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PO-33 - Heparin suppresses progression of small cell lung cancer (SCLC) in an orthotopic mouse model
S188
Abstracts / Thrombosis Research 140S1 (2016) S168–S200
PO-31 Circulating tumour cells and hypercoagulability: a lethal relationship in metastatic breast cancer C.C. Kirwan1,2, A.C. Clarke1, S.J. Howell1,3, J. Castle1 1 Institute of Cancer Sciences, University of Manchester, 2Department of Academic Surgery, University Hospital of South Manchester, 3Christie Hospital NHS Foundation Trust, Manchester, United Kingdom Introduction: Circulating tumour cells (CTCs) are a marker of poor prognosis and are associated with increased risk of venous thromboembolism in metastatic breast cancer. Aim: We aimed to correlate presence of CTCs and markers of hyper coagulability (D-dimer, fibrinogen and thrombin-antithrombin [TAT]) with survival in metastatic breast cancer. Materials and Methods: In a prospective study, enumeration of CTCs (CellSearch) and D-dimer, fibrinogen and TAT (ELISA) were measured at a single timepoint in 50 MBC (median age 59, range 36-82) patients undergoing active treatment. Survival data was determined at a median follow-up of 366 days (range 58-986). Results: To date, 25 patients have died (median survival 566 days, range 135-978). CTCs (>1/7.5ml) were identified in 13 patients (range 2-31) and were associated with increased markers of hypercoagulability [D-dimer: median 1814 (IQR 2700) vs 755 (IQR 735) ng/ml, p=0.004; fibrinogen: median 4.2 (IQR 1.9) vs 3.2 (1.3) g/l, p=0.05; TAT: median 6.2(IQR 6.3) vs 4.7 (5.2) ng/ml, p=0.1]. CTCs were associated with visceral compared to just bony metastases (p=0.03) and their presence was associated with a trend for reduced survival (295 days (CI: 0-652) vs 737 days (CI: 186-1288), p=0.1). There was no correlation between CTCs /markers of hypercoagulability and age, oestrogen receptor, progesterone receptor or Her2 status. D-dimer, fibrinogen and TAT all inversely correlated with survival and were all significantly higher in patients dying within 1 year (D-dimer: 1098 (IQR 1122) vs 723 (IQR 735) ng/ml, p=0.03; fibrinogen: 4.4 (1.1) vs 3.2 (0.8) g/l, p=0.004; TAT: 8.1 (6.3) vs 4.7(3.1) ng/ml, p=0.03 [analysis excludes patients with <1 year follow-up, n=13]). D-dimer >1,500 ng/ml was associated with significantly reduced survival (295 days [CI: 0-615] vs 836 days [4041267], p=0.05). On Cox regression, D-dimer, but not fibrinogen or TAT was associated with an increased risk of death (HR 1.3 per 1,000 ng/ml D-dimer, p=0.07). Conclusions: The correlation between CTCs, hypercoagulability and reduced survival in metastatic breast cancer suggests a possible role for the coagulation system in supporting tumour cell metastasis and is therefore a potential therapeutic target.
PO-32 Patient, tumour and operative factors influencing perioperative hypercoagulability in colorectal cancer H.W. Clouston1,2, P.A. Rees1,2, H. Shaker1,2, S. Duff 2, C.C. Kirwan1,2 1 Institute of Cancer Sciences, University of Manchester, 2Department of Academic Surgery, University Hospital of South Manchester, United Kingdom Introduction: Up to 6% of patients develop venous thromboembolism (VTE) following elective colorectal cancer surgery despite thromboprophylaxis. Clinical practices for perioperative thromboprophylaxis remains variable, particularly the use and duration of extended thromboprophylaxis. Identification of factors associated with a prolonged postoperative hypercoagulable state may allow the development of algorithms that allow more targeted thromboprophylaxis. Aim: To identify patient, tumour and surgical risk factors for prolonged (two and six weeks) hypercoagulability in colorectal cancer patients undergoing surgical resection. Materials and Methods: In a prospective cohort study (Cancer-induced Hypercoagulability As a Marker of Prognosis [CHAMPion]), plasma d-dimer was measured at 2 and 6 weeks post-operatively in patients undergoing elective, curative resection for colorectal cancer. Hypercoagulability (raised D-dimer) at 2 and 6 weeks was correlated with patient, tumour and operative factors.
Results: Of the 62 patients recruited (median age 69 years [range 39-90]), 37 were male. D-dimer was increased in females compared to males at six weeks (geometric mean (GM) 1,287 ng/ml [95% CI 944 – 1,755 vs. 821ng/ml (95% CI 633 – 1064) p=0.03]. Age, smoking, hypertension, use of antiplatelet medication, BMI and WHO performance status were not associated with a prolonged hypercoagulable state. There were no tumour factors (including size/T stage/lymph node involvement/differentiation) associated with a prolonged hypercoagulable state. D-dimer was increased in patients undergoing open surgery (n=39) compared to laparoscopic surgery (n=23) at 2 weeks (GM 2,337ng/ml [95% CI 1,806-3,023] vs. 1,212ng/ml [95% CI 898-1,629], p=0.001) and 6 weeks (GM 1,162ng/ml [95% CI 818-1647] vs. 723 ng/ml [95% CI 533-982]p=0.04). Operative time was not associated with prolonged hypercoagulability. D-dimer had a trend to be increased at 2 weeks in patients receiving perioperative blood transfusions (n=8) compared to those that did not (n=54) (GM 2,618 ng/ml [95% CI 1,525-4,536] vs. 1613 ng/ml [95% CI 1,236 – 2,100] p=0.08). Conclusions: Even in this relatively small cohort of patients female gender, open surgery and receiving a blood transfusion are associated with ongoing hypercoagulability up to six weeks post operation. This may represent a group where thromboprophylaxis should be targeted.
Poster Session 4: Anticoagulants and cancer
PO-33 Heparin suppresses progression of small cell lung cancer (SCLC) in an orthotopic mouse model S. Taromi1, J. Catusse1, D.v. Elverfeldt2, W. Reichardt2, B. Ledig3, R. Zeiser1, M. Burger1 1 Department of Hematology/Oncology, University Medical Center, 2Department of Radiology, Medical Physics, University Medical Center; Freiburg, Germany; 3 LEO Pharma GmbH, Neu-Isenburg, Germany Introduction: Lung cancer is the leading cause of cancer-related death worldwide. Small cell lung cancer (SCLC) is thereby a highly aggressive neuroendocrine carcinoma representing about 15% of all lung cancer cases. Due to the highly metastatic behavior and multidrug resistance, the longterm survival of patients is very low. Aim: Current clinical studies revealed an increased survival of SCLC patients treated with heparin. Thus, the role of heparin in SCLC progression was analyzed with the focus on cell adhesion, cell survival and metastasis formation. Materials and Methods: Heparins were tested for their capacities to alter migration, adhesion and viability of SCLC cells in vitro as well as tumor growth and metastasis formation in vivo. Results: Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) both strongly inhibited migration as well as adhesion of SCLC cells to fibronectin and stromal cells. In addition, Heparin induced cellular apoptosis and also increased apoptotic effects of conventional chemotherapeutics in vitro. To investigate the role of LMWH on metastasis formation in vivo, an orthotopic xenograft mouse model with spontaneous metastasis formation has been established. The primary tumors in this mouse model show a marked capacity to metastasize to characteristic distant organs, reflecting advanced steps of malignant progression. Treatment of tumor-bearing mice with LMWH suppressed progression of SCLC. Conclusions: Administration of LMWH in addition to the conventional treatment might reduce metastasis formation and development of chemoresistance, leading to an improved survival rate of patients suffering from SCLC.
Abstracts / Thrombosis Research 140S1 (2016) S168–S200
PO-31 Circulating tumour cells and hypercoagulability: a lethal relationship in metastatic breast cancer C.C. Kirwan1,2, A.C. Clarke1, S.J. Howell1,3, J. Castle1 1 Institute of Cancer Sciences, University of Manchester, 2Department of Academic Surgery, University Hospital of South Manchester, 3Christie Hospital NHS Foundation Trust, Manchester, United Kingdom Introduction: Circulating tumour cells (CTCs) are a marker of poor prognosis and are associated with increased risk of venous thromboembolism in metastatic breast cancer. Aim: We aimed to correlate presence of CTCs and markers of hyper coagulability (D-dimer, fibrinogen and thrombin-antithrombin [TAT]) with survival in metastatic breast cancer. Materials and Methods: In a prospective study, enumeration of CTCs (CellSearch) and D-dimer, fibrinogen and TAT (ELISA) were measured at a single timepoint in 50 MBC (median age 59, range 36-82) patients undergoing active treatment. Survival data was determined at a median follow-up of 366 days (range 58-986). Results: To date, 25 patients have died (median survival 566 days, range 135-978). CTCs (>1/7.5ml) were identified in 13 patients (range 2-31) and were associated with increased markers of hypercoagulability [D-dimer: median 1814 (IQR 2700) vs 755 (IQR 735) ng/ml, p=0.004; fibrinogen: median 4.2 (IQR 1.9) vs 3.2 (1.3) g/l, p=0.05; TAT: median 6.2(IQR 6.3) vs 4.7 (5.2) ng/ml, p=0.1]. CTCs were associated with visceral compared to just bony metastases (p=0.03) and their presence was associated with a trend for reduced survival (295 days (CI: 0-652) vs 737 days (CI: 186-1288), p=0.1). There was no correlation between CTCs /markers of hypercoagulability and age, oestrogen receptor, progesterone receptor or Her2 status. D-dimer, fibrinogen and TAT all inversely correlated with survival and were all significantly higher in patients dying within 1 year (D-dimer: 1098 (IQR 1122) vs 723 (IQR 735) ng/ml, p=0.03; fibrinogen: 4.4 (1.1) vs 3.2 (0.8) g/l, p=0.004; TAT: 8.1 (6.3) vs 4.7(3.1) ng/ml, p=0.03 [analysis excludes patients with <1 year follow-up, n=13]). D-dimer >1,500 ng/ml was associated with significantly reduced survival (295 days [CI: 0-615] vs 836 days [4041267], p=0.05). On Cox regression, D-dimer, but not fibrinogen or TAT was associated with an increased risk of death (HR 1.3 per 1,000 ng/ml D-dimer, p=0.07). Conclusions: The correlation between CTCs, hypercoagulability and reduced survival in metastatic breast cancer suggests a possible role for the coagulation system in supporting tumour cell metastasis and is therefore a potential therapeutic target.
PO-32 Patient, tumour and operative factors influencing perioperative hypercoagulability in colorectal cancer H.W. Clouston1,2, P.A. Rees1,2, H. Shaker1,2, S. Duff 2, C.C. Kirwan1,2 1 Institute of Cancer Sciences, University of Manchester, 2Department of Academic Surgery, University Hospital of South Manchester, United Kingdom Introduction: Up to 6% of patients develop venous thromboembolism (VTE) following elective colorectal cancer surgery despite thromboprophylaxis. Clinical practices for perioperative thromboprophylaxis remains variable, particularly the use and duration of extended thromboprophylaxis. Identification of factors associated with a prolonged postoperative hypercoagulable state may allow the development of algorithms that allow more targeted thromboprophylaxis. Aim: To identify patient, tumour and surgical risk factors for prolonged (two and six weeks) hypercoagulability in colorectal cancer patients undergoing surgical resection. Materials and Methods: In a prospective cohort study (Cancer-induced Hypercoagulability As a Marker of Prognosis [CHAMPion]), plasma d-dimer was measured at 2 and 6 weeks post-operatively in patients undergoing elective, curative resection for colorectal cancer. Hypercoagulability (raised D-dimer) at 2 and 6 weeks was correlated with patient, tumour and operative factors.
Results: Of the 62 patients recruited (median age 69 years [range 39-90]), 37 were male. D-dimer was increased in females compared to males at six weeks (geometric mean (GM) 1,287 ng/ml [95% CI 944 – 1,755 vs. 821ng/ml (95% CI 633 – 1064) p=0.03]. Age, smoking, hypertension, use of antiplatelet medication, BMI and WHO performance status were not associated with a prolonged hypercoagulable state. There were no tumour factors (including size/T stage/lymph node involvement/differentiation) associated with a prolonged hypercoagulable state. D-dimer was increased in patients undergoing open surgery (n=39) compared to laparoscopic surgery (n=23) at 2 weeks (GM 2,337ng/ml [95% CI 1,806-3,023] vs. 1,212ng/ml [95% CI 898-1,629], p=0.001) and 6 weeks (GM 1,162ng/ml [95% CI 818-1647] vs. 723 ng/ml [95% CI 533-982]p=0.04). Operative time was not associated with prolonged hypercoagulability. D-dimer had a trend to be increased at 2 weeks in patients receiving perioperative blood transfusions (n=8) compared to those that did not (n=54) (GM 2,618 ng/ml [95% CI 1,525-4,536] vs. 1613 ng/ml [95% CI 1,236 – 2,100] p=0.08). Conclusions: Even in this relatively small cohort of patients female gender, open surgery and receiving a blood transfusion are associated with ongoing hypercoagulability up to six weeks post operation. This may represent a group where thromboprophylaxis should be targeted.
Poster Session 4: Anticoagulants and cancer
PO-33 Heparin suppresses progression of small cell lung cancer (SCLC) in an orthotopic mouse model S. Taromi1, J. Catusse1, D.v. Elverfeldt2, W. Reichardt2, B. Ledig3, R. Zeiser1, M. Burger1 1 Department of Hematology/Oncology, University Medical Center, 2Department of Radiology, Medical Physics, University Medical Center; Freiburg, Germany; 3 LEO Pharma GmbH, Neu-Isenburg, Germany Introduction: Lung cancer is the leading cause of cancer-related death worldwide. Small cell lung cancer (SCLC) is thereby a highly aggressive neuroendocrine carcinoma representing about 15% of all lung cancer cases. Due to the highly metastatic behavior and multidrug resistance, the longterm survival of patients is very low. Aim: Current clinical studies revealed an increased survival of SCLC patients treated with heparin. Thus, the role of heparin in SCLC progression was analyzed with the focus on cell adhesion, cell survival and metastasis formation. Materials and Methods: Heparins were tested for their capacities to alter migration, adhesion and viability of SCLC cells in vitro as well as tumor growth and metastasis formation in vivo. Results: Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) both strongly inhibited migration as well as adhesion of SCLC cells to fibronectin and stromal cells. In addition, Heparin induced cellular apoptosis and also increased apoptotic effects of conventional chemotherapeutics in vitro. To investigate the role of LMWH on metastasis formation in vivo, an orthotopic xenograft mouse model with spontaneous metastasis formation has been established. The primary tumors in this mouse model show a marked capacity to metastasize to characteristic distant organs, reflecting advanced steps of malignant progression. Treatment of tumor-bearing mice with LMWH suppressed progression of SCLC. Conclusions: Administration of LMWH in addition to the conventional treatment might reduce metastasis formation and development of chemoresistance, leading to an improved survival rate of patients suffering from SCLC.