Hypercoagulation Screening As a Marker of Thrombosis and Poor Disease Prognosis in Cancer Patients: The Hypercan Prospective Study

Introduction Malignant tumor progression and poor prognosis have been repeatedly associated with the occurrence of hypercoagulation and overt thrombotic events. The HYPERCAN is an ongoing prospective Italian multicentre study, structured in two sub-projects that involve respectively non-cancer and cancer subjects. The HYPERCAN sub-project on cancer patients aims to evaluate whether thrombotic markers may predict for malignant disease recurrence and/or for venous thromboembolic events (VTE) in these patients.

Methods Consecutive adult patients with limited resected or metastatic non-small cell-lung (NSCLC), gastric, colorectal, or breast cancers are enrolled, after informed written consent, and followed up for 5 years or death. Enrollment will be continued for up to 3 years (total 4,000 patients planned). Blood sample collection is planned according to tumor stage. Particularly, for metastatic disease, patient citrated whole blood is collected: 1. at enrollment, 2. after the 3^rd cycle of anticancer therapy, 3. after the 6^thcycle of anticancer therapy, 4. at the end of treatment, or earlier if disease progression. For patients with limited disease, whole blood samples are collected at enrollment (i.e. after surgery, before starting any medical anticancer treatment), and thereafter once a year for 4 years, or at disease recurrence. At each time point, information on treatment, clinical response, and disease outcome, are collected. Plasma samples and clinical information are centralized at the Division of Immunohematology and Transfusion Medicine - Bergamo Hospital (coordinating center). Patient plasma is tested for a preliminary panel of hemostatic markers (D-dimer, Fibrinogen) and thrombin generation (TG).

Results Between April 2012 and February 2014, 1,113 cancer patients were enrolled into the study. Follow-up data were available for 1,045 patients (359 metastatic/686 limited-resected) with NSCLC (n=252), gastric (n=74), colorectal (n=163) and breast (n=556) cancers, with an observation median time of 340 days. Forty-eight patients (4.6%) developed VTE with a median time of 123 days from enrollment. VTE was more frequent in metastatic compared to limited resected cancer patients (9.2% vs 2.2%); colorectal and lung cancer patients showed the highest VTE rate, 8.5% and 7.9%, respectively, independently of tumor stage. Currently plasma from 474 patients (196 metastatic/278 limited resected) were tested. Increased D-dimer and fibrinogen levels at enrollment showed to be significant risk factors for VTE by Kaplan-Meier analysis (HR: 5.4, 95% CI 2.2-13.2 p=0.000 for D-dimer; HR: 4.3, 95% CI 1.8-10.4 p=0.004 for fibrinogen) as well as the endogenous thrombin potential (HR: 4.5, 95% CI 1.8-11.4 p=0.000) and the TG peak (HR: 4.0, 95% CI 1.5-10.2 p=0.009). In the group with limited resected disease, the cumulative incidence of recurrence was 3.2% with a median time of 186 days. Increased D-dimer and fibrinogen levels at enrollment were predictive for disease recurrence by Kaplan-Meier analysis (HR: 9.9, 95% CI 2.4-40.1 p=0.001 for D-dimer; HR: 5.9, 95% CI 1.5-23.6 p=0.012 for fibrinogen).

Conclusions These early results reveal that tumor stage and site, as well as elevated levels of D-dimer, fibrinogen and TG at enrollment, are associated with an increased risk of VTE in cancer patients. In subjects with limited resected cancer, elevated D-dimer and fibrinogen levels also predict for disease recurrence. These results support the hypothesis that testing for relatively easy plasma markers of thrombosis may be worth for monitoring the cancer response to therapy beyond the thrombotic risk.

Project funded by AIRC “5xMILLE” n. 12237 grant from the “Italian Association for Cancer Research (AIRC)”.