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Candesartan fails to reduce left ventricular ejection fraction in early-stage breast cancer
The concomitant use of candesartan during or after trastuzumab therapy failed to protect against left ventricular ejection fraction in women with early-stage breast cancer, according to the results of a randomized clinical trial.
However, the ERBB2 germline single nucleotide polymorphism Ala1170Pro may aid in the identification of patients at an increased risk for cardiotoxic effects related to trastuzumab (Herceptin, Genentech/Roche), results showed.
“Although trastuzumab is generally well tolerated, cardiac dysfunction is an important adverse effect, especially in women who were previously or concomitantly treated with anthracycline-based chemotherapy,” Jan H.M. Schellens, MD, PhD, head of the department of clinical pharmacology at Netherlands Cancer Institute and professor of clinical pharmacology at Utrecht University, and colleagues wrote. “The most frequent clinical manifestation of trastuzumab-related cardiotoxic effects is diminished systolic left ventricular function measured with left ventricular ejection fraction (LVEF).”
Sandra M. Swain
Ana Barac
Prior research has suggested that angiotensin II–receptor blockers may effectively reduce or prevent anthracycline-related cardiotoxic events.
Schellens and colleagues conducted a randomized controlled trial to determine whether interventional treatment with the angiotensin II–receptor antagonist candesartan could reduce or prevent treatment-related cardiotoxic events.
The study included data from 206 women (mean age, 49 years; range, 25-69) treated for early-stage breast cancer at 19 hospitals in the Netherlands. All women had HER-2–positive disease and were under consideration for adjuvant anthracycline-based chemotherapy, followed by trastuzumab.
The researchers randomly assigned women to 78 weeks of 32 mg daily candesartan or placebo (n = 103 for each). Treatment with candesartan began on the same day as trastuzumab initiation and continued for 26 weeks after complete trastuzumab.
The occurrence of a cardiac event — defined as a decline in LVEF of more than 15% or a decrease below the absolute value 45% — during trastuzumab treatment or within 40 weeks of discontinuing trastuzumab served as the primary endpoint.
Secondary endpoints included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers, and whether genetic variability in germline ERBB2 correlated with trastuzumab-related cardiotoxic events.
The median follow-up was 21 months (range, 6-27) in the candesartan arm and 21 months (range, 5-25) in the placebo arm.
Forty-eight patients (candesartan, n = 27; placebo, n = 21) discontinued treatment early.
The study failed its primary endpoint, as researchers observed a 3.8% (95% CI, –7 to 15) increase in cardiac events in the candesartan arm. Twenty events occurred in the candesartan arm, compared with 16 events in the placebo arm.
Patients assigned candesartan had a 2-year incidence of cardiac events of 0.28 (95% CI, 0.13-0.4), compared with 0.16 (95% CI, 0.08-0.22) in the placebo group.
Baseline LVEF ( 55% vs. < 55%) served as a prognostic factor for cardiac events (OR = 0.24; 95% CI, 0.11-0.53).
Both treatment arms had similar adverse event rates. Twelve patients — six per arm — discontinued treatment due to adverse events, including dizziness, hypotension, headache, myalgia, fever, thrombosis, psychological stress and dyspnea.
The candesartan arm had a median baseline NT-proBNP value of 62 pmol/L (range, 35-106), compared with 70 pmol/L (range, 44-123) in the placebo arm. The baseline values of hs-TnT were 14 g/L (range, 7-20) in the candesartan arm and 13 g/L in the placebo arm. The researchers did not observe an association between LVEF and NT-proBNP or hs-TnT.
The Ala1170Pro homozygous genotype appeared associated with a lower likelihood of developing cardiac events regardless of treatment group (OR = 0.09; 95% CI, 0.02-0.45). No other SNP appeared associated with cardiac events.
“Our study does not support a role for the use of this drug as scheduled in conjunction with trastuzumab in this population of patients with breast cancer,” Schellens and colleagues wrote.
Future cardio-oncology trials should include a more diverse patient population, Sandra M. Swain, MD, FACP, medical director of Washington Cancer Institute of MedStar Washington Hospital Center, and Ana Barac, MD, PhD, cardiology faculty member at MedStar Washington Hospital Center, wrote in an accompanying editorial.
“A low incidence of events ... indicates that inclusions of patients with higher cardiovascular risk will be needed in the future studies and that a risk-based prevention approach may offer a higher yield,” Swain and Barac wrote. “We commend Boekhout and colleagues for including ERBB2 genotype polymorphisms in their analysis, which demonstrated an association between the presence of proline in the ERBB2 gene Ala1170Pro position and increased risk [for] cardiac events.”
Although the trial failed to meet its primary endpoint, it may signal future research in the cardio-oncology sphere, Swain and Barac wrote.
“Despite leaving many open questions, this important investigation demonstrates the feasibility of rigorous scientific trial approach to cardioprevention and heralds a new era of clinical trials in cardio-oncology,” Swain and Barac concluded. – by Cameron Kelsall
Disclosure: The Netherlands Cancer Institute and Roche provided funding for this study. AstraZeneca provided the study drug and placebo. The researchers, Barac and Swain report no relevant financial disclosures.