TICONC: Ticagrelor May Cut Tumor-Induced Platelet Aggregation in Cancer Patients

When cancer cells and platelets mix, the risk of metastasis and cancer-related deep vein thrombosis (DVT) and pulmonary embolism (PE) increases, but a small, proof-of-concept study suggests that the P2Y12 inhibitor ticagrelor (Brilinta; AstraZeneca) may disrupt these processes.

Although some studies have suggested aspirin can reduce metastatic cancer spread, it is a relatively weak antiplatelet agent, noted senior author David Adlam, DPhil (University of Leicester, England), in an email. “However, it is not known if more modern and more potent antiplatelet drugs might have greater antimetastatic or anti-cancer-induced thrombosis effects.”

Ticagrelor is approved for the prevention of atherothrombotic events in ACS patients and for the secondary prevention of CV events in high-risk patients with prior MI. More recently, it received an additional indication for primary prevention of MI or stroke in high-risk patients with CAD.

For the Ticagrelor-Oncology (TICONC) study, published online, June 16, 2020, ahead of print in JACC: CardioOncology, Adlam and colleagues, with first author Joy R. Wright, PhD (University of Leicester), sought to investigate ticagrelor’s potential to inhibit cancer-induced platelet activation, degranulation, and aggregation, as well as platelet-facilitated cancer-cell adhesion. The two-phase study consisted of a preliminary in vitro model of platelet-tumor cell interaction and a crossover-design study in healthy donors and patients with metastatic breast or colon cancer.

Well-Tolerated, Does Not Interfere With Other Therapies

For the in vitro component of TICONC, ticagrelor significantly impeded the development of large platelet-platelet aggregates and activation induced by the breast and colorectal tumor cells; aspirin monotherapy did not.

For the in vivo study, investigators enrolled 22 healthy participants and 16 patients with metastatic breast or colon cancer. After randomization, the participants received 75 mg of aspirin once a day or 90 mg of ticagrelor twice a day for 2 weeks followed by a 2-week washout period. They then crossed over to ticagrelor if they had taken aspirin, or aspirin if they had taken ticagrelor, and continued for 2 weeks followed by a final 2 weeks on aspirin and ticagrelor combined (dual antiplatelet therapy phase [DAPT]).

In the 10 patients with colorectal cancer, 2 weeks of ticagrelor monotherapy appeared to inhibit spontaneous platelet aggregation compared to baseline. By contrast, aspirin did not reduce platelet aggregation in the colorectal cancer patients, but instead appeared to increase spontaneous aggregation in breast cancer patients and in healthy controls, supporting the hypothesis that ticagrelor’s effects in reducing platelet aggregation are seen in patients with higher levels of spontaneous platelet aggravation at baseline. According to Adlam, however, aspirin is still a possible contender and is being examined in the ADD-ASPIRIN study in patients with nonmetastatic solid tumors. He also said TICONC makes a strong case for similar studies adding ticagrelor and other well-studied antiplatelets as potential prophylaxis in cancer to mediate platelet inhibition.

“One of the key aspects is that these drugs are already widely used and their safety profile in a cardiovascular context is well known,” Adlam commented. “Repurposing drugs is a much quicker process then developing new drugs and so exploring the anticancer effects of existing drugs holds great potential for early translation.”

The therapies were well tolerated, with only one patient withdrawing from the study. This occurred in a patient with colorectal cancer who developed hematuria during the DAPT phase that resolved with discontinuation of the drugs.

Different Cancers, Different Reactions

TICONC highlights some differences between cancer types, Adlam said, and suggests there is much left to learn about which patients have the greatest potential to benefit from taking ticagrelor or similar agents.

“One advantage of antiplatelet drugs is that they are unlikely to interfere greatly with other established cancer treatments, as they have a different mechanism of action,” he noted. “Also, because cancer-induced thrombosis and platelet-relevant mechanisms of metastasis are common to many cancers, these drugs have promise across many cancer types, rather than being developed for a single cancer type (or even subtypes) as [is the case] for many modern anticancer drugs, which focus on tumor-specific mechanisms.”

In an editorial, Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY), and colleagues say based on these results, large-scale trials of ticagrelor or other antiplatelet agents are warranted in oncology patients.

“Just as in patients with coronary artery disease, a strategy of tailoring antiplatelet therapy according to individual risk features, including tumor type, tumor burden, and concomitant anticancer therapy may enable clinicians to optimize the trade-off between the beneficial and side effects of antiplatelet therapy even in patients with cancer,” Mehran and colleagues write.

To TCTMD, Adlam stressed clinical trials will be needed to confirm the risk-benefit balance of this type of treatment, adding “this study is a ‘call to arms’ that such studies are now needed.”