Clotting and Cancer: What’s the Connection?


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Image Credit: National Cancer Institute (NCI)

What We Already Know

In the body, there is a tight relationship between cancer development and growth, treatment, and the clotting system. Cancer cells produce substances that “thicken” the blood, so men and women with cancer have a significantly higher risk of developing blood clots. On average, people with cancer are 4-7 times more likely to have blood clots than similar people without cancer. Additionally, patients with cancer being treated for blood clots with traditional anticoagulants have a higher risk of bleeding than patients without cancer.

The importance of this connection is highlighted by a dedicated conference, the International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC). The ICTHIC meeting features educational and scientific presentations on epidemiology, biology, prevention, and treatment of clotting and bleeding related to cancer.

The 8th meeting just took place in Bergamo, Italy. World-renowned clinicians and laboratory scientists once again met and updated colleagues. Highlights included multiple presentations and discussions about risk factors for and treatment of cancer-associated venous thrombosis, blood test-based biomarkers assessing the risk of the development or recurrence of clots, lab studies investigating the mechanisms of the tight relationship between the development, progression, and treatment of cancer and thrombosis, and clinical data regarding the treatment or prevention of blood clots in patients with cancer. Special lectures included Dr. Wolfram Ruf delivering the 4th Simon Karpatkin memorial lecture on “Targeting clotting proteins in cancer therapy” where he described years of research on tissue factors involved in cancer growth and spread (metastasis). Dr. Frederick Rickles described the history of the ICTHIC from its inception in 2001 and how the field has progressed since then with an improvement in both the science in the lab and in the treatment methods and diagnostics used in the patient clinic setting.

What’s New?

Much of this year’s conference focused on venous thromboembolism (VTE), which is most commonly manifested by deep vein thrombosis (DVT = blood clots usually in legs/pelvis) and pulmonary embolism (PE = blood clots in lungs). However, it is now clear that patients with cancer also suffer from a higher rate of arterial thrombosis, meaning that they experience a higher rate of heart attacks and stroke.

In the initial Plenary session on Epidemiology, Dr. Babak Navi, Assistant Professor of Neurology at Weill Cornell Medicine (WCM), presented data on the risk of heart attacks and stroke in women with breast cancer. In collaboration with colleagues at Memorial Sloan Kettering Cancer Center, he used data from a large database of patients with Medicare. This dataset showed that women diagnosed with breast cancer have a higher risk of a heart attack or stroke in the first year after diagnosis compared to similar women without breast cancer.

What We’ve Discovered

This year at ICTHIC, we presented data that followed up on a small pilot study presented at the 7th ICTHIC Meeting in 2014 in which Drs. Choe, Tagawa, and others from WCM’s Meyer Cancer Center and the Englander Institute for Precision Medicine utilized genomic data from men with different types of prostate cancer. Patients with advanced prostate cancer had higher expression of genes involved in coagulation and thrombosis compared to patients with early stage (localized) prostate cancer. Interestingly, patients with NEPC had different gene expression compared to patients with metastatic castration-resistant prostate cancer.

Historically, multiple studies showed that patients with cancer and blood clots had more recurrent clots compared to similar patients without cancer. This led to a change in practice starting in 2003 and now many patients use injectable medications (low molecular weight heparin) as opposed to the traditional oral medications (such as warfarin/Coumadin).

Shortly after this change in best practice, we launched a collaborative study with the University of Southern California, testing one of these injectable low molecular weight heparins (tinzaparin) for the treatment of patients with cancer and blood clots. Part of the study included regular and ongoing blood draws in order to examine the biology of the blood in these patients. In the Plenary session on the treatment of cancer-related blood clots, Dr. Tagawa from WCM and Drs. Piatek, Liebman and others from USC presented the results of this study to a global audience.

The results showed that Tinzaparin performed well when examining recurrent blood clot and bleeding rates. In addition, a blood test at the initial diagnosis of the clot called D-dimer was associated with the chance of a recurrent blood clot 6 months later. The team continues to investigate a number of additional blood test biomarkers from patients with and without blood clots in this study. We hope to be able to identify patients who are most likely to develop a blood clot and for those that do, who is most likely to have recurrence of their blood clot. In the future, this may lead to individualization of the type and/or length of treatment.

What We’re Still Trying to Find Out

WCM and other investigators continue to delve into the problem of neuroendocrine prostate cancer (NEPC), an increasingly common lethal form of the disease. Clinicians dealing with this disease believe that men with this variant of prostate cancer suffer from more blood clots than those with the more common types. However, we still don’t know whether this is related to bulkier tumors, the propensity of treating physicians to use platinum-chemotherapy (which is associated with clots), or underlying disease biology.

In addition to gaining additional insight for individual patients using biomarkers, we are also continuing to develop new drugs for the treatment of clots in patients with cancer. Several new oral agents work in patients without cancer with preliminary data in cancer patients, as well. WCM physicians are joining a global study comparing one of these new oral drugs with the standard injectable medication.

Dr. Tagawa Presents Updated Results of ATL101 at AACR

At the annual American Association for Cancer Research in Washington, DC last week, Dr. Scott Tagawa presented updated combined analysis of 4 Phase I and Phase II studies involving 114 patients treated with ATL101. The analysis demonstrated that PSMA imaging might be used to predict the response to ATL101 radioimmunotherapy.ATL101 is a new targeted radiotherapy experimental drug for treating prostate cancer. ATL101 combines the humanized J591 monoclonal antibody targeting prostate-specific membrane antigen (PSMA) plus the Lutetium-177 radioisotope, creating the first tumor-specific delivery system able to target radiation to radio-sensitive prostate cancer cells wherever they are in the body.

From the sponsor’s press release:

14 patients were evaluable for semi-quantitative analysis of planar gamma images acquired after injection of ATL101 (35 patients from phase I at dose of 10-75 mCi/m²; 47 patients from Phase II at dose of 65-70 mCi/m² and 39 patients from phase I with a fractionated schedule at dose of 40-90 mCi/m²). 22 patients were also evaluable after injection of Indium-111 labeled J591 and treatment by Yttrium-90 labeled J591 at dose of 5-20mCi/m². Patients were sorted into 3 groups: low PSMA expression group included one third of patients, with no uptake (18%) or with weakly positive images (16%); high PSMA expression group included one half of patients, with tumor image as intense (26%) or more intense (24%) than liver. The 16 % remaining patients had intermediate uptake.

Significant correlation was found between higher PSMA expression (high vs. low) and higher response rates (RR) to treatment defined as >30% decline in PSA (RR=32% vs. 12.5%, p=0.01). RR was itself significantly correlated to longer survival. An association between PSMA expression by imaging and reduction in circulating tumor cell counts was also found (p=0.07). Further studies will examine quantitative molecular imaging with anti-PSMA PET/CT as recently published in animal models (Morris et al, 2013 ASCO Genitourinary Cancers Symposium).

Click here to read the complete press release.

Weill Cornell Researchers: Encouraging Results from J591 Study

Dr. Tagawa
Dr. Tagawa

Weill Cornell researchers recently published findings from a Phase II study of the lutetium-177-labeled monoclonal antibody J591 (called Lu-J591).

J591 is a man-made monoclonal antibody that is able to recognize a protein antigen (PSMA) expressed on virtually all prostate cancer cells, and more so in men with treatment-resistant metastatic disease. When a tiny tag of radioactive material is attached to the J591 antibody, that specifically targets prostate cancer cells, and delivered systemically this is known as “radioimmunotherapy.” Dr. Scott Tagawa and colleagues at Weill Cornell have been conducting clinical trials of the precision radioimmunotherapeutic J591 to determine its ability to eradicate prostate cancer cells.

In the recently published study, 47 prostate cancer patients with PSA progression after hormonal therapies with or without chemotherapy were treated with Lu-J591. 10.6 percent experienced more than 50% PSA decline, and 36.2% experienced more than 30% decline. Among those treated at the maximum tolerated dose, 46.9% had more than 30% PSA decline. Furthermore, 75% of patients with radiographically measurable disease had some measure of disease control; 67% of those assessed for circulating tumor cells had more than 50% decline in tumor cell counts 4 to 6 weeks after treatment.

The researchers concluded that a single dose of Lu-J591 was well tolerated and they found a measurable response rate. The authors conclude that Lu-J591 is a promising new therapeutic strategy to explore.

Click here to read the published abstract. Click here to read an article about the study and the findings.