Adverse Cardiovascular Events Associated With Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Metastatic Breast Cancer.

Background Cyclin-dependent kinase (CDK) 4 and 6 inhibitors have significantly improved survival in patients with hormone receptor-positive metastatic breast cancer. There are few data regarding the epidemiology of cardiovascular adverse events (CVAEs) with these therapies. Methods and Results Using the OneFlorida Data Trust, adult patients without prior cardiovascular disease who received at least 1 CDK4/6 inhibitor were included in the analysis. CVAEs identified from International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes included hypertension, atrial fibrillation(AF)/atrial flutter (AFL), heart failure/cardiomyopathy, ischemic heart disease, and pericardial disease. Competing risk analysis (Fine-Gray model) was used to determine the association between CDK4/6 inhibitor therapy and incident CVAEs. The effect of CVAEs on all-cause death was studied using Cox proportional hazard models. Propensity-weight analyses were performed to compare these patients to a cohort of patients treated with anthracyclines. A total of 1376 patients treated with CDK4/6 inhibitors were included in the analysis. CVAEs occurred in 24% (35.9 per 100 person-years). CVAEs were slightly higher in patients who received CKD4/6 inhibitors compared with anthracyclines (P=0.063), with higher death rate associated with the development of AF/AFL or cardiomyopathy/heart failure in the CDK4/6 group. The development of cardiomyopathy/heart failure and AF/AFL was associated with increased all-cause death (adjusted hazard ratio [HR], 4.89 [95% CI, 2.98-8.05]; and 5.88 [95% CI, 3.56-9.73], respectively). Conclusions CVAEs may be more common with CDK4/6 inhibitors than previously recognized, with increased death rates in these patients who develop AF/AFL or heart failure. Further research is needed to definitively determine cardiovascular risk associated with these novel anticancer treatments.

Atrial Fibrillation and Cancer Patients: Mechanisms and Management.

PURPOSE OF REVIEW: Cancer-related mortality has significantly declined over the past several decades as a result of improved screening, diagnostics, and therapeutics. Although cancer patients and survivors are living longer, there is increased risk of both short-term and long-term cardiovascular complications, including arrhythmia. In this review, we highlight the current evidence detailing the connections between atrial fibrillation and cancer, provide insight into the mechanisms driving this relationship, and share practical considerations for the management of atrial fibrillation in cancer patients and cancer survivors. RECENT FINDINGS: Atrial fibrillation is an increasingly recognized condition among cancer patients, with epidemiological data showing increased incidence and worse outcomes in patients with cancer. Studies also describe a bidirectional relationship between cancer and atrial fibrillation, attributable in part to shared risk factors but also potentially due to shared biology. Cancer treatment-associated arrhythmia is an active area of investigation, with ongoing research to identify the mechanisms and pathophysiology behind this phenomenon. Furthermore, management of atrial fibrillation in patients with cancer presents unique challenges, particularly in management of anti-coagulation. Cancer patients have increased risk of developing atrial fibrillation due to the shared risk factors and biology of the two conditions. Moreover, various cancer therapeutics are known to be arrhythmogenic; however, mechanisms remain unclear. Further research is needed to better understand the pathophysiology of atrial fibrillation in cancer patient in order to establish prevention and treatment strategies specific to this population.

Characterization of Pericarditis following Allogeneic Hematopoietic Cell Transplantation.

Pericarditis is an uncommon cardiac complication following allogeneic hematopoietic cell transplantation (alloHCT), with limited data characterizing its incidence, presentation, and management. The etiology of pericarditis in this setting is poorly understood and may include conditioning-related toxicity, infection, or graft-versus-host disease (GVHD). The objective of the present study was to characterize the clinical presentation, management, and outcomes of post-alloHCT pericarditis observed at a single center. This retrospective case-control study of consecutive adults undergoing alloHCT over 5 years was conducted to identify patients who developed pericarditis. Pericarditis was diagnosed using clinical, electrocardiography, and echocardiography findings. Identified cases were compared with a cohort of patients who underwent alloHCT during the same period but did not develop pericarditis. A total of 620 patients underwent alloHCT over the 5-year period, 20 of whom developed pericarditis (3.2% incidence). One patient had a pre-alloHCT history of pericarditis. All but 3 patients had received anthracycline therapy and 1 patient had received chest irradiation before undergoing alloHCT. Patients with pericarditis were more likely than patients without pericarditis to have received total body irradiation (odds ratio [OR], 4.57; P = .003) or cyclophosphamide (OR, 2.35; P = .07) as conditioning or GVHD prophylaxis. Fourteen patients experienced their initial episode of pericarditis before day +100 post-alloHCT, with a median time to onset at day +7. Six patients had their initial episode on day +100 or later, with a median time to onset at day +268. Only 1 patient had active, previously diagnosed GVHD, and 3 patients were on systemic steroid therapy at the time of pericarditis diagnosis. Pericarditis was treated primarily with colchicine (median duration 91 days). Seven episodes of recurrence occurred in 5 patients. Two patients experienced cardiac tamponade following their initial diagnosis, and 3 developed tamponade at recurrence. Recurrence was more common in patients who received no or <90 days of colchicine compared with those who received ≥90 days (45.5% vs 0%; P = .02). No cardiac-related deaths occurred. Overall survival was 85% at a median follow-up of 30 months post-alloHCT. Pericarditis occurred in 3.2% of patients in this single-center study, with cases observed both before and after day +100 and some cases occurring ≥1 year after alloHCT. Colchicine was an effective intervention, with ≥90 days of treatment associated with reduced recurrence. Pericarditis should be considered in patients presenting with chest pain following alloHCT.

Investigating disparities: the effect of social environment on pancreatic cancer survival in metastatic patients.

BACKGROUND: Pancreatic adenocarcinoma (PCA) incidence is higher in Black compared to White patients. Beyond race, neighborhood socioeconomic status (nSES) may also inform disparities. However, these effects on metastatic pancreatic adenocarcinoma (mPCA) are not well-studied. The aim of this study was to explore whether nSES influences survival in patients with mPCA. METHODS: nSES measures were derived from U.S. census data at the census tract (CT) level. We correlated medical records of mPCA patients (diagnosed 2010-2016; n=370) to nSES measures retrospectively via a geocode derived from patient address. Multivariable cox proportional hazards models were used to identify patient-level (age, sex, race, marital status, treatment (radiation/chemo/surgery), PCA family history, stage, Jewish ancestry, tobacco use, BMI, diabetes, and statin use) and nSES measures (deprivation, racial concentration, stability, transportation access, immigration) associated with mPCA survival; P values <0.05 were significant. RESULTS: Eighty-two percent of patients were White; less than one-third of patients resided in highly deprived neighborhoods. Three hundred thirty-three mPCA patient deaths occurred, with a survival ranging from 7-9 months (median 8 months). Patient-level factors including younger age, receipt of chemotherapy or initial surgery and statin use, were associated with improved survival, whereas neighborhood stability (i.e., a higher % of residents still living in the same house as 1 year ago) was significantly associated with poor pancreatic survival. CONCLUSIONS: Our findings suggest nSES has limited effect on survival of mPCA patients as compared to clinical variables. This may be due to the aggressive nature of this cancer, however, additional studies with larger, more diverse cohorts are needed to better understand the effect of nSES on survival of patients with mPCA.

p85α is a microRNA target and affects chemosensitivity in pancreatic cancer.

BACKGROUND: We previously identified a correlation between increased expression of the phosphoinositide 3-kinase (PI3K) regulatory subunit p85α and improved survival in human pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to investigate the impact of changes in p85α expression on response to chemotherapy and the regulation of p85α by microRNA-21 (miR-21). MATERIALS AND METHODS: PDAC tumor cells overexpressing p85α were generated by viral transduction, and the effect of p85α overexpression on sensitivity to gemcitabine was tested by MTT assay. Primary human PDAC tumors were stained for p85α and miR-21 via immunohistochemistry and in situ hybridization, respectively. Additionally, PDAC cells were treated with miR-21 mimic, and changes in p85α and phospho-AKT were assessed by Western blot. Finally, a luciferase reporter assay system was used to test direct regulation of p85α by miR-21. RESULTS: Higher p85α expression resulted in increased sensitivity to gemcitabine (P < 0.01), which correlated with decreased PI3K-AKT activation. Human tumors demonstrated an inverse correlation between miR-21 and p85α expression levels (r = -0.353, P < 0.001). In vitro, overexpression of miR-21 resulted in decreased levels of p85α and increased phosphorylation of AKT. Luciferase reporter assays confirmed the direct regulation of p85α by miR-21 (P < 0.01). CONCLUSIONS: Our results demonstrate that p85α expression is a determinant of chemosensitivity in PDAC. Additionally, we provide novel evidence that miR-21 can influence PI3K-AKT signaling via its direct regulation of p85α. These data provide insight into potential mechanisms for the known relationship between increased p85α expression and improved survival in PDAC.