The progression of breast cancer from early-stage to metastatic disease results from a series of events during which malignant cells invade and travel within the bloodstream to distant sites, leading to a clonogenic accumulation of tumor cells in non-breast tissue. While mechanistically complex, an emerging literature supports hemostatic elements as an important patient factor that facilitates the metastatic potential of breast cancer. Hemostatic elements involved include platelets, coagulation, and fibrinolysis. Key steps in breast tumor progression, including cellular transformation, proliferation, tumor cell survival, and angiogenesis, can be mediated by components of the hemostatic system. Thus, the hemostatic system provides potential targets for novel therapeutic approaches to breast cancer therapy with drugs in current use and in development. The present article provides a comprehensive overview of the evidence and mechanisms supporting the roles played by platelets, coagulation activation, and the fibrinolytic system in breast cancer progression.

Platelets and their granular contents influence both angiogenesis and breast cancer progression. This study was performed to assess the effect of breast cancer and its treatment on platelet biology and the response to inhibition of the platelet P2Y12 receptor. Receptor-specific platelet activation and inhibition was studied for three platelet-associated proteins important in cancer angiogenesis and progression, vascular endothelial growth factor (VEGF), thrombospondin1 (TSP1), and transforming growth factor beta 1 (TGF-β1). Twenty-four women with active breast cancer and 10 healthy controls not receiving antiplatelet therapy participated in the study. Ex vivo activation of platelets in whole blood was accomplished using PAR1AP, PAR4AP, convulxin, and ADP. Platelet inhibition was accomplished using the P2Y12 receptor antagonist cangrelor (the in vitro equivalent of clopidogrel). VEGF, TSP1, and TGF-β1 were measured using standard ELISA. Platelet activation by ADP, PAR1, PAR4, and collagen receptors increased VEGF, TSP1, and TGF-β1 secretion in patients with breast cancer. Agonist-induced release of VEGF was greater in cancer patients as compared to healthy controls (p = 0.02 for ADP, p < 0.001 for PAR1AP, PAR4AP, and convulxin) despite a decrease in the efficiency of VEGF secretion in patients with breast cancer. These differences were not observed for TSP1 and TGF-β1 secretion. P2Y12 receptor inhibition decreased VEGF, TSP1, and TGF-β1 secretion. In patients with cancer, cangrelor inhibited TSP1 release to a greater extent than VEGF and TGF-β1 release. In patients with breast cancer, the magnitude of platelet inhibition achieved by cangrelor was greater than that achieved with healthy controls for all agonists and platelet proteins studied. While platelets are known to influence progression of breast cancer, our results show that breast cancer and its treatment influence the platelet phenotype by increasing the secretion of pro-angiogenic proteins following platelet activation, modulating the efficiency of platelet protein release as well as increasing the response to antiplatelet therapy.

Background The relationship between metastatic colorectal cancer (mCRC) and venous thromboembolism (VTE) is poorly defined in the modern era. Our objective was to examine impact of putative risk factors including newer treatments and anti‐angiogenic therapy on VTE incidence and survival in a modern older mCRC cohort. Methods This is a SEER‐Medicare cohort analysis of mCRC patients diagnosed in 2004–2009. Risk factor analysis was conducted using Cox models adjusted for sex, diagnosis age, race, primary tumor location, comorbidity, and prior VTE history, with cancer treatments as time‐varying covariates. Main outcomes were VTE incidence and overall survival. Results Ten thousand nine hundred and seventy six mCRC cases with mean age 77.9 years (range 65–107), 49.7% women, 83.5% white. There were 1306 VTE cases corresponding to 13.7% incidence at 1 year and 20.3% at 3 years. Independent VTE predictors included female sex (HR 1.27; 95% CI 1.14–1.42), African American race (HR 1.49; 1.27–1.73), prior VTE history (HR 16.3; 12.1–22.1), and right sided cancers (HR 1.16; 1.04–1.29). After adjustment, any therapy and bevacizumab (HR 0.68, 0.58–0.78) in particular were protective. Overall survival was 40.1% (39.4–41.3) at 1 year but improved significantly with any treatment. VTE following diagnosis of mCRC was associated with inferior OS (HR 1.09; 1.02–1.15). Conclusions In this large contemporary mCRC cohort, effective systemic therapy including anti‐angiogenic treatment was associated with lower VTE risk. Overall survival was poor, and modestly worse if a patient had a VTE at any time during treatment.

Background:The relationship between metastatic colorectal cancer (CRC) and venous thromboembolism (VTE) is not well defined in the modern treatment era. Previous population-based studies date back to a period marked by inpatient intravenous heparin therapy and inferior survival due to paucity of therapeutic anti-cancer options, and before the advent of newer therapies including oxaliplatin, irinotecan, and anti-angiogenic treatment with bevacizumab. The objectives of this retrospective study were to examine the impact of multiple putative risk factors on VTE incidence in a large representative modern cohort of older patients with metastatic CRC. Methods:We performed a retrospective analysis of SEER-Medicare data on elderly patients with metastatic CRC diagnosed in 2004-2011. VTE and associated risk factors were analyzed using multivariate Cox proportional hazards models adjusted for sex, age at diagnosis, race, ethnicity, tumor anatomy (left/right/unknown), calendar year of diagnosis, Charlson comorbidity score, location of SEER registry and urban residence, with time-varying covariates for use of cancer therapies. Results:Of 339,778 records, 11,086 metastatic colon cancer cases were identified. 1,338 cases had VTE with a cumulative incidence of 13% at 1 year and 19% at 3 years. The mean age was 77.9 years (range 65-106). 49.7% were women and 83.5% white. 60.5% had a Charlson comorbidity score of zero at diagnosis; 6% had scores of 6-18. Significant predictors of VTE included female sex (Hazard Ratio (HR) 1.22; 95% Confidence Interval (CI) 1.10, 1.36; P<0.001), younger age at diagnosis (HR 1.25 per decade of age; CI 1.15, 1.37; P<0.001), urban residence (HR 1.20; CI 1.03, 1.40; P=0.02), right sided colon cancers (HR 1.19; CI, 1.06, 1.33 P=0.003), and current use of 5-fluorouracil (HR 1.33; CI 1.04, 1.70; P=0.02). The risk of VTE was significantly reduced when on bevacizumab (HR 0.77; CI 0.63, 0.93; P=.006), or irinotecan therapy (HR 0.59; CI 0.47, 0.75; P<0.001) and in those with more comorbid conditions (HR 0.97 per point of Charlson score; CI 0.935, 0.998; P=0.04). Conclusion: The higher incidence of VTE seen in right sided colon cancers may be related to biologically aggressive tumors associated with poor survival as reported in recent studies. The lower risk of VTE in older, sicker patients was unexpected and may reflect the effect of competing mortality. In this large contemporary cohort, anti-angiogenic therapy was not associated with a higher risk of VTE; the apparent protective effects of bevacizumab and irinotecan may represent treatment assignment bias. Disclosures No relevant conflicts of interest to declare.

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