year reduction in the risk of death. Neither of these two datasets included the benefits obtained from newer therapies, such as trastuzumab and other targeted therapies, yet both demonstrate that improvements in systemic therapy have resulted in demonstrable improvements in survival for patients with metastatic disease.
Targeted therapy with the monoclonal antibody trastuzumab has further improved both survival and quality of life in patients with ERBB2 (formerly HER2/neu) positive metastatic breast cancer (3). Patient selection based on amplification of the ERBB2 gene was critical to the success of this therapy and highlights the need to address breast cancer in biologically meaningful subtypes (see Chapter 29, ERBB2 Testing: Assessment of Status for Targeted Therapies, and Chapter 50, Adjuvant Treatment of ERBB2-Positive Breast Cancer, for a detailed discussion). Whether or not this rationale can be applied to the role of local surgery in the setting of metastatic disease is now a matter of great interest and debate.
HISTORICAL PERSPECTIVE
Conventional wisdom suggests that surgical excision of the primary tumor is unlikely to offer the patient any survival advantage and therefore should be reserved for the palliation of symptoms. However, this approach stems from a time before modern advances in systemic treatments and supportive care. Patients with metastatic cancer were often debilitated, not considered fit for general anesthesia, and often had bulky tumors in the breast and axilla that required extensive surgical procedures for complete extirpation. Survival after the diagnosis of metastatic disease was often brief, leading to the desire to avoid unnecessary morbidity from surgery. In the modern era, this concern is largely outdated, as many patients will experience prolonged survival (4, 5) and the morbidity of common surgical procedures for breast cancer is exceedingly low (6).
Other historical arguments against surgery have included the desire to follow easily measurable disease for response to therapy, and the fear that removal of the primary tumor would result in increased angiogenesis and growth of otherwise dormant metastatic disease (7, 8). Animal models suggest that resection of the primary tumor may be accompanied by release of growth-enhancing factors and induction of temporary immunosuppression (9, 10). Further, circulating antiangiogenic factors, such as angiostatin and endostatin, are felt to result directly or indirectly from the presence of the primary tumor, and function to at least partially control angiogenesis of existing dormant micrometastatic tumors (11). According to the angiogenesis concept, upon removal of the primary tumor, angiogenesis is switched on and dormant cells begin to grow. Although this has been documented in the Lewis lung animal model (8), there are few data to support this theory in humans.
BREAST CANCER GROWTH AND METASTASIS
The growth mechanisms of breast cancer have important implications both biologically and clinically. The fundamental question that has been debated over the past century is whether breast cancer is a local disease that spreads in an orderly fashion and becomes systemic, or whether breast cancer is a systemic disease at its inception. These two opposing theories, classically referred to as the Halstead and Fisher paradigms, formed the basis for breast cancer treatment in the 20th Century. The increasing acceptance of the Fisher paradigm over Halstead’s theory resulted in a shift away from more radical surgery to increasing use of systemic therapies in recent decades; however, the increasing body of evidence demonstrating that local control does impact survival suggests that the truth is likely in the middle. Breast cancer may be, but is not universally, systemic at its inception, and local-regional treatments are important.
At present, metastatic disease is largely incurable and remains so due to a limited understanding of the molecular mechanisms of metastasis. A variety of models suggesting that genetic alterations resulting in metastases are acquired over time are unstable and may overgrow the primary tumor have been proposed. Experimental evidence supporting these theories exist, but their relevance to metastatic breast cancer in humans is uncertain. In the genomic era, new concepts of metastatic dissemination have been proposed. The ability of gene expression profiles of human primary breast cancers to predict metastatic potential (12) suggests that the ability to metastasize is an early and perhaps inherent, genetically predetermined property of the primary tumor cell. Support for this concept includes the finding of similar gene expression profiles from pairs of human primary breast tumors and their distant metastases (13), as well as similar gene expression patterns between premalignant, preinvasive, and invasive breast cancers (14). Kang et al. (15) have proposed that within the population of tumor cells with metastatic capacity, subpopulations of cells also have a superimposed tissue-specific gene expression profile that predicts the site of metastasis. Mathematical models suggest that not only does this “escapee” cell have the capacity to seed distant sites, but it may also metastasize back to the primary tumor (self-seed), thereby contributing both to the ongoing growth and destruction at the site of primary disease, as well as to an ever-growing source of disseminating tumor cells (16). Within the context of metastatic breast cancer, this theory of self-seeding would strongly support complete excision of the primary tumor.
The analysis of human-disseminated cancer cells has led to another model, termed the parallel evolution model, which proposes that the dissemination of metastatic cancer cells occurs early and is independent of later changes that may be acquired in tumor cells at the primary site (17). This theory is based on the finding that disseminated tumor cells in the bone marrow of patients without metastatic disease do not share the same genomic abnormalities as cells from the primary tumor; however, in patients with known metastatic disease, these cells are similar to the primary tumor. This theory challenges the concept of clonal genomic evolution, yet the true biologic potential, and therefore clinical significance, of disseminated cells found in the bone marrow of patients with early-stage disease is unknown, and multimodal therapy, including surgery, remains standard care for these patients (18).
Finally, there is an growing body of evidence supporting the cancer stem cell theory. This theory proposes that rare cells with indefinite proliferative potential are responsible for the formation and growth of tumors (19), and have the exclusive potential to proliferate and form metastasis (20). Other areas of investigation that may contribute to the understanding of the role of local treatment in metastatic disease include the study of the tumor microenvironment and the immune system (16, 21).
In contrast to the conventional model, the newer concepts of metastases all support removal of the primary tumor to reduce either self-seeding, tumor cell dissemination, or the population of native cancer stem cells, followed by effective systemic therapy. There is a biologic rationale that supports a proper evaluation of the role of surgery for the primary tumor in stage IV disease, and this question is increasingly important as outcomes in stage IV disease continue to improve with newer targeted systemic agents. The question also has wider implications than for the population of women who present with stage IV disease and an intact primary, such as for those women who present with a synchronous in-breast recurrence and distant metastases.
LOCAL CONTROL AND SURVIVAL
It is now well established that local control does impact survival in stage I to III breast cancer, and this is particularly evident in patients with positive nodes and those at higher risk of local relapse (22). If preventing local recurrence decreases the incidence of distant relapse in earlier-stage disease, a natural extension of this argument is to consider whether optimizing local control, by removal of the intact primary tumor, may benefit select patients with metastatic disease. In 2002 Khan et al. (23) first challenged the traditional thinking with a report of 16,023 patients presenting between 1990 and 1993 with stage IV disease as captured by the National Cancer Database (NCDB) of the American College of Surgeons. Surprisingly, 9,162 (57.2%) patients underwent either partial [3,513] or total mastectomy [5,649] in the setting of stage IV disease, and surgical removal of the primary tumor was associated with a 39% reduction in the risk of death. Adding further support to the argument for local control, women treated surgically with clear margins had a 3-year survival of 35%, as compared to 26% for those with positive margins, and 17% for those not having surgery (p < .0001). Additional studies, both population-based and single-institution series, examining survival outcomes relative to surgical resection or radiotherapy (24) of the intact primary tumor, have now reported remarkably similar results, with an observed reduction in the hazard of death ranging from 40% to 50% (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 and 41).
Since the first such publication by Khan et al., at least 19 retrospective studies have evaluated the role of local therapy for the primary tumor in patients presenting with de novo stage IV breast cancer. The six multi-institutional registry and population-based studies provide information on over 27,000 patients, 14,443 (52%) of whom underwent surgery for the primary tumor, with all but one study, which excluded patients who received systemic therapy before surgery (29) demonstrating an association between surgery and improved survival (Table 68-1). Similarly, the single-institution studies provide information on over 4,000 patients, 1,670 (41%) of whom underwent surgery for the primary tumor, with over half of the studies demonstrating a similar association between surgery and improved survival (Table 68-2). However, nearly all of these studies also revealed that surgery for the primary tumor was more likely to be pursued in women who were younger, had fewer metastatic sites, and had bone-only or estrogen-receptor (ER) positive disease, leading some to question whether these results truly reflected a consistent benefit from local therapy or consistent bias in patient selection.
TABLE 68-1 Population-Based and Tumor Registry Series Examining the Impact of Surgery for the Primary Tumor in Patients Presenting with Stage IV Breast Cancer
b Matched-pair analysis. HR, hazard ratio; CI, confidence interval; OS, overall survival; MVA, multivariate analysis; NCBD, National Cancer Database Study; BCSS, breast cancer-specific survival; DSS, diseasespecific survival; ER, estrogen receptor; SEER, National Cancer Institute Surveillance, Epidemiology, and End Results; RT, radiation therapy; NR, not reported; NA, not applicable; MGH, Massachusetts General Hospital; BWH, Dana-Farber Cancer Institute, Brigham and Women’s Hospital; NCCN, National Comprehensive Cancer Network.
TABLE 68-2 Single-Institution Series Examining the Impact of Surgery for the Primary Tumor in Patients Presenting with Stage IV Breast Cancer
a Dana-Farber Cancer Institute, Brigham and Women’s Hospital; and Massachusetts General Hospital.
b Number of patients having surgery as only form of local therapy.
c HR is for local therapy: surgery + RT versus no local therapy.
d National Cancer Center Hospital, Okayama, Japan. HR, hazard ratio; CI, confidence interval; OS, overall survival; MVA, multivariate analysis; MDACC, University of Texas MD Anderson Cancer Center; NR, not reported; PFS, progression-free survival; RT, radiation therapy; ER, estrogen receptor; PR, progesterone receptor; CNS, central nervous system; LRT, local-regional therapy; TTFP, time to first progression; NS, not significant; MSKCC, Memorial Sloan-Kettering Cancer Center.
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