Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial

Abstract

Purpose: To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.

Patients and methods: Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months.

Results: Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%.

Conclusion: The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.

Figure 1. Trial Schema

Treatment schedule. Doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) given 3-weekly for 4 cycles followed by; weekly paclitaxel (80 mg/m²) for 12 weeks (Arm A); paclitaxel, followed by weekly trastuzumab (4 mg/kg loading dose, followed by 2 mg/kg) for 52 weeks (Arm B); or weekly paclitaxel plus trastuzumab for 12 weeks, followed by weekly trastuzumab alone for 40 weeks (Arm C). AC, doxorubicin plus cyclophosphamide; q3w, every 3 weeks; qw, weekly; OBS, observation; LVEF, left ventricular ejection fraction.

Figure 2. Cumulative Incidence of Cardiac Events

AC, doxorubicin plus cyclophosphamide; T, paclitaxel; H, trastuzumab.

Figure 3. Recovery of Cardiac Function in Patients With Congestive Heart Failure

A, Arm A (n=2); B, Arm B (n=18); C, Arm C (n=19); LVEF, left ventricular ejection fraction; AC, doxorubicin plus cyclophosphamide