Prophylactic Intervention Improves Cardiac Safety in HER2-Positive Breast Cancer

Edith Pituskin, PhD

Prophylactic administration of standard heart failure medications helped preserve left ventricular ejection fraction (LVEF) in patients treated with trastuzumab (Herceptin) for HER2-positive metastatic breast cancer, according to findings presented at the 2015 San Antonio Breast Cancer Symposium.

In the three-arm study there was a 3% (±4) and a 1% (±5) decrease in LVEF from baseline for patients treated prophylactically with the angiotensin-converting enzyme (ACE) inhibitor perindopril or the beta-blocker bisoprolol, respectively. In the placebo arm, LVEF declined by 5% (±5). Overall, in the placebo arm 8 trastuzumab dose interruptions due to drops in LVEF versus 1 in each of the investigational arms (P <.05).

“Prophylactic use of standard heart failure pharmacotherapy protects against trastuzumab associated declines in LVEF, which reduces trastuzumab interruptions due to LV dysfunction,” said lead investigator Edith Pituskin, PhD, assistant clinical professor, Department of Oncology University of Alberta Cross Cancer Institute. “This is the first effective intervention for trastuzumab-associated left ventricular dysfunction.”

In the three-arm study, labeled MANTICORE, patients were randomized to receive placebo (n = 30), perindopril (n = 33), or bisoprolol (n = 31). The median age of patients in the trial was 51 years and all had stage I (37%), stage II (28%), and stage III (35%) HER2-positive breast cancer. The mean body surface was 1.8 (±0.21).

Across the study, most patients were treated with TCH (docetaxel, carboplatin, and trastuzumab) in the placebo (77%), perindopril (67%), and bisoprolol (87%) arms. The mean trastuzumab dose was 101.7 mg/kg (±8.5), 106.1 mg/kg (±8.5), and 103.5 mg/kg (±6.9). Prior to trastuzumab, 41% of patients had received previous left-sided radiation therapy.

The dose of beta or ACE inhibition was uptitrated as tolerated in the first 3 weeks and then continued for the duration of the trial (12 months). For perindopril, the maximum dose was 8 mg. For bisoprolol, patients received a maximum dose of 10 mg. Participants underwent a multiparametric cardiovascular magnetic resonance at baseline and then at month-3, -12, and -24.

The primary endpoint of the study was to prevent left ventricular remodeling with the use of the ACE inhibitor and beta-blocker. At the analysis, this endpoint was not significantly met; however, as the data mature, it could reach statistical significance, said Pituskin.

Prior to treatment, the left ventricular end-diastolic volume index (LVEDVi) was 76 ml/m² in the placebo arm versus 67 and 69 ml/m² in the perindopril and bisoprolol arms, respectively. Post protocol LVEDVi was 79-, 74-, and 76-ml/m² with a change in baseline of 4-, 7-, and 8-ml/m² for placebo, perindopril, and bisoprolol, respectively.

The pre-treatment LVEF was 61%, 62%, and 62% and the post-treatment LVEF was 56%, 59%, and 61%, for placebo, perindopril, and bisoprolol, respectively. In a multivariate analysis for prediction of change in LVEF, the three factors that emerged as independent factors were baseline LVEF and treatment with perindopril or bisoprolol.

Baseline LVEF was associated with a decline in LVEF of 0.494% (95% CI, 0.684-0.303; P <.001). Perindopril was associated with a 2.615% change in LVEF (95% CI, 0.557-4.673; P = .013). The change in LVEF with bisoprolol was 4.735% (95% CI, 2.668-6.802; P <.001).

Pretreatment systolic and diastolic blood pressure was 124/75, 126/78, and 121/74 in the placebo, perindopril, and bisoprolol arms, respectively. The heart rate across each arm was 76, 82, and 72, respectively.

After receiving 17 cycles of trastuzumab, the systolic and diastolic blood pressure was 122/75, 117/70, and 118/72 in the placebo, ACE inhibitor, and beta-blocker arms, respectively. The heart rates were 72, 74, and 62.

Findings from the MANTICORE study add to the PRADA trial, which randomized 120 patients to placebo, the beta-blocker metoprolol, or the angiotensin receptor blocker candesartan. Findings from this study were recently presented at the American Heart Association’s annual meeting.

PRADA found a 0.8% decline in LVEF from baseline in the group taking candesartan versus a 2.6% in the placebo group. Metoprolol did not yield a change in LVEF versus placebo.

“We want to do our best to optimally treat our patients’ cancer, while minimizing the risks of long-term toxicities from their cancer treatments,” Erica Mayer, MD, a senior physician in the Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute, said in a statement when the findings were presented. “The best way to prevent toxicity is to prevent the exposure in the first place.”

Larger trials and longer follow-up will be required, in order to verify the findings from both studies. However, the early results show promise for preventive strategies for LVEF decline in patients treated with trastuzumab.

References:

1. Pituskin E, Mackey JR, Koshman S, et al. Prophylactic beta blockade preserves left ventricular ejection fraction in HER2-overexpressing breast cancer patients receiving trastuzumab: Primary results of the MANTICORE randomized controlled trial. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S1-05.
2. Gulati G, Heck SL, Hoffmann P, et al. Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Primary Results of a Randomized, 2 x 2 Factorial, Placebo-Controlled, Double-Blind Clinical Trial. Presented at: 2015 American Heart Association Scientific Sessions; November 7-11, 2015; Orlando, FL.