Platelet RNA profiling to screen for cancer in patients with unprovoked venous thromboembolism

Cancer induces a hypercoagulable state which results in a 4- to 7-fold
increased risk of deep vein thrombosis or pulmonary embolism, collectively
termed venous thromboembolism (VTE), compared to patients without cancer.5
Conversely, VTE may be the first sign of a cancer that has not yet become
clinically overt, i.e. occult cancer. Particularly when VTE develops in the
absence of identifiable risk factors, i.e. unprovoked VTE, the risk is high.
Contemporary studies report a risk of 4% to 6% among patients with unprovoked
VTE within the first 12 months following the VTE diagnosis.
Over the past decades, many different approaches to screen for occult cancer in
patients with unprovoked VTE have been evaluated. These aim at early cancer
diagnosis to reduce cancer-related morbidity and mortality. Screening
strategies are often classified as either *limited* or *extensive*, wherein
limited screening usually consists of at least a thorough medical history and
physical examination, basic blood work-up, and a chest X-ray. The extensive
screening strategies commonly extend the limited work-up by, for example,
imaging (e.g. CT abdomen or whole-body PET-CT) or tumour markers (e.g. PSA,
CEA, or CA-125).

Recently, the Canadian SOME trial compared a limited screening strategy with
limited screening plus extensive abdominal CT in 854 patients with unprovoked
VTE.1 CT-scanning of the abdomen included a virtual gastroscopy and
colonoscopy, biphasic liver scan, pancreatogram and uniphasic bladder scan.
Patients were followed for 12 months. Overall, cancer was detected in 14 of 431
patients (3.2%) allocated to limited screening and 19 of 423 (4.5%) patients
allocated to extensive screening (P=0.28). The proportion of these cancers that
were missed by the initial screening was 4 of 14 (28%) in the limited screening
group and 5 of 19 (26%) in the extensive screening group (P=1.0). The authors
concluded that CT-based extensive screening does not have a benefit over
limited screening. Based on these results, limited screening for cancer in
patients with unprovoked VTE is now considered standard of care in most parts
of the world.

Despite advances in diagnostic techniques, limited screening still misses a
substantial proportion of cancers in patients with unprovoked VTE. Contemporary
studies have reported sensitivities of only 40% to 70%. Given the huge and
often fatal impact of a late cancer diagnosis, there is an urgent clinical need
to improve occult cancer detection in patients with unprovoked VTE.
Recently, platelet RNA profiling has been introduced as a novel biomarker for
cancer diagnosis.4 Confrontation of platelets with tumor cells results in an
altered RNA signature of platelets via transfer of tumor-associated
biomolecules. These platelets are then designated as *tumour-educated
platelets*. This RNA profile of tumour-educated platelets appears to be
fundamentally different from the profile of healthy donors allowing for its use
as a pan-cancer diagnostic tool. In a study of 228 patients with various
cancers and 55 healthy donors, platelet RNA profiling was associated with a
sensitivity of 96% and a specificity of 92% for detecting cancer. In addition,
the platelet RNA profile was able to indetify the most likely tumor type with
considerable accuracy, correctly classifying cancer patients in 50% to 75% of
cases. This promising, novel technique appears to have a high discriminatory
performance, but needs external validation in target populations before
clinical application.

The primary objective of the present study is to evaluate the accuracy of
platelet RNA profiling for occult cancer detection in patients of 40 years or
older with a first episode of unprovoked VTE, in an investigator-initiated,
multinational, prospective, observational, cohort study.
Secondary objectives of the present study include evaluation of a novel
approach proteomic analysis and circulating tumor DNA assay for occult cancer
detection and evaluation of biomarker-based risk scores for bleeding and
recurrent VTE.

Investigator-initiatied, multinational, observational, prospective cohort study

The burden for patients consists of blood withdrawals at day 1 (32ml) and day
90 (12 ml), and a structured interview for signs and symptoms of cancer,
recurrent VTE, and bleeding at days 90 (15 min, clinic visit), 180 (10 min, by
phone), and 365 (10 min, by phone). A telephone visit at 24 months will be
scheduled for those who consented for additional follow-up visits.

There are no risks for participants. There is no expected benefit for patients.