Management of Breast Cancer Solitary Metastases

Liver

The liver is an uncommon site for solitary first metastasis in breast cancer, having been reported to occur only 3% to 9% of the time. Eventually, breast cancer liver metastases (BCLM) are found in 55% to 75% of autopsies performed on patients who died of breast cancer. Hepatic metastases usually occur at later stages of disseminated disease and carry a poor prognosis, with a median survival of 6 months. These patients are not candidates for resection and can be treated only with systemic therapy. Even with systemic chemotherapy, the median survival for patients with metastatic disease to the liver only or with limited disease elsewhere is approximately 19 months using pretaxane chemotherapy regimens or 22 to 26 months with taxane-containing regimens. Hormonal therapy is generally of limited use because most hepatic metastases are hormone receptor–negative; however, estrogen receptor–positive hepatic metastasis is not a rare phenomenon. Hence, surgery has been proposed as a potential therapeutic tool for increasing survival in patients with isolated liver metastasis. Indications for local management of liver metastases include pain, bleeding that is refractory to medical therapy, or biliary obstruction.

In a case control study comparing patients receiving medical treatment to untreated individuals, Sadot and colleagues from Memorial Sloan Kettering Cancer Center investigated the role of hepatic resection or ablation for isolated BCLM. The goal was to assess the effectiveness of surgical treatment for patients with isolated liver metastases from breast cancer. A total of 67 (8%) patients with isolated BCLM were included in an analysis of 2150 BCLM patients who received therapy at a single facility (surgery/ablation: 69; medical: 98), with a median follow-up for survivors of 73 months. Patients who underwent surgery were more likely to have primary breast cancers that were estrogen receptor–positive and to have undergone adjuvant chemotherapy and radiotherapy. In the surgical cohort, the hepatic tumor burden was lower, and the delay between breast cancer diagnosis and BCLM was considerably longer (53 vs. 30 months). With 10 patients (15%) still free of recurrence after 5 years, surgical therapy patients had a median recurrence-free period of 28.5 months (95% confidence interval [CI] 19–38). OS did not differ significantly between the medicinal and surgical cohorts (median OS: 50 vs. 45 months; 5-year OS: 38% vs. 39%). The authors came to the conclusion that hepatic resection and/or ablation did not confer a survival benefit. With surgical intervention, considerable recurrence-free intervals can be achieved. Selected patients may be candidates for surgical surgery with the intention of delaying systemic chemotherapy.

Abbott and colleagues from the MD Anderson Cancer Center studied their institutional experience with 86 breast patients with metastases limited to the liver who underwent hepatic resection. The primary aims were to document OS and DFS and to identify predictors of survival that could be assessed preoperatively to optimize patient counseling, risk-benefit analyses, and outcome. Fifty-nine patients (69%) had estrogen receptor– or progesterone receptor–positive primary breast neoplasms. Fifty-three patients (62%) had a solitary BCLM, and 73 (85%) had BCLM 5 cm or smaller. Sixty-five patients (76%) received prehepatectomy hormonal and/or chemotherapy. Four patients (6%) had progressive disease as the best response, and 19 patients (30%) had progressive disease before hepatectomy ( P < 0.001). Seventy percent of patients who received preoperative chemotherapy or hormonal therapy had either response or stable disease immediately before hepatectomy. No postoperative deaths were observed. At a 62-month median follow-up, the DFS and OS were 14 and 57 months, respectively. On univariate analysis, estrogen receptor/progesterone receptor status of the primary breast neoplasm, best radiographic response, and preoperative radiographic response were associated with OS. On multivariate analysis, estrogen receptor–negative primary breast disease and preoperative progressive disease were associated with decreased OS. From their study, they concluded that resection of BCLM in patients with estrogen receptor–positive disease that is responding to chemotherapy is associated with improved survival. The timing of operative intervention may be critical; resection before progression is associated with a better outcome.

Van Walsum and colleagues on behalf of the Dutch Liver Surgeons Group evaluated the effectiveness and safety of resection of liver metastasis from breast cancer and to identify prognostic factors for OS. A total of 32 female patients were identified. Intraoperative and postoperative complications occurred in 3 and 11 patients, respectively. There was no postoperative mortality. After a median follow-up period of 26 months, 5-year survival rate and median OS after partial liver resection were 37% and 55 months, respectively. The 5-year DFS was 19% with a median time to recurrence of 11 months. Solitary metastases were the only independent significant prognostic factor at multivariate analysis. Van Walsum and colleagues concluded that resection of liver metastases from breast cancer is safe and might provide a survival benefit in a selected group of patients. Especially in patients with solitary liver metastasis, the option of surgery in the multimodality management of patients with disseminated breast cancer should be considered.

Adam and colleagues offered hepatic resection to all patients with BCLM, provided that curative resection was feasible and extrahepatic disease was controlled with medical and/or surgical therapy. The outcomes of 85 consecutive patients with BCLM treated from 1984 to 2004 were reviewed. BCLM were solitary in 38% of patients and numbered more than three in 31% of patients. After a median follow-up of 38 months, the median survival and 5-year survival rate were 32 months and 37%, respectively. Median survival and 5-year DFS were 20 months and 21%, respectively. Study variables associated with a poor survival were failure to respond to preoperative chemotherapy, an R2 resection, and the absence of repeat hepatectomy. In addition, patients who were treated with repeat hepatectomy had a higher 5-year OS rate (81%) compared with patients with unresectable liver recurrences and patients without any hepatic recurrence after first hepatic resection but with extrahepatic metastatic disease. Their analysis determined that DFS was not an independent prognostic factor. Interestingly, the median survivals were longer in the group of patients treated from 1994 to 2004 versus 1983 to 1993. This improved survival might be a reflection of better diagnostic technology and surgical techniques. Adam and coinvestigators concluded that favorable outcomes can be achieved even in patients with medically controlled or surgically resected extrahepatic disease, indicating that surgery should be considered more frequently in the multidisciplinary care of patients with BCLM.

Patient selection and operative criteria for hepatic resection are still controversial; however, important criteria are likely to be fewer than four metastases, no extrahepatic disease, and demonstrated disease regression or stability with systemic therapy before resection. At a minimum, a patient should have a normal performance status and normal liver function tests. Pocard and Selzner agreed that the size and number of hepatic metastases were important factors. Patients in whom liver metastasis was found more than 1 year after resection of the primary cancer had a significantly better outcome than those with early (<1 year) metastatic disease. The type of liver resection, the lymph node status at the time of the primary cancer resection, and the use of neoadjuvant high-dose chemotherapy had no significant impact on patient survival in their series. Martinez and colleagues showed that survival was greater in patients with estrogen receptor–positive primary tumor and metastases, HER2/neu-positive metastases, two or fewer metastases, and age greater than 50 years at metastasectomy.

The preference is for patients to receive chemotherapy before hepatic resection. Extensive preoperative staging evaluation before considering hepatic resection for BCLM is recommended. Diagnostic laparoscopy is recommended to avoid a nontherapeutic laparotomy if extrahepatic disease based on preoperative imaging is suggested. Hepatic resection is preferable if metastases can be safely removed with a negative surgical margin. Radiofrequency ablation (RFA) should be reserved for those patients with tumors not amenable to safe resection or used as an adjunct to resection. RFA has been used for local control of BCLM; the reported series show a median survival of between 30 and 60 months, with no treatment-related deaths and only three serious treatment-related adverse events (AEs) in 164 patients reported. Despite this, skepticism remains over the efficacy of BCLM ablation due to the heterogeneity of patient inclusion and selective nature of reporting. Veltri and colleagues studied RFA of hepatic metastases from breast cancer as an adjunctive tool in the multimodal treatment of advanced disease. The study examined 45 patients (mean age, 55 years) with 87 metastases (mean size, 23 mm) in terms of AEs, complete ablation (CA), time to progression, and survival at the initial follow-up assessment and during the subsequent follow-up (mean, 30 months). Nine negative outcomes (two significant problems, 2.3%) were found. Ninety percent of patients had CA at the first follow-up; 19.7% had relapsed, with an 8-month time to progression. Both the 30-mm criterion ( P = 0.0062) and the difference between the mean diameter of the tumor retained after CA (22 mm) the tumor that remained after treatment failure (30 mm) were very significant ( P = 0.0005). At 1, 2, and 3 years, the OS rate was 90%, 58%, and 44%, respectively. The local efficacy of RFA did not achieve statistical significance at univariate analysis. The scientists came to the conclusion that, although RFA of breast cancer–related hepatic metastases has a high local effectiveness in tumors up to 30 mm, it is not important in predicting survival.

Randomized trials are needed to formulate robust evidence-based recommendations and direct the necessary allocation of health care resources. Transarterial catheter embolization has emerged as a potential treatment option for direct liver delivery and possible better systemic toxicity profile.

Lung

Isolated lung metastases have been reported to occur in 10% to 20% of all women with breast cancer. Approximately 3% of all women with breast cancer develop a solitary pulmonary lesion detectable by chest radiograph, of which 33% to 40% are breast metastases. Considering the low morbidity and mortality rate, lung metastasectomy is the best treatment option in selected patients with lung metastases from breast cancer.

To evaluate the pooled 5-year OS rate and the prognostic factors for pulmonary metastasectomy from breast cancer, Fan and colleagues conducted a comprehensive review and meta-analysis of predictive factors for excision of solitary pulmonary metastases in breast cancer patients. In total, 1937 patients from 16 studies were included in this meta-analysis. After pulmonary metastasectomy, the overall 5-year survival rate was 46% (95% CI 43%–49%). The disease-free interval (DFI) (3 years), the number of pulmonary metastases (>1), the incomplete resection of metastases (HR = 2.06, HR = 1.31, and HR = 2.30), and the hormone receptor status of the metastases (negative) were the poor prognostic factors. Using this information, the authors came to the conclusion that surgery, with a relatively high 5-year OS rate after pulmonary metastasectomy (46%), may be a promising treatment for pulmonary metastases in breast cancer patients who have a good performance status and limited disease. The primary indicators of poor prognosis were DFI (3 years), inadequate metastatic resection, the number of pulmonary metastases (>1), and the presence of hormone receptor–positive metastases (negative).

Meimarakis and colleagues looked into whether pulmonary metastasectomy lengthens OS in patients with initial breast cancer and what prognostic factors might help someone decide in favor of thoracic surgery. The study evaluated the median OS of 81 women who had pulmonary primary breast cancer metastases removed, while matched patients from the Munich Tumor Registry who had not undergone resection served as controls.

R0 resection was accomplished in 81.5% of the patients, and this was linked to significantly longer median OS than R1 or R2 resection (103.4 vs. 23.6 vs. 20.2 months, respectively; P = 0.001). As independent predictive variables for long-term survival, multivariate analysis identified R0 resection, number (n = 2), size (3 cm), and estrogen receptor and/or progesterone receptor positivity of metastases. Only in the univariate analysis did the presence of metastases in the mediastinal and hilar lymph nodes correspond with a lower survival rate. According to a matched pair study, pulmonary metastasectomy considerably increased survival. The researchers came to the conclusion that metastasectomy increases OS in individuals with isolated pulmonary primary breast cancer metastases. Patients who have metastases or many pulmonary lesions and have negative hormone receptor status are more likely to experience a disease relapse and should be constantly monitored. For this group, additive therapy specific to the biologic subtype identified by hormone receptor expression ought to be taken into account.

The significance of breast cancer metastasectomy is yet unknown, despite the fact that resection of pulmonary metastases is a standard treatment in other primary. Welter and colleagues looked into the various justifications for metastasectomy, as well as the clinical results of patients who had undergone surgery for pulmonary breast cancer metastases. A retrospective review of 47 patients who had pulmonary metastases from breast cancer that were histologically confirmed revealed that, in 26.7% of cases, the metastases were graded higher than the main tumor, and in 13.3% of cases they were graded lower. In 27, 6, and 14 cases, respectively, R0, R1, and R2 resections were completed. In 28.2% of the examined instances, the metastases’ estrogen receptor status was different from that of the main tumor. Four of the 16 patients who were evaluated had different HER2/neu receptor status. In at least one excision specimen, 53.2% of patients had a tumor disseminated surrounding the metastasis in lymphatic or blood arteries, according to the histologic studies. Major problems occurred at a rate of 5.8%. Thirty-two months passed after the first pulmonary metastasectomy, and 36% of patients survived for 5 years. The estrogen receptor status was the primary prognostic predictor, with a 5-year survival rate of 76% for patients who tested positive compared to 12.1% for patients who tested negative ( P = 0.002). For the status of the HER2/neu receptor, a similar survival difference was discovered ( P = 0.037). Age, the quantity of metastases, the initial tumor stage, complete versus incomplete resection, lymphatic spread, and lymph node or parietal pleural involvement were not shown to have any prognostic significance. According to Welter and colleagues, chemotherapy and antihormone therapy are to blame for the increase in life expectancy among breast cancer patients with pulmonary metastases. To adapt medical treatment to estrogen receptor and HER2/neu expression and to conclusively rule out primary lung cancer, tissue from the lung metastasis is required. Although there is no support for a curative strategy in cases of confirmed lung metastases, some individuals may gain from it. Friedel and colleagues evaluated the data from the International Registry of Lung Metastasis, including 467 patients who had lung metastases from breast cancer, with regard to long-term survival and prognostic factors. In 84%, a complete resection was possible, with 5-, 10-, and 15-year survival rates of 38%, 22%, and 20%, respectively. Positive prognostic factors were a DFI of longer than 36 months, with 5-, 10-, and 15-year survival rates of 45%, 26%, and 21%, respectively. Solitary lung metastasis was associated with a survival rate of 44% after 5 years and 23% after 10 and 15 years, but this was not statistically different from the outcome of patients undergoing resection of multiple metastases. In the Friedel study, there were no significant differences among the kinds of resection used (wedge or segmental resection, lobectomy, pneumonectomy) in completely resected patients.

Retrospective data for 33 individuals who received 43 curative resections of breast cancer pulmonary metastases were examined by Kycler and colleagues. The DFI, the quantity and distribution of lung metastases, the diameter (in millimeters) of the metastases, and the degree of pulmonary resection were all evaluated as potential prognostic markers that might affect survival, specifically survival after lung metastasectomy. Following metastasectomy, the median survival time for 33 patients with pulmonary breast cancer metastatic lesions was 73.2 months. A median 5-year survival rate was 54.5%. For patients with DFI more than 36 months ( P = 0.0007), complete metastasectomy ( P = 0.0153), unilateral pulmonary metastases ( P = 0.0267), and patients who underwent numerous procedures ( P = 0.0211), there was a statistically significant difference in survival time. Multivariate analysis revealed a significant relationship between the factors of complete metastasis resection ( P = 0.0275) and long-term prognosis for patients with DFI more than 36 months ( P = 0.0446). Analysis of the survival rates for individuals with single pulmonary metastasis, with various tumor sizes, and following various pulmonary resection techniques revealed no appreciable variations. It was determined that, for some patients, resecting lung metastases from breast cancer may significantly improve survival. DFI longer than 36 months and full resection of the metastases have been established as predictive factors for survival following metastasectomy. The outcomes also demonstrated the safety of lung metastasectomy using traditional surgery, as well as its low perioperative morbidity and mortality rates. Significant prognostic factors associated with survival include the number of metastases, DFI longer than 12 months, and complete resection. Yoshimoto and coworkers demonstrated that the surgical approach to lung metastases from breast cancer may prolong survival in certain subgroups of patients to a greater extent than with systemic therapy alone. In addition, survival times were significantly longer for patients who initially presented with clinical stage I at breast surgery than those with stage II to IV.

As part of the metastatic workup, it is important to obtain histologic diagnosis and differentiate between a metastatic lesion and a primary lung cancer. Early identification of the tumor is critical for appropriate treatment strategies. Proper aggressive evaluation can afford treatment of lung cancer and influence survival. Rena and colleagues studied the role of surgery in the diagnosis and treatment of a solitary pulmonary nodule (SPN) in patients who had received previous surgery for breast cancer. A total of 79 consecutive patients between 1990 and 2003 who had previously undergone curative resection for breast cancer and subsequently underwent surgery for an SPN were reviewed. Surgical diagnosis was obtained by open procedure before 1996 (37 cases), as well as by video-assisted thoracoscopic surgery (VATS) after 1996 (33 of 42 cases, nine open procedures) and intraoperative evaluation. Histology of SPN was primary lung cancer in 38 patients, pulmonary metastasis of breast cancer in 27, and benign condition in 14. The researchers concluded that VATS is a good procedure for diagnostic management and pathologic confirmation of peripheral SPN to determine appropriate surgical treatment.