Background The measurement of thrombin generation (TG) potential by the calibrated automated thrombogram (CAT) assay provides a strong contribution in identifying patients at high risk of early disease recurrence (E-DR). However, CAT assay still needs standardization and clinical validation. Objective In this study, we aimed to validate the role of TG for E-DR prediction by means of the fully automated ST Genesia system. Methods A prospective cohort of 522 patients from the HYPERCAN study with newly diagnosed resected high-risk breast cancer was included. Fifty-two healthy women acted as controls. Plasma samples were tested for protein C, free-protein S, and TG by ST Genesia by using the STG-ThromboScreen reagent with and without thrombomodulin (TM). Results In the absence of TM, patients showed significantly higher peak and ETP compared with controls. In the presence of TM, significantly lower inhibition of ETP and Peak were observed in patients compared with controls. E-DR occurred in 28 patients; these patients had significantly higher peak and endogenous thrombin potential (ETP) in the absence of TM compared with disease-free patients. Multivariable analysis identified mastectomy, luminal B HER2-neg, triple negative subtypes, and ETP as independent risk factors for E-DR. These variables were combined to generate a risk assessment score, able to stratify patients in three-risk categories. The E-DR rates were 0, 4.7, and 13.5% in the low-, intermediate-, and high-risk categories (hazard ratio = 8.7; p < 0.05, low vs. high risk). Conclusion Our data validate the ETP parameter with a fully automated standardized system and confirm its significant contribution in identifying high-risk early breast cancer at risk for E-DR during chemotherapy.
Background: Abnormalities of laboratory coagulation tests are common in cancer patients, underlying a subclinical hypercoagulable state. Due to the reciprocal interaction between coagulation and cancer, the biomarkers of hemostatic system activation are under evaluation as a tool for predicting cancer outcomes, disease progression, and mortality. Aim: In this analysis of a prospective cohort of patients with newly diagnosed metastatic gastro-intestinal (GI) cancer, we wanted to evaluate whether the pre-chemotherapy abnormalities of hemostatic biomarkers may predict for early-disease progression (E-DP), i.e. within 6 months from cancer diagnosis, and for 1-year overall survival (1-year OS). Methods: The study cohort included 304 newly diagnosed metastatic GI cancer patients, candidate to chemotherapy associated or not with immunotherapy, enrolled from March 2012 to March 2019 in the HYPERCAN study (ClinicalTrials.gov, ID# NCT02622815), an ongoing Italian prospective, multicenter, observational study; 191 healthy subjects acted as a control group. At diagnosis, before starting any curative chemotherapy, plasma samples were collected and tested for the following hypercoagulation biomarkers: D-dimer and fibrinogen by an automated coagulometer analyzer (ACL TOP500, Werfen Group), and prothrombin fragment 1+2 (F1+2) by ELISA (Siemens). In addition, thrombin generation (TG) potential was evaluated by Calibrated Automated Thrombogram (CAT) assay at 5 pM tissue factor and endogenous thrombin potential (TG ETP) and TG peak were analyzed. Clinical data [i.e. age, sex, BMI, ECOG Performance Status (ECOG-PS), relevant comorbidies] and the hemochromocytometric parameters were recorded at enrollment, whereas E-DP was clinically monitored every 3 chemotherapy cycles and during follow-up. Results: A cohort of 304 (205M/99F) metastatic GI cancer patients (206 colorectal and 98 gastric cancers) with a median age of 66 years (min-max: 29-85) was available for analysis. At enrollment, patients presented with a hypercoagulable state, as shown by significantly higher (p<0.001) plasma levels of D-dimer, fibrinogen and F1+2, and significantly higher (p<0.01) TG peak and TG ETP values than controls. After 6 months from the start of chemotherapy, E-DP had occurred in 80 patients, providing a cumulative incidence of 29.6% (CI 95% 24.1-35.1). E-DP subjects had significantly (p<0.05) higher baseline D-dimer levels and TG ETP value than non-E-DP patients. Correlation analyses showed that pre-chemotherapy fibrinogen (β = -0.127; p=0.048), D-dimer (β = -0.198; p=0.002) and TG ETP (β = -0.133; p=0.034) levels were significantly and inversely associated with time to E-DP. By Multivariate Cox regression analysis, gastric cancer diagnosis (HR=1.546), pre-chemotherapy D-dimer (HR=1.001) and TG ETP values (HR=1.001) were identified as independent risk factors for E-DP. After 1 year from the start of chemotherapy, 228 patients were dead and the OS was 66.6% (CI 95% 61.3-71.9). Patients who died within 1 year showed higher baseline D-dimer, F1+2, fibrinogen, TG peak and TG ETP values compared to the remaining subjects. Multivariate Cox regression identified independent risk factors for 1-year OS the followings: gastric cancer diagnosis (HR=2.237), D-Dimer (HR=1.001) and TG ETP (HR=1.001) levels, white blood cell count (HR=1.094), ECOG-PS>1 (HR=3.858), and chemotherapy plus immunotherapy treatment (HR=2.274). Conclusion: Our results show that, in newly diagnosed metastatic gastrointestinal cancer patients, before the start of antitumor treatment, a procoagulant state exists. Among the different hemostatic parameters evaluated, D-dimer and TG ETP appear as candidate biomarkers to predict for 6-month DP and 1-year OS. In particular, in this setting, the role of TG as a prognostic biomarker emerges for the first time in a large prospective cohort of GI cancer patients. Project funded by "5xMILLE" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)" Disclosures Santoro: Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Arqule, Sanofi: Consultancy; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, MSD: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy, Speakers Bureau; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy.
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