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

Purpose: Cardiac 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 methods: In 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 anthracycline-related decline in cardiac function were also identified.

Results: At 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.

Conclusion: The 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.

Trial registration: ClinicalTrials.gov NCT00004067.

Fig 1.

CONSORT diagram of cardiac follow-up and events for the National Surgical Adjuvant Breast and Bowel Project B-31 trial. Evaluable cohort for comparison of cardiac dysfunction (n = 1,830). AC, doxorubicin and cyclophosphamide; ACP, doxorubicin, cyclophosphamide, and paclitaxel; ACPH, doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab; CHF, congestive heart failure; H, trastuzumab; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; P, paclitaxel.

Fig 2.

Cumulative incidence of cardiac events in National Surgical Adjuvant Breast and Bowel Project B-31. ACP, doxorubicin, cyclophosphamide, and paclitaxel; ACPH, doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab; HR, hazard ratio.

Fig 3.

(A to F) Histograms of doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab (ACPH) cohorts with left ventricular dysfunction in National Surgical Adjuvant Breast and Bowel Project B-31. (A,D) ACPH symptomatic patients meeting criteria for cardiac event (CE; A) in the cohort at nadir left ventricular ejection fraction (LVEF) and (D) in the cohort at follow-up; (B,E) ACPH symptomatic patients not meeting criteria for CE (B) in the cohort at nadir LVEF and (E) in the cohort at follow-up; (C,F) ACPH asymptomatic patients who stopped as a result of ↓ LVEF (C) in the cohort at nadir LVEF and (F) in the cohort at follow-up.

Fig 4.

(A) Predicted probability of cardiac event (CE) at year 5 by Cardiac Risk Score (CRS) in National Surgical Adjuvant Breast and Bowel Project B-31. (Some examples are as follows: [a] age 45 years, left ventricular ejection fraction [LVEF] = 65%, CRS = 48.3, risk of CE = 2%; and [b] age 65 years, LVEF = 55%, CRS = 86.1, risk of CE = 13%). (B) Calibration plot. Observed and predicted probabilities of not experiencing a cardiac event. (See Table A1 for the CRS of each of the patients receiving doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab who experienced a CE.)

Fig 5.

Mean left ventricular ejection fraction (LVEF) measurements over time in National Surgical Adjuvant Breast and Bowel Project B-31. Vertical bars represent 95% CIs. ACP, doxorubicin, cyclophosphamide, and paclitaxel; ACPH, doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab.