Long-Term Cardiac Safety Analysis of NCCTG N9831 (Alliance) Adjuvant Trastuzumab Trial

Abstract

Purpose: Significant improvement in survival outcomes has been established with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive early breast cancer treatment. However, trastuzumab may increase the risk of cardiac toxicity, and long-term evaluation of its incidence and risk factors are warranted.

Methods: NCCTG (Alliance) N9831 trial compared adjuvant doxorubicin and cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab followed by trastuzumab alone (arm C) in patients with HER2-positive breast cancer. Cumulative incidence of cardiac events (CE) and left ventricular ejection fraction (LVEF) were evaluated in 1,944 women who proceeded to post-AC therapy. Risk factors for trastuzumab-induced cardiac toxicity were identified by Cox regression models.

Results: The 6-year cumulative incidence of CE was 0.6% in arm A, 2.8% in arm B, and 3.4% in arm C. At a median follow-up of 9.2 years, only two additional CHF diagnoses (of 1,046 patients) occurred beyond our previously reported follow-up time of 3.75 years. LVEF recovered in the majority of the patients who developed CHF. There were two cardiac deaths in arm A and one each in arms B and C. Age of 60 years or older, registration LVEF less than 65%, and use of antihypertensive medications were associated with an increased risk of CE in arms B and C.

Conclusion: The cumulative incidence of CE at 6 years was slightly higher with the addition of trastuzumab; however, the late development of CE is infrequent. Trastuzumab (in the context of anthracycline- and taxane-based therapy) continues to have a favorable benefit-risk ratio.

Fig 1.

CONSORT diagram for follow-up and cardiac events for NCCTG N9831 adjuvant trastuzumab trial. AC, doxorubicin plus cyclophosphamide; CHF, congestive heart failure; LLN, lower limit of normal; LVEF, left ventricular ejection fraction.

Fig 2.

(A) The 6-year median (range) left ventricular ejection fraction (LVEF) values in treatment arms A, B, and C. Arm A, 61% (34% to 77%); arm B, 61% (25% to 78%); and arm C, 60% (41.2% to 89%). (B) The 6-year median (range) LVEF change from baseline in treatment arms A, B, and C. Arm A, −3.0% (−33% to 19%); arm B, −2.5% (−34.9% to 20%); and arm C, −3.0% (−28% to 28%).

Fig 3.

(A) Cumulative incidence of cardiac events by treatment arm. (B) Cumulative incidence of cardiac events for nontrastuzumab arm (arm A) versus trastuzumab arms (arms B and C). AC, doxorubicin plus cyclophosphamide; T, paclitaxel; H, trastuzumab.

Fig 4.

Recovery of cardiac function (left ventricular ejection fraction [LVEF]) in patients with congestive heart failure. (A) No. of patients in arm A = 6; (B) arm B = 19; (C) arm C = 20. Bolded lines represent the average LVEF levels of all patients in each arm through time, and nonbolded lines in each arm represent the LVEF level of an individual patient through time.

Fig 5.

Forest plot for univariable risk factors associated with an increased risk of cardiac event in patients who proceeded to post–doxorubicin plus cyclophosphamide therapy. Left ventricular ejection fraction (LVEF) of 65 or greater, age 50 years or younger, body mass index (BMI) of 24.9 or less, white ethnicity, and patients who did not receive radiotherapy were used as reference in each of the groups. HR, hazard ratio.

Fig 6.

Predicted probability of cardiac event (CE) using cardiac risk score (CRS). Plotting the CRS calculated from the formula derived by the investigators of the B-31 trial against the predicted probability of cardiac events resulted in similar findings as were reported in B-31. As the CRS increases, the predicted probability of a CE increases as well.

Fig A1.

NCCTG N9831 clinical trial schema. Doxorubicin (A) 60 mg/m²; cyclophosphamide (C) 600 mg/m²; paclitaxel 80 mg/m²; trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly (qw). Eval, evaluation; LVEF, left ventricular ejection fraction; q3w, every 3 weeks.