Long-term survival and cure model following liver resection for breast cancer metastases.
ABSTRACT: Long-term survival is still rarely achieved with current systemic treatment in patients with breast cancer liver metastases (BCLM). Extended survival after hepatectomy was examined in a select group of BCLM patients.Hepatectomy for BCLM was performed in 139 consecutive patients between 1985 and 2012. Patients who survived < 5 years were compared to those who survived ? 5 years from first diagnosis of hepatic metastases. Predictive factors for survival were analyzed. Statistically cured, defined as those patients who their hazard rate returned to that of the general population, was analyzed.Of the 139, 43 patients survived ? 5 years. Significant differences between patient groups (< 5 vs. ? 5 years) were mean time interval between primary tumor and hepatic metastases diagnosis (50 vs. 43 months), mean number of resected tumors (3 vs. 2), positive estrogen receptors (54% vs. 79%), microscopic lymphatic invasion (65% vs. 34%), vascular invasion (63% vs. 37%), hormonal therapy after resection (34% vs. 74%), number of recurrence (40% vs. 65%) and repeat hepatectomy (1% vs. 42%), respectively. The probability of statistical cure was 14% (95% CI 1.4-26.7%) in these patients.Hepatectomy combined with systemic treatment can provide a chance of long-term survival and even cure in selected patients with BCLM. Microscopic vascular/lymphatic invasion appears to be a novel predictor for long-term survival after hepatectomy for BCLM and should be part of the review when discussing multidisciplinary treatment strategies.
Project description:BACKGROUND:Combined with systemic therapy, the surgical intervention for breast cancer liver metastases (BCLM) is increasingly accepted but lacks convincing evidence. The aim of this study was to evaluate the disease control efficacy of hepatic surgery in isolated BCLM patients. METHODS:Between 2012 and 2017, metastatic breast cancer patients with isolated liver metastasis and regular follow-up were identified. Cohort design was conducted to compare the progression-free survival (PFS) between the surgical and nonsurgical BCLM patients. Univariate analysis and multivariate Cox regression survival analyses were performed to identify significant prognostic factors. RESULT:In all, 148 isolated BCLM patients were enrolled and 95 participants received hepatic surgery for metastatic lesions. With median follow-up of 36.47 months, there was no significant difference between hepatic surgical group and nonsurgical group for PFS (median PFS: 11.17 months vs 10.10 m, P = .092). Based on the multivariate analysis, the disease-free interval (DFI) was an independent prognostic factor for isolated BCLM patients. Among the surgical group, BCLM patients who had ideal response after first salvage systemic treatment experienced the best long-term survival (median PFS: 14.20 months). CONCLUSION:For isolated BCLM patients with ideal response in first-line medical treatment, surgical intervention (hepatectomy, radiofrequency ablation) combining with systemic treatment could bring improved progression-free survival compared to sole systemic treatment, indicating that hepatic surgery may be considered as a therapeutic choice for selected isolated BCLM patients in clinical practice.
Project description:To evaluate the efficacy of surgical treatment for patients with isolated breast cancer liver metastases (BCLM).Single-arm retrospective studies have shown promising results associated with surgery for isolated BCLM; however, this treatment remains controversial and its role is not well-defined.A review of 2150 patients with BCLM who underwent treatment in a single institution was conducted, and 167 (8%) patients with isolated BCLM were identified. A case-control study was conducted to compare outcomes in patients with isolated BCLM who underwent surgery and/or ablation to patients who underwent conventional medical therapy.A total of 167 patients were included (surgery/ablation: 69; medical: 98), with a median follow-up for survivors of 73 months. Patients in the surgical cohort more frequently had estrogen receptor-positive tumors and received adjuvant chemotherapy and radiotherapy for their primary breast tumor. The hepatic tumor burden was less and the interval from breast cancer diagnosis to BCLM was significantly longer (53 vs 30 months) in the surgical cohort. Patients undergoing surgical treatment had a median recurrence-free interval of 28.5 months (95% confidence interval (CI): 19-38) with 10 patients (15%) recurrence free after 5 years. There was no significant difference in overall survival (OS) between the surgical and medical cohorts (median OS: 50 vs 45 months; 5-year OS: 38% vs 39%).Hepatic resection and/or ablation was not associated with a survival advantage. However, significant recurrence-free intervals can be accomplished with surgical treatment. Surgical intervention might be considered in highly selected patients with the goal of providing time off of systemic chemotherapy.
Project description:The genome?wide copy number analysis of circulating tumor cells (CTCs) provides a promising prognostic biomarker for survival in breast cancer liver metastasis (BCLM) patients. The present study aimed to confirm the prognostic value of the presence of CTCs in BCLM patients. We previously developed an assay for the genome?wide pattern differences in copy number variations (CNVs) as an adjunct test for the routine imaging and histopathologic diagnosis methods to distinguish newly diagnosed liver metastases and recurrent liver metastases. Forty?three breast cancer patients were selected for this study in which 23 newly diagnosed and 20 recurrent liver metastases were diagnosed by histopathology and 18F?FDG PET/CT imaging. CTCs were counted from all patients using the CellSearch system and were confirmed by cytomorphology and three?color immunocytochemistry. Genomic DNA of single CTCs was amplified using multiple annealing and looping based amplification cycles (MALBAC). Then, we compared the CTC numbers of newly diagnosed and recurrent BCLM patients using Illumina platforms. A high CTC frequency (>15 CTCs/7.5 ml blood) was found to be correlated with disease severity and metastatic progression, which suggests the value for CTCs in the diagnosis of BCLM in comparison with pathohistology and PET/CT imaging (P>0.05). Moreover, CTCs isolated from BCLM patients remained an independent prognostic detection factor associated with overall survival (P=0.0041). Comparison between newly diagnosed and recurrent liver metastases revealed different frequencies of CNVs (P>0.05). Notably, the CNV pattern of isolated CTCs of recurrent BCLM patients was similar to recurrent liver metastases (nearly 82% of the gain/loss regions). Functional enrichment analysis identified 25 genes as a CNV signature of BCLM. Among them, were defensin and ??defensin genes, which are significantly associated with anti?angiogenesis and immunomodulation signaling pathways. High CTC frequencies are effective in the evaluation and differentiation between newly diagnosed liver metastases from recurrent liver metastases. Future clinical studies will be necessary to fully determine the prognostic potential of CTC cluster signatures in patients with BCLM.
Project description:For a selection of patients with colorectal liver metastases (CRLM), liver resection is a curative option. In order to predict long-term survival, clinicopathologic risk scores have been developed, but little is known about histologic factors and their prognostic value for disease-free and overall survival. The objective of the present study was to assess possible prognostic histologic factors in patients with solitary CRLM treated with liver resection who did not receive neoadjuvant treatment.Patients with solitary CRLM who underwent liver resection between 1992 and 2011 were evaluated for clinical prognostic factors. Histologic analyses on tumor thickness at the tumor-normal interface, presence of a fibrotic capsule, intrahepatic vascular invasion, lymphatic invasion, or bile duct invasion and perineural growth were performed, using immunohistochemistry.A total of 124 patients were analyzed with a median follow-up of 41 months (range 1-232 months). There was no association between histologic factors and disease-free survival in multivariate analysis. In multivariate analysis, intrahepatic lymphatic invasion was associated with a decreased overall survival (41.9 vs. 61.0 months; p = 0.041), especially in combination with vascular invasion (n = 15) (28.1 vs. 62.2 months; p < 0.0001). In addition, size over 50 mm (29.2 vs. 65.9 months; p = 0.004) and interval less than 12 months between resection of the primary tumor and diagnosis of liver metastasis (49.0 vs. 91.5 months: p = 0.019) were also independent adverse prognostic factors.Intrahepatic lymphatic invasion, especially in combination with vascular invasion, is an important adverse prognostic factor for overall survival in patients with solitary CRLM after liver resection.
Project description:Data on surgical management of breast liver metastasis are limited. We sought to determine the safety and long-term outcome of patients undergoing hepatic resection of breast cancer liver metastases (BCLM).Using a multi-institutional, international database, 131 patients who underwent surgery for BCLM between 1980 and 2014 were identified. Clinicopathologic and outcome data were collected and analyzed.Median tumor size of the primary breast cancer was 2.5 cm (IQR: 2.0-3.2); 58 (59.8%) patients had primary tumor nodal metastasis. The median time from diagnosis of breast cancer to metastasectomy was 34 months (IQR: 16.8-61.3). The mean size of the largest liver lesion was 3.0 cm (2.0-5.0); half of patients (52.0%) had a solitary metastasis. An R0 resection was achieved in most cases (90.8%). Postoperative morbidity and mortality were 22.8% and 0%, respectively. Median and 3-year overall-survival was 53.4 months and 75.2%, respectively. On multivariable analysis, positive surgical margin (HR 3.57, 95% CI 1.40-9.16; p = 0.008) and diameter of the BCLM (HR 1.03, 95% CI 1.01-1.06; p = 0.002) remained associated with worse OS.In selected patients, resection of breast cancer liver metastases can be done safely and a subset of patients may derive a relatively long survival, especially from a margin negative resection.
Project description:Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for anti-metastatic treatment. In our study, high-throughput sequencing-based high-throughput screening (HTS2) and a breast cancer lung metastasis (BCLM)-associated gene signature were combined to discover anti-metastatic drugs. After screening of thousands of compounds, we identified Ponatinib as a BCLM inhibitor. Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models. Mechanistically, Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein. Notably, JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients. Collectively, we established a novel approach for the discovery of anti-metastatic drugs, identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM. Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.
Project description:Background:Although hepatectomy is the standard and only curative treatment for colorectal liver metastases, recurrence occurs in various organs, including the remnant liver, lung, peritoneum, and others. The outcomes and predictive factors of repeat metastasectomy for recurrence after initial hepatectomy remains controversial. Methods:We retrospectively assessed a consecutive series of 132 patients who underwent hepatectomy for colorectal liver metastases in a single institute. Results:There were 99 recurrence cases after initial hepatectomy, and 42 patients underwent metastasectomy (first repeat metastasectomy) to achieve R0 (17 liver cases, 16 lung cases, and 9 multiple or other cases), while 19 patients underwent subsequent second repeat metastasectomy (4 liver cases, 7 lung cases, and 8 multiple or other cases). Among the 99 recurrent cases after initial hepatectomy, the 5-year overall survival rate of the patients who underwent first repeat metastasectomy was significantly higher than that of chemotherapy/BSC (best supportive care) patients (60% vs. 14%, P < 0.0001). Furthermore, among the 26 recurrent cases after first repeat metastasectomy, the 5-year overall survival rate of the patients who underwent second repeat metastasectomy was significantly higher than that of chemotherapy/BSC patients (P = 0.024). A multivariate analysis revealed that lack of adjuvant chemotherapy, a short (<12 months) disease-free interval, and right-side colon primary were the independent poor prognostic factors for the overall survival after first repeat metastasectomy. Conclusion:The current study indicated that repeat metastasectomy for recurrence after initial hepatectomy for colorectal liver metastases could achieve a longer survival time, especially for patients with favorable predictive factors.
Project description:Partial hepatectomy is a potentially curative therapy for intrahepatic cholangiocarcinoma (ICC). Unfortunately, the overall surgical prognosis remains dismal and the actual 10-year survival has not been reported. This study aimed to document 10-year actual survival rates, identify the prognostic factors associated with 10-year survival rate, and analyze the characteristics of patients who survived ? 10 years. Among 251 patients who underwent curative liver resection for ICC between 2003 and 2006 at the Eastern Hepatobiliary Surgery Hospital, 21 patients (8.4%) survived ? 10 years. The 5-, 7-, and 10-year overall survival rates were 32.3%, 22.3% and 8.4%, respectively. The 10-year cumulative incidence of ICC-related death and recurrence were 80.9% and 85.7%, respectively. Multivariate analysis based on competing risk survival analysis identified that tumor > 5 cm was independently associated with ICC-related death and recurrence (hazard ratios: 1.369 and 1.445, respectively), in addition to carcinoembryonic antigen (CEA) >10 U/mL, carbohydrate antigen 19-9 (CA19-9) >39 U/mL, multiple nodules, vascular invasion, nodal metastasis and local extrahepatic invasion. Patients who survived ? 10 years had a longer time to first recurrence, lower levels of CEA, CA19-9 and alkaline phosphatase, less perioperative blood loss, solitary tumor, smaller tumor size, and absence of nodal metastasis or local extrahepatic invasion. In conclusion, a 10-year survival after liver resection for ICC is possible and can be expected in approximately 8.4% of patients.
Project description:Tumor lymphangiogenesis is accompanied by a higher incidence of sentinel lymph node metastasis and shorter overall survival in several types of cancer. We asked whether tumor lymphangiogenesis might also occur in distant organs with established metastases and whether it might promote further metastatic spread of those metastases to other organs. Using mouse metastasis models, we found that lymphangiogenesis occurred in distant lung metastases and that some metastatic tumor cells were located in lymphatic vessels and draining lymph nodes. In metastasis-bearing lungs of melanoma patients, a higher lymphatic density within and around metastases and lymphatic invasion correlated with poor outcome. Using a transgenic mouse model with inducible expression of vascular endothelial growth factor C (VEGF-C) in the lung, we found greater growth of lung metastases, with more abundant dissemination to other organs. Our findings reveal unexpected contributions of lymphatics in distant organs to the promotion of growth of metastases and their further spread to other organs, with potential clinical implications for adjuvant therapies in patients with metastatic cancer.
Project description:Pancreatic cancer is a disease with a poor prognosis. Most patients are diagnosed at an advanced and unresectable stage. Even if the primary cancer is radically removed, postoperative recurrence frequently occurs. Generally, metastatic liver tumors from pancreatic cancer are not indicated for surgical treatment. Here we evaluate the results of performing hepatectomy for liver metastases of pancreatic cancer. In our institute, six patients with liver metastases from pancreatic cancer were treated by partial hepatectomy. Overall 1-, 3- and 5-year survival rates of six patients after hepatectomy were 66.7%, 33.3% and 16.7%, respectively, and one patient was alive for 65.4 months. Performing a hepatectomy for liver metastases of pancreatic cancer, when combined with a pancreas resection, was recently considered to be a safe operation, and one that might offer prolonged survival for highly selected patients with curative resection of liver metastases. In the future, it will be necessary to develop new multi-modality therapies to improve the prognosis of pancreatic cancer.