Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR).

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.

CONTEXT: The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs. OBJECTIVE: To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer. DATA SOURCES: A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008). STUDY SELECTION: Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer. DATA EXTRACTION: Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE. DATA SYNTHESIS: Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20). CONCLUSIONS: Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

The role of targeted therapy and biomarkers in breast cancer treatment.

Breast cancer is the most prevalent life-threatening cancer in women and the second leading cause of cancer associated deaths. Consequently, optimizing breast cancer therapy to increase cure rates in early stage disease and improve life expectancy and palliation for patients with metastasis is a critical need and major area of research in medical oncology. This article focuses on the development of personalized therapy in breast cancer though the use of targeted therapies and their associated biomarkers. Topics reviewed include the historic advances in targeting the HER2 receptor and the current avenues being studied to circumvent resistance; new developments in the management of triple negative and metastatic breast cancer; and the challenges and pitfalls associated with targeting angiogenesis. Using these as examples, many of the innovations and challenges in the treatment of women with breast cancer are explored.

Association between pharmaceutical support and basic science research on erythropoiesis-stimulating agents.

BACKGROUND: To our knowledge, no prior research has evaluated the association between pharmaceutical industry funding and basic science research results. When erythropoiesis-stimulating agents (ESAs) were licensed to treat chemotherapy-associated anemia, basic science concerns related to potential cancer stimulation were raised. We evaluated associations between pharmaceutical industry support and reported findings evaluating ESA effects on cancer cells. METHODS: Articles identified in MEDLINE and EMBASE databases (1988-2008) investigating basic science findings related to ESA administration in the solid tumor setting were reviewed. Outcomes included information on erythropoietin receptors (EpoRs), Epo-induced signaling events, cellular function, and qualitative conclusions. Information on study funding (academic investigators with no reported funding from ESA manufacturers [64 studies], academic investigators with grant funding from ESA manufacturers [7 studies], and investigators employed by the ESA manufacturers [3 studies]) was evaluated. Some studies did not include information on each outcome. RESULTS: Investigators without funding from ESA manufacturers were more likely than academic investigators with such funding or investigators employed by ESA manufacturers to identify EpoRs on solid tumor cells (100%, 60%, and 67%, respectively; P = .009), Epo-induced signaling events (94%, 0%, and 0%, respectively; P = .001), or changes in cellular function (57%, 0%, and 0%, respectively; P = .007) and to conclude that ESAs had potentially harmful effects on cancer cells (57%, 0%, and 0%, respectively; P = .008). CONCLUSIONS: Researchers who do not have pharmaceutical industry support are more likely than those with pharmaceutical support to identify detrimental in vitro effects of ESAs. The potential for conflicts of interest to affect basic science research should be considered.