Seven-Year Follow-Up Assessment of Cardiac Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab As Adjuvant Therapy for Patients With Node-Positive, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

Abstract

A B S T R A C T PurposeCardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. Patients and MethodsIn National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracyclinerelated decline in cardiac function were also identified. ResultsAt 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. ConclusionThe late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab.

Trastuzumab in Female Breast Cancer Patients With Reduced Left Ventricular Ejection Fraction

“…Intriguingly, there is paucity of data on this important topic, primarily because patients with baseline reduction of cardiac function were excluded from the enrollment in prospective clinical trials or the analysis of retrospective cohort studies. One exception is the NSABPB‐31 trial, which found that patients with an LVEF in the range of 50% to 54% were at a significantly higher risk for HF, and developed a 5‐year cardiac risk score based on age and baseline LVEF 27. Not over 5 years but over the duration of trastuzumab therapy, the current study made similar observations, ie, patients with a reduced cardiac function at baseline were at a higher risk of developing HF.…”

“…In most recent clinical trials, the proportion of patients developing symptomatic HF during trastuzumab has been relatively low (0.6% to 3.8%) 27, 30, 31, 32, 33. In fact, the HERA (HERceptin Adjuvant) trial showed an HF incidence of only 0.8% and decreases in LVEF of ≥10% from baseline to an LVEF of <50% in only 7.2% of patients 34.…”

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…In a late follow‐up of the NSABP B‐31 trial, older age and lower baseline LVEF (50–54%) were associated with trastuzumab‐induced cardiotoxicity 11. Risk of cardiotoxicity appears to increase progressively with increasing age in several studies 11, 48, 50, 57.…”

“…In a meta‐analysis of 15 studies, a body mass index >25 or >30 kg/m 2 was associated with 1.32 (95% CI, 1.06–1.80) and 1.47 (95% CI, 0.95–2.28) times the odds of cardiotoxicity compared with a normal body mass index 58. Cardiac risk scores have been developed to predict the risk of cardiotoxicity associated with trastuzumab, including several risk factors such as age, hypertension, diabetes mellitus, coronary artery disease, atrial fibrillation or flutter, renal dysfunction, and use of adjuvant chemotherapy 11, 57. However, lack of prospective independent validation limits the use of such tools.…”

Cardiac Imaging: Multimodality Advances and Surveillance Strategies in Detection of Cardiotoxicity

“…CMR should always be considered when 2DE-derived LVEF is suboptimally visualized and/or serially noted to have discrepant findings, particularly in patients with lower limit of normal LVEF (2DE has been known to overestimate the LVEF in this population compared to CMR) [18]. Borderline low baseline LVEF holds a confirmed predictive value to identify among women treated for breast cancer those at risk of CTRCD [65,66]. However, a normal baseline LVEF assessment alone does not formally exclude the occurrence of chemotherapy-induced cardiac events: congestive HF has also been reported in 2.1 and 4.2% of patients with a baseline LVEF of ≥65% and 55-64%, respectively [65].…”